Investigational status

“LB-102 is a novel, once-daily, orally administered investigational small molecule and potential first benzamide antipsychotic in the United States for the treatment of neuropsychiatric disorders.” (opens the source at this quote in a new tab)

“Currently, participation in one of our clinical trials is the only way to access our investigational products.” (opens the source at this quote in a new tab)

Current development phase

“LB-102 is currently in late-stage clinical development for schizophrenia (pivotal Phase 3 NOVA-2 trial) and bipolar depression (Phase 2 ILLUMINATE-1 trial).” (opens the source at this quote in a new tab)
“Concurrently with the Phase 3 NOVA-2 trial, we are enrolling an outpatient, open label trial (NOVA-3) to accrue the requisite safety population required to support NDA submission as well as other clinical trials and non-clinical studies typically required by FDA for an NDA approval.” (opens the source at this quote in a new tab)

Phase 2 NOVA-1 trial: completed, topline results January 2025, published in JAMA Psychiatry

“The topline results from the trial were announced in January 2025.” (opens the source at this quote in a new tab)
“We designed our Phase 2 acute schizophrenia trial to be potentially registrational by including a large sample size (n=359), robust statistical analyses, as well as numerous sensitivity analyses.” (opens the source at this quote in a new tab)

“Published results from the Phase 2 NOVA-1 trial of LB-102 in schizophrenia in JAMA Psychiatry.” (opens the source at this quote in a new tab)

Phase 3 NOVA-2 trial: initiated March 2026

“today announced the initiation of its pivotal Phase 3 trial (NOVA-2) evaluating the efficacy and safety of LB-102 as a treatment for schizophrenia.” (opens the source at this quote in a new tab)
“The trial is designed to enroll approximately 460 patients with acute exacerbation of schizophrenia at approximately 25 sites in the U.S.” (opens the source at this quote in a new tab)
“Patients will be randomized 1:1:1 to receive either 50 mg or 100 mg of LB-102 or placebo for six weeks.” (opens the source at this quote in a new tab)

“We initiated a six-week Phase 3 trial of LB-102 in patients with schizophrenia in March 2026.” (opens the source at this quote in a new tab)

Phase 3 NOVA-3 trial: 52-week open-label safety trial, enrolling

“The 52-week open-label safety and tolerability trial (NOVA-3), evaluating the long-term safety and tolerability of LB-102 in patients with stable schizophrenia, is enrolling eligible patients who have completed NOVA-2, as well as de novo patients.” (opens the source at this quote in a new tab)

“Phase 3, open label, multicenter study designed to assess the long term safety and tolerability of LB-102 for the treatment of adult patients with stable schizophrenia” (opens the source at this quote in a new tab)

FDA end-of-phase 2 feedback on the registration package

“Based on positive end-of-Phase 2 feedback from the FDA, as well as historical precedent, we believe that our Phase 2 acute schizophrenia trial may serve as one of two pivotal trials required for approval of a new drug application, or NDA, in the United States.” (opens the source at this quote in a new tab)
“Based on recent positive feedback from the FDA, our current strategy is to utilize our recently completed Phase 2 trial in acute schizophrenia as one of two adequate and well-controlled trials required for FDA approval.” (opens the source at this quote in a new tab)

“FDA noted, in writing, that our Phase 2 trial appeared to have many of the characteristics of an adequate and well-controlled trial – providing an opportunity for approval with one successful Phase 3 trial” (opens the source at this quote in a new tab)
“Streamlined path to approval in SCZ with a single Phase 3 trial based on positive FDA feedback” (opens the source at this quote in a new tab)

“Based on positive results and prior FDA feedback, we believe NOVA-2, together with the open label extension trial, and data from our Phase 2 (NOVA-1) trial, will support the potential U.S. approval of LB-102 for the treatment of schizophrenia.” (opens the source at this quote in a new tab)

Status of NOVA-1 as one of two adequate and well-controlled trials: company caveats

“However, there is no guarantee that our Phase 2 trial will serve as one of the two pivotal trials required for FDA approval, and in such case, we may be required to conduct an additional pivotal trial in acute schizophrenia.” (opens the source at this quote in a new tab)
“The adequacy of our Phase 2 trial to support registration will be a matter of review by the FDA at the time of NDA submission and will depend on the totality of the data included in our submission, including the results of our planned Phase 3 trial.” (opens the source at this quote in a new tab)
“The FDA may also not agree with our determination that our Phase 2 acute schizophrenia trial may serve as one of the two pivotal trials required for approval of an NDA in the United States.” (opens the source at this quote in a new tab)

Safety database required to support an NDA

“In addition to our 6-week Phase 3 trial, the design of which we shared with the FDA as part of our end-of-Phase 2 interaction, we anticipate the FDA will require 1,500 patient exposures to support an approval in schizophrenia.” (opens the source at this quote in a new tab)
“To support approval, the safety population must include at least 1,500 cumulative patient exposures to LB-102, including at least 100 patients with greater than or equal to one year of exposure and 300 patients with greater than or equal to six months of exposure.” (opens the source at this quote in a new tab)
“As a result, we expect to enroll approximately 900 patients in our planned open label safety trial.” (opens the source at this quote in a new tab)

NOVA-2 topline timing: moved in July 2026 to the first half of 2027

“NEW YORK, July 22, 2026 (GLOBE NEWSWIRE)” (opens the source at this quote in a new tab)
“today announced that based on enrollment projections, it now expects to report topline results from the pivotal Phase 3 NOVA-2 clinical trial of LB-102 in patients with schizophrenia in the first half of 2027 and to schedule a pre-NDA meeting with the FDA thereafter in the second half of 2027.” (opens the source at this quote in a new tab)
“Based on the pace of enrollment since initiating NOVA-2, we now expect to report topline results in the first half of 2027, ahead of our prior guidance of the second half of 2027, and to schedule a pre-NDA meeting soon thereafter in the second half of 2027,” (opens the source at this quote in a new tab)

“Discussion of the Phase 3 trial program in schizophrenia, its upcoming topline data readout expected in the first half of 2027, and ongoing pre-commercial planning activities” (opens the source at this quote in a new tab)

Pre-NDA meeting timing

“The Company expects to schedule a pre-NDA meeting with the FDA thereafter in the second half of 2027.” (opens the source at this quote in a new tab)

“Topline data expected 1H 2027” (opens the source at this quote in a new tab)
“Pre-NDA meeting expected 2H 2027” (opens the source at this quote in a new tab)

Pre-NDA meeting and NDA sequence stated in March 2026, before the July 2026 timing update

“If our Phase 3 trial is positive, we plan to hold a pre-NDA meeting with the FDA in the first quarter of 2028 to seek agreement from FDA on the suitability of our data to support an NDA submission for the treatment of schizophrenia with potential for submission of such NDA thereafter.” (opens the source at this quote in a new tab)

Regulatory submission

No evidence found.

Launch

No evidence found.

Fast track, breakthrough therapy, or priority review designation

No evidence found.

Planned NDA pathway under section 505(b)(1) or section 505(b)(2)

No evidence found.

New chemical entity status and regulatory exclusivity

“LB-102 is a new chemical entity and a methylated derivative of amisulpride, a second-generation antipsychotic drug approved in over 50 countries, not including the United States, because the development and regulatory requirements of the U.S. Food and Drug Administration, or FDA, for amisulpride were incompatible with patent coverage on the drug.” (opens the source at this quote in a new tab)
“The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity.” (opens the source at this quote in a new tab)

Patent protection: composition of matter expiry

“As of March 1, 2026, we owned approximately 43 patents and pending patent applications in the United States and foreign jurisdictions relating to LB-102, including five issued U.S. patents and thirteen issued foreign patents, three pending U.S. patent applications, twenty pending foreign applications, and two pending Patent Cooperation Treaty, or PCT, applications.” (opens the source at this quote in a new tab)
“The issued patents covering the composition of matter of LB-102 and method of treating schizophrenia are expected to expire in 2037, and any patents that may be issued from the pending patent applications are expected to expire between 2037 and 2047, in each case, without taking into account any possible patent term adjustment or extensions or terminal disclaimers and assuming payment of all appropriate maintenance, renewal, and annuity fees.” (opens the source at this quote in a new tab)
“We expect the patent term adjustment or extension to be up to five years.” (opens the source at this quote in a new tab)

“Robust IP portfolio with issued COM protection through ~2041 (including potential PTE)” (opens the source at this quote in a new tab)
“Includes estimated patent term extension (PTE), composition of matter (COM) IP expires 2037” (opens the source at this quote in a new tab)

Predominantly negative symptoms of schizophrenia: planned program

“On track to receive FDA feedback by end of 2026” (opens the source at this quote in a new tab)
“Exploring label-enabling Phase 3b trial designs” (opens the source at this quote in a new tab)

Pipeline in other indications: bipolar depression (ILLUMINATE-1) and adjunctive major depressive disorder

“today announced the initiation of a Phase 2 trial evaluating the efficacy and safety of LB-102 in patients with bipolar depression.” (opens the source at this quote in a new tab)
“The two-arm, six-week, outpatient trial is expected to enroll approximately 320 patients with bipolar 1 depression at approximately 30 sites in the U.S.” (opens the source at this quote in a new tab)

“The Phase 2 ILLUMINATE-1 trial evaluating the efficacy and safety of LB-102 in patients with bipolar 1 depression is enrolling patients, with topline data expected in the first quarter of 2028.” (opens the source at this quote in a new tab)
“Initiation of the Phase 2 trial in the adjunctive treatment of MDD is expected in early 2027, with topline data expected in the first half of 2029.” (opens the source at this quote in a new tab)
“The proceeds are intended to fund expansion of LB-102 into new indications, potentially including negative symptoms of schizophrenia and Alzheimer’s disease psychosis/agitation, and for general corporate purposes.” (opens the source at this quote in a new tab)

Long-acting injectable formulation in development

“We are also developing a long-acting injectable, or LAI, formulation of LB-102, which may improve compliance, a common issue in patients with schizophrenia and bipolar disorder.” (opens the source at this quote in a new tab)
“We have commenced LAI formulation development and expect to continue these efforts in 2026.” (opens the source at this quote in a new tab)
“We believe that the success of the 50 mg dose in our schizophrenia Phase 2 trial affords the opportunity to develop an LAI.” (opens the source at this quote in a new tab)

“LAI Formulation development in 2026” (opens the source at this quote in a new tab)

Development outside the United States

“We are conducting this trial entirely in the United States at approximately 25 sites, a similar number of sites as were utilized in our Phase 2 acute schizophrenia trial and there is a significant overlap between the sites utilized in our Phase 2 trial and those we are utilizing in the Phase 3 trial.” (opens the source at this quote in a new tab)
“While we are developing LB-102 for acute schizophrenia initially in the United States and potentially in other jurisdictions where amisulpride is not approved, we currently plan to develop LB-102 to treat bipolar depression and adjunctive MDD globally” (opens the source at this quote in a new tab)
“If approved for schizophrenia, we expect to commercialize the oral formulation of LB-102 in jurisdictions where amisulpride is unavailable as a generic, and we expect to commercialize an LAI form of LB-102 worldwide.” (opens the source at this quote in a new tab)

Marketing application, scientific advice, or designation from a regulator outside the United States

No evidence found.

Manufacturer: LB Pharmaceuticals Inc

“LB Pharmaceuticals Inc.” (opens the source at this quote in a new tab)

“We currently own global rights to LB-102 and intend to retain commercialization rights in the United States.” (opens the source at this quote in a new tab)

Product names: development code and chemical names

Field	Quoted record
Preferred substance name	“LB-102”
Unique ingredient identifier	“N81WKW91XF”
Formula	“C18H29N3O4S”
Synonym	“N'-METHYL AMISULPRIDE”
Systematic name	“4-(METHYLAMINO)-N-(((2RS)-1-ETHYLPYRROLIDIN-2-YL)METHYL)-5-(ETHYLSULFONYL)-2-METHOXYBENZAMIDE.”
Chemical Abstracts Service registry number	“2227154-23-4”

“A Single Ascending Dose (SAD; Part A) and Multiple Ascending Dose (MAD; Part B) Phase 1 Study of LB-102 N-Methyl amisulpride) in healthy volunteers.” (opens the source at this quote in a new tab)

“In addition, our lead product candidate, LB-102, is an N-methylated version of amisulpride, a drug already approved in certain parts of Europe for the treatment of schizophrenia, predominantly negative symptoms of schizophrenia and dysthymia.” (opens the source at this quote in a new tab)

International nonproprietary name, United States adopted name, and brand name

No evidence found.

Therapeutic class

“LB-102 is a novel, patent-protected benzamide antipsychotic drug that we designed to improve upon the clinical profile of amisulpride and address its limitations.” (opens the source at this quote in a new tab)
“Our lead product candidate, LB‑102, is a Phase 3 oral small molecule in development for the treatment of schizophrenia.” (opens the source at this quote in a new tab)

“LB-102 is a potent and selective antagonist of D2, D3, and 5-HT7 receptors with few off-target effects and broad therapeutic potential across psychosis and mood disorders.” (opens the source at this quote in a new tab)

Oral tablet: phase 3 NOVA-2

Arm or intervention	Quoted record
Experimental arm 1	“LB-102 (50 mg tablet)”
Experimental arm 2	“LB-102 (100 mg tablet)”
Intervention description	“LB-102 oral tablet given for six weeks”
Placebo	“Placebo tablet given orally for six weeks”

Strengths studied: phase 2 NOVA-1

“Patients in this study will be randomized 3:3:3:1 to receive either: placebo, 50 mg QD LB-102, 75 mg QD LB-102, or 100 mg QD LB-102” (opens the source at this quote in a new tab)
“LB-102 will be dosed orally once a day.” (opens the source at this quote in a new tab)
“Matched placebo tablets” (opens the source at this quote in a new tab)

Strengths studied: open-label NOVA-3

“LB-102 flexible dosing 50 mg - 100 mg” (opens the source at this quote in a new tab)

Oral capsule: phase 1 receptor occupancy study

“LB-102 (N-Methyl amisulpride) formulated capsule will be administered orally once daily for one day in 4 subjects.” (opens the source at this quote in a new tab)

Strengths studied: phase 1 single and multiple ascending dose study

Cohort	Quoted record
Part A Cohort 1	“LB-102 50 mg (n=6) or Matching Placebo (n=2) x 1 day”
Part A Cohort 2	“LB-102 15 mg (n=6) or Matching Placebo (n=2) x 1 day”
Part A Cohort 3	“LB-102 100 mg (n=6) or Matching Placebo (n=2) x 1 day”
Part A Cohort 4	“LB-102 200 mg (n=6) or Matching Placebo (n=2) x 1 day”
Part A Cohort 5	“LB-102 150 mg (n=6) or Matching Placebo (n-2) x 1 day”
Part B Cohort 6	“LB-102 50 mg (n=6) or Matching Placebo (n=2) BID x 7 days (QD on Day 7)”
Part B Cohort 7	“LB-102 100 mg (n=6) or Matching Placebo (n=2) BID x 7 days (QD on Day 7)”
Part B Cohort 8	“LB-102 75 mg (n=6) or Matching Placebo (n=2) BID x 7 days (QD on Day 7)”

Doses selected to inform commercial use

“To better inform potential future commercial use of LB-102, we are studying the effects of two doses, 50 mg LB-102 or 100 mg LB-102, versus placebo in this trial, and patients will be randomized in a 1:1:1 ratio across the three arms of the trial.” (opens the source at this quote in a new tab)
“All patients will start at their assigned dose level without titration.” (opens the source at this quote in a new tab)

“Doses selected to inform use in commercial setting” (opens the source at this quote in a new tab)

Commercial dosage form, strengths, and package configurations

No evidence found.

Product price and anticipated annual cost of treatment

Not applicable.

Mechanistic and chemical classification

“LB-102 is a dopamine D2/3 and 5HT7 antagonist.” (opens the source at this quote in a new tab)

“We believe an effective LAI form of LB-102 has the potential to benefit patients worldwide, as relatively few approved agents are available as long-acting formulations and there are no benzamide class LAIs currently available or in development worldwide.” (opens the source at this quote in a new tab)

Anatomical Therapeutic Chemical classification of the parent compound amisulpride

ATC level	Quoted record
N05A	“ANTIPSYCHOTICS”
N05AL	“Benzamides”
N05AL05	“amisulpride”

AHFS Pharmacologic-Therapeutic Classification and ATC code assigned to LB-102

No evidence found.

Indication under development

“Our lead product candidate, LB‑102, is a Phase 3 oral small molecule in development for the treatment of schizophrenia.” (opens the source at this quote in a new tab)
“Our ongoing Phase 3 trial (NOVA-2) is enrolling individuals with acute schizophrenia, defined as a sudden and severe worsening of psychotic symptoms such as hallucinations, delusions, and other positive symptoms.” (opens the source at this quote in a new tab)

Population studied in the phase 3 NOVA-2 trial

“This is a Phase 3, randomized, double blind, placebo controlled, fixed dose, multicenter study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of LB-102 100 mg once daily (QD) and LB-102 50 mg QD versus placebo QD for the treatment of adult patients with an acute exacerbation of schizophrenia” (opens the source at this quote in a new tab)
“Diagnosis of schizophrenia as defined by DSM-5” (opens the source at this quote in a new tab)
“18 Years to 65 Years” (opens the source at this quote in a new tab)

Population studied in the phase 2 NOVA-1 trial

“Male and female patients 18 to 55 years of age inclusive at the time of informed consent with a diagnosis of schizophrenia as defined by DSM-5 criteria and confirmed by the MINI 7.0.2 .” (opens the source at this quote in a new tab)
“Must be willing to be hospitalized for the duration of the inpatient period of the study.” (opens the source at this quote in a new tab)

Population studied in the open-label NOVA-3 trial

“Phase 3, open label, multicenter study designed to assess the long term safety and tolerability of LB-102 for the treatment of adult patients with stable schizophrenia who are experiencing inadequate response or who are having issues with side effects, general tolerability, or overall effectiveness of their current antipsychotic medication and desire to change medications, or who have completed their participation in current LB-102 clinical studies” (opens the source at this quote in a new tab)

Proposed labeled indication submitted to a regulator

No evidence found.

Receptor target profile

“LB-102, a novel, once-daily, oral investigational small molecule, is a selective antagonist of D2, D3, and 5HT-7 receptors that is being advanced as a potential first benzamide in the U.S. for the treatment of neuropsychiatric disorders.” (opens the source at this quote in a new tab)

“LB-102 (Fig. 1) is a N methylated version of amisulpride, a dopamine inhibitor developed in the 1980s and approved in more than 50 countries outside the United States for the treatment of schizophrenia.” (opens the source at this quote in a new tab)

Receptor binding affinities of LB-102, amisulpride, and their enantiomers

Antagonist	D2 KI (nM)	5-HT7 KI (nM)
Amisulpride, S enantiomer	“n.d.”	“900 ± 1300”
Amisulpride, racemate	“1.1 ± 0.12”	“44 ± 3”
Amisulpride, R enantiomer	“n.d.”	“22 ± 1.5”
LB-102 (racemate)	“0.82 ± 0.02”	“31 ± 1”
LB-103 (S enantiomer of LB-102)	“0.4 ± 0.04”	“>1000”
LB-104 (R enantiomer of LB-102)	“14.4 ± 2.2”	“15.6 ± 0.9”

“As well, within experimental uncertainty, LB-102 and amisulpride bind to the D2 receptor with a Kd of 1 nM.” (opens the source at this quote in a new tab)
“The racemic benzamide affinity for the 5-HT7 receptor is approximately 30-fold weaker than its D2 receptor affinity though potentially still pharmacologically relevant.” (opens the source at this quote in a new tab)

Enantiomer pharmacology: S enantiomer at D2 and D3, R enantiomer at 5-HT7

“Curiously, the studies herein reveal that racemic dosing is required to engage both targets since the D2 receptor has an almost 40-fold selectivity for the S enantiomer, while the 5-HT7 receptor has greater than 50-fold preference for the R enantiomer.” (opens the source at this quote in a new tab)
“The benzamides display polypharmacy if dosed as a racemate: antipsychotic activity is provided by targeting D2/3 receptors with the S enantiomer, while antidepressant effects are provided by targeting the 5-HT7 receptor with the R enantiomer.” (opens the source at this quote in a new tab)
“Based on the findings in this report, racemic LB-102 will be advanced to the clinic rather than the enantiomerically pure S LB-103.” (opens the source at this quote in a new tab)

Limits of the in vitro 5-HT7 data

“The absence of in vivo 5-HT7 receptor occupancy studies in animals or humans limits our ability to reliably model 5-HT7 in vivo occupancy since in vitro binding affinities rarely translate well to in vivo occupancies.” (opens the source at this quote in a new tab)
“Reliably modeling 5-HT7 occupancy in humans will require a competing PET ligand study, as has been done with the D2/3 receptors.” (opens the source at this quote in a new tab)

D3 receptor affinity and comparison with amisulpride

“Binding to D2 and D3 receptors was similar to amisulpride (Ki of 2.8 nM against D2 and 3.2 nM against D3).” (opens the source at this quote in a new tab)

“LB-102 bound similarly to the dopamine D2 and D3 receptors, with a Ki (inhibition constant) of 0.82 nM compared to amisulpride’s reported Ki of 1.1 nM, and had a similar affinity for the 5-HT7 receptor with a Ki of 31 nM compared to amisulpride’s reported Ki of 44 nM.” (opens the source at this quote in a new tab)

“LB-102 was specifically engineered to address the blood-brain barrier issues observed with amisulpride: LB-102 retains high-affinity antagonism at D2/D3 (Ki = 0.8nM) and serotonin (5-HT7; Kᵢ = 31nM) receptors with greater passive membrane diffusion into the brain.” (opens the source at this quote in a new tab)

Off-target receptor binding

“Compared to other commonly prescribed antipsychotic drugs, both LB-102 and amisulpride have weaker binding to other off-target CNS receptors that are commonly associated with adverse side effects such as anxiety, weight gain, or metabolic syndrome such as 5HT2C.” (opens the source at this quote in a new tab)

Rationale for N-methylation of amisulpride

“Selective N-methylation of amisulpride produces LB-102/LB-103, designed to decrease hydrophilicity to improve BBB permeability, increase brain and lower plasma exposure.” (opens the source at this quote in a new tab)

“The methylation we incorporated into LB-102 was designed to improve the tolerability and efficacy profile of amisulpride by addressing its shortcomings, such as limited blood-brain barrier, or BBB, permeability and dosing frequency.” (opens the source at this quote in a new tab)
“Enhanced BBB permeability was expected to improve the potency of the molecule with respect to dopamine receptor binding and enable the use of lower doses compared with amisulpride.” (opens the source at this quote in a new tab)
“The use of lower doses was hypothesized to improve the tolerability profile.” (opens the source at this quote in a new tab)

“Because of amisulpride’s poor membrane permeability, high doses are required to achieve plasma concentrations associated with dopamine RO > 60%.” (opens the source at this quote in a new tab)

Lipophilicity of LB-102 and amisulpride

“the measured Log P for amisulpride was 1.52 while that for LB-102 was 1.72; the measured pKas for amisulpride and LB-102 were 9.32 and 9.36, respectively” (opens the source at this quote in a new tab)
“The role of the methyl group in this equilibrium is unclear and was beyond the scope of the current work.” (opens the source at this quote in a new tab)

Characterization in an independent narrative review

“LB-102, a newly identified N-methylated analog of amisulpride, exhibits enhanced lipophilicity at lower doses, as demonstrated in a phase 1 study, indicating significant promise for therapeutic applications.” (opens the source at this quote in a new tab)

Dose-dependent presynaptic and postsynaptic dopamine receptor effects

“Moreover, at low doses, LB-102 and amisulpride have selectivity for pre-synaptic autoreceptors that serves to increase dopamine signaling which is underactive in depression.” (opens the source at this quote in a new tab)

“At high doses, postsynaptic D2/D3 receptor blockade suppresses dopamine signaling, which is overactive in psychosis” (opens the source at this quote in a new tab)

Class context: limbic selectivity of amisulpride

“In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors.” (opens the source at this quote in a new tab)
“In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors.” (opens the source at this quote in a new tab)

“In animals, at high doses it blocks post-synaptic D2 receptors located in the limbic structures in preference to those in the striatum.” (opens the source at this quote in a new tab)
“In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.” (opens the source at this quote in a new tab)

Class context: 5-HT7 antagonism and the antidepressant activity of amisulpride

“The work of Abbas et al., consisting of rodent in vivo studies, as well as the examination of a panel of off-target receptors, identified the serotonin 5-HT7 receptor as the likely mediator of amisulpride’s antidepressant activity.” (opens the source at this quote in a new tab)

“These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.” (opens the source at this quote in a new tab)

Limbic versus striatal selectivity measured for LB-102

No evidence found.

In vivo 5-HT7 receptor occupancy of LB-102

No evidence found.

PET dopamine receptor occupancy study in healthy volunteers: design

“The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET) with 11C raclopride as a radiotracer.” (opens the source at this quote in a new tab)
“Sixteen healthy volunteers (7 female, 9 male) ages 18 to 55 years and with a body mass index (BMI) between 18 and 30 kg/m2 were enrolled in the study.” (opens the source at this quote in a new tab)
“Subjects in Cohorts 1 to 3 received single doses and subjects in Cohort 4 received once daily doses over 4 days” (opens the source at this quote in a new tab)

Striatal D2/D3 receptor occupancy at steady state by dose

“Importantly, this 70% RO is in the midpoint of the 60–80% range typically sought for dopamine inhibitors in the treatment of schizophrenia and shows very little variability (~10%) over the course of 24 h.” (opens the source at this quote in a new tab)
“Initially, all four subjects in Cohort 4 were to receive 100 mg LB-102; the first two subjects demonstrated higher than expected dopamine receptor occupancy at 100 mg QD for four days, approaching 90%.” (opens the source at this quote in a new tab)
“It was decided to reduce dosing to 50 mg for the final two subjects out of an abundance of caution.” (opens the source at this quote in a new tab)

“Under steady-state conditions, at the 50 mg dose of LB-102, the average receptor occupancy was approximately 70%, and at the 100 mg dose, it was approximately 80%.” (opens the source at this quote in a new tab)

Time course of receptor occupancy relative to plasma concentration

“Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions.” (opens the source at this quote in a new tab)
“dopamine RO remains significant after plasma concentrations have dropped below 10 ng/mL” (opens the source at this quote in a new tab)
“the observation of 40% dopamine RO a full two days after a single 75 mg dose of LB-102 was unexpected” (opens the source at this quote in a new tab)
“Additionally, it is possible that this prolonged receptor occupancy is due to a metabolite of LB-102, though data to date indicate that LB-102 is not appreciably (<5%) metabolized.” (opens the source at this quote in a new tab)

“We observed that single doses of LB-102 led to a linear, dose-dependent dopamine receptor occupancy that achieved maximal levels at approximately eight hours post-dose and persisted for at least 24 hours” (opens the source at this quote in a new tab)

“A correlation between dopamine RO and plasma LB-102 concentration could not be established.” (opens the source at this quote in a new tab)

Target occupancy window of 60% to 80%

“Previous reports analyzing receptor occupancy of multiple antipsychotic drugs have found that occupancies of 60% to 80% correlate with maximum efficacy and tolerability in the treatment of schizophrenia.” (opens the source at this quote in a new tab)
“Receptor occupancy above 80% can be associated with an increased risk of EPS.” (opens the source at this quote in a new tab)

“This aligns with PET data showing that while 50 mg achieves approximately 70% D2/D3 occupancy, 100 mg exceeds 80%.” (opens the source at this quote in a new tab)
“Notably, the level of receptor occupancy with LB-102 100 mg was not accompanied by a disproportionate increase in any antipsychotic-induced parkinsonism, suggesting LB-102 maintains a favorable therapeutic index even at high levels of receptor engagement.” (opens the source at this quote in a new tab)

Occupancy compared with published amisulpride doses

“Single oral doses, based on prior experience and analogy to amisulpride, had RO of 60–80% at ~400 mg and the chronic dosing of LB-102 replicated this at only 50 mg.” (opens the source at this quote in a new tab)

“The dopamine receptor occupancy levels seen in the imaging trial at 50 mg of LB-102 are approximately equivalent to those observed with 300 to 400 mg of amisulpride.” (opens the source at this quote in a new tab)

“This modification allows LB-102 to attain therapeutically relevant levels of D2/D3 receptor occupancy (60%-80%) over 24 hours at 5- to 8-fold lower systemic exposures, also enabling once-daily dosing.” (opens the source at this quote in a new tab)

PET study limitations

“Limitations of this study include a small number of RO observations at steady state but allowed bracketing 50 and 100 mg.” (opens the source at this quote in a new tab)
“Sizing of this study was based on prior experience with PET imaging studies and did not take statistical powering assumptions into account.” (opens the source at this quote in a new tab)

Prolactin elevation in healthy volunteers

“LB-102 was generally safe and well-tolerated, and clinical lab values were unremarkable at all doses, save for prolactin which was transiently elevated in the majority of subjects treated with LB-102; there were no clinical observations associated with the increases in prolactin elevation.” (opens the source at this quote in a new tab)

“there were 11 cases of elevated prolactin (≥100 μg/L; 50 mg QD, N = 3; 10 mg QD, N = 1; 100 mg QD, N = 1; 150 mg QD, N = 1; 50 mg BID, N = 2; 100 mg BID, N = 1; 75 mg BID, N = 2)” (opens the source at this quote in a new tab)

“Prolactin was measured at baseline and at last visit, average prolactin at baseline was 7.5 ng/mL (SD 2.9) which increased, on average, to 30.8 (SD 13.0) at final visit.” (opens the source at this quote in a new tab)

“Prolactin elevation, a common laboratory finding of most antipsychotic drugs that act as dopamine antagonists that is believed to be the result of inhibition of dopamine receptors in the pituitary, was observed at all those doses.” (opens the source at this quote in a new tab)

Prolactin elevation in NOVA-1

“Elevated prolactin levels at day 28 were reported across all arms (placebo, 5.2%, mean [SD] increase, 1.3 [6.0] ng/mL; 50 mg, 91.0%, mean [SD] increase, 59.9 [55.1] ng/mL; 75 mg, 94.0%, mean [SD] increase, 51.4 [52.0] ng/mL; 100 mg, 87.5%, mean [SD] increase, 51.2 [48.1] ng/mL” (opens the source at this quote in a new tab)

QTc interval in healthy volunteers

“There was evidence of transient QT interval prolongation at the 200 mg dose, none of which resulted in clinical observation or triggered stopping criteria.” (opens the source at this quote in a new tab)

“Additionally, because QTcF interval was fairly prolonged from pre-dose values (20- 46 msec) in all healthy volunteers taking 200 mg LB-102 QD (Cohort 4), the dosage for Cohort 5 was reduced to 150 mg LB-102 QD.” (opens the source at this quote in a new tab)
“1 case of mild ECG QTcF prolongation (458 msec, 200 mg LB-102 QD)” (opens the source at this quote in a new tab)
“At the highest dose (200 mg LB-102), QTcF prolongation was noted; however, predefined stopping criteria were not met.” (opens the source at this quote in a new tab)

“There were no abnormal ECG readings; the average change in QTcf from baseline was -1 ms.” (opens the source at this quote in a new tab)

QTc interval in NOVA-1

Parameter	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
QTc, mean (SD) change from baseline to day 28, millisecond	“4.9 (13.39)”	“4.3 (12.55)”	“5.4 (9.44)”	“1.2 (12.56)”
Mean change ≥30 millisecond, No. participants (%)	“5 (4.7)”	“1 (0.9)”	“1 (2.8)”	“1 (0.9)”
Mean change ≥60 millisecond, No. participants (%)	“0”	“0”	“0”	“0”

“Stopping criteria were not met at any dose level.” (opens the source at this quote in a new tab)

Concentration-QTc modeling and a thorough QT study

No evidence found.

Preclinical behavioral models

“LB-102 had equivalent or better results than similar doses of amisulpride in the LMA model of hyperactivity.” (opens the source at this quote in a new tab)
“In our head-to-head preclinical rat model of cognition, the Novel Object Recognition model, and in a mouse model of stereotypy or excessive repetition, the Apomorphine Induced Climbing model, we observed that the effects of treatment with LB-102 were statistically indistinguishable from that of amisulpride.” (opens the source at this quote in a new tab)

“In scPCP treated rats in a catalepsy test to measure EPS potential, no catalepsy was observed and LB-102 and LB-103 were indistinguishable from amisulpride” (opens the source at this quote in a new tab)

Preclinical receptor occupancy in mice

“Dopamine D2/3 receptor occupancies in mice, presented below, resulting from 100 mg/kg oral doses of LB-102 and amisulpride in mice were determined to be 68% and 38%, respectively, consistent with greater Log P and increased plasma concentrations of LB-102 observed in a Phase 1 clinical study” (opens the source at this quote in a new tab)

Preclinical pharmacokinetic, receptor occupancy, and efficacy model

“Direct measurement of rodent brain concentrations indicates that blood brain barrier permeation is rate limiting and that brain concentrations lag behind and then persist beyond observed plasma concentrations.” (opens the source at this quote in a new tab)
“As modeled in rodents, a 30 mg/kg dose of LB- 102 achieves D2 occupancy of 74% at peak occupancy and provides for 16 out of 24 hours of D2 occupancy when analyzed as the Area Under the Response Curve (AURC).” (opens the source at this quote in a new tab)

“Receptor occupancy and behavioral responses are delayed relative to plasma concentrations and persist much longer than predicted by plasma levels.” (opens the source at this quote in a new tab)

Single ascending dose in healthy volunteers: parameters by dose

Parameter	10 mg (N = 6)	50 mg (N = 6)	100 mg (N = 6)	150 mg (N = 6)	200 mg (N = 6)
Cmax, mean (SD), ng/mL	“24.1 (10.728)”	“176 (52.786)”	“348.167 (141.832)”	“596.5 (117.527)”	“975.667 (253.995)”
Tmax, median (min, max), h	“3 (3, 3)”	“3 (2, 4)”	“3.01 (1, 4)”	“3 (3, 4)”	“1.75 (1.5, 3)”
t½, mean (SD), h	“13.75 (3.9375)”	“11.933 (1.7797)”	“14.146 (3.9617)”	“11.969 (1.8897)”	“12.997 (3.5854)”
AUC0-24, mean (SD), ng•h/mL	“198.807 (66.9513)”	“1336.105 (167.6764)”	“2303.664 (533.1684)”	“4067.23 (685.9163)”	“5983.093 (833.9816)”
AUC0-inf, mean (SD), ng•h/mL	“252.637 (69.857)”	“1595.938 (189.1599)”	“2809.785 (477.7622)”	“4363.577 (745.7299)”	“7002.109 (820.7252)”
CL/F, mean (SD), L/h	“42.44 (12.598)”	“31.7 (3.794)”	“36.56 (6.935)”	“33.05 (5.25)”	“28.89 (3.381)”

Absorption and half-life

“In Part A (SAD), LB-102 was rapidly absorbed and LB-102 concentration generally declined from peak in an apparent biphasic manner.” (opens the source at this quote in a new tab)

“The half-life of LB-102 was slightly greater than 12 hours, and maximum drug levels were observed approximately three hours after administration.” (opens the source at this quote in a new tab)

“A phase 1 trial demonstrated LB-102 has rapid absorption (time to peak drug concentration, [Tmax] approximately 3 hours), nearly dose-proportional exposure across 10 to 200 mg, and a terminal half-life of 12 to 14 hours, with transient prolactin elevation and mild extrapyramidal symptoms occurring when occupancy exceeded 80%.” (opens the source at this quote in a new tab)

Dose proportionality

“exposure (as measured by Cmax, AUC0-t, and AUC0-inf) increased in a slightly greater than dose-proportional manner” (opens the source at this quote in a new tab)
“Apparent clearance (CL/F) appeared to decrease as dose increased (42.44 L/h to 28.89 L/h).” (opens the source at this quote in a new tab)
“Exposure to LB-102 increased in a dose-proportional manner.” (opens the source at this quote in a new tab)
“Apparent clearance at steady state to LB-102 appeared to be similar as the dose increased.” (opens the source at this quote in a new tab)

Steady state and accumulation with twice-daily dosing

“In Part B (MAD), trough concentrations of LB-102 and amisulpride plateaued before the morning dose on Day 4.” (opens the source at this quote in a new tab)
“After multiple doses, there was slight to moderate accumulation of LB-102 across dose levels with mean accumulation ratio based on Cmax after the first dose and last dose (RCmax) values ranged from 1.121 to 1.798 and with mean accumulation ratio based on AUC after the first and last dose (RAUC) values ranged from 1.472 to 1.925.” (opens the source at this quote in a new tab)

Metabolism to amisulpride in humans

“In Part A (SAD), amisulpride was formed quickly over time after a single dose of LB-102 (median Tmax, range = 2 to 3.5 hours) and generally declined with an approximate biphasic disposition of comparable shape to LB-102 but at approximately 2.5% of LB-102 abundance.” (opens the source at this quote in a new tab)
“In fact, amisulpride was not detected in healthy volunteers taking 10 mg LB-102 QD (Cohort 2).” (opens the source at this quote in a new tab)
“Mean amisulpride t½ ranged from approximately 8.921 to 14.614 hours.” (opens the source at this quote in a new tab)
“Amisulpride had a higher accumulation than LB-102 across dose levels with mean RCmax values ranged from 1.317 to 2.016 and with mean RAUC values ranged from 1.801 to 2.232.” (opens the source at this quote in a new tab)

“The metabolism of LB-102 will be studied more completely in a subsequent study.” (opens the source at this quote in a new tab)

Metabolism in rodents

“N-demethylation of LB-102 (generating amisulpride) is the dominate elimination pathway.” (opens the source at this quote in a new tab)

“LB-102 displays a demethylation burst (possibly 1st pass) followed by a steady state having equal proportions of LB-102 and demethylated metabolite (amisulpride).” (opens the source at this quote in a new tab)

Plasma exposure compared with published amisulpride values

“We observed the plasma exposure of 50 mg of LB-102 to be 1,648 ng*h/mL.” (opens the source at this quote in a new tab)
“In a previous third-party study of amisulpride, plasma exposure was reported at 667 ng*h/mL.” (opens the source at this quote in a new tab)

“Plasma concentrations of LB-102 were ~2.5 times greater than published values of amisulpride at the same dose, suggesting LB-102 could be dosed substantially lower than amisulpride” (opens the source at this quote in a new tab)

Membrane permeability and brain penetration

“The ability of LB-102 to cross the BBB was estimated using a standard in vitro membrane permeability assay.” (opens the source at this quote in a new tab)
“In this assay, the permeability of LB-102 was approximately 200-fold greater than that of amisulpride.” (opens the source at this quote in a new tab)

“This may be due to the increased lipophilicity of LB-102 and increased residence time in brain, which may be due to more than just lipophilicity alone” (opens the source at this quote in a new tab)
“Future work may include more direct measurements of LB-102 in brain to further validate the hypothesis of its potential improved brain kinetics and potential to be an effective antipsychotic with antidepressant action while enjoying a low side effect potential.” (opens the source at this quote in a new tab)

Food effect: company expectation

“No expected food effect or DDIs” (opens the source at this quote in a new tab)

Class context: pharmacokinetics of oral amisulpride

“Absolute bioavailability is 48%.” (opens the source at this quote in a new tab)
“As plasma protein binding is low (16%) drug interactions are unlikely.” (opens the source at this quote in a new tab)
“Amisulpride is weakly metabolised: two inactive metabolites, accounting for approximately 4% of the dose, have been identified.” (opens the source at this quote in a new tab)
“The elimination half-life of amisulpride is approximately 12 hours after an oral dose.” (opens the source at this quote in a new tab)
“Amisulpride is eliminated unchanged in the urine.” (opens the source at this quote in a new tab)
“Kinetic profile of amisulpride is not influenced by diet.” (opens the source at this quote in a new tab)
“A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, Tmax and Cmax of amisulpride but no changes were seen after a high fat meal.” (opens the source at this quote in a new tab)

Class context: excretion of intravenous amisulpride

“After intravenous administration of amisulpride, 74% and 23% of the administered dose was recovered in urine and feces, respectively.” (opens the source at this quote in a new tab)
“Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects suggesting that amisulpride undergoes active renal secretion.” (opens the source at this quote in a new tab)

Food effect study results for LB-102

No evidence found.

Absolute bioavailability, plasma protein binding, volume of distribution, mass balance, and routes of excretion of LB-102

No evidence found.

Pharmacokinetics of LB-102 in participants with schizophrenia

No evidence found.

FDA-approved prescribing information, contraindications, boxed warning, and REMS

“We currently have no products approved for commercial sale or for which regulatory approval to market has been sought.” (opens the source at this quote in a new tab)

Risks described to NOVA-1 investigators

“Administration of second generation antipsychotics (SGAs) (including the metabolite of LB-102, amisulpride) can result in extrapyramidal symptoms, weight gain, elevations in lipids and blood sugar, sedation, dry mouth, constipation, dizziness, and falls due to low blood pressure, QTcF prolongation, cognitive impairment, and prolactin elevation.” (opens the source at this quote in a new tab)
“The effect of LB-102 on pregnant women and fetal development is unknown.” (opens the source at this quote in a new tab)

NOVA-1: adverse events by dose

Outcome, No. (%)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
Any TEAE	“74 (69.2)”	“62 (57.4)”	“27 (75.0)”	“60 (55.6)”
Any treatment-related TEAE	“49 (45.8)”	“34 (31.5)”	“17 (47.2)”	“23 (21.3)”
Any serious TEAE	“1 (0.9)”	“1 (0.9)”	“1 (2.8)”	“2 (1.9)”
TEAE leading to early withdrawal	“2 (1.9)”	“3 (2.8)”	“3 (8.3)”	“2 (1.9)”
Insomnia	“27 (25.2)”	“23 (21.3)”	“14 (38.9)”	“24 (22.2)”
Weight (increase)	“13 (12.1)”	“8 (7.4)”	“3 (8.3)”	“4 (3.7)”
Blood prolactin (increase)	“7 (6.5)”	“6 (5.6)”	“3 (8.3)”	“0”
Hyperprolactinemia	“4 (3.7)”	“2 (1.9)”	“3 (8.3)”	“0”
Somnolence	“1 (0.9)”	“4 (3.7)”	“2 (5.6)”	“0”
Blood creatine phosphokinase (increase)	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”	“3 (2.8)”
Alanine aminotransferase (increase)	“3 (2.8)”	“1 (0.9)”	“2 (5.6)”	“1 (0.9)”
Constipation	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”	“0”

NOVA-1: extrapyramidal symptoms, dystonia, and akathisia

“Extrapyramidal symptom incidence was low across all groups (placebo, 2 [1.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 1 [0.9%]; 100 mg, 1 [2.8%]), as was dystonia (placebo, 1 [0.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 3 [2.8%]; 100 mg, 1 [2.8%]).” (opens the source at this quote in a new tab)
“Evaluation of the SAS, BARS, and AIMS demonstrated values that remained stable over time, with little to no emergence of any antipsychotic-induced parkinsonism, akathisia, tardive dyskinesia, or other involuntary motor AEs.” (opens the source at this quote in a new tab)
“Severe TEAEs were reported in 5 participants (1.4%), including dystonia (75 mg, n = 1), psychotic disorder (100 mg, n = 1), schizophrenia (placebo, n = 2), and death (placebo, n = 1).” (opens the source at this quote in a new tab)

Preferred term	LB-102 50 mg (N=107)	LB-102 75 mg (N=108)	LB-102 100 mg (N=36)	Placebo (N=108)
Dystonia	“0”	“3 (2.8%)”	“1 (2.8%)”	“1 (0.9%)”
Akathisia	“1 (0.9%)”	“2 (1.8%)”	“0”	“1 (0.9%)”
Extrapyramidal disorder	“0”	“1 (0.9%)”	“1 (2.8%)”	“2 (1.9%)”
Total EPS	“1 (1.0%)”	“6 (5.6%)”	“2 (5.6%)”	“4 (3.7%)”

“one SAE in the 75 mg cohort (dystonia – deemed possibly related to treatment)” (opens the source at this quote in a new tab)

NOVA-1: hyperprolactinemia and prolactin-related adverse events

“Clinical AEs related to prolactin increase were reported in 5 participants, including galactorrhea (50 mg, n = 2; 75 mg, n = 1), breast enlargement (100 mg, n = 1), and erectile dysfunction (100 mg, n = 1).” (opens the source at this quote in a new tab)
“Elevated prolactin was reported from 6.5% of those receiving LB-102 50 mg to 8.3% of those receiving LB-102 100 mg; by comparison, data for amisulpride indicate significantly higher rates of hyperprolactinemia (25%-100%).” (opens the source at this quote in a new tab)

Parameter	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
Prolactin, mean (SD) change from baseline to day 28, ng/mL	“59.9 (55.11)”	“51.4 (52.02)”	“51.2 (48.07)”	“1.3 (6.03)”

Adverse event	LB-102 50 mg (N=107)	LB-102 75 mg (N=108)	LB-102 100 mg (N=36)	Placebo (N=108)
Hyperprolactinemia	“11 (10.3%)”	“8 (7.4%)”	“6 (16.7%)”	“0”
Galactorrhea	“2 (1.9%)”	“1 (0.9%)”	“0”	“0”
Breast enlargement	“0”	“0”	“1 (2.8%)”	“0”
Erectile dysfunction	“0”	“0”	“1 (2.8%)”	“0”
Total related to prolactin	“2 (1.9%)”	“1 (0.9%)”	“2 (5.6%)”	“0”

NOVA-1: QTc interval

“There were no clinically meaningful changes in blood pressure, pulse rate, or body temperature from baseline to day 28, and no notable shifts observed in QTcF (Fridericia-corrected QT interval) values” (opens the source at this quote in a new tab)

“An increase in QTcF to >500 msec for male and female patients.” (opens the source at this quote in a new tab)
“An increase in QTcF of >60 msec over Baseline.” (opens the source at this quote in a new tab)

“QTc Prolongation Minimal QT prolongation (4.3-5.4 ms); no patients met pre-specified stopping criteria” (opens the source at this quote in a new tab)

NOVA-1: weight gain and metabolic parameters

“Weight increase was the only TEAE to occur in 5% or more of the total population at a rate at least twice that observed with placebo but was not dose-dependent (placebo, 4 [3.7%], mean increase, 2.1 kg; 50 mg, 13 [12.1%], mean increase, 4.3 kg; 75 mg, 8 [7.4%], mean increase, 3.3 kg; 100 mg, 3 [8.3%], mean increase, 2.9 kg).” (opens the source at this quote in a new tab)
“A 7% or greater weight increase, using a last-observation-carried-forward approach, was reported by 61 participants (placebo, 11 [10.4%], mean increase, 6.9 kg; 50 mg, 27 [25.7%], mean increase, 8.2 kg; 75 mg, 20 [18.7%], mean increase, 7.2 kg; 100 mg, 3 [8.8%], mean increase, 7.2 kg)” (opens the source at this quote in a new tab)
“Site-level smoking restrictions and limited opportunity for physical activity, combined with minimal dietary or food restrictions, may have contributed to weight gain, limiting the ability to fully assess the metabolic profile of LB-102 under real-world outpatient conditions.” (opens the source at this quote in a new tab)

Parameter, mean (SD) change from baseline to day 28	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
Weight, kg	“4.3 (3.2)”	“3.3 (2.8)”	“2.9 (2.5)”	“2.0 (2.9)”
Fasting glucose, mg/dL	“2.3 (24.52)”	“2.0 (13.62)”	“7.0 (19.39)”	“0.2 (12.07)”
Total cholesterol, mg/dL	“7.7 (24.75)”	“5.4 (23.98)”	“5.8 (25.52)”	“0.8 (25.06)”

“Over the course of the trial, we observed approximately 1.6 kg placebo-adjusted weight gain on a last observation carried forward basis.” (opens the source at this quote in a new tab)
“Despite the weight gain observed in the four-week trial, no clinically meaningful signal in metabolic parameters such as cholesterol, LDL, HDL, triglycerides or fasting glucose were observed.” (opens the source at this quote in a new tab)

NOVA-1: sedation, somnolence, and insomnia

“Across 251 dosed subjects, only one case of sedation was reported.” (opens the source at this quote in a new tab)

“TEAEs were generally balanced across treatment arms, except insomnia (more frequent with 75 mg) and weight increase.” (opens the source at this quote in a new tab)
“Common baseline comorbidities (ie, insomnia, anxiety, headache, and agitation) were among the most common TEAEs, suggesting that some TEAEs may represent the re-emergence, exacerbation, or fluctuation of preexisting symptoms rather than new, drug-related effects.” (opens the source at this quote in a new tab)

NOVA-1: orthostasis, suicidal ideation, and discontinuations

“there were no reports of orthostasis among patients treated with LB-102 in the trial” (opens the source at this quote in a new tab)
“one SAE in the 50 mg cohort (suicidal ideation – deemed possibly related to treatment)” (opens the source at this quote in a new tab)

“Other discontinuation-related TEAEs included psychotic disorder, suicidal ideation, alanine aminotransferase increase, lipase increase, toothache, COVID-19, and dystonia.” (opens the source at this quote in a new tab)

Phase 1: dose-limiting acute dystonia and maximum tolerated dose

“As a result of two cases of EPS (acute dystonia) at 200 mg in the MAD portion of the study, dosing of that arm was discontinued and doses for the remaining cohort were decreased to 150 mg/day.” (opens the source at this quote in a new tab)
“There were four instances of EPS (acute dystonia), typically associated with dopamine receptor occupancy in excess of 80%, one at 100 mg QD, one at 75 mg BID, and two at 100 mg BID.” (opens the source at this quote in a new tab)

“4 cases of moderate dystonia (200 mg QD, N = 1; 100 mg BID, N = 2; 75 mg BID, N = 1)” (opens the source at this quote in a new tab)
“Due to 2 TEAEs in the same SOC (acute dystonic reaction), treatment was halted in all healthy volunteers taking 100 mg LB-102 BID (Cohort 7) and the 2 healthy volunteers in Cohort 7 taking placebo.” (opens the source at this quote in a new tab)
“The MTD of LB-102 was identified as 150 mg per day as either 150 mg QD or 75 mg BID.” (opens the source at this quote in a new tab)

“At 50 mg and 100 mg QD, two of the doses evaluated in our Phase 2 trial (and the doses being evaluated in our Phase 3 trial) we observed no adverse events associated with QT prolongation, sedation, weight gain or EPS in our Phase 1 trial.” (opens the source at this quote in a new tab)

PET study: tolerability at 50 mg to 100 mg

“No episodes of acute dystonia were reported or observed, consistent with a prior study in healthy adults in which acute EPS was observed at higher doses of LB-102 (75 mg twice daily i.e. 150 mg/day).” (opens the source at this quote in a new tab)

Duration of controlled safety exposure

“The NOVA 1 trial was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment.” (opens the source at this quote in a new tab)

Class context: U.S. boxed warning on antipsychotic use in elderly patients with dementia-related psychosis

“WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS” (opens the source at this quote in a new tab)
“Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.” (opens the source at this quote in a new tab)
“Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.” (opens the source at this quote in a new tab)

“Amisulpride is not licensed for the treatment of dementia-related behavioural disturbances.” (opens the source at this quote in a new tab)

Class context: amisulpride labeling on QT prolongation

“BARHEMSYS causes dose- and concentration-dependent prolongation of the QT interval” (opens the source at this quote in a new tab)
“Avoid use in patients with congenital long QT syndrome and in patients taking droperidol.” (opens the source at this quote in a new tab)
“In 40 healthy Caucasian and Japanese subjects, the maximum mean difference (95% upper confidence bound) in QTcF from placebo after baseline-correction (ΔΔQTcF) was 5.0 (7.1) milliseconds after a 2-minute intravenous infusion of 5 mg BARHEMSYS and 23.4 (25.5) milliseconds after an 8- minute intravenous infusion of 40 mg BARHEMSYS” (opens the source at this quote in a new tab)

“Caution should be exercised when amisulpride is prescribed in patients with known cardiovascular disease or family history of QT prolongation and concomitant use with neuroleptics should be avoided.” (opens the source at this quote in a new tab)

“Amisulpride has been associated with QT prolongation.” (opens the source at this quote in a new tab)
“amisulpride is a weak inhibitor of human ether-a-go-go-related gene (hERG) potassium channels, and it has been shown that QT prolongation is dependent on amisulpride systemic exposure” (opens the source at this quote in a new tab)
“pharmacovigilance data on amisulpride from the United Kingdom covering 16,000 patient exposure years had 8 incidences of QT prolongation with all 8 events occurring in patients concurrently taking clozapine, a drug known to prolong the QT interval” (opens the source at this quote in a new tab)
“At therapeutic doses of amisulpride up to 1,200 mg/day, literature reports of cardiac toxicity due to QT prolongation are extremely rare.” (opens the source at this quote in a new tab)

Class context: amisulpride labeling on hyperprolactinemia

“Amisulpride causes an increase prolactin levels.” (opens the source at this quote in a new tab)
“Cases of benign pituitary tumours such as prolactinoma have been observed during Amisulpride therapy (see section 4.8).” (opens the source at this quote in a new tab)
“In case of very high levels of prolactin or clinical signs of pituitary tumour (such as visual field defect and headache), pituitary imaging should be performed.” (opens the source at this quote in a new tab)

“Serum prolactin concentrations were measured in Study 1 where 5% (9/176) of BARHEMSYS-treated patients vs 1% (1/166) of placebo-treated patients had increased blood prolactin reported as an adverse reaction.” (opens the source at this quote in a new tab)

Class context: contraindications in oral amisulpride labeling

Contraindication	Quoted text
Hypersensitivity	“Hypersensitivity to the active substance or to other ingredients of the medicinal product.”
Prolactin-dependent tumours	“Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas or breast cancer (see sections 4.4 and 4.8)”
Phaeochromocytoma	“Phaeochromocytoma”
Children	“Children up to puberty”
Levodopa	“Combination with levodopa (see section 4.5)”

Class context: other warnings in oral amisulpride labeling

“As with other neuroleptics, neuroleptic malignant syndrome (NMS) may occur.” (opens the source at this quote in a new tab)
“Amisulpride may lower the seizure threshold.” (opens the source at this quote in a new tab)
“Severe liver toxicity has been reported with amisulpride use.” (opens the source at this quote in a new tab)
“Therefore, gradual withdrawal of amisulpride is advisable.” (opens the source at this quote in a new tab)

Safety beyond 4 weeks of treatment, tardive dyskinesia, and neuroleptic malignant syndrome with LB-102

No evidence found.

Age range studied

“Eligible participants were adults (aged 18-55 years) with a primary diagnosis of schizophrenia” (opens the source at this quote in a new tab)

“18 Years to 65 Years (Adult, Older Adult )” (opens the source at this quote in a new tab)

“Healthy adult male and female subjects between 18 to 55 years of age inclusive at the screening visit.” (opens the source at this quote in a new tab)

Sex and race of NOVA-1 participants

“There were 359 participants randomized (mean [SD] age, 39.1 [9.3] years; 69 female [19.2%]; 290 male [80.8%]” (opens the source at this quote in a new tab)
“Many sites had a trial population that was predominantly Black, reflecting the urban US clinical settings in which recruitment for many sites occurred.” (opens the source at this quote in a new tab)

Renal impairment: NOVA-1 exclusion criteria

“Creatinine ≥2 mg/dL or ≥176.8 μmol/L” (opens the source at this quote in a new tab)
“Estimated creatinine clearance of <45 mL/min, calculated using the Cockcroft-Gault equation, at Screening” (opens the source at this quote in a new tab)

Hepatic impairment: NOVA-1 exclusion criteria

“AST >2 × ULN” (opens the source at this quote in a new tab)
“ALT >2 × ULN” (opens the source at this quote in a new tab)
“Patients with chronic hepatitis B or hepatitis C may be included after discussion with the Medical Monitor provided that their condition is stable and values for liver function test meet the specified criteria of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 × upper limit of normal (ULN).” (opens the source at this quote in a new tab)

Cardiac conduction and cardiovascular disease: NOVA-1 exclusion criteria

“Interval between Q and T wave corrected for heart rate using Fridericia’s formula (QTcF) interval >450 msec for males and females” (opens the source at this quote in a new tab)
“PR interval ≥200 msec” (opens the source at this quote in a new tab)
“Intraventricular conduction delay with QRS duration >120 msec” (opens the source at this quote in a new tab)
“Patients with known ischemic heart disease or any history of myocardial infarction, congestive heart failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass surgery.” (opens the source at this quote in a new tab)

Cardiac conduction: PET study exclusion criteria

“The subject has a history of QT prolongation or dysrhythmia or a family history of prolonged QT interval or sudden death.” (opens the source at this quote in a new tab)
“QTcF interval > 450 msec for males and females” (opens the source at this quote in a new tab)

Medical exclusions in NOVA-2

“Known ischemic heart disease or any history of myocardial infarction, congestive heart failure (whether controlled or uncontrolled), angioplasty, stenting, or coronary artery bypass surgery” (opens the source at this quote in a new tab)
“History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the patient” (opens the source at this quote in a new tab)
“Insulin dependent diabetes” (opens the source at this quote in a new tab)

Medical exclusions in NOVA-3

“History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other” (opens the source at this quote in a new tab)

Pregnancy, lactation, and contraception

“The effect of LB-102 on pregnant women and fetal development is unknown.” (opens the source at this quote in a new tab)
“Females who are breastfeeding or who have a positive pregnancy test result prior to receiving trial medication.” (opens the source at this quote in a new tab)
“Sexually active females of childbearing potential and male patients who are not practicing 2 different methods of birth control with their partner during the trial and for 30 days after the last dose of trial medication or who would not remain abstinent during the trial and for 30 days after the last dose.” (opens the source at this quote in a new tab)
“Male patients or male partners of female patients should not donate sperm until 90 calendar days after the last dose of study drug.” (opens the source at this quote in a new tab)

“Sexually active m/f not willing to adhere to highly effect birth control” (opens the source at this quote in a new tab)
“Breast feeding” (opens the source at this quote in a new tab)

“Sexually active M/F patients not willing to use highly effective contraception” (opens the source at this quote in a new tab)

Suicidality: exclusion criteria

“Risk for suicidal behavior during the study as determined by the Investigator’s clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS)” (opens the source at this quote in a new tab)
“on items 4 or 5 (C-SSRS – Ideation) with the most recent episode occurring within the 6 months before Screening” (opens the source at this quote in a new tab)
“to any of the 5 items (C-SSRS – Suicidal Behavior) with an episode occurring within the 12 months before Screening” (opens the source at this quote in a new tab)

“Risk of suicidal behavior” (opens the source at this quote in a new tab)

Substance use: exclusion criteria and restrictions

“Patients who met DSM-5 criteria for substance abuse or dependence within the past 1 year, including alcohol and benzodiazepines, but excluding caffeine and nicotine.” (opens the source at this quote in a new tab)
“subjects are required to abstain from alcohol and cannabis use during the trial” (opens the source at this quote in a new tab)
“Smoking is allowed, under supervision.” (opens the source at this quote in a new tab)

Other excluded groups in NOVA-1

“Patients who presented with a first episode of schizophrenia based on the clinical judgment of the Investigator and patients with diagnosed schizophrenia equal to or less than a year.” (opens the source at this quote in a new tab)
“History of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (dose and duration as per the label) or required clozapine within the last 12 months.” (opens the source at this quote in a new tab)
“Patients with insulin-dependent diabetes mellitus (i.e., any patients using insulin) are excluded.” (opens the source at this quote in a new tab)
“Patients with epilepsy or a history of seizures (with the exception of febrile seizure).” (opens the source at this quote in a new tab)
“Patients with a history of neuroleptic malignant syndrome.” (opens the source at this quote in a new tab)

Planned study in elderly healthy volunteers

“Elderly HV Phase 1 trial (safety / PK)” (opens the source at this quote in a new tab)

Class context: amisulpride in renal impairment

“In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CRCL) between 30-60 ml/min and to a third in patients with CRCL between 10-30 ml/min.” (opens the source at this quote in a new tab)
“The AUC of amisulpride in mild renal failure increased two fold and almost tenfold in moderate renal failure (see section 4.2).” (opens the source at this quote in a new tab)

“In subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m2) and no requirement for dialysis, the Cmax of amisulpride after a single 10 mg intravenous dose was not greater than that in healthy subjects with normal renal function, and the AUC(0-∞) was approximately twice as high.” (opens the source at this quote in a new tab)

Class context: amisulpride in hepatic impairment, elderly patients, children, and lactation

“Hepatic insufficiency: since the drug is weakly metabolised a dosage reduction should not be necessary in patients with hepatic insufficiency.” (opens the source at this quote in a new tab)
“Limited pharmacokinetic data in elderly subjects (> 65 years) show that a 10-30 % rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg.” (opens the source at this quote in a new tab)
“Therefore, the use of amisulpiride from puberty to the age of 18 years is not recommended; in children up to puberty amisulpride is contraindicated, as its safety has not yet been established.” (opens the source at this quote in a new tab)

“Based on case reports in published literature, amisulpride is present in human milk at concentrations that are 11- to 20-fold higher than human plasma in patients taking multiple oral doses of amisulpride (200 to 400 mg/day).” (opens the source at this quote in a new tab)

QTc and laboratory exclusion thresholds in NOVA-2 and NOVA-3

No evidence found.

Renal impairment study, hepatic impairment study, pediatric data, and data in adults older than 65 years for LB-102

No evidence found.

Company statement on expected drug interactions

“No expected food effect or DDIs” (opens the source at this quote in a new tab)

NOVA-1 protocol: prohibited CYP2D6 inhibitors and CYP3A4 inhibitors and inducers

“Table 6.3 below provides a select list of CYP2D6 inhibitors and CYP3A4 inhibitors and inducers that are prohibited within 14 days of randomization and for the duration of the trial.” (opens the source at this quote in a new tab)

NOVA-1 protocol: prohibited antipsychotics and other psychotropic medications

“Patients who are currently taking oral antipsychotic medications, monoamine oxidase inhibitors (MAOIs), anticonvulsants (e.g., lamotrigine, Depakote), tricyclic antidepressants (e.g., imipramine, desipramine), selective serotonin reuptake inhibitors, and any other antidepressants or any other psychoactive medications (except lorazepam, zolpidem, zaleplon, eszopiclone, or similar benzodiazepines, diphenhydramine, benztropine, and propranolol).” (opens the source at this quote in a new tab)

Alcohol, cannabis, and smoking

“Participants were not permitted to smoke, consume alcohol, cannabis, or illicit substances, so pharmacologic interactions with these substances were not evaluated.” (opens the source at this quote in a new tab)

Class context: metabolism and transport of amisulpride

“In vitro, amisulpride was not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.” (opens the source at this quote in a new tab)
“Amisulpride is a substrate for P-gp, BCRP, OCT1, MATE1 and MATE2-K, but not a substrate for OATP1B1, OATP1B3, OAT1, OAT3 and OCT2.” (opens the source at this quote in a new tab)
“No clinical drug interaction trials have been conducted with BARHEMSYS.” (opens the source at this quote in a new tab)

“Co-administration of amisulpride and clozapine may lead to an increase in plasma levels of amisulpride” (opens the source at this quote in a new tab)

Class context: QT-prolonging drugs in amisulpride labeling

“To avoid potential additive effects, avoid use of BARHEMSYS in patients taking droperidol.” (opens the source at this quote in a new tab)
“ECG monitoring is recommended in patients taking other drugs known to prolong the QT interval (e.g., ondansetron)” (opens the source at this quote in a new tab)

“Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval, e.g., class IA antiarrythmics (e.g., quinidine, disopyramide) and class III antiarrythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and antimalarials (e.g., mefloquine) (see section 4.4)” (opens the source at this quote in a new tab)

Clinical drug interaction studies with LB-102

No evidence found.

In vitro CYP and transporter substrate findings for LB-102

No evidence found.

Restrictions on QT-prolonging medications in the LB-102 trial protocols

No evidence found.

Class context: CYP and transporter inhibition by amisulpride

“In vitro, amisulpride did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, or induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4.” (opens the source at this quote in a new tab)
“Amisulpride inhibits MATE1 and MATE2-K transporters.” (opens the source at this quote in a new tab)
“Amisulpride does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 at therapeutic concentrations.” (opens the source at this quote in a new tab)

Class context: pharmacodynamic interactions in amisulpride labeling

“Reciprocal antagonism of effects occurs between dopamine agonists (e.g., levodopa) and BARHEMSYS.” (opens the source at this quote in a new tab)

“Levodopa: reciprocal antagonism of effects between levodopa and neuroleptics.” (opens the source at this quote in a new tab)
“Amisulpride may enhance the central effects of alcohol” (opens the source at this quote in a new tab)
“CNS depressants including narcotics, anaesthetics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytic drugs, clonidine and derivatives” (opens the source at this quote in a new tab)
“Antihypertensive drugs and other hypotensive medications” (opens the source at this quote in a new tab)
“Amisulpride may oppose the effect of dopamine agonists e.g. bromocriptine, ropinirole.” (opens the source at this quote in a new tab)

Class context: drug and disease interactions in amisulpride labeling

“As with other antidopaminergic agents, caution should be also exercised when prescribing Amisulpride to patients with Parkinson's disease since it may cause worsening of the disease.” (opens the source at this quote in a new tab)
“Hyperglycaemia has been reported in patients treated with some atypical antipsychotic agents, including amisulpride, therefore patients with an established diagnosis of diabetes mellitus or with risk factors for diabetes who are started on amisulpride, should get appropriate glycaemic monitoring.” (opens the source at this quote in a new tab)

Clinical drug interaction studies with LB-102

No evidence found.

In vitro CYP inhibition, CYP induction, and transporter inhibition by LB-102

No evidence found.

Phase 1 single and multiple ascending dose study

“cohorts of six volunteers received doses ranging from 10 mg up to 200 mg” (opens the source at this quote in a new tab)
“In the multiple ascending dose, or MAD, portion of this trial, cohorts of six volunteers received doses of 50 mg to 100 mg twice-daily for one week.” (opens the source at this quote in a new tab)

“LB-102 75 mg (n=6) or Matching Placebo (n=2) BID x 7 days (QD on Day 7)” (opens the source at this quote in a new tab)

“The MTD of LB-102 was identified as 150 mg per day as either 150 mg QD or 75 mg BID.” (opens the source at this quote in a new tab)

PET receptor occupancy study

“In Cohort 1, all four subjects were dosed with 50 mg LB-102. In Cohort 2, all subjects were dosed with 100 mg LB-102, and in Cohort 3 all subjects were dosed with 75 mg LB-102.” (opens the source at this quote in a new tab)

NOVA-1: fixed doses of 50 mg, 75 mg, and 100 mg once daily

“The randomization ratio was 3:3:3:1 to oral once-daily placebo; LB-102 50 mg; LB-102 75 mg; or LB-102 100 mg, with a smaller sample planned in the arm receiving 100 mg.” (opens the source at this quote in a new tab)

“Participants in each cohort received once-daily doses for four weeks.” (opens the source at this quote in a new tab)
“All patients started at the planned dose level without titration.” (opens the source at this quote in a new tab)

NOVA-1: dose rationale

“Based on the mechanism of action of LB-102 at dopamine D2 and 5HT7 receptors, data from animal models, and PET dopamine RO data, it is hypothesized that LB-102 will have antipsychotic effects at doses ranging from 50 mg/day to 100 mg/day.” (opens the source at this quote in a new tab)

“Because we were able to achieve 70% receptor occupancy under steady-state conditions with a once-daily dose of 50 mg of LB-102, we chose to advance this as the lowest dose in our Phase 2 trial (n=107 participants) while exploring the potential of higher doses at 75 mg (n=108 participants) and 100 mg (n=36 participants).” (opens the source at this quote in a new tab)
“Based on previous results, we believed that there was a potential for the 100 mg dose to result in receptor occupancy above 80%.” (opens the source at this quote in a new tab)

NOVA-2: fixed doses of 50 mg and 100 mg once daily

“This is a Phase 3, randomized, double blind, placebo controlled, fixed dose, multicenter study designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of LB-102 100 mg once daily (QD) and LB-102 50 mg QD versus placebo QD for the treatment of adult patients with an acute exacerbation of schizophrenia” (opens the source at this quote in a new tab)

“To better inform potential future commercial use of LB-102, we are studying the effects of two doses, 50 mg LB-102 or 100 mg LB-102, versus placebo in this trial, and patients will be randomized in a 1:1:1 ratio across the three arms of the trial.” (opens the source at this quote in a new tab)
“All patients will start at their assigned dose level without titration.” (opens the source at this quote in a new tab)

NOVA-3: flexible dosing

“LB-102 flexible dosing 50 mg - 100 mg” (opens the source at this quote in a new tab)

Dose the company intends to commercialize

“Doses selected to inform use in commercial setting” (opens the source at this quote in a new tab)
“Simple QD dosing, starting therapeutic dose without titration” (opens the source at this quote in a new tab)

Comparison with the amisulpride dose

“The recommended dose of amisulpride for acute schizophrenia ranges from 400 mg to 800 mg per day, which may be increased up to 1,200 mg per day.” (opens the source at this quote in a new tab)
“The high doses of amisulpride increase systemic exposure to the drug, contribute to some of its side effects, and limit its ability to be formulated into an LAI” (opens the source at this quote in a new tab)

“Improved potency, lowering required dose and reducing systemic exposure – 50 mg LB-102 ≈ 400 mg amisulpride” (opens the source at this quote in a new tab)

“For acute psychotic episodes, oral doses between 400 mg/day and 800 mg/day are recommended.” (opens the source at this quote in a new tab)
“No specific titration is required when initiating the treatment.” (opens the source at this quote in a new tab)

Context: doses in the bipolar depression trial

“Dosing of LB-102 will start at 25 mg QD fixed dose for the first 3 weeks. At the start of Week 4, the dose of LB-102 may be increased to 50 mg QD based on the Clinical Global Impression Scale, Bipolar Version (CGI BP) improvement score.” (opens the source at this quote in a new tab)

Proposed labeled dose, maximum dose, and dose adjustment in renal or hepatic impairment

No evidence found.

Route and frequency

“LB-102 will be dosed orally once a day.” (opens the source at this quote in a new tab)

“Results from the study did suggest that once-a-day dosing of LB-102 could be effective in treating schizophrenia (amisulpride is typically dosed twice daily).” (opens the source at this quote in a new tab)

“Amisulpride can be administered once a day at oral doses up to 400mg, higher dose should be split into two separate doses.” (opens the source at this quote in a new tab)

NOVA-1: tablets administered per dose

“LB-102 tablets are 50 mg in strength.” (opens the source at this quote in a new tab)
“The placebo tablets will match the 50 mg tablets in appearance.” (opens the source at this quote in a new tab)
“Tablet-splitting procedures are outlined in the Pharmacy Manual.” (opens the source at this quote in a new tab)

Dose	Number of active tablets	Number of placebo tablets	Total number of tablets per dose
Placebo	“0”	“2.5”	“2.5”
50 mg	“1”	“1.5”	“2.5”
75 mg	“1.5”	“1”	“2.5”
100 mg	“2”	“0.5”	“2.5”

NOVA-2: oral tablets for six weeks

“LB-102 100 mg given orally for 6 weeks” (opens the source at this quote in a new tab)
“LB-102 oral tablet given for six weeks” (opens the source at this quote in a new tab)

Phase 1 PET study: capsule formulation, dosing time, and food

“a single dose of LB-102 was administered orally as a powder in capsule on day 1 of the study and in Cohort 4 once a day for four days” (opens the source at this quote in a new tab)
“Dose administration was scheduled for 8:00 AM (±1 h) each dosing day, following the collection of vital signs and a 12-lead ECG.” (opens the source at this quote in a new tab)
“The dose was given with water and subjects had the option to eat breakfast after dosing.” (opens the source at this quote in a new tab)

Setting: inpatient dosing in NOVA-1 and NOVA-2

“To facilitate enrollment of acutely ill patients and optimize treatment compliance, a 4-week inpatient hospitalization is required following the initial screening phase.” (opens the source at this quote in a new tab)

“Willing to be hospitalized for duration of the study” (opens the source at this quote in a new tab)

Setting: outpatient dosing in NOVA-3

“Concurrently with the Phase 3 NOVA-2 trial, we are enrolling an outpatient, open label trial (NOVA-3) to accrue the requisite safety population required to support NDA submission as well as other clinical trials and non-clinical studies typically required by FDA for an NDA approval.” (opens the source at this quote in a new tab)

Long-acting injectable formulation in development

“We are also developing an LAI formulation of LB-102, which may improve treatment adherence, a common issue in patients with schizophrenia and bipolar disorder.” (opens the source at this quote in a new tab)

Fasted or fed dosing conditions in NOVA-1, NOVA-2, and NOVA-3

No evidence found.

Missed dose instructions and administration with other medications

No evidence found.

Current access through clinical trials only

“Currently, participation in one of our clinical trials is the only way to access our investigational products.” (opens the source at this quote in a new tab)
“We encourage patients interested in our investigational products to learn more about our ongoing studies by visiting www.clinicaltrials.gov.” (opens the source at this quote in a new tab)

Expanded access policy

“Consistent with our commitment to bringing safe and effective therapies to patients, we are focused on enrolling and conducting the clinical trials necessary to gain regulatory approvals to make our investigational products available to patients as quickly and safely as possible.” (opens the source at this quote in a new tab)
“Treating physicians may request information about our Expanded Access policy by contacting clinicaltrials@lbpharma.us. LB Pharmaceuticals will respond to inquiries within 5 business days of receipt.” (opens the source at this quote in a new tab)

Continued access for NOVA-2 completers through the open-label trial

“Patients who complete NOVA-2 will be able to continue in the Open Label Extension trial that will also enroll de novo patients.” (opens the source at this quote in a new tab)

Commercial preparation

“While we have hired a Chief Commercial Officer to lead the development of our commercial strategy, we do not currently have a commercial organization for the marketing, sales, market access and distribution of prescription pharmaceutical products.” (opens the source at this quote in a new tab)
“We expect to manage future sales, marketing, market access and distribution through internal resources and third-party relationships.” (opens the source at this quote in a new tab)

“As we approach our pivotal NOVA-2 clinical trial results and continue preparing for the potential launch of LB-102 in schizophrenia, Joe’s extensive experience guiding companies from pivotal data through commercialization will be a tremendous asset.” (opens the source at this quote in a new tab)

Manufacturing and supply

“We do not own or operate, and currently have no plans to establish, any manufacturing facilities.” (opens the source at this quote in a new tab)
“Additionally, we intend to rely on third-party CDMOs for later-stage development and commercial manufacturing, if our product candidates receive marketing approval.” (opens the source at this quote in a new tab)
“Key starting material is manufactured by a limited number of CDMOs. The final drug substance is manufactured at a single CDMO.” (opens the source at this quote in a new tab)
“To adequately meet our projected commercial manufacturing needs, our CDMOs will need to scale-up production, or we will need to secure additional suppliers.” (opens the source at this quote in a new tab)

Planned commercial territories and partnering

“We currently own global rights to LB-102 and intend to retain commercialization rights in the United States.” (opens the source at this quote in a new tab)
“In addition, we will opportunistically explore commercialization partnerships, particularly with entities that have strong capabilities in geographies outside of the United States.” (opens the source at this quote in a new tab)

Distribution channel, specialty pharmacy requirement, and risk evaluation and mitigation strategy

No evidence found.

NOVA-1: discontinuation and washout of prior antipsychotics

“Starting on the first day of the screening phase, after written informed consent for the study has been provided, all antipsychotic or other psychotropic medications will be stopped with clinically appropriate titration down as per the Investigator’s clinical judgment.” (opens the source at this quote in a new tab)
“The prohibited psychotropic agent must be discontinued and washed out at least 5 half-lives prior to Baseline.” (opens the source at this quote in a new tab)
“Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and a half injection cycles before Baseline.” (opens the source at this quote in a new tab)
“Any patient unable to be safely discontinued from current antipsychotic therapy or other psychotropic medications will not be eligible for the study.” (opens the source at this quote in a new tab)

“Participants must have been free from antipsychotic treatment for 2 or more weeks (or ≥5 times the treatment half-life) before baseline assessment.” (opens the source at this quote in a new tab)

“Prior to initiating dosing, patients underwent a seven-day wash-out period, a length of time that an enrolled patient may not receive any treatment before they begin the trial.” (opens the source at this quote in a new tab)

NOVA-1: prohibited psychotropic medications

“Patients who are currently taking oral antipsychotic medications, monoamine oxidase inhibitors (MAOIs), anticonvulsants (e.g., lamotrigine, Depakote), tricyclic antidepressants (e.g., imipramine, desipramine), selective serotonin reuptake inhibitors, and any other antidepressants or any other psychoactive medications (except lorazepam, zolpidem, zaleplon, eszopiclone, or similar benzodiazepines, diphenhydramine, benztropine, and propranolol).” (opens the source at this quote in a new tab)
“The medications should not be discontinued solely to make the patient eligible for enrollment in the study.” (opens the source at this quote in a new tab)

NOVA-1: permitted rescue medications

“Psychotropic medications are prohibited except for lorazepam as needed for agitation, restlessness, irritability, or hostility; zolpidem, zaleplon, or eszopiclone for insomnia; diphenhydramine or benztropine for EPS; and propranolol for akathisia.” (opens the source at this quote in a new tab)
“every administration must be considered and approved by the Investigator prior to administration” (opens the source at this quote in a new tab)
“Allow nighttime use only (prn); exclude regular use; exclude daytime use; exclude use within 12 hours of a study visit” (opens the source at this quote in a new tab)
“During the End of Stabilization period, the use of lorazepam, benztropine, and propranolol is not restricted.” (opens the source at this quote in a new tab)

NOVA-1: dose limits for permitted rescue medications

Medication	Study period	Dose permitted
Lorazepam	Screening phase through day 7	“Maximum of 6 mg/day”
Lorazepam	Day 8 through day 14	“Maximum of 4 mg/day”
Lorazepam	Day 15 through day 28	“Maximum of 2 mg/day”
Benztropine	Screening phase through day 28	“Maximum 4 mg/day”
Propranolol	Screening phase through day 28	“Maximum of 40 mg/day”

NOVA-1: prohibited CYP2D6 inhibitors and CYP3A4 inhibitors and inducers

“Table 6.3 below provides a select list of CYP2D6 inhibitors and CYP3A4 inhibitors and inducers that are prohibited within 14 days of randomization and for the duration of the trial.” (opens the source at this quote in a new tab)

NOVA-1: electroconvulsive therapy and transcranial magnetic stimulation

“Patients who received electroconvulsive therapy within 90 days of Screening.” (opens the source at this quote in a new tab)
“Patients who received Transcranial Magnetic Stimulation (TMS) within 90 days of Screening.” (opens the source at this quote in a new tab)

NOVA-1: comorbid conditions at baseline

“The most common comorbid conditions at baseline were insomnia, anxiety, headache, depressive symptoms, and agitation” (opens the source at this quote in a new tab)

NOVA-1: unauthorized concomitant medications

“The inpatient setting minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications; further studies are needed to assess whether these findings are generalizable to an outpatient population.” (opens the source at this quote in a new tab)

Phase 1: treatment of acute dystonia

“Subjects with moderate dystonia were treated with either Benadryl or Cogentin.” (opens the source at this quote in a new tab)

NOVA-3: prior oral antipsychotic treatment

“Taking oral antipsychotic treatment for at least 30 days” (opens the source at this quote in a new tab)
“who are experiencing inadequate response or who are having issues with side effects, general tolerability, or overall effectiveness of their current antipsychotic medication and desire to change medications, or who have completed their participation in current LB-102 clinical studies” (opens the source at this quote in a new tab)

Reported use of rescue and concomitant medications in NOVA-1

No evidence found.

Permitted and prohibited concomitant medications in NOVA-2 and NOVA-3

No evidence found.

Use of LB-102 in combination with another antipsychotic

No evidence found.

HEDIS Adherence to Antipsychotic Medications for Individuals With Schizophrenia (SAA): definition and rationale

“The percentage of persons 18 years of age and older during the measurement period, with schizophrenia or schizoaffective disorder, who were dispensed and remained on an antipsychotic medication for at least 80% of their treatment period.” (opens the source at this quote in a new tab)
“Non-adherence increases risk of re-hospitalization, emergency psychiatric treatment, functional decline and death.” (opens the source at this quote in a new tab)
“Measuring antipsychotic medication adherence may encourage efforts aimed at reducing medication nonadherence and, in turn, lead to lower relapse rates and fewer hospitalizations.” (opens the source at this quote in a new tab)

HEDIS Diabetes Screening for People With Schizophrenia or Bipolar Disorder Who Are Using Antipsychotic Medications (SSD): definition and rationale

“The percentage of persons 18–64 years of age with schizophrenia, schizoaffective disorder or bipolar disorder who were dispensed an antipsychotic medication and had a diabetes screening test during the measurement period.” (opens the source at this quote in a new tab)
“Diabetes screening is important for anyone with schizophrenia, schizoaffective disorder or bipolar disorder, and the added risk associated with antipsychotic medications contributes to the need to screen for diabetes.” (opens the source at this quote in a new tab)

HEDIS Diabetes Monitoring for People With Diabetes and Schizophrenia (SMD): definition and rationale

“The percentage of persons 18–64 years of age with schizophrenia or schizoaffective disorder and diabetes who had both an LDL-C test and an HbA1c test during the measurement period.” (opens the source at this quote in a new tab)
“In addition to general diabetes risk factors, diabetes is promoted in patients with schizophrenia by initial and current treatment with olanzapine and mid-potency first-generation antipsychotics (FGA), as well as by current treatment with low-potency FGAs and clozapine (1).” (opens the source at this quote in a new tab)

HEDIS Cardiovascular Monitoring for People With Cardiovascular Disease and Schizophrenia (SMC): definition and rationale

“The percentage of persons 18–64 years of age with schizophrenia or schizoaffective disorder and cardiovascular disease, who had an LDL-C test during the measurement period.” (opens the source at this quote in a new tab)
“Among patients with co-occurring schizophrenia and metabolic disorders, rates of nontreatment were 62.4% for hypertension and 88.0% for hyperlipidemia.” (opens the source at this quote in a new tab)
“Atypical antipsychotic medications elevate the risk of metabolic conditions, relative to typical antipsychotic medications (4).” (opens the source at this quote in a new tab)

HEDIS Follow-Up After Hospitalization for Mental Illness (FUH): definition and rationale

“The percentage of discharges for persons 6 years of age and older who were hospitalized for a principal diagnosis of mental illness, or any diagnosis of intentional self-harm, and had a mental health follow-up service.” (opens the source at this quote in a new tab)
“The percentage of discharges for which the person received follow-up within 30 days after discharge.” (opens the source at this quote in a new tab)
“The percentage of discharges for which the person received follow-up within 7 days after discharge.” (opens the source at this quote in a new tab)
“Early interventions and proactive management of potential challenges can reduce risk of readmission and promote sustained well-being.” (opens the source at this quote in a new tab)

HEDIS Follow-Up After Emergency Department Visit for Mental Illness (FUM): definition and rationale

“The percentage of emergency department (ED) visits for persons 6 years of age and older with a principal diagnosis of mental illness, or any diagnosis of intentional self-harm, and had a mental health follow-up service.” (opens the source at this quote in a new tab)
“The percentage of ED visits for which the person received follow-up within 30 days of the ED visit (31 total days).” (opens the source at this quote in a new tab)
“The percentage of ED visits for which the person received follow-up within 7 days of the ED visit (8 total days).” (opens the source at this quote in a new tab)
“Evidence suggests that patients who fail to receive aftercare following their emergency psychiatric visit have 6 times higher odds of returning to the ED within 2 months, compared with patients who received aftercare (5).” (opens the source at this quote in a new tab)

HEDIS Metabolic Monitoring for Children and Adolescents on Antipsychotics (APM): pediatric measure, for context

“Assesses the percentage of children and adolescents with ongoing antipsychotic medication use who had metabolic testing during the year.” (opens the source at this quote in a new tab)
“Given these risks and the potential lifelong consequences, metabolic monitoring (blood glucose and cholesterol testing) is an important component of ensuring appropriate management of children and adolescents on antipsychotic medications.” (opens the source at this quote in a new tab)

NCQA 2027 Health Plan Ratings: SAA, FUH, and FUM scored for commercial, Medicare, and Medicaid plans, and SSD for Medicaid plans

“2027 Health Plan Ratings Required HEDIS® and CAHPS® Measures” (opens the source at this quote in a new tab)
“Commercial & Medicaid HEDIS MY 2026 & CAHPS MY 2026 (Reporting Year 2027)” (opens the source at this quote in a new tab)

Measure	Display name	Weight
SAA	“Adherence to antipsychotic medications for individuals with schizophrenia”	“1”
SSD	“Diabetes screening for individuals with schizophrenia or bipolar disorder”	“1”
FUH	“Follow-up after hospitalization for mental illness”	“1”
FUM	“Follow-up after ED for mental illness”	“1”

CMS 2027 Medicaid Adult Core Set: mandatory behavioral health measures that apply to schizophrenia

“2027 Mandatory Adult Core Set Measures” (opens the source at this quote in a new tab)
“Follow-Up After Hospitalization for Mental Illness: Age 18 and Older (FUH-AD)” (opens the source at this quote in a new tab)
“Diabetes Screening for People With Schizophrenia or Bipolar Disorder Who Are Using Antipsychotic Medications (SSD-AD)” (opens the source at this quote in a new tab)
“Diabetes Care for People with Serious Mental Illness: Glycemic Status > 9.0% (HPCMI-AD)” (opens the source at this quote in a new tab)
“Follow-Up After Emergency Department Visit for Mental Illness: Age 18 and Older (FUM-AD)” (opens the source at this quote in a new tab)
“Adherence to Antipsychotic Medications for Individuals With Schizophrenia (SAA-AD)” (opens the source at this quote in a new tab)
“The Adult Core Set includes the NCQA version of the measure, which is adapted from the CMS measure.” (opens the source at this quote in a new tab)

National performance: state Medicaid medians on SAA-AD and SSD-AD, 2023 Adult Core Set

“Adherence to these antipsychotics for the treatment of schizophrenia can reduce the risk of relapse or hospitalization.” (opens the source at this quote in a new tab)
“A median of 62 percent of adults age 18 and older during calendar year 2022 with schizophrenia or schizoaffective disorder remained on an antipsychotic medication for at least 80 percent of their treatment period.” (opens the source at this quote in a new tab)
“A median of 77 percent of adults ages 18 to 64 with schizophrenia, schizoaffective disorder, or bipolar disorder who were dispensed an antipsychotic had a diabetes screening test during calendar year 2022.” (opens the source at this quote in a new tab)

National performance: state Medicaid medians on FUH-AD and FUM-AD, 2023 Adult Core Set

“A median of 32 percent of discharges for adults ages 18 to 64 who were hospitalized for treatment of selected mental illness or intentional self-harm diagnoses from January 1 to December 1, 2022 had a follow-up visit within 7 days after discharge.” (opens the source at this quote in a new tab)
“A median of 54 percent of discharges for adults ages 18 to 64 who were hospitalized for treatment of selected mental illness or intentional self-harm diagnoses from January 1 to December 1, 2022 had a follow-up visit within 30 days after discharge.” (opens the source at this quote in a new tab)
“A median of 35 percent of ED visits for adults ages 18 to 64 with mental illness or intentional self-harm diagnoses from January 1 to December 1, 2022 had a follow-up visit within 7 days.” (opens the source at this quote in a new tab)
“A median of 51 percent of ED visits for adults ages 18 to 64 with mental illness or intentional self-harm diagnoses from January 1 to December 1, 2022 had a follow-up visit within 30 days.” (opens the source at this quote in a new tab)

Quality metrics among Medicaid beneficiaries with schizophrenia: national claims, 2018

“Across the US 688,437 patients with schizophrenia were identified.” (opens the source at this quote in a new tab)
“The proportion of patients adherent to any AP was 56% (range: 19-73%).” (opens the source at this quote in a new tab)
“Within 30 days post-discharge from an inpatient admission, 22% (range: 8-58%) of patients had an outpatient visit, and 12% (range: 4-48%) had a readmission.” (opens the source at this quote in a new tab)

Quality metrics among fee-for-service Medicare beneficiaries with schizophrenia: national claims, 2019

“We identified 314,888 beneficiaries with schizophrenia.” (opens the source at this quote in a new tab)
“Among those with hospitalizations, 18.4% and 27.3% had readmission within 7 and 30 days and 56% and 67% had a physician visit and AP fill within 30 days post-discharge, respectively.” (opens the source at this quote in a new tab)
“Overall, 81% of beneficiaries were deemed adherent to their AP medications.” (opens the source at this quote in a new tab)

Attainment of the HEDIS antipsychotic continuity measure in Medicaid claims and associated factors

“Among the 12,990 patients who received an antipsychotic during the study period, 48.6% successfully achieved the continuity criteria in the measurement year.” (opens the source at this quote in a new tab)
“After controlling for other covariates, the odds of adherence were improved by adherence at baseline (odds ratio [OR], 9.42; 95% confidence interval [CI], 8.55–10.39).” (opens the source at this quote in a new tab)

Adherence and outcomes: gaps in antipsychotic coverage and rehospitalization in California Medicaid

“Compliance behavior was estimated by using a retrospective review of California Medicaid pharmacy refill and medical claims for 4,325 outpatients for whom antipsychotics were prescribed for treatment of schizophrenia from 1999 to 2001.” (opens the source at this quote in a new tab)
“For example, the presence of any gap in medication coverage was associated with increased risk of hospitalization, including gaps as small as one to ten days (odds ratio [OR]=1.98).” (opens the source at this quote in a new tab)
“A gap of 11 to 30 days was associated with an OR of 2.81, and a gap of more than 30 days was associated with an OR of 3.96.” (opens the source at this quote in a new tab)

Adherence and outcomes: Medicaid inpatient admissions and costs attributable to gaps in antipsychotic treatment

“In the United States, there are roughly 87 000 annual acute care inpatient admissions of Medicaid patients for the treatment of schizophrenia.” (opens the source at this quote in a new tab)
“These admissions include a total of approximately 930 000 hospital days at a total cost of $806 million.” (opens the source at this quote in a new tab)
“Improving adherence to eliminate gaps in antipsychotic medication treatment could lower the number of acute care admissions by approximately 12.3% (95% confidence interval [CI]: 11.7%–12.6%) and reduce the number of inpatient treatment days by approximately 13.1% (CI: 9.8%–16.5%) resulting in a savings of approximately $106 million (95% CI: $79.0 million–$133.0 million) in inpatient care costs for the national Medicaid system.” (opens the source at this quote in a new tab)

Follow-up after hospitalization and outcomes: outpatient visit within 30 days and readmission risk

“Among inpatients with schizophrenia (N=25,401) or bipolar disorder (N=46,375), overall and stratified associations were examined between receipt of an outpatient follow-up visit in the 30 days postdischarge and hospital readmission during days 31-120 postdischarge.” (opens the source at this quote in a new tab)
“Receipt of a follow-up visit within 30 days of discharge was associated with a slightly lower adjusted odds ratio (AOR) of hospital readmission during days 31-120 postdischarge (schizophrenia, AOR=.88, 95% confidence interval [CI]=.81-.96; bipolar disorder, AOR=.91, CI=.85-.98).” (opens the source at this quote in a new tab)
“For patients with schizophrenia, the strongest observed inverse association of follow-up care with readmission risk was among inpatients whose index admissions were 13 to 30 days long (AOR=.73, CI=.61-.89).” (opens the source at this quote in a new tab)

Follow-up after hospitalization: rates and antipsychotic-related predictors in national Medicaid claims

“Of the 59,567 hospital discharges, 41.7% received schizophrenia-related outpatient visits in 7 days and 59.3% in 30 days following hospital discharge.” (opens the source at this quote in a new tab)
“The adjusted odds of 30-day follow-up outpatient visits were significantly related to preadmission outpatient mental health visits (AOR = 3.72; 99% CI, 3.44-4.03), depot (AOR = 2.83; 99% CI, 2.53-3.18) or oral (AOR = 1.73; 99% CI, 1.62-1.84) antipsychotics as compared with no antipsychotics, and absence of a substance use disorder diagnosis (AOR = 1.35; 99% CI, 1.25-1.45).” (opens the source at this quote in a new tab)

LB-102-specific effect on quality measures

No evidence found.

Summary

No trial has compared LB-102 with an active drug. NOVA-1 had no active comparator arm, the company states that it has not conducted a head-to-head clinical trial against amisulpride, and the phase 3 NOVA-2 trial compares LB-102 50 mg and 100 mg with placebo over 6 weeks. Every comparison in this section is therefore indirect, across trials that differ in duration, baseline severity, and placebo response.

In NOVA-1 (4 weeks, 359 participants randomized, mean baseline PANSS total score about 94), the least-squares mean difference from placebo in PANSS total score at week 4 was -5.0 points with 50 mg (95% CI -8.0 to -2.1), -4.7 points with 75 mg (95% CI -7.7 to -1.7), and -6.8 points with the exploratory 100 mg dose (95% CI -11.1 to -2.6; 36 participants). The placebo group improved by 9.3 points. Post hoc Hedges g was 0.61, 0.41, and 0.83.

Amisulpride, the parent compound, is approved in Europe for acute and chronic schizophrenia at 400 to 800 mg per day for acute episodes (up to 1200 mg per day in individual cases), with doses above 400 mg divided in two. In the United States it is approved only as intravenous BARHEMSYS for postoperative nausea and vomiting. The company states that dopamine receptor occupancy at 50 mg of LB-102 is approximately equivalent to that at 300 to 400 mg of amisulpride. In the 2019 network meta-analysis of 32 oral antipsychotics (402 studies, 53,463 participants), amisulpride had the largest standardized mean difference from placebo for positive symptoms (-0.69, 95% CrI -0.86 to -0.52) and was one of five drugs that reduced overall symptoms significantly more than many other drugs. The NOVA-1 authors cite its overall-symptom estimate as -0.73 (95% CrI -0.89 to -0.58), beside -0.56 for olanzapine and -0.55 for risperidone. The meta-analysis authors note that no placebo-controlled amisulpride study was available for overall symptoms and that confidence in the evidence was often low or very low. In the 2013 multiple-treatments meta-analysis (212 trials, 43,049 participants), the amisulpride estimate was 0.66 (95% CrI 0.53 to 0.78). In BeSt InTro (144 participants, 52 weeks), the PANSS total score fell by 32.7 points with amisulpride, 21.9 points with aripiprazole, and 23.3 points with olanzapine. In predominant negative symptoms, amisulpride was superior to placebo across 4 trials with 590 participants (standardized mean difference 0.47, 95% CI 0.23 to 0.71).

Placebo-subtracted PANSS total score differences in the registration trials of other oral agents were as follows. Xanomeline-trospium: -9.6 points (EMERGENT-2, 5 weeks, 252 participants) and -8.4 points (EMERGENT-3, 5 weeks, 256 participants), with a pooled estimate of -9.9 points across three 5-week trials (640 participants). An independent meta-analysis of the same three trials (690 participants) gave a standardized mean difference of -0.56 (95% CI -0.72 to -0.40); the company presentation states that the LB-102 100 mg effect sizes (0.83 in completers and 0.64 by mixed model) are greater than that value. Lumateperone 42 mg: -4.2 points (4 weeks, 450 participants) and -5.8 points (4 weeks, 335 participants). Cariprazine: -6.0 to -10.4 points across three 6-week trials (711, 604, and 439 participants). Brexpiprazole: -3.1 to -8.7 points across two 6-week trials. Lurasidone: -2.1 to -16.2 points across three 6-week trials (473, 489, and 482 participants). Olanzapine and samidorphan: -6.4 points (4 weeks, 401 participants dosed). Meta-analyses of placebo-controlled antipsychotic trials report that placebo response has increased over time and that the drug-placebo difference decreased with later publication year, lower baseline severity, and longer study duration.

In NOVA-1, mean prolactin rose by 51.2 to 59.9 ng/mL in the LB-102 groups and by 1.3 ng/mL with placebo. Elevated prolactin at day 28 was reported in 87.5% to 94.0% of LB-102 participants and 5.2% of placebo participants, and 5 participants had a prolactin-related clinical adverse event. In the 2019 network meta-analysis, mean differences from placebo in prolactin ranged from -77.05 ng/mL (clozapine) to 48.51 ng/mL (paliperidone), and amisulpride was one of eight drugs with significantly elevated prolactin. Mean weight change over 4 weeks was 2.9 to 4.3 kg with LB-102 and 2.0 kg with placebo; a weight increase of 7% or more occurred in 9% to 26% of LB-102 participants and 10% of placebo participants; the company reports approximately 1.6 kg of placebo-adjusted weight gain. The network meta-analysis range for weight gain against placebo was -0.16 kg (ziprasidone) to 3.21 kg (zotepine), and the NOVA-1 authors place LB-102 between xanomeline-trospium (-0.37 kg) and olanzapine (2.78 kg). Mean QTc change was 4.3 to 5.4 milliseconds with LB-102 and 1.2 milliseconds with placebo; the network meta-analysis range was -2.21 milliseconds (lurasidone) to 23.90 milliseconds (sertindole). Extrapyramidal symptom incidence in the publication was 0% to 2.8% with LB-102 and 1.9% with placebo. The company total, which adds dystonia and akathisia, was 1.0%, 5.6%, and 5.6% at 50 mg, 75 mg, and 100 mg and 3.7% with placebo. In EMERGENT-2, extrapyramidal symptoms were reported in 0% of both groups, nausea in 19% and vomiting in 14% of xanomeline-trospium participants, and weight gain in 0% of xanomeline-trospium participants and 1% of placebo participants.

Among investigational agents, emraclidine did not meet the primary endpoint in two 6-week phase 2 trials reported in November 2024. Brilaroxazine 50 mg differed from placebo by 10.1 points at week 4 in the phase 3 RECOVER trial (412 participants), and the FDA recommended a second phase 3 trial. Ulotaront was not superior to placebo in the 6-week phase 3 DIAMOND 1 trial (435 participants), and in DIAMOND 2 (464 participants) its reductions were numerically larger than with placebo (-16.4 and -18.1 points against -14.3 points). Iclepertin did not meet its primary and key secondary endpoints for cognition in the phase 3 CONNEX program (1,840 participants). NBI-1117568 20 mg once daily differed from placebo by 7.5 points at week 6 in phase 2, and a phase 3 program began in 2025. ML-007C-MA twice daily differed from placebo by 4.5 points in the phase 2 ZEPHYR trial (307 participants) reported in July 2026. Adjunctive xanomeline-trospium differed from placebo by 2.0 points in the phase 3 ARISE trial (P = 0.11). Evenamide added to current antipsychotic therapy differed from placebo by 2.5 points at 4 weeks (291 participants). The FDA approved milsaperidone (BYSANTI) for schizophrenia in February 2026 and a lumateperone relapse-prevention supplement in April 2026, and an application for olanzapine extended-release injection (TEV-749) is under review with a decision expected in the fourth quarter of 2026. SEP-4199, a non-racemic amisulpride, was studied in bipolar I depression, and its phase 3 trial was terminated after 83 participants enrolled.

No editorial accompanying the NOVA-1 publication was identified, and no network meta-analysis or indirect treatment comparison that includes LB-102 was identified. A 2026 review describes LB-102 as a potential first benzamide antipsychotic for the United States market with an effect size of 0.61 at 50 mg. A 2025 review states that hyperprolactinemia “may limit its usability in the future”. A NOVA-1 investigator stated that the full clinical value will depend on phase 3 data, longer-term metabolic and endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons.

NOVA-1 primary endpoint: PANSS total score change and difference from placebo at week 4

Measure	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg	Placebo
Baseline PANSS total score, mean (SD)	“93.9 (7.53)”	“93.6 (7.79)”	“93.9 (9.01)”	“93.8 (8.17)”
Least-squares mean change (SE)	“−14.3 (1.10)”	“−14.0 (1.11)”	“−16.1 (1.91)”	“−9.3 (1.08)”
Least-squares mean difference from placebo (SE) [95% CI]	“−5.0 (1.51) [−8.0 to −2.1]”	“−4.7 (1.53) [−7.7 to −1.7]”	“−6.8 (2.17) [−11.1 to −2.6]”	“NA”
P value	“<.001”	“.002”	“.002”	“NA”

“A total of 359 participants (mean [SD] age, 39.1 [9.3] years; 290 male [80.8%]; mean baseline PANSS total score = approximately 94 across groups) were randomized and included in the safety and intention-to-treat populations (placebo, n = 108; 50 mg, n = 107; 75 mg, n = 108; 100 mg, n = 36).” (opens the source at this quote in a new tab)
“LB-102 100 mg treatment resulted in a significant LS mean (SE) change from baseline to week 4 in PANSS total score of −16.1 (1.91; P = .002 vs placebo; post hoc Hedges g = 0.83 [Δ = 0.64]).” (opens the source at this quote in a new tab)
“Hereafter, P values were not multiplicity controlled.” (opens the source at this quote in a new tab)

NOVA-1 effect size placed beside established oral antipsychotics by the trial authors

“The magnitude of effect falls within the range reported for established oral antipsychotics in multiepisode acute schizophrenia in a large network meta-analysis (eg, standardized mean difference [95% credible interval]: amisulpride, −0.73 [−0.89 to −0.58]; olanzapine, −0.56 [−0.62 to −0.50]; risperidone, −0.55 [−0.62 to −0.48])” (opens the source at this quote in a new tab)
“although methodological differences warrant cautious interpretation” (opens the source at this quote in a new tab)
“The reduction in PANSS total score observed with LB-102 after 4 weeks of treatment is consistent with early trajectories reported for amisulpride over 3 to 6 weeks in the pragmatic Best Intro trial, acknowledging design and population differences.” (opens the source at this quote in a new tab)
“Clinical efficacy with LB-102 50 mg was demonstrated by a 14.3-point mean reduction from baseline to week 4 in PANSS total score vs placebo, corresponding to a Hedges g of 0.61 (Δ = 0.50) effect size, with directionally consistent results for 75 mg (Hedges g = 0.41, Δ = 0.45) and 100 mg (Hedges g = 0.83, Δ = 0.64).” (opens the source at this quote in a new tab)

NOVA-1 effect size beside amisulpride and xanomeline-trospium: company presentation

“Results for LB-102 are near the top of effect size (ES) reported for approved first-line APs” (opens the source at this quote in a new tab)
“ES for 100 mg dose are in the range of those previously reported for amisulpride” (opens the source at this quote in a new tab)
“ES for 100 mg dose across both methods are greater than those reported for Cobenfy (0.56)” (opens the source at this quote in a new tab)
“Effect size is calculated by taking the difference in average PANSS change between two groups (an active treatment arm and placebo) and dividing it by the pooled standard deviation.” (opens the source at this quote in a new tab)

NOVA-2 phase 3 design: placebo-controlled, with no active comparator arm

“The Phase 3 trial is a three-arm, inpatient, double-blinded, placebo-controlled, oral once-daily dose of LB-102 in patients with acute schizophrenia, with a six-week treatment duration.” (opens the source at this quote in a new tab)
“To better inform potential future commercial use of LB-102, we are studying the effects of two doses, 50 mg LB-102 or 100 mg LB-102, versus placebo in this trial, and patients will be randomized in a 1:1:1 ratio across the three arms of the trial.” (opens the source at this quote in a new tab)

LB-102 against amisulpride: no head-to-head clinical trial, company statement

“We have not conducted head-to-head clinical trials to date comparing LB-102 to amisulpride” (opens the source at this quote in a new tab)

LB-102 against amisulpride: design goals stated by the company

“LB-102 is a new chemical entity and a methylated derivative of amisulpride, a second-generation antipsychotic drug approved in over 50 countries, not including the United States, because the development and regulatory requirements of the U.S. Food and Drug Administration, or FDA, for amisulpride were incompatible with patent coverage on the drug.” (opens the source at this quote in a new tab)
“The methylation we incorporated into LB-102 was designed to improve the tolerability and efficacy profile of amisulpride by addressing its shortcomings, such as limited blood-brain barrier, or BBB, permeability and dosing frequency.” (opens the source at this quote in a new tab)
“Enhanced BBB permeability was expected to improve the potency of the molecule with respect to dopamine receptor binding and enable the use of lower doses compared with amisulpride.” (opens the source at this quote in a new tab)
“By dosing LB-102 at a lower level, we are aiming to decrease side effects common to amisulpride and other antipsychotic drugs currently used to treat schizophrenia.” (opens the source at this quote in a new tab)
“If approved for schizophrenia, we expect to commercialize the oral formulation of LB-102 in jurisdictions where amisulpride is unavailable as a generic, and we expect to commercialize an LAI form of LB-102 worldwide.” (opens the source at this quote in a new tab)

LB-102 against amisulpride: dose and dopamine receptor occupancy

“The dopamine receptor occupancy levels seen in the imaging trial at 50 mg of LB-102 are approximately equivalent to those observed with 300 to 400 mg of amisulpride.” (opens the source at this quote in a new tab)
“The recommended dose of amisulpride for acute schizophrenia ranges from 400 mg to 800 mg per day, which may be increased up to 1,200 mg per day.” (opens the source at this quote in a new tab)
“Another drawback of amisulpride is that it is typically dosed twice-daily, which can lead to lower adherence relative to therapies with less frequent dosing schedules.” (opens the source at this quote in a new tab)

“LB-102 was specifically engineered to address the blood-brain barrier issues observed with amisulpride” (opens the source at this quote in a new tab)
“A human positron emission tomography (PET) study demonstrated that at steady state, once-daily LB-102 50 mg produced 60% to 80% striatal dopamine receptor occupancy with minimal variation across 24 hours.” (opens the source at this quote in a new tab)
“Comparatively, amisulpride requires steady state doses of 400 mg to achieve approximately 70% occupancy.” (opens the source at this quote in a new tab)
“However, the overall clinical utility of amisulpride is constrained by low blood-brain barrier permeability, necessitating twice-daily dosing at higher levels to achieve therapeutic occupancy (60%-80%), resulting in systemic exposures that result in the potential for AEs, including QTc prolongation and hyperprolactinemia.” (opens the source at this quote in a new tab)

“50 mg LB-102 ≈ 400 mg amisulpride” (opens the source at this quote in a new tab)

LB-102 against amisulpride: preclinical head-to-head studies and plasma exposure

“In this assay, the permeability of LB-102 was approximately 200-fold greater than that of amisulpride.” (opens the source at this quote in a new tab)
“LB-102 had equivalent or better results than similar doses of amisulpride in the LMA model of hyperactivity.” (opens the source at this quote in a new tab)
“we observed that the effects of treatment with LB-102 were statistically indistinguishable from that of amisulpride” (opens the source at this quote in a new tab)
“We observed the plasma exposure of 50 mg of LB-102 to be 1,648 ng*h/mL. In a previous third-party study of amisulpride, plasma exposure was reported at 667 ng*h/mL.” (opens the source at this quote in a new tab)

Amisulpride regulatory status: schizophrenia indication in Europe and intravenous antiemetic indication in the United States

“Amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterised by predominant negative symptoms.” (opens the source at this quote in a new tab)

“BARHEMSYS is a dopamine-2 (D2) antagonist indicated in adults for:” (opens the source at this quote in a new tab)
“Prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class.” (opens the source at this quote in a new tab)

“Despite amisulpride’s efficacy and tolerability profile, it has not received regulatory approval in the United States for the treatment of any neuropsychiatric disorders, including schizophrenia, because the development and regulatory requirements of the FDA were incompatible with patent coverage on the drug.” (opens the source at this quote in a new tab)

Oral amisulpride dosing: European summary of product characteristics

“For acute psychotic episodes, oral doses between 400 mg/day and 800 mg/day are recommended. In individual cases, the daily dose may be increased up to 1200 mg/day.” (opens the source at this quote in a new tab)
“No specific titration is required when initiating the treatment.” (opens the source at this quote in a new tab)
“For patients characterised by predominant negative symptoms (deficit syndrome), oral doses between 50 mg/day and 300 mg/day are recommended.” (opens the source at this quote in a new tab)
“Amisulpride can be administered once a day at oral doses up to 400mg, higher dose should be split into two separate doses.” (opens the source at this quote in a new tab)
“In renal insufficiency, the dose should be reduced to half in patients with creatinine clearance (CRCL) between 30-60 ml/min and to a third in patients with CRCL between 10-30 ml/min.” (opens the source at this quote in a new tab)

Amisulpride efficacy standing: network meta-analysis of 32 oral antipsychotics

“We identified 54 417 citations and included 402 studies with data for 53 463 participants.” (opens the source at this quote in a new tab)
“Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants).” (opens the source at this quote in a new tab)
“Clozapine, amisulpride, zotepine, olanzapine, and risperidone reduced overall symptoms significantly more than many other drugs” (opens the source at this quote in a new tab)
“The SMDs for the 17 (81%) drugs that significantly reduced positive symptoms compared with placebo ranged between −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole” (opens the source at this quote in a new tab)
“The SMDs for the 18 (86%) antipsychotics that significantly reduced negative symptoms compared with placebo ranged between −0·62 (95% CrI −0·84 to −0·39) for clozapine to −0·22 (−0·33 to −0·11) for iloperidone” (opens the source at this quote in a new tab)
“Clozapine, amisulpride, olanzapine, and, to a lesser extent, zotepine and risperidone reduced negative symptoms significantly more than many other drugs.” (opens the source at this quote in a new tab)
“Amisulpride was among the most efficacious antipsychotics, but no placebo-controlled study was available, making this evidence entirely indirect.” (opens the source at this quote in a new tab)
“Nevertheless, amisulpride was significantly superior to placebo in older patients (≥60 years of age; SMD 0·86) and in patients with predominant negative symptoms (SMD 0·47).” (opens the source at this quote in a new tab)
“However, overlapping CrIs between antipsychotics suggest that differences between most individual drugs were not significant.” (opens the source at this quote in a new tab)
“The confidence in evidence was often low or very low.” (opens the source at this quote in a new tab)

Amisulpride tolerability standing: network meta-analysis of 32 oral antipsychotics

“Olanzapine, asenapine, lurasidone, sertindole, haloperidol, amisulpride, risperidone, and paliperidone were associated with significantly elevated prolactin levels (mean difference range 4·47–48·51 ng/mL).” (opens the source at this quote in a new tab)
“In general, older antipsychotics were associated often with more extrapyramidal motor side-effects and prolactin elevation (with noticeable exceptions, such as amisulpride, paliperidone, and risperidone), whereas many newer antipsychotics produced more weight gain and sedation.” (opens the source at this quote in a new tab)
“The following drugs were significantly better than haloperidol starting with the best: clozapine, perazine, sertindole, placebo, olanzapine, quetiapine, asenapine, aripiprazole, thioridazine, amisulpride, iloperidone, brexpiprazole, paliperidone, ziprasidone, risperidone, lurasidone, zotepine, and chlorpromazine” (opens the source at this quote in a new tab)
“Heterogeneity was low to moderate for most outcomes, moderate to high for use of antiparkinson medication, and high for prolactin elevation.” (opens the source at this quote in a new tab)

Weight gain, prolactin, QTc, akathisia, and antiparkinson medication use across oral antipsychotics: network meta-analysis ranges

“Mean differences compared to placebo for weight gain (28 317 participants) ranged from −0·16 kg (−0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from −77·05 ng/mL (−120·23 to −33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from −2·21 ms (−4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole).” (opens the source at this quote in a new tab)
“Seven (50%) of 14 antipsychotics caused significantly more QTc prolongation than placebo with mean differences ranging from 3·43 ms (95% CrI 0·94–6·00) for quetiapine to 23·90 ms (95% CrI 20·56–27·33) for sertindole” (opens the source at this quote in a new tab)
“Risk ratios for the 21 (66%) of 32 antipsychotics that were associated with significantly increased use of antiparkinson medication compared with placebo ranged from 1·61 (95% CrI 1·17–2·10) for paliperidone to 6·14 (4·81–6·55) for pimozide” (opens the source at this quote in a new tab)
“The hierarchy was similar to use of antiparkinson medication, with significant risk ratios for 20 (67%) of 30 drugs ranging from 1·95 (95% CrI 1·30–2·74) for aripiprazole to 23·81 (7·41–142·86) for zuclopenthixol” (opens the source at this quote in a new tab)
“In contrast to our previous report, we present QTc prolongation in original units (ms), which facilitates clinical interpretation; lurasidone and the partial dopamine agonists were the most benign drugs.” (opens the source at this quote in a new tab)

Amisulpride in the multiple-treatments meta-analysis of 15 antipsychotic drugs

“We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo.” (opens the source at this quote in a new tab)
“clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63” (opens the source at this quote in a new tab)
“Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine).” (opens the source at this quote in a new tab)
“Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole).” (opens the source at this quote in a new tab)

Amisulpride against conventional antipsychotics and placebo: meta-analysis of 18 randomized controlled trials

“Eighteen randomized controlled trials of amisulpride (N=2,214) were found. In 11 studies of acutely ill patients it proved to be consistently more effective than conventional antipsychotics for global schizophrenic symptoms (measured with the Brief Psychiatric Rating Scale) and negative symptoms.” (opens the source at this quote in a new tab)
“Amisulpride is to date the only atypical antipsychotic for which several studies of patients suffering predominantly from negative symptoms have been published. In four such studies amisulpride was significantly more effective than placebo.” (opens the source at this quote in a new tab)
“Amisulpride was associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics.” (opens the source at this quote in a new tab)

Amisulpride in first-episode schizophrenia: EUFEST open randomised trial

“498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year.” (opens the source at this quote in a new tab)
“The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone.” (opens the source at this quote in a new tab)
“However, symptom reductions were virtually the same in all the groups, at around 60%.” (opens the source at this quote in a new tab)

Amisulpride as first-step treatment in first-episode schizophrenia: OPTiMiSE

“Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1).” (opens the source at this quote in a new tab)
“Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1.” (opens the source at this quote in a new tab)
“15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87).” (opens the source at this quote in a new tab)

Amisulpride against aripiprazole and olanzapine over 52 weeks: BeSt InTro

“144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients).” (opens the source at this quote in a new tab)
“After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025).” (opens the source at this quote in a new tab)
“We observed weight gain and increases of serum lipids and prolactin in all groups.” (opens the source at this quote in a new tab)
“Side-effect differences among the groups were generally small.” (opens the source at this quote in a new tab)

Amisulpride for predominant negative symptoms: systematic review and meta-analysis

“in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71)” (opens the source at this quote in a new tab)
“Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression.” (opens the source at this quote in a new tab)

Company characterization of the comparative evidence for amisulpride

“Amisulpride was ranked as the second most effective antipsychotic drug, after clozapine, in the 2019 Lancet meta-analysis of clinical trials on antipsychotic drugs.” (opens the source at this quote in a new tab)
“This analysis also found that amisulpride was 20% more effective at reducing overall symptoms of schizophrenia compared to risperidone, which is a first-line treatment for schizophrenia in the United States.” (opens the source at this quote in a new tab)
“A 2025 third-party study in European Neuropsychopharmacology highlighted that its overall treatment effect on symptoms was 0.56 using an approach similar to that which was used in the 2019 Lancet meta-analysis.” (opens the source at this quote in a new tab)
“Amisulpride’s effect size was greater than that of Cobenfy for the treatment of schizophrenia.” (opens the source at this quote in a new tab)
“Amisulpride has also been shown to have a relatively low rates of EPS (11%), long-term weight gain, and cardiovascular risk compared with other second-generation antipsychotic drugs.” (opens the source at this quote in a new tab)

“Among the highest effect sizes (0.73) compared with approved APs” (opens the source at this quote in a new tab)
“Requires high doses for SCZ (400-800 mg) increasing systemic exposure” (opens the source at this quote in a new tab)

Xanomeline-trospium: EMERGENT-2 design and primary endpoint

“EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia.” (opens the source at this quote in a new tab)
“From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125).” (opens the source at this quote in a new tab)
“The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61).” (opens the source at this quote in a new tab)

Xanomeline-trospium: EMERGENT-2 adverse events

“The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]).” (opens the source at this quote in a new tab)
“Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).” (opens the source at this quote in a new tab)

Xanomeline-trospium: EMERGENT-3 design and primary endpoint

“EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine.” (opens the source at this quote in a new tab)
“A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group).” (opens the source at this quote in a new tab)
“At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium, −20.6; placebo, −12.2; least squares mean difference, −8.4; 95% CI, −12.4 to −4.3; P < .001; Cohen d effect size, 0.60).” (opens the source at this quote in a new tab)

Xanomeline-trospium: EMERGENT-3 adverse events and discontinuation

“Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups.” (opens the source at this quote in a new tab)
“The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]).” (opens the source at this quote in a new tab)
“A total of 46 participants (36.8%) in the xanomeline-trospium group and 38 participants (29.0%) in the placebo group discontinued the trial early, with the most common reasons being withdrawal of consent followed by AEs.” (opens the source at this quote in a new tab)

Xanomeline-trospium: pooled efficacy across the three 5-week EMERGENT trials

“In pooled analyses, xanomeline/trospium significantly improved Positive and Negative Syndrome Scale (PANSS) total score at week 5 versus placebo (least squares mean difference, –9.9; 95% confidence interval, –12.4, –7.3; p < 0.0001; Cohen’s d effect size, 0.65).” (opens the source at this quote in a new tab)
“A total of 640 participants (xanomeline/trospium, n = 314; placebo, n = 326) comprised the mITT population, which was used for the primary efficacy analysis in the individual trials and in pooled efficacy analyses.” (opens the source at this quote in a new tab)
“First, pooled results reflect the short-term nature of the individual trials; the 52-week EMERGENT-4 and EMERGENT-5 trials will offer insight into long-term efficacy of xanomeline/trospium. Second, the EMERGENT trials lacked an active treatment comparator arm and additional research is needed to directly compare xanomeline/trospium effects against other antipsychotics.” (opens the source at this quote in a new tab)

Xanomeline-trospium: pooled safety across the three 5-week EMERGENT trials

“The pooled safety population comprised 683 participants from the acute trials. Discontinuation rates were similar between groups (xanomeline/ trospium, 27.6%; placebo, 22.7%).” (opens the source at this quote in a new tab)
“Treatment-emergent AEs were reported by 67.9% (xanomeline/trospium) and 51.3% (placebo) of participants, and 51.8% (xanomeline/trospium) and 29.4% (placebo) experienced AEs deemed related to treatment.” (opens the source at this quote in a new tab)
“Rates of EPS, somnolence, and weight gain were low in both groups.” (opens the source at this quote in a new tab)

Xanomeline-trospium: independent meta-analysis of the three 5-week placebo-controlled trials

“Xanomeline-trospium (k = 3, schizophrenia acute exacerbation, RoB=low, baseline N = 690, males=75.5 %, age=44.3 + 11.0, duration=5 weeks) outperformed placebo on PANSS total (SMD=-0.56, 95 % confidence interval/CI=-0.72/-0.40), positive (SMD=-0.59, 95 %CI=-0.75/-0.43), negative (SMD=-0.33, 95 %CI=-0.49/-0.17)” (opens the source at this quote in a new tab)
“Risk of ≥7 % weight gain (RR=0.46, 95 %CI=0.25-0.87, NNT=19), low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol levels were reduced, while risk was increased for vomiting, hypertension, nausea, dry mouth, dyspepsia, constipation (RR=7.60, 95 %CI=1.50-38.57 to RR=2.72, 95 %CI=1.63-4.55), any adverse event (RR=1.33, 95 %CI=1.18-1.51, NNT=6), triglyceride levels and supine heart rate (GRADE=moderate to high).” (opens the source at this quote in a new tab)
“Conversely, the risk was not increased for any other, serious, or severe adverse events or all-cause discontinuation.” (opens the source at this quote in a new tab)

Xanomeline-trospium: COBENFY prescribing information, primary efficacy results at week 5

“The efficacy of COBENFY for the treatment of schizophrenia in adults was evaluated in two placebo-controlled studies with identical designs (N = 470). Study 1 (NCT04659161) and Study 2 (NCT04738123) were five-week, randomized, double-blind, placebo-controlled, multi-center studies in adult patients with a diagnosis of schizophrenia according to the DSM-5 criteria.” (opens the source at this quote in a new tab)

Study	Treatment group	N	Mean baseline PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
Study 1 (NCT04659161)	COBENFY	“117”	“98.2 (8.9)”	“-21.2 (1.7)”	“-9.6 (-13.9, -5.2)”
Study 1 (NCT04659161)	Placebo	“119”	“97.7 (9.4)”	“-11.6 (1.6)”	Not reported
Study 2 (NCT04738123)	COBENFY	“114”	“96.9 (8.8)”	“-20.6 (1.6)”	“-8.4 (-12.4, -4.3)”
Study 2 (NCT04738123)	Placebo	“120”	“96.5 (8.8)”	“-12.2 (1.6)”	Not reported

Xanomeline-trospium: COBENFY prescribing information, dosing, titration, and food restriction

“The recommended starting dosage is one 50 mg/20 mg capsule (contains 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days.” (opens the source at this quote in a new tab)
“Increase the dosage to one 100 mg/20 mg capsule (contains 100 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least five days.” (opens the source at this quote in a new tab)
“The dosage may be increased to one 125 mg/30 mg capsule (contains 125 mg of xanomeline and 30 mg of trospium chloride) orally twice daily based on patient tolerability and response” (opens the source at this quote in a new tab)
“Administer COBENFY orally at least one hour before a meal or at least two hours after a meal” (opens the source at this quote in a new tab)
“Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment” (opens the source at this quote in a new tab)

Xanomeline-trospium: COBENFY prescribing information, most common adverse reactions (at least 5% and at least twice the placebo rate)

“nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease” (opens the source at this quote in a new tab)
“The adverse reaction findings are based on two pooled 5-week, placebo-controlled, flexible-dose studies in 504 adult patients with schizophrenia in which COBENFY or placebo was started at an initial dose of 50 mg/20 mg twice daily for the first 2 days followed by 100 mg/20 mg twice daily for the remainder of Week 1 (Days 3 to 7).” (opens the source at this quote in a new tab)

Xanomeline-trospium: COBENFY prescribing information, contraindications

“COBENFY is contraindicated in patients with:” (opens the source at this quote in a new tab)
“urinary retention” (opens the source at this quote in a new tab)
“moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment” (opens the source at this quote in a new tab)
“gastric retention” (opens the source at this quote in a new tab)
“untreated narrow-angle glaucoma” (opens the source at this quote in a new tab)

Lumateperone: Study 301 design and primary endpoint at day 28

“Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks.” (opens the source at this quote in a new tab)
“The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]).” (opens the source at this quote in a new tab)
“In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], −4.2; 95% CI, −7.8 to −0.6; P = .02; effect size [ES], −0.3) and the CGI-S (LSMD, −0.3; 95% CI, −0.5 to −0.1; P = .003; ES, −0.4).” (opens the source at this quote in a new tab)
“For 28 mg of lumateperone, the LSMD from baseline to day 28 was −2.6 (95% CI, −6.2 to 1.1; P = .16; ES, −0.2) on the PANSS total score and −0.2 (95% CI, −0.5 to 0.0; P = .02; ES, −0.3) on the CGI-S.” (opens the source at this quote in a new tab)

Lumateperone: effect size beside brexpiprazole, cariprazine, and lurasidone as stated by the Study 301 authors

“The effect sizes for PANSS total (0.30) and CGI-S (0.39) reduction in this study are broadly comparable with standard of care and, especially, newly approved antipsychotic effect sizes for overall reduction in symptoms (PANSS total), including brexpiprazole (0.26), cariprazine (0.34), and lurasidone (0.36).” (opens the source at this quote in a new tab)
“Second, the 4-week treatment duration may not elucidate the safety profile associated with longer-term treatment or address maintenance of effectiveness” (opens the source at this quote in a new tab)

Lumateperone: CAPLYTA prescribing information, primary efficacy results at week 4

“Study 1 (NCT01499563) was a four-week, randomized, double-blind, placebo-controlled, multi-center study in adult patients with a diagnosis of schizophrenia according to the DSM-IV-TR criteria.” (opens the source at this quote in a new tab)
“A total of 335 patients were randomized to receive CAPLYTA 42 mg, CAPLYTA 84 mg (two times the recommended daily dose), an active comparator, or placebo. The study was not designed to allow for efficacy comparison of CAPLYTA and the active comparator.” (opens the source at this quote in a new tab)
“A total of 450 patients were randomized to receive CAPLYTA 28 mg (two-thirds the recommended daily dose), CAPLYTA 42 mg, or placebo.” (opens the source at this quote in a new tab)
“The recommended dosage of CAPLYTA is 42 mg administered orally once daily with or without food. Dose titration is not required.” (opens the source at this quote in a new tab)

Study	Treatment group	N	Mean baseline PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
Study 1	CAPLYTA 42 mg	“84”	“88.1 (11.0)”	“-13.2 (1.7)”	“-5.8 (-10.5, -1.1)”
Study 1	Placebo	“85”	“86.3 (13.1)”	“-7.4 (1.7)”	Not reported
Study 2	CAPLYTA 42 mg	“150”	“90.0 (9.6)”	“-14.5 (1.3)”	“-4.2 (-7.8, -0.6)”
Study 2	Placebo	“150”	“89.0 (10.3)”	“-10.3 (1.3)”	Not reported

Cariprazine: VRAYLAR prescribing information, primary efficacy results at week 6

“The efficacy of VRAYLAR for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (mean age of 37 years, aged 18 to 60 years; 31% were female; and 45% were Caucasian) who met Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity.” (opens the source at this quote in a new tab)
“Study 1: In a 6-week, placebo-controlled trial (N = 711) involving three fixed doses of VRAYLAR (1.5, 3, or 4.5 mg/day) and an active control (risperidone), all VRAYLAR doses and the active control were superior to placebo on the PANSS total score and the CGI-S.” (opens the source at this quote in a new tab)
“Study 2: In a 6-week, placebo-controlled trial (N = 604) involving two fixed doses of VRAYLAR (3 or 6 mg/day) and an active control (aripiprazole), both VRAYLAR doses and the active control were superior to placebo on the PANSS total score and the CGI-S.” (opens the source at this quote in a new tab)
“Study 3: In a 6-week, placebo-controlled trial (N = 439) involving two flexible-dose range groups of VRAYLAR (3 to 6 mg/day or 6 to 9 mg/day), both VRAYLAR groups were superior to placebo on the PANSS total score and the CGI-S.” (opens the source at this quote in a new tab)

Study	Treatment group	Mean baseline PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
Study 1	VRAYLAR 1.5 mg/day	“97.1 (9.1)”	“-19.4 (1.6)”	“-7.6 (-11.8, -3.3)”
Study 1	VRAYLAR 3 mg/day	“97.2 (8.7)”	“-20.7 (1.6)”	“-8.8 (-13.1, -4.6)”
Study 1	VRAYLAR 4.5 mg/day	“96.7 (9.0)”	“-22.3 (1.6)”	“-10.4 (-14.6, -6.2)”
Study 1	Placebo	“97.3 (9.2)”	“-11.8 (1.5)”	Not reported
Study 2	VRAYLAR 3 mg/day	“96.1 (8.7)”	“-20.2 (1.5)”	“-6.0 (-10.1, -1.9)”
Study 2	VRAYLAR 6 mg/day	“95.7 (9.4)”	“-23.0 (1.5)”	“-8.8 (-12.9, -4.7)”
Study 2	Placebo	“96.5 (9.1)”	“-14.3 (1.5)”	Not reported
Study 3	VRAYLAR 3 to 6 mg/day	“96.3 (9.3)”	“-22.8 (1.6)”	“-6.8 (-11.3, -2.4)”
Study 3	VRAYLAR 6 to 9 mg/day	“96.3 (9.0)”	“-25.9 (1.7)”	“-9.9 (-14.5, -5.3)”
Study 3	Placebo	“96.6 (9.3)”	“-16.0 (1.6)”	Not reported

Brexpiprazole: REXULTI prescribing information, primary efficacy results at week 6

“The efficacy of REXULTI in the treatment of adults with schizophrenia was demonstrated in two 6-week randomized, double-blind, placebo-controlled, fixed-dose clinical studies in patients who met DSM-IV-TR criteria for schizophrenia.” (opens the source at this quote in a new tab)
“In Study 3, REXULTI at both 2 mg once daily and 4 mg once daily was superior to placebo on the PANSS total score. In Study 4, REXULTI 4 mg once daily was superior to placebo on the PANSS total score (Table 13).” (opens the source at this quote in a new tab)
“Patients in the REXULTI groups initiated treatment at 1 mg once daily on Days 1 to 4. The REXULTI dosage was increased to 2 mg on Days 5 to 7.” (opens the source at this quote in a new tab)

Study	Treatment group	N	Mean baseline PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
Study 3	REXULTI 2 mg/day	“180”	“95.9 (13.8)”	“-20.7 (1.5)”	“-8.7 (-13.1, -4.4)”
Study 3	REXULTI 4 mg/day	“178”	“94.7 (12.1)”	“-19.7 (1.5)”	“-7.6 (-12.0, -3.1)”
Study 3	Placebo	“178”	“95.7 (11.5)”	“-12.0 (1.6)”	Not reported
Study 4	REXULTI 2 mg/day	“179”	“96.3 (12.9)”	“-16.6 (1.5)”	“-3.1 (-7.2, 1.1)”
Study 4	REXULTI 4 mg/day	“181”	“95.0 (12.4)”	“-20.0 (1.5)”	“-6.5 (-10.6, -2.4)”
Study 4	Placebo	“180”	“94.6 (12.8)”	“-13.5 (1.5)”	Not reported

Lurasidone: LATUDA prescribing information, primary efficacy results at week 6 in the PANSS studies

“The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6- week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended- release) was included in two studies to assess assay sensitivity.” (opens the source at this quote in a new tab)
“Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.” (opens the source at this quote in a new tab)
“Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.” (opens the source at this quote in a new tab)
“Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.” (opens the source at this quote in a new tab)

Study	Treatment group	Mean baseline PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
Study 3	LATUDA 40 mg/day	“96.6 (10.7)”	“-25.7 (2.0)”	“-9.7 (-15.3, -4.1)”
Study 3	LATUDA 120 mg/day	“97.9 (11.3)”	“-23.6 (2.1)”	“-7.5 (-13.4, -1.7)”
Study 3	Olanzapine 15 mg/day	“96.3 (12.2)”	“-28.7 (1.9)”	“-12.6 (-18.2, -7.9)”
Study 3	Placebo	“95.8 (10.8)”	“-16.0 (2.1)”	Not reported
Study 4	LATUDA 40 mg/day	“96.5 (11.5)”	“-19.2 (1.7)”	“-2.1 (-7.0, 2.8)”
Study 4	LATUDA 80 mg/day	“96.0 (10.8)”	“-23.4 (1.8)”	“-6.4 (-11.3, -1.5)”
Study 4	LATUDA 120 mg/day	“96.0 (9.7)”	“-20.5 (1.8)”	“-3.5 (-8.4, 1.4)”
Study 4	Placebo	“96.8 (11.1)”	“-17.0 (1.8)”	Not reported
Study 5	LATUDA 80 mg/day	“97.7 (9.7)”	“-22.2 (1.8)”	“-11.9 (-16.9, -6.9)”
Study 5	LATUDA 160 mg/day	“97.5 (11.8)”	“-26.5 (1.8)”	“-16.2 (-21.2, -11.2)”
Study 5	Quetiapine extended-release 600 mg/day	“97.7 (10.2)”	“-27.8 (1.8)”	“-17.5 (-22.5, -12.4)”
Study 5	Placebo	“96.6 (10.2)”	“-10.3 (1.8)”	Not reported

Olanzapine and samidorphan: ENLIGHTEN-2 weight gain compared with olanzapine at week 24

“Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24.” (opens the source at this quote in a new tab)
“Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant).” (opens the source at this quote in a new tab)
“Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50).” (opens the source at this quote in a new tab)
“Schizophrenia symptom improvement was similar between treatment groups.” (opens the source at this quote in a new tab)

Olanzapine and samidorphan: ENLIGHTEN-1 PANSS total score at week 4

“This 4-week, phase 3, randomized, double-blind, placebo- and olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation.” (opens the source at this quote in a new tab)
“401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: -6.4 ± 1.8 [P < .001] and -0.38 ± 0.12 [P = .002], respectively).” (opens the source at this quote in a new tab)
“Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of -5.3 ± 1.84 [P = .004] and -0.44 ± 0.12 [P < .001], respectively).” (opens the source at this quote in a new tab)

Olanzapine and samidorphan: LYBALVI prescribing information, PANSS total score at week 4

“The study was designed to compare LYBALVI with placebo, not with olanzapine.” (opens the source at this quote in a new tab)
“The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine.” (opens the source at this quote in a new tab)

Treatment group	N	Baseline mean PANSS total score (SD)	LS mean change from baseline (SE)	Placebo-subtracted difference (95% CI)
LYBALVI 10 mg/10 mg or 20 mg/10 mg	“(N=132)”	“101.8 (11.6)”	“-23.9 (1.3)”	“–6.4 (-10.0, -2.8)”
Olanzapine 10 mg or 20 mg	“(N=132)”	“100.6 (12.1)”	“-22.8 (1.3)”	“-5.3 (-8.9, -1.7)”
Placebo	“(N=133)”	“102.7 (11.9)”	“-17.5 (1.3)”	Not reported

Olanzapine and samidorphan: LYBALVI prescribing information, weight change at week 24 and opioid contraindication

“Treatment with LYBALVI was associated with statistically significantly less weight gain than treatment with olanzapine, and with a smaller proportion of patients who gained ≥10% body weight (Table 8).” (opens the source at this quote in a new tab)
“Patients on stable, chronic olanzapine therapy were not specifically studied, so the weight effect of switching from olanzapine to LYBALVI is unknown.” (opens the source at this quote in a new tab)
“LYBALVI is contraindicated in patients using opioids or undergoing acute opioid withdrawal.” (opens the source at this quote in a new tab)

Treatment group	N	Baseline mean weight, kg (SD)	LS mean percent change from baseline (SE)	Olanzapine-subtracted difference (95% CI)	Patients with at least 10% weight gain, %	Olanzapine-subtracted risk difference (95% CI)
LYBALVI 10 mg/10 mg or 20 mg/10 mg	“(N=266)”	“77.0 (13.7)”	“4.2 (0.7)”	“-2.4 (-3.9, -0.9)”	“17.8”	“-13.7 (-22.8, -4.6)”
Olanzapine 10 mg or 20 mg	“(N=272)”	“77.5 (13.5)”	“6.6 (0.7)”	Not reported	“29.8”	Not reported

Branded oral antipsychotics: label-based efficacy comparison presented in the LB Pharmaceuticals annual report

“In the table below, we show the efficacy and side effect profiles of branded antipsychotic drugs approved for treatment of schizophrenia in the United States based on the approved labels.” (opens the source at this quote in a new tab)
“Caplyta efficacy data is based on four-week data from one Phase 2 trial and one Phase 3 trial (n=335; n=450). Cobenfy data is based on five-week data from two Phase 3 trials (n=236; n=234). Rexulti data is based on six-week data from two Phase 3 trials (n=674 total). Vraylar data is based on six-week data from three Phase 3 trials (n=1,655 total).” (opens the source at this quote in a new tab)

Drug	Placebo-corrected reduction in PANSS	Recommended dosage	Dosing frequency
Caplyta	“5.8 (Trial 1) 4.2 (Trial 2)”	“42 mg”	“Once-daily”
Cobenfy	“9.6 (Trial 1) 8.4 (Trial 2)”	“Up to 125 mg/30 mg”	“Twice-daily, 1 hour before or at least 2 hours after meals”
Rexulti	“7.6 (Trial 1) 6.5 (Trial 2)”	“4 mg”	“Once-daily”
Vraylar	“7.6 – 10.4 (Trial 1) 6.0 – 8.8 (Trial 2) 6.8 – 9.9 (Trial 3)”	“1.5 - 6 mg”	“Once-daily”

Cross-trial comparison caveat: variability of PANSS results across trials, as stated by LB Pharmaceuticals

“As this assessment requires patients or raters to undertake a questionnaire regarding symptoms at protocol specified timepoints in the trial, it is, however, inherently subjective, which can increase the variability of clinical results across clinical trials and creates a significant degree of uncertainty in determining overall clinical benefit.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: no active comparator in NOVA-1 and a 9-point placebo reduction

“The trial did not include an active comparator group, and thus, no direct comparison can be made with other medications.” (opens the source at this quote in a new tab)
“Although LB-102 demonstrated a statistically significant improvement in PANSS total score vs placebo, the 9-point reduction observed with placebo may reflect inpatient stabilization or design-related factors (eg, number of treatment arms and site participation).” (opens the source at this quote in a new tab)
“The NOVA 1 trial was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: no active comparator in the EMERGENT trials

“Second, the EMERGENT-3 trial did not include an active comparator group and, thus, only cross-trial comparisons can be made as opposed to direct comparisons of xanomeline-trospium with other currently available antipsychotic medications.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: adverse reaction rates across trials, as stated in FDA labeling

“Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: effect sizes in 167 placebo-controlled trials, industry sponsorship, and rising placebo response

“The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38.” (opens the source at this quote in a new tab)
“Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.” (opens the source at this quote in a new tab)
“Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: trial characteristics associated with placebo response

“The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses.” (opens the source at this quote in a new tab)
“In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: moderators with different effects on drug response and placebo response

“Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades.” (opens the source at this quote in a new tab)
“Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes.” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: drug-placebo difference by publication year, baseline severity, and study duration

“In 106 trials examined, the mean change observed in placebo cells increased significantly with year of publication (N = 39, r = 0.52, p = 0.001), while the mean change in effective dose medication cells decreased significantly (N = 208, r = −0.26, p < 0.001).” (opens the source at this quote in a new tab)
“indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity, and with increasing study duration” (opens the source at this quote in a new tab)
“Medication treatment in comparator studies was associated with significantly more improvement than medication treatment in placebo-controlled trials (t = 2.73, df 93, p = 0.008).” (opens the source at this quote in a new tab)

Cross-trial comparison caveat: patient and design factors associated with placebo response, 1970 to 2010

“Both placebo SMC and study quality increased over time. Younger age, shorter duration of illness, greater baseline symptom severity, and shorter trial duration were significantly associated with greater placebo response, while country (United States compared with other countries) was not.” (opens the source at this quote in a new tab)
“More study sites, fewer university or Veterans Affairs treatment settings, and a lower percentage of patients assigned to receive placebo were associated with a greater placebo response, but these were not independent of publication year.” (opens the source at this quote in a new tab)

NOVA-1 tolerability: weight, prolactin, glucose, cholesterol, and QTc change from baseline to day 28

Measure	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Placebo (n = 108)
Weight, mean (SD) change, kg	“4.3 (3.2)”	“3.3 (2.8)”	“2.9 (2.5)”	“2.0 (2.9)”
Weight increase of 7% or more, number of participants (%)	“27 (26%)”	“20 (19%)”	“3 (9%)”	“11 (10%)”
Prolactin, mean (SD) change, ng/mL	“59.9 (55.11)”	“51.4 (52.02)”	“51.2 (48.07)”	“1.3 (6.03)”
Fasting glucose, mean (SD) change, mg/dL	“2.3 (24.52)”	“2.0 (13.62)”	“7.0 (19.39)”	“0.2 (12.07)”
Total cholesterol, mean (SD) change, mg/dL	“7.7 (24.75)”	“5.4 (23.98)”	“5.8 (25.52)”	“0.8 (25.06)”
QTc, mean (SD) change, milliseconds	“4.9 (13.39)”	“4.3 (12.55)”	“5.4 (9.44)”	“1.2 (12.56)”
QTc mean change of 30 milliseconds or more, number of participants (%)	“5 (4.7)”	“1 (0.9)”	“1 (2.8)”	“1 (0.9)”

NOVA-1 tolerability: prolactin elevation and prolactin-related adverse events

“Elevated prolactin levels at day 28 were reported across all arms (placebo, 5.2%, mean [SD] increase, 1.3 [6.0] ng/mL; 50 mg, 91.0%, mean [SD] increase, 59.9 [55.1] ng/mL; 75 mg, 94.0%, mean [SD] increase, 51.4 [52.0] ng/mL; 100 mg, 87.5%, mean [SD] increase, 51.2 [48.1] ng/mL; to convert to micrograms per liter, multiply by 1)” (opens the source at this quote in a new tab)
“Clinical AEs related to prolactin increase were reported in 5 participants, including galactorrhea (50 mg, n = 2; 75 mg, n = 1), breast enlargement (100 mg, n = 1), and erectile dysfunction (100 mg, n = 1).” (opens the source at this quote in a new tab)

NOVA-1 tolerability: weight increase

“Weight increase was the only TEAE to occur in 5% or more of the total population at a rate at least twice that observed with placebo but was not dose-dependent (placebo, 4 [3.7%], mean increase, 2.1 kg; 50 mg, 13 [12.1%], mean increase, 4.3 kg; 75 mg, 8 [7.4%], mean increase, 3.3 kg; 100 mg, 3 [8.3%], mean increase, 2.9 kg).” (opens the source at this quote in a new tab)
“A 7% or greater weight increase, using a last-observation-carried-forward approach, was reported by 61 participants (placebo, 11 [10.4%], mean increase, 6.9 kg; 50 mg, 27 [25.7%], mean increase, 8.2 kg; 75 mg, 20 [18.7%], mean increase, 7.2 kg; 100 mg, 3 [8.8%], mean increase, 7.2 kg)” (opens the source at this quote in a new tab)
“Site-level smoking restrictions and limited opportunity for physical activity, combined with minimal dietary or food restrictions, may have contributed to weight gain, limiting the ability to fully assess the metabolic profile of LB-102 under real-world outpatient conditions.” (opens the source at this quote in a new tab)

“Over the course of the trial, we observed approximately 1.6 kg placebo-adjusted weight gain on a last observation carried forward basis.” (opens the source at this quote in a new tab)
“Despite the weight gain observed in the four-week trial, no clinically meaningful signal in metabolic parameters such as cholesterol, LDL, HDL, triglycerides or fasting glucose were observed.” (opens the source at this quote in a new tab)

NOVA-1 tolerability: extrapyramidal symptoms, akathisia, and QTc

“Extrapyramidal symptom incidence was low across all groups (placebo, 2 [1.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 1 [0.9%]; 100 mg, 1 [2.8%]), as was dystonia (placebo, 1 [0.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 3 [2.8%]; 100 mg, 1 [2.8%]).” (opens the source at this quote in a new tab)
“Evaluation of the SAS, BARS, and AIMS demonstrated values that remained stable over time, with little to no emergence of any antipsychotic-induced parkinsonism, akathisia, tardive dyskinesia, or other involuntary motor AEs.” (opens the source at this quote in a new tab)
“There were no clinically meaningful changes in blood pressure, pulse rate, or body temperature from baseline to day 28, and no notable shifts observed in QTcF (Fridericia-corrected QT interval) values” (opens the source at this quote in a new tab)

NOVA-1 adverse events of special interest as reported by the company

Adverse event	LB-102 50 mg (N=107)	LB-102 75 mg (N=108)	LB-102 100 mg (N=36)	Placebo (N=108)
Dystonia	“0”	“3 (2.8%)”	“1 (2.8%)”	“1 (0.9%)”
Akathisia	“1 (0.9%)”	“2 (1.8%)”	“0”	“1 (0.9%)”
Extrapyramidal disorder	“0”	“1 (0.9%)”	“1 (2.8%)”	“2 (1.9%)”
Total extrapyramidal symptoms	“1 (1.0%)”	“6 (5.6%)”	“2 (5.6%)”	“4 (3.7%)”
Total adverse events related to prolactin increase	“2 (1.9%)”	“1 (0.9%)”	“2 (5.6%)”	“0”
Hyperprolactinemia	“11 (10.3%)”	“8 (7.4%)”	“6 (16.7%)”	“0”
Sedation	“0”	“1 (0.9%)”	“0”	“0”
QTcF change from baseline at day 28, milliseconds	“4.9”	“4.3”	“5.4”	“1.2”

“Change from baseline to Week 4 in SAS, AIMS, and BARS demonstrated no difference between treatment arms and placebo and there were no reports of orthostasis among patients treated with LB-102 in the trial.” (opens the source at this quote in a new tab)

NOVA-1 tolerability placed beside amisulpride, xanomeline-trospium, and olanzapine by the trial authors

“Elevated prolactin was reported from 6.5% of those receiving LB-102 50 mg to 8.3% of those receiving LB-102 100 mg; by comparison, data for amisulpride indicate significantly higher rates of hyperprolactinemia (25%-100%).” (opens the source at this quote in a new tab)
“Weight gain with LB-102 ranged from 3.5 kg (75 mg) to 4.6 kg (50 mg) compared with 2.1 kg with placebo, between weight-neutral xanomeline and trospium chloride (−0.37 kg; 95% CI, −1.19 to 0.46 vs placebo)” (opens the source at this quote in a new tab)
“olanzapine (2.78 kg; 95% CI, 2.44-3.13 vs placebo)” (opens the source at this quote in a new tab)
“Extrapyramidal symptoms, QTc prolongation, and hepatic enzyme changes with LB-102 remained similar to placebo.” (opens the source at this quote in a new tab)
“The phase 2 results demonstrate a manageable metabolic profile for LB-102, narrowing the longstanding trade-off between potency and tolerability traditionally seen with amisulpride and other antipsychotics.” (opens the source at this quote in a new tab)

Extrapyramidal symptom rates beside amisulpride and other dopamine D2 antagonists and partial agonists: company presentation

“EPS rates (including akathisia) observed with other D2 antagonists and partial agonists can reach more than 30%” (opens the source at this quote in a new tab)
“EPS rates with LB-102 lower than amisulpride despite 70-80% RO for LB-102” (opens the source at this quote in a new tab)
“We observed ~1.6 kg placebo adjusted weight gain while preserving metabolic neutrality” (opens the source at this quote in a new tab)

Amisulpride prolactin, extrapyramidal, weight, and QT statements: European summary of product characteristics

“Common: amisulpride causes an increase in plasma prolactin levels which is reversible after drug discontinuation. This may result in galactorrhoea, amenorrhoea, gynaecomastia, breast pain, and erectile dysfunction.” (opens the source at this quote in a new tab)
“The incidence of extrapyramidal symptoms which is dose related, remains very low in the treatment of patients with predominantly negative symptoms with doses of 50-300 mg/day.” (opens the source at this quote in a new tab)
“Rare: QT interval prolongation, ventricular arrhythmias such as torsade de pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, sudden death (see Section 4.4).” (opens the source at this quote in a new tab)
“Caution is advised when prescribing amisulpride with medicines known to prolong the QT interval” (opens the source at this quote in a new tab)

Amisulpride QT prolongation: United States intravenous label and company statements

“QT Prolongation: Occurs in a dose- and concentration-dependent manner.” (opens the source at this quote in a new tab)

“Amisulpride has been associated with QT prolongation.” (opens the source at this quote in a new tab)
“At therapeutic doses of amisulpride up to 1,200 mg/day, literature reports of cardiac toxicity due to QT prolongation are extremely rare.” (opens the source at this quote in a new tab)
“pharmacovigilance data on amisulpride from the United Kingdom covering 16,000 patient exposure years had 8 incidences of QT prolongation with all 8 events occurring in patients concurrently taking clozapine, a drug known to prolong the QT interval” (opens the source at this quote in a new tab)

Metabolic effects of 18 antipsychotics: network meta-analysis

“Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6–8).” (opens the source at this quote in a new tab)
“Mean differences for weight gain compared with placebo ranged from −0·23 kg (95% CI −0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine” (opens the source at this quote in a new tab)
“We did not find evidence of weight gain with ziprasidone, haloperidol, fluphenazine, aripiprazole, lurasidone, cariprazine, amisulpride, or flupenthixol when compared with placebo. We found evidence of weight gain with brexpiprazole, risperidone and paliperidone, quetiapine, iloperidone, sertindole, olanzapine, zotepine, and clozapine” (opens the source at this quote in a new tab)
“Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles.” (opens the source at this quote in a new tab)

Emraclidine (M4 positive allosteric modulator): EMPOWER-1 and EMPOWER-2 primary endpoint at week 6

“today announced that its two Phase 2 EMPOWER trials investigating emraclidine as a once-daily, oral monotherapy treatment for adults with schizophrenia who are experiencing an acute exacerbation of psychotic symptoms, did not meet their primary endpoint of showing a statistically significant reduction (improvement) in the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score compared to the placebo group at week 6.” (opens the source at this quote in a new tab)
“In the EMPOWER trials, emraclidine was well-tolerated with a safety profile comparable to that observed in the Phase 1b trial.” (opens the source at this quote in a new tab)

Trial and arm	Participants	Least squares mean change in PANSS total score at week 6 (95% CI)
EMPOWER-1, placebo	“N= 127”	“-13.5 (-17.0, -10.0)”
EMPOWER-1, emraclidine 10 mg once daily	“N = 125”	“-14.7 (-18.1, -11.2)”
EMPOWER-1, emraclidine 30 mg once daily	“N = 127”	“-16.5 (-20.0, -13.1)”
EMPOWER-2, placebo	“N = 128”	“-16.1 (-19.4, -12.8)”
EMPOWER-2, emraclidine 15 mg once daily	“N = 122”	“-18.5 (-22.0, -15.0)”
EMPOWER-2, emraclidine 30 mg once daily	“N = 123”	“-14.2 (-17.6, -10.8)”

Emraclidine: independent review of the placebo response in the EMPOWER trials

“These exceptionally high placebo responses (13.5–16.1 points) eliminated drug-placebo separation despite drug effects comparable to Phase Ib” (opens the source at this quote in a new tab)

Emraclidine: impairment charge and the phase 2 dose-ranging study started in 2025

“For the period from the acquisition date through December 31, 2024, operating losses attributable to Cerevel Therapeutics were $4.9 billion, inclusive of an intangible asset impairment charge of $4.5 billion related to emraclidine.” (opens the source at this quote in a new tab)

“This study will assess adverse events, change in disease activity, and how oral emraclidine moves through the body in adult participants with schizophrenia” (opens the source at this quote in a new tab)
“Approximately 268 participants will be enrolled across roughly 32 sites in the United States.” (opens the source at this quote in a new tab)
“Participants in Part A will be assigned to oral emraclidine or placebo administered for 14 days or up to 21 days depending on cohort.” (opens the source at this quote in a new tab)

Field	Quoted record
Phase	“Phase 2”
Study start (actual)	“2025-08-04”
Primary completion (estimated)	“2028-02”

Brilaroxazine (serotonin-dopamine modulator): RECOVER phase 3 primary endpoint at week 4

“RECOVER is a global Phase 3, randomized, double-blind, placebo-controlled, multicenter study designed to assess the safety and efficacy of brilaroxazine in 412 patients with acute schizophrenia compared to placebo.” (opens the source at this quote in a new tab)
“Brilaroxazine was administered at fixed doses of 15 mg or 50 mg once daily for 28 days.” (opens the source at this quote in a new tab)
“The trial successfully met its primary endpoint, with brilaroxazine at the 50 mg dose achieving a statistically significant and clinically meaningful 10.1-point reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo (-23.9 brilaroxazine 50 mg vs. -13.8 placebo, p<0.001) at week 4.” (opens the source at this quote in a new tab)
“The 15 mg dose of brilaroxazine was numerically superior to placebo on the primary endpoint and most secondary endpoints, and reached statistical significance on two key secondary endpoints.” (opens the source at this quote in a new tab)

Brilaroxazine: RECOVER tolerability findings at 4 weeks

“No significant change in bodyweight, blood glucose levels, lipids levels, or endocrine hormones (prolactin, thyroid hormone) compared to placebo” (opens the source at this quote in a new tab)
“Akathisia and extrapyramidal symptoms <1% reported for brilaroxazine 50 mg and none for 15 mg” (opens the source at this quote in a new tab)
“Low discontinuation rates with brilaroxazine that were less than placebo (16% in brilaroxazine 50mg and 19% in brilaroxazine 15mg vs. 22% placebo)” (opens the source at this quote in a new tab)

Brilaroxazine: 1-year open-label extension

“Once daily brilaroxazine led to robust broad-spectrum efficacy that was sustained over 1-year and was generally well tolerated with a discontinuation rate of 35% in this long-term study.” (opens the source at this quote in a new tab)
“Mild weight gain (1.52 kg) reported in the pooled brilaroxazine dose group over 1-year treatment.” (opens the source at this quote in a new tab)

Brilaroxazine: FDA recommendation of a second phase 3 trial and RECOVER-2 timing

“In written feedback, the FDA recommended a second Phase 3 clinical trial for brilaroxazine in patients with schizophrenia to, among other things, generate additional efficacy data and expand the safety dataset.” (opens the source at this quote in a new tab)
“The RECOVER-2 trial will be similar in design to the completed RECOVER Phase 3 trial of brilaroxazine.” (opens the source at this quote in a new tab)

“FDA feedback on use of a new form of brilaroxazine in RECOVER-2 trial expected Q4 2026” (opens the source at this quote in a new tab)
“Patient enrollment of the RECOVER-2 Phase 3 trial expected to initiate in 1H 2027, subject to receipt of additional financing” (opens the source at this quote in a new tab)

Ulotaront (TAAR1 agonist): DIAMOND 1 and DIAMOND 2 phase 3 primary endpoint at week 6

“The multicenter, randomized, double-blind, parallel-group, fixed-dosed DIAMOND 1 study, evaluated the efficacy, safety, and tolerability of ulotaront (50 mg/day and 75 mg/day) versus placebo over six weeks in 435 acutely psychotic adults with schizophrenia.” (opens the source at this quote in a new tab)
“In the DIAMOND 1 study all three groups showed a reduction in the Positive and Negative Syndrome Scale (PANSS) total score over time, however neither ulotaront treatment group was superior to placebo on the primary endpoint of change from baseline in PANSS total score at Week 6 (least squares [LS] mean: -16.9 and -19.6 in ulotaront 50 mg/day and 75 mg/day-treated patients, respectively, compared to -19.3 in placebo-treated patients).” (opens the source at this quote in a new tab)
“The multicenter, randomized, double-blind, parallel-group, fixed-dosed DIAMOND 2 study, evaluated the efficacy, safety, and tolerability of ulotaront (75 mg/day and 100 mg/day) versus placebo over six weeks in 464 acutely psychotic adults with schizophrenia.” (opens the source at this quote in a new tab)
“At Week 6 both ulotaront treatment groups showed numerically larger mean reductions in PANSS total score from baseline compared to placebo (LS mean: -16.4 and -18.1 in ulotaront 75 mg/day and 100 mg/day-treated patients, respectively, compared to -14.3 in placebo-treated patients).” (opens the source at this quote in a new tab)
“In both the DIAMOND 1 study and the DIAMOND 2 study, a large placebo effect was observed which may have masked the molecule’s therapeutic effect.” (opens the source at this quote in a new tab)

Ulotaront: pooled effect size of TAAR1 agonists relative to dopamine-blocking antipsychotics

“ulotaront and ralmitaront demonstrated only modest improvements in acute schizophrenia (pooled SMD 0.15, 95% CI: − 0.05 to 0.34), substantially smaller than traditional antipsychotics, which typically show effect sizes ranging from 0.24 to 0.89” (opens the source at this quote in a new tab)

Ulotaront: registration plan for schizophrenia after the DIAMOND results

No evidence found.

Iclepertin (GlyT1 inhibitor) for cognitive impairment: CONNEX phase 3 program topline results

“Boehringer Ingelheim today announced top-line results from the Phase III CONNEX clinical program in cognitive impairment in adults with schizophrenia, showing primary and key secondary endpoints were not met.” (opens the source at this quote in a new tab)
“Overall, no statistically significant effects on cognition or functioning were observed in patients treated with iclepertin versus placebo at six months.” (opens the source at this quote in a new tab)
“The CONNEX clinical program enrolled 1,840 patients in 41 countries.” (opens the source at this quote in a new tab)
“Boehringer Ingelheim decided to discontinue the long-term extension trial, CONNEX-X, effective immediately.” (opens the source at this quote in a new tab)

Iclepertin: CONNEX primary endpoint in the peer-reviewed report

“Adults aged 18-50 years with schizophrenia were randomised 1:1 using interactive response technology to oral 10 mg iclepertin or placebo once daily for 26 weeks in combination with standard-of-care antipsychotic therapy.” (opens the source at this quote in a new tab)
“At week 26, there was no significant difference between treatment groups in the primary endpoint.” (opens the source at this quote in a new tab)
“The adjusted mean difference for iclepertin versus placebo for MCCB overall composite T-score was 0·127 [95% CI -0·396 to 0·650]; p=0·63” (opens the source at this quote in a new tab)

NBI-1117568 (direclidine, M4 selective agonist): phase 2 primary endpoint at week 6

“The NBI-'568-SCZ2028 dose-finding study met its primary endpoint for the once-daily 20 mg dose.” (opens the source at this quote in a new tab)
“It demonstrated a clinically meaningful and statistically significant reduction from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 6 with a placebo-adjusted mean reduction of 7.5 points (p=0.011 and effect size of 0.61) and an 18.2-point reduction from baseline.” (opens the source at this quote in a new tab)

Arm	Participants	Least squares mean change in PANSS total score at week 6	Difference from placebo
Placebo	“N=68”	“-10.8”	“-”
20 mg once daily	“N=35”	“-18.2”	“-7.5 (p=0.011)”
40 mg once daily	“N=38”	“-12.6”	“-1.9 (p=0.282)”
60 mg once daily	“N=34”	“-13.7”	“-2.9 (p=0.189)”
30 mg twice daily	“N=26”	“-15.8”	“-5.0 (p=0.090)”

NBI-1117568: phase 2 tolerability

“Adverse events with the highest incidence were somnolence, dizziness, and headache.” (opens the source at this quote in a new tab)
“NBI-'568 was not associated with a greater increase in weight than placebo. Few extrapyramidal symptoms adverse events were reported.” (opens the source at this quote in a new tab)

NBI-1117568: phase 3 program and expected readout

“The Phase 3 study is a global double-blind, placebo-controlled trial evaluating NBI-1117568 in adults with a primary diagnosis of schizophrenia who are experiencing an acute exacerbation or relapse of symptoms.” (opens the source at this quote in a new tab)
“The study is expected to enroll approximately 280 patients.” (opens the source at this quote in a new tab)

“We have initiated a comprehensive Phase 3 clinical program for direclidine in schizophrenia (with initial topline data expected in 2027), including studies evaluating efficacy in patients experiencing an acute relapse of schizophrenia and long-term safety.” (opens the source at this quote in a new tab)

Evenamide (glutamate modulator) as add-on therapy: study 008A primary endpoint at 4 weeks

“Study 008A was a four-week, international, randomized, double-blind and placebo-controlled add-on Phase II/III study performed in 45 centers in 11 countries in Europe, Asia and Latin America.” (opens the source at this quote in a new tab)
“291 patients were randomized to treatment either with evenamide or placebo as add-on to their current antipsychotic therapy.” (opens the source at this quote in a new tab)
“In the study, the addition of 30 mg (bid) of evenamide to the patients’ current antipsychotic medication was associated with a highly statistically significant (p-value 0.006) reduction in the PANSS Total Score of 10.2 points, compared to 7.6 points in patients treated with placebo at day 29; the least square mean difference (LS mean difference) was 2.5.” (opens the source at this quote in a new tab)

“the absolute difference of the two treatment groups for the PANSS Total at Day 29, primary efficacy endpoint, was = 2·5 [p-value<0.05] that is associated with a Cohen's d effect size = 0·33” (opens the source at this quote in a new tab)

Evenamide: ENIGMA-TRS phase 3 program status in September 2026

“ENIGMA-TRS 1 evaluates evenamide as an add-on therapy to current antipsychotics, including clozapine, in patients with treatment-resistant schizophrenia (TRS).” (opens the source at this quote in a new tab)
“Topline data from the 12-week treatment period are expected in Q1 2027.” (opens the source at this quote in a new tab)

“today announced that it has been informed by the U.S. Food and Drug Administration (FDA) that the hold on the enrollment of new patients will remain in place at U.S. sites in the Phase 3 ENIGMA-TRS 2 study with evenamide.” (opens the source at this quote in a new tab)
“Enrollment in the study continues outside the U.S.” (opens the source at this quote in a new tab)

Xanomeline-trospium as adjunctive therapy: ARISE phase 3 primary endpoint at week 6

“The ARISE clinical trial (KAR-012) is a Phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study evaluating Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment in adults with schizophrenia who have inadequate response to their current antipsychotic treatment.” (opens the source at this quote in a new tab)
“In the Phase 3 trial, adjunctive Cobenfy treatment demonstrated a 2.0-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo with an atypical antipsychotic at Week 6, which did not reach the threshold for statistical significance for the primary endpoint (P = 0.11).” (opens the source at this quote in a new tab)

Measure	Xanomeline-trospium plus antipsychotic	Placebo plus antipsychotic	Least squares mean difference (95% CI)	P value
Change in PANSS total score at week 6, least squares mean (SE)	“-14.3 (1.01)”	“-12.2 (0.98)”	“-2.0 (-4.5, 0.5)”	“0.11”

ML-007C-MA (M1/M4 agonist with fesoterodine): ZEPHYR phase 2 primary endpoint at week 5

“ZEPHYR is a randomized, double-blind, placebo-controlled trial at 25 US sites that evaluated the efficacy, safety, and tolerability of ML-007C-MA in inpatient adult participants with schizophrenia experiencing an acute exacerbation of psychosis.” (opens the source at this quote in a new tab)
“A total of 307 participants were randomized 1:1:1 to receive either placebo, ML-007C-MA 210/3 mg twice daily, or ML-007C-MA 330/6 mg once daily.” (opens the source at this quote in a new tab)
“In the modified intent-to-treat (mITT) population, the BID arm achieved an effect size of 0.37 (Cohen’s d) and these participants experienced a mean 4.5-point improvement in PANSS total score versus placebo (p=0.015).” (opens the source at this quote in a new tab)
“The 330/6 mg once-daily (QD) dose, which results in lower daily exposure than BID dosing, demonstrated numerical improvement over placebo, but did not achieve statistical significance on the primary endpoint.” (opens the source at this quote in a new tab)
“Data support proceeding with an additional trial, also designed to be registrational, to replicate this result; Company to engage with FDA at End-of-Phase 2 Meeting” (opens the source at this quote in a new tab)

Milsaperidone (BYSANTI): FDA approval for schizophrenia in February 2026

“today announced that the U.S. Food and Drug Administration (FDA) has approved BYSANTI™ (milsaperidone) tablets, a first line therapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adults.” (opens the source at this quote in a new tab)
“In clinical studies BYSANTI™ demonstrated bioequivalence to iloperidone across the therapeutic dosing spectrum enabling it to leverage well-established knowledge of efficacy and safety derived from a rich clinical development program and more than 100,000 patient-years of real-world experience with Fanapt® (iloperidone).” (opens the source at this quote in a new tab)
“Vanda anticipates commercial availability of BYSANTI™ in Q3 of 2026.” (opens the source at this quote in a new tab)

Lumateperone (CAPLYTA): FDA approval of relapse prevention data in April 2026

“Johnson & Johnson announced today that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) based on long-term data evaluating the safety and efficacy of CAPLYTA® (lumateperone) for the prevention of relapse in schizophrenia.” (opens the source at this quote in a new tab)
“Patients who received CAPLYTA® had a 63 percent lower risk of relapse compared with placebo (hazard ratio = 0.37), and 84 percent of patients were relapse-free over six months.” (opens the source at this quote in a new tab)

Olanzapine extended-release subcutaneous injection (TEV-749): NDA under FDA review

“announced today that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for olanzapine extended-release injectable suspension (TEV-'749) for the treatment of schizophrenia in adults.” (opens the source at this quote in a new tab)
“Currently, there is no long-acting olanzapine formulation without an FDA-required Risk Evaluation and Mitigation Strategy (REMS), which mandates administration in a certified healthcare facility and requires a 3-hour post-injection monitoring period.” (opens the source at this quote in a new tab)

“A PDUFA decision from the FDA is expected for TEV-'749 in Q4 2026.” (opens the source at this quote in a new tab)
“For period one of the study (first 8 weeks), 675 patients were randomized to receive a subcutaneous injection of once-monthly olanzapine LAI (low, medium or high dose) or placebo in a 1:1:1:1 ratio.” (opens the source at this quote in a new tab)

Roluperidone for negative symptoms: confirmatory phase 3 trial started in March 2026

“today announced that the first patient has been screened in its global, confirmatory Phase 3 clinical trial evaluating roluperidone as monotherapy for the treatment of negative symptoms of schizophrenia.” (opens the source at this quote in a new tab)
“The Phase 3 trial will enroll approximately 380 patients across roughly 40 clinical sites worldwide, including the United States (US) and multiple European countries.” (opens the source at this quote in a new tab)

Motivista (CT-155) prescription digital therapeutic: FDA 510(k) clearance for negative symptoms in July 2026

“Motivista (CT-155) is a prescription digital therapeutic indicated for the treatment of negative symptoms of schizophrenia as an adjunct to clinician-managed outpatient care, including antipsychotic therapy, in patients 18 years of age and older with clinically stable positive symptoms.” (opens the source at this quote in a new tab)

SEP-4199 (non-racemic amisulpride): enantiomer ratio and receptor rationale

“We report the discovery of SEP‐4199, a nonracemic 85:15 ratio of aramisulpride (potently targeting the 5‐HT7 receptor) and esamisulpride (yielding D2 receptor occupancy < 50% at therapeutic doses).” (opens the source at this quote in a new tab)
“In contrast, for D2R, esamisulpride was the more‐potent enantiomer (4.43 ± 0.70 nM) relative to aramisulpride (140 ± 31 nM).” (opens the source at this quote in a new tab)

SEP-4199: phase 2 trial in bipolar I depression

“Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression.” (opens the source at this quote in a new tab)
“Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P = 0.054; effect size [ES], 0.31) and 400 mg/d (P = 0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P = 0.016; ES, 0.34) and 400 mg/d (P = 0.024; ES, 0.31).” (opens the source at this quote in a new tab)
“median increases in prolactin were +83.6 μg/L on 200 mg/d, +95.2 μg/L on 400 mg/d compared with 0.0 μg/L on placebo.” (opens the source at this quote in a new tab)

SEP-4199: phase 3 trial in bipolar I depression terminated

Field	Quoted record
Title	“A Clinical Study of an Investigational Drug for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder.”
Sponsor	“Sumitomo Pharma America, Inc.”
Phase	“Phase 3”
Recruitment status	“Terminated”
Reason stopped	“Company decided not to move forward with further accrual.”
Enrollment (actual)	“83”
Primary completion (actual)	“2023-10-18”

SEP-4199: clinical trial in schizophrenia

No evidence found.

Independent review of new pharmacological approaches for schizophrenia: LB-102

“LB-102 (LB Pharmaceuticals), a methylated derivative of amisulpride, is positioned as a potential first-in-class benzamide antipsychotic for the U.S. market” (opens the source at this quote in a new tab)
“The 50 mg dose demonstrated an effect size of 0.61 with a favorable safety profile, including a low incidence of extrapyramidal symptoms and minimal metabolic effects” (opens the source at this quote in a new tab)
“This multidimensional efficacy pattern positions LB-102 as a candidate for comprehensive disease management beyond traditional positive symptom control.” (opens the source at this quote in a new tab)

Independent review of novel antipsychotic drugs: hyperprolactinemia as a possible limit on LB-102 use

“Overall, LB-102 was well tolerated, although a transient increment of prolactin levels was observed in the majority of the subjects” (opens the source at this quote in a new tab)
“Amisulpride is known to cause hyperprolactinemia in patients, even at low dosages, and it will be important to evaluate the prevalence and the severity of hyperprolactinemia during the treatment with LB-102, which may limit its usability in the future” (opens the source at this quote in a new tab)

Independent reviews: LB-102 among investigational treatments for negative symptoms and among amisulpride analogs

“Among investigational medications, NMDAR agonists, muscarinic agonists, and LB-102 remain under study.” (opens the source at this quote in a new tab)

“LB-102, a newly identified N-methylated analog of amisulpride, exhibits enhanced lipophilicity at lower doses, as demonstrated in a phase 1 study, indicating significant promise for therapeutic applications.” (opens the source at this quote in a new tab)

Clinician commentary on the NOVA-1 publication: investigator caveats and an uninvolved clinician

“He noted, however, that NOVA-1 was a short, 4-week phase 2 inpatient study without an active comparator.” (opens the source at this quote in a new tab)
“The real and full clinical value will depend on phase 3 data, longer-term metabolic/endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons” (opens the source at this quote in a new tab)
“said McIntyre, who wasn’t involved in the study” (opens the source at this quote in a new tab)
“LB-102 has been modified to improve bioavailability, allowing for lower doses and better tolerability and the safety. It’s a promising new asset that seems to have replicated efficacy across psychotic, negative, and depressive symptoms” (opens the source at this quote in a new tab)

Trade press appraisal of the NOVA-1 publication: evidence payers are expected to require

“The decision to run a placebo-controlled acute study is standard for the indication, but the commercial bar is higher: effect size must be competitive with established agents, and tolerability advantages need to be both clinically meaningful and durable.” (opens the source at this quote in a new tab)
“Payers and health systems will look for head-to-head or switching data to justify adoption over low-cost generics, particularly as long-acting injectables continue to gain share for adherence management.” (opens the source at this quote in a new tab)
“Longer-term extensions will be important to characterize relapse prevention and a broader safety profile beyond four to six weeks, which could unlock a maintenance label and clearer comparative positioning.” (opens the source at this quote in a new tab)

Trade press comparison of NOVA-1 topline results with xanomeline-trospium and NBI-1117568

“Compared to placebo, patients on the low and middle doses of LB-102, respectively, had 5- and 4.7-point reductions in PANSS scores. The reduction in the smaller cohort that took the exploratory top dose was 6.8 points.” (opens the source at this quote in a new tab)
“Bristol Myers Squibb’s Cobenfy achieved an 8.4-point PANSS improvement over placebo after five weeks in a phase 3 trial that enrolled 256 people with schizophrenia experiencing acute psychosis. Neurocrine Biosciences saw placebo-adjusted improvements of up to 7.5 points in a phase 2 study of its would-be Cobenfy rival.” (opens the source at this quote in a new tab)
“LB Pharma saw one case of sedation across the 251 patients who took LB-102. Average placebo-adjusted weight gain was 2 kg.” (opens the source at this quote in a new tab)

Editorial or invited commentary accompanying the JAMA Psychiatry publication of NOVA-1

No evidence found.

Network meta-analysis or indirect treatment comparison that includes LB-102

No evidence found.

Direct head-to-head clinical comparison of LB-102 with amisulpride, xanomeline-trospium, or another antipsychotic

No evidence found.

Definition: disorder of thought, perception, emotion, and social interaction

“Schizophrenia is a mental disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions. Although the course of schizophrenia varies among individuals, schizophrenia is typically persistent and can be both severe and disabling.” (opens the source at this quote in a new tab)

“Schizophrenia is characterized by positive psychotic symptoms such as hallucinations, delusions, disorganized speech, and disorganized or catatonic behavior; negative symptoms such as reduced motivation and expressiveness; and cognitive impairments affecting executive function, memory, and mental processing speed.” (opens the source at this quote in a new tab)

Definition: ICD-11 description of schizophrenia (6A20)

“Schizophrenia is characterised by disturbances in multiple mental modalities, including thinking (e.g., delusions, disorganisation in the form of thought), perception (e.g., hallucinations), self-experience (e.g., the experience that one's feelings, impulses, thoughts, or behaviour are under the control of an external force), cognition (e.g., impaired attention, verbal memory, and social cognition), volition (e.g., loss of motivation), affect (e.g., blunted emotional expression), and behaviour (e.g., behaviour that appears bizarre or purposeless, unpredictable or inappropriate emotional responses that interfere with the organisation of behaviour).” (opens the source at this quote in a new tab)
“Persistent delusions, persistent hallucinations, thought disorder, and experiences of influence, passivity, or control are considered core symptoms. Symptoms must have persisted for at least one month in order for a diagnosis of schizophrenia to be assigned.” (opens the source at this quote in a new tab)

Etiology: interaction of genetic and environmental risk factors

“Multifaceted interactions between genetic and environmental risk factors give rise to schizophrenia. These risk factors also affect early brain development and shape the biological response to life experiences, thereby influencing the onset and progression of the disorder.” (opens the source at this quote in a new tab)
“Thus, schizophrenia is a polygenic disorder resulting from the combined effects of multiple genes spread across the genome, each contributing modestly.” (opens the source at this quote in a new tab)

Heritability: twin studies

“The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%).” (opens the source at this quote in a new tab)

“By using a multigroup twin model, we found evidence for substantial additive genetic effects-the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia-joint estimate, 11% (95% confidence interval, 3%-19%).” (opens the source at this quote in a new tab)

Common genetic variants: genome-wide association study of 76,755 people with schizophrenia

“Schizophrenia has a heritability of 60–80%, much of which is attributable to common risk alleles. Here, in a 2-stage genome-wide association study of up to 76,755 people with schizophrenia and 243,649 controls, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes expressed in CNS neurons, excitatory and inhibitory, but not other tissues or cell types.” (opens the source at this quote in a new tab)

Rare variants: 22q11.2 deletion

“While linked common genetic variants have less impact on risk, rare mutations have a more significant impact.” (opens the source at this quote in a new tab)
“One such rare mutation is the chromosome 22q11.2 deletion, which increases lifetime risk 25-fold.” (opens the source at this quote in a new tab)

Environmental risk factors: cannabis use

“A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers.” (opens the source at this quote in a new tab)

“Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2–4·1), increasing to nearly five-times increased odds for daily use of high-potency types of cannabis (4·8, 2·5–6·3).” (opens the source at this quote in a new tab)

Environmental risk factors: obstetric and perinatal complications

“The meta-analytic synthesis of the prospective population-based studies revealed that three groups of complications were significantly associated with schizophrenia: 1) complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia); 2) abnormal fetal growth and development: (low birthweight, congenital malformations, reduced head circumference), and 3) complications of delivery (uterine atony, asphyxia, emergency Cesarean section). Pooled estimates of effect sizes were generally less than 2.” (opens the source at this quote in a new tab)

“152 studies relating to 98 risk or protective factors were eligible for analysis.” (opens the source at this quote in a new tab)
“any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26)” (opens the source at this quote in a new tab)
“hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23)” (opens the source at this quote in a new tab)

Environmental risk factors: urbanicity

“The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.” (opens the source at this quote in a new tab)

Environmental risk factors: migration

“The mean weighted relative risk for developing schizophrenia among first-generation migrants (40 effect sizes) was 2.7 (95% confidence interval [CI]=2.3-3.2). A separate analysis performed for second-generation migrants (seven effect sizes) yielded a relative risk of 4.5 (95% CI=1.5-13.1).” (opens the source at this quote in a new tab)

“The meta-analysis yielded a RR, adjusted for age and sex, of 2.13 (95% CI 1.99–2.27) for NAPD and 2.94 (95% CI 2.28–3.79) for APD. The RRs diminished, but persisted after adjustment for SES.” (opens the source at this quote in a new tab)

Environmental risk factors: childhood adversity

“There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34–3.31).” (opens the source at this quote in a new tab)

Risk and protective factors: umbrella review of 170 putative factors

“Fifty‐five meta‐analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra‐high‐risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96‐6.00) showed convincing evidence of association.” (opens the source at this quote in a new tab)

Global incidence: Global Burden of Disease Study 2021

“In 2021, approximately 1.2 million individuals worldwide (~0.015% of the global population) experienced an incident episode of schizophrenia (95% UI: 1 008 000-1 473 000). The age-standardized incidence rate for schizophrenia worldwide was 15.4 per 100 000 individuals (95% UI = 12.7-18.6), and the crude was 15.5 per 100 000 individuals (95% UI = 12.8-18.7).” (opens the source at this quote in a new tab)
“When examining age-specific crude incidence rates, rates were numerically higher for men than women for all age ranges, and incidence rates were highest among individuals ages 20-24 years for both sexes as opposed to all other age ranges” (opens the source at this quote in a new tab)
“For example, age-standardized incidence rates decreased by 4.2% in High-Income North America between 1990 and 2021 (95% UI = −5.8% to −2.6%) and increased in Eastern Europe by 5.0% (95% UI = 3.4%-6.5%) with no statistically significant change in other regions.” (opens the source at this quote in a new tab)

Global incidence: Global Burden of Disease Study 2019

“From 1990 to 2019, schizophrenia raw prevalence (14.2 to 23.6 million), incidence (941,000 to 1.3 million), and DALYs (9.1 to 15.1 million) increased by over 65%, 37%, and 65% respectively, while age-standardized estimates remained stable globally.” (opens the source at this quote in a new tab)

Global incidence: systematic review and meta-analysis, 2002 to 2017

“From 56 721 records identified, 177 met inclusion criteria. The pooled incidence of all psychotic disorders was 26·6 per 100 000 person-years (95% CI 22·0–31·7).” (opens the source at this quote in a new tab)
“The incidence of schizophrenia was available from 36 incidences from 26 citations and varied from 2·7 per 100 000 person-years (1·4–5·3) in Cavan-Monaghan (Ireland)” (opens the source at this quote in a new tab)
“Pooled incidence was lower in first contact studies (13·1 per 100 000 person-years [9·0–15·0]) than in population registers (32·8 [23·2–46·5]; figure 4).” (opens the source at this quote in a new tab)

Global incidence: systematic review of 1,458 rates from 33 countries

“Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4).” (opens the source at this quote in a new tab)

United States incidence: commercial insurance and New York State Medicaid claims, 2019

“In this study incidence of schizophrenia was examined only in the 10 year continuously insured cohort, and was defined as the individuals with a diagnosis of schizophrenia in 2019 who had no prior diagnosis of schizophrenia in the preceding 10 years (1/1/2009-12/31/2018).” (opens the source at this quote in a new tab)
“Incidence was higher in Medicaid (0.19%, 95% CI: 0.18–0.20; n = 1,489 newly diagnosed in 2019); than in MarketScan (0.07%, 95% CI: 0.07–0.08; n = 712), and for males than females (Medicaid: 0.21%, 95% CI: 0.20–0.23 vs. 0.18%, 95% CI: 0.16–0.19; MarketScan: 0.08%, 95% CI: 0.07–0.09 vs. 0.07%, 95% CI: 0.07–0.08).” (opens the source at this quote in a new tab)

United States incidence: Medicaid beneficiaries in six states, 2012 to 2017

“Annual prevalence of schizophrenia ranged between 2.30% and 2.71% and annual incidence between 0.31% and 0.39% during 2012-2016.” (opens the source at this quote in a new tab)

United States incidence: weighted national claims estimate, 2022

“Researchers identified a total 653,666 patients with schizophrenia in 2022. Among them, 97,565 patients had incident schizophrenia.” (opens the source at this quote in a new tab)
“After weighting, the national prevalence of schizophrenia was estimated at 0.45% and the national incidence of schizophrenia was estimated at 0.08%” (opens the source at this quote in a new tab)

United States incidence of first-episode psychosis: five health care systems, 2007 to 2013

“Estimated true incidence rates were 86 per 100,000 per year among those aged 15 to 29 and 46 per 100,000 in those aged 30 to 59.” (opens the source at this quote in a new tab)

Incidence by sex

“The incidence risk ratios for men to develop schizophrenia relative to women were 1.42 (95% confidence interval [CI], 1.30-1.56) when all studies were included in the analysis (49 effect sizes), 1.31 (95% CI, 1.13-1.51) when studies that minimized selection biases were analyzed separately (23 effect sizes), and 1.39 (95% CI, 1.15-1.68) when only high-quality studies were included (11 effect sizes).” (opens the source at this quote in a new tab)

Age at onset

“Schizophrenia is typically diagnosed in the late teens years to early thirties, and tends to emerge earlier in males (late adolescence – early twenties) than females (early twenties – early thirties).” (opens the source at this quote in a new tab)

“Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks.” (opens the source at this quote in a new tab)
“schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20–34)” (opens the source at this quote in a new tab)

Global prevalence: Global Burden of Disease Study 2021

“In 2021, there were approximately 23.2 million individuals worldwide living with schizophrenia (~0.3% of the global population). The worldwide age-standardized prevalence rate was 277.7 per 100 000 (95% UI = 229.8-329.1), and the crude rate was 293.8 per 100 000 individuals (95% UI = 243.4-347.5). Crude prevalence rates were highest among individuals ages 35-39 for both sexes as compared to all other age groups.” (opens the source at this quote in a new tab)

Global prevalence: Global Burden of Disease Study 2016

“The global age-standardized point prevalence of schizophrenia in 2016 was estimated to be 0.28% (95% uncertainty interval [UI]: 0.24–0.31). No sex differences were observed in prevalence. Age-standardized point prevalence rates did not vary widely across countries or regions. Globally, prevalent cases rose from 13.1 (95% UI: 11.6–14.8) million in 1990 to 20.9 (95% UI: 18.5–23.4) million cases in 2016.” (opens the source at this quote in a new tab)

Global prevalence: World Health Organization estimate

“Schizophrenia affects approximately 1 in 300 (0.29% or 27 million) people worldwide, rising to 1 in 206 people (0.49%) among adults aged 20 and over” (opens the source at this quote in a new tab)

Point, period, and lifetime prevalence: systematic review of 188 studies

“The median values per 1,000 persons (10%–90% quantiles) for the distributions for point, period, lifetime, and lifetime morbid risk were 4.6 (1.9–10.0), 3.3 (1.3–8.2), 4.0 (1.6–12.1), and 7.2 (3.1–27.1), respectively. Based on combined prevalence estimates, we found no significant difference (a) between males and females, or (b) between urban, rural, and mixed sites.” (opens the source at this quote in a new tab)

Twelve-month and lifetime prevalence: systematic review of 65 studies, 1990 to 2013

“Among 21 studies reporting 12-month prevalence, the median estimate was 0.33 % with an interquartile range (IQR) of 0.26 %–0.51 %. The median estimate of lifetime prevalence among 29 studies was 0.48 % (IQR: 0.34 %–0.85 %).” (opens the source at this quote in a new tab)

Prevalence of psychotic disorders: systematic review and meta-analysis of 73 studies

“Across these studies, the pooled median point and 12-month prevalence for persons was 3.89 and 4.03 per 1000 respectively; and the median lifetime prevalence was 7.49 per 1000.” (opens the source at this quote in a new tab)

Lifetime prevalence cited in the American Psychiatric Association guideline

“The lifetime prevalence of schizophrenia is estimated to be approximately 0.7% (McGrath et al. 2008; Moreno-Küstner et al. 2018; van der Werf et al. 2014), although findings vary depending on the study location, demographic characteristics of the sample, the approach used for case-finding, the method used for diagnostic confirmation, and the diagnostic criteria used.” (opens the source at this quote in a new tab)

United States prevalence: National Institute of Mental Health summary

“Across studies that use household-based survey samples, clinical diagnostic interviews, and medical records, estimates of the prevalence of schizophrenia and related psychotic disorders in the U.S. range between 0.25% and 0.64%.” (opens the source at this quote in a new tab)

United States prevalence: Mental and Substance Use Disorders Prevalence Study, adults aged 18 to 65 years

“The Mental and Substance Use Disorders Prevalence Study (MDPS) was conducted between October 2020 and October 2022. Interviewers administered a structured clinical interview for the DSM-5 (N=5,679 participants; N=4,764 in households).” (opens the source at this quote in a new tab)
“The prevalence estimates of lifetime and past-year schizophrenia spectrum disorders were 1.8% (95% CI=1.3%–2.5%) and 1.2% (95% CI=0.9%–1.8%), respectively.” (opens the source at this quote in a new tab)
“The prevalence rates of lifetime and past-year schizophrenia spectrum disorders were two to four times higher than previously reported.” (opens the source at this quote in a new tab)

“The study provides prevalence rates of mental and substance use disorders including past-year and lifetime schizophrenia spectrum disorders (defined as including schizophrenia, schizoaffective disorder, and schizophreniform disorder)” (opens the source at this quote in a new tab)
“The study sample included adults aged 18 to 65 residing in households, prisons, homeless shelters, and state psychiatric hospitals in the United States.” (opens the source at this quote in a new tab)
“Approximately 3.7 million adults aged 18 to 65 (1.8 percent) had a lifetime history of schizophrenia spectrum disorders. A total of 1.2 percent of adults aged 18 to 65 (approximately 2.5 million adults) met diagnostic criteria for a schizophrenia spectrum disorder in the past year.” (opens the source at this quote in a new tab)

United States prevalence: National Comorbidity Survey Replication

“The MI prevalence estimate of NAP (standard error in parentheses) is 3.1 (1.5) per 1000 population lifetime and 1.4 (1.0) per 1000 past 12 months.” (opens the source at this quote in a new tab)

United States diagnosed prevalence: multiple claims databases, 2002

“The 12-month prevalence of diagnosed schizophrenia in the USA in 2002 was estimated at 5.1 per 1000 lives. The Medicaid population was identified with the highest prevalence rate among the populations studied.” (opens the source at this quote in a new tab)

United States diagnosed prevalence: weighted national claims estimate, 2022

“Per 100,000 people, the weighted prevalence of schizophrenia in the United States was an estimated 448.5, according to the study.” (opens the source at this quote in a new tab)
“By payer type, the highest prevalence of schizophrenia was among patients with Medicare Advantage, followed by Medicaid Fee-for-Service and Medicaid.” (opens the source at this quote in a new tab)

United States diagnosed prevalence by payer: commercial insurance and Medicaid

“The prevalence of schizophrenia in the total population was higher in Medicaid (2.13%, 95% CI: 2.12–2.15; n = 94,153 of 4,414,153) than in MarketScan (0.134%, 95% CI: 0.132–0.135; n = 21,963 of 16,365,997).” (opens the source at this quote in a new tab)
“In addition, prevalence increased over the lifespan in the Medicaid population, but decreased in the employment based MarketScan database beginning in early adulthood.” (opens the source at this quote in a new tab)
“Estimates of the prevalence of schizophrenia in the United States vary from 0.3 to 1.6% in community-based samples, 1.02% in uninsured samples, and 0.13% in commercial insurance samples to 1.66–5.11% in Medicaid” (opens the source at this quote in a new tab)

“Schizophrenia prevalence was 0.11% and 0.99% in commercially and Medicaid-insured patients, respectively.” (opens the source at this quote in a new tab)

“Annual prevalence of schizophrenia ranged between 2.30% and 2.71% and annual incidence between 0.31% and 0.39% during 2012-2016. In 2017, only states with the highest incidence and prevalence rates (KS, MS, MO) had data, resulting in higher prevalence (4.01%) and incidence (0.52%).” (opens the source at this quote in a new tab)

Payer mix: health insurance coverage of United States adults with schizophrenia

“The sample contained 328 records representing 493,006 noninstitutionalized civilian persons with schizophrenia. Eighty-seven percent had Medicaid or Medicare, 8% received care through the Veterans Health Administration, and 15% had private insurance for at least one day during the year. About 7% were uninsured all of the year.” (opens the source at this quote in a new tab)

“People with SSDs were less likely than people without SSDs to be uninsured (0.3% vs. 9.0%, AOR 0.02, CI=0.01–0.1). Coverage was predominantly by Medicaid (70.7%), Medicare (26.0%), or both (23.1%); 17.7% had private insurance.” (opens the source at this quote in a new tab)

“More patients with schizophrenia are covered by Medicare and Medicaid compared with commercial payers in the United States, according to results from a 2022 claims analysis presented in a poster at Psych Congress.” (opens the source at this quote in a new tab)

Diagnosed prevalence and incidence by payer, including Medicare: weighted national claims estimate, 2022

“Projection analyses revealed the prevalence rate of schizophrenia in the U.S in 2022 was 0.45% (1.10% Medicare Fee-for-Service; 0.91% Medicaid, 1.10% Medicare Advantage, and 0.07% commercial), with an incidence rate of 0.08% (0.16% Medicare Fee-for-Service, 0.17% Medicaid, 0.17% Medicare Advantage, and 0.02% commercial).” (opens the source at this quote in a new tab)

Prodrome: duration and transition to psychosis from the clinical high-risk state

“Of the 764 participants identified as being at CHR-P, 94 converted to psychosis and 92 of these had recorded estimates of prodrome onset.” (opens the source at this quote in a new tab)
“Results identified a mean prodrome duration of 21.6 months.” (opens the source at this quote in a new tab)
“one third of CHR-P patients who convert will do so by 1 year after CHR-P syndrome onset, another third 1–2 years after onset, and the final third more than 2 years after onset.” (opens the source at this quote in a new tab)

“In this meta-analysis of 130 longitudinal studies, including 9222 individuals at clinical high risk for psychosis from 74 cohorts, the risk of developing psychosis continued increasing after 2 years, cumulating to 25% at 3 years and reaching 35% at 10 years.” (opens the source at this quote in a new tab)

“There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years.” (opens the source at this quote in a new tab)

Course: episodic or progressive pattern after onset

“At least one third of people with schizophrenia achieve complete remission of symptoms” (opens the source at this quote in a new tab)
“Some people with schizophrenia experience worsening and remission of symptoms periodically throughout their lives, others a gradual worsening of symptoms over time.” (opens the source at this quote in a new tab)

“Insidious onset, childhood or adolescent onset, poor premorbid adjustment, substance use, and cognitive impairment are indicative of a poor prognostic outcome in schizophrenia. Acute onset and living in a developed country signal comparatively better prognostic factors.” (opens the source at this quote in a new tab)

Relapse after response to treatment of a first episode

“The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse.” (opens the source at this quote in a new tab)
“Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]).” (opens the source at this quote in a new tab)

Relapse after antipsychotic discontinuation

“Six studies were identified that met our criteria and these reported a weighted mean one-year recurrence rate of 77% following discontinuation of antipsychotic medication. By two years, the risk of recurrence had increased to over 90%. By comparison, we estimated the one-year recurrence rate for patients who continued antipsychotic medication to be 3%.” (opens the source at this quote in a new tab)

“We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27% vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3). Fewer patients given antipsychotic drugs than placebo were readmitted (10% vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted.” (opens the source at this quote in a new tab)

“Relapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients.” (opens the source at this quote in a new tab)

Remission and recovery rates

“We identified 50 studies with data suitable for inclusion. The median proportion (25%–75% quantiles) who met our recovery criteria was 13.5% (8.1%–20.0%).” (opens the source at this quote in a new tab)

“The pooled rate of remission among 12301 individuals with FEP was 58% (60 studies, mean follow-up 5.5 years).” (opens the source at this quote in a new tab)
“The pooled prevalence of recovery among 9642 individuals with FEP was 38% (35 studies, mean follow-up 7.2 years).” (opens the source at this quote in a new tab)

All-cause mortality relative to the general population

“Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population.” (opens the source at this quote in a new tab)

“On the basis of the standardized mortality ratio, people with schizophrenia have a two- to threefold increased risk of dying (median standardized mortality ratio = 2.6 for all-cause mortality), and this differential gap in mortality has increased over recent decades.” (opens the source at this quote in a new tab)

Mortality in United States Medicaid beneficiaries with schizophrenia

“The cohort included 1,138,853 individuals, 4,807,121 years of follow-up, and 74,003 deaths, of which 65,553 had a known cause.” (opens the source at this quote in a new tab)
“Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100,000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6).” (opens the source at this quote in a new tab)
“Accidental deaths (119.7 per 100,000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100,000 person-years).” (opens the source at this quote in a new tab)

Life expectancy and years of potential life lost

“Schizophrenia was associated with a weighted average of 14·5 years of potential life lost (95% CI 11·2-17·8), and was higher for men than women (15·9, 13·8-18·0 vs 13·6, 11·4-15·8).” (opens the source at this quote in a new tab)
“The overall weighted average life expectancy was 64·7 years (95% CI 61·1-71·3), and was lower for men than women (59·9 years, 95% CI 55·5-64·3 vs 67·6 years, 63·1-72·1).” (opens the source at this quote in a new tab)

“The estimated average potential life lost for individuals with schizophrenia in the U.S. is 28.5 years.” (opens the source at this quote in a new tab)

Cause-specific mortality

“Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4)” (opens the source at this quote in a new tab)

“Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4).” (opens the source at this quote in a new tab)

Suicide: lifetime risk and rates

“The estimate of lifetime suicide prevalence in those observed from first admission or illness onset was 5.6% (95% confidence interval, 3.7%-8.5%).” (opens the source at this quote in a new tab)
“This study estimates that 4.9% of schizophrenics will commit suicide during their lifetimes, usually near illness onset.” (opens the source at this quote in a new tab)

“Consensus on the lifetime risk of suicide was a rate of approximately 5%. Risk factors with a strong association with later suicide included being young, male, and with a high level of education.” (opens the source at this quote in a new tab)

“The total suicide rate per 100 000 person-years was 74.00, which is 4.5 times higher than that for the general US population (SMR, 4.54; 95% CI, 4.35-4.73) and included a rate of 88.96 for men and 56.33 for women, which are 3.4 (SMR, 3.39; 95% CI, 3.22-3.57) and 8.2 (SMR, 8.16; 95% CI, 7.60-8.75) times higher, respectively, than the rates for the general US population.” (opens the source at this quote in a new tab)
“In this cohort study of 668 836 patients with schizophrenia and Medicare coverage, the risk of suicide was higher compared with the general US population and was highest among those aged 18 to 34 years and lowest among those 65 years and older.” (opens the source at this quote in a new tab)

“About 4%−10% of persons with schizophrenia die by suicide, with rates that are highest among males in the early course of the disorder” (opens the source at this quote in a new tab)

Mortality by antipsychotic exposure: 20-year Finnish cohort

“The cumulative mortality rates during maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use.” (opens the source at this quote in a new tab)

Dopamine hypothesis: presynaptic striatal dopamine dysfunction

“Forty-four studies were identified that compared in vivo striatal dopaminergic function in 618 patients with schizophrenia with 606 controls using positron emission tomography or single photon emission computed tomography.” (opens the source at this quote in a new tab)
“There was a highly significant elevation (p<0.0001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen’s d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D2/3 receptor availability (Cohen’s d=0.26), but this was not evident in drug-naïve patients and was influenced by the imaging approach used.” (opens the source at this quote in a new tab)
“The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic-affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release.” (opens the source at this quote in a new tab)

“Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3).” (opens the source at this quote in a new tab)

Dopamine hypothesis: dysregulation as the final common pathway to psychosis

“The hypothesis has 4 distinctive components.” (opens the source at this quote in a new tab)
“interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia.” (opens the source at this quote in a new tab)
“Second, the locus of dopamine dysregulation moves from being primarily at the D2 receptor level to being at the presynaptic dopaminergic control level.” (opens the source at this quote in a new tab)

“Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits.” (opens the source at this quote in a new tab)

Dopamine D2 receptor blockade as the common mechanism of antipsychotics

“These show that at clinical doses all currently licensed antipsychotic drugs block striatal D2 receptors. Furthermore, a threshold striatal D2 blockade is required for antipsychotic efficacy, but this is not sufficient—some patients show little improvement despite high D2 occupancy.” (opens the source at this quote in a new tab)

“all licensed first‐line treatments for schizophrenia operate primarily via antagonism of the dopamine D2 receptor” (opens the source at this quote in a new tab)
“In particular, dopamine blockade is not an effective treatment for negative and cognitive symptoms” (opens the source at this quote in a new tab)

“Current pharmacological treatments operate using the same mechanism, blockade of dopamine D2 receptor, which contribute to their adverse effects.” (opens the source at this quote in a new tab)

D2 receptor occupancy thresholds for response and adverse effects

“The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively.” (opens the source at this quote in a new tab)

“Additionally, the nigrostriatal pathway is linked to extrapyramidal motor side effects caused by D2 receptor blockers, while the tuberoinfundibular pathway is associated with the hyperprolactinemia observed with D2 receptor blocker use.” (opens the source at this quote in a new tab)

Dopamine synthesis capacity in treatment-resistant schizophrenia

“Patients who had responded to antipsychotic treatment showed significantly higher K(i)(cer) striatal values than did patients with treatment-resistant illness (effect size=1.11) and healthy volunteers (effect size=1.12).” (opens the source at this quote in a new tab)
“There were no significant differences between patients with treatment-resistant illness and healthy volunteers in the whole striatum or any of its subdivisions.” (opens the source at this quote in a new tab)

Dopamine D3 receptor

“The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation. Antipsychotics bind in vitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors in vivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies.” (opens the source at this quote in a new tab)
“In animals, D3 receptor antagonists reverse behavioral manifestations of NMDA receptor blockade and improve cognitive performances in various paradigms.” (opens the source at this quote in a new tab)

Serotonin 5-HT7 receptor: antagonism by amisulpride

“In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties.” (opens the source at this quote in a new tab)
“We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated here could explain its antidepressant actions in vivo.” (opens the source at this quote in a new tab)
“These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.” (opens the source at this quote in a new tab)

Role of the 5-HT7 receptor in the pathophysiology of schizophrenia

No evidence found.

Glutamate and NMDA receptor hypofunction

“The administration of NMDA receptor antagonists, such as phencyclidine and ketamine, to healthy controls has been repeatedly shown to induce manifestations similar to the positive, negative and cognitive symptoms of schizophrenia” (opens the source at this quote in a new tab)
“Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder.” (opens the source at this quote in a new tab)

“Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate” (opens the source at this quote in a new tab)

“In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia.” (opens the source at this quote in a new tab)

Muscarinic acetylcholine receptor pathways

“Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia.” (opens the source at this quote in a new tab)

“Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity.” (opens the source at this quote in a new tab)

“muscarinic receptor 4 positive allosteric modulators specifically inhibit dorsal striatal dopamine release, with efficacy demonstrated in some clinical trials” (opens the source at this quote in a new tab)

Structural brain changes

“Lateral ventricle enlargement by about 25%, coupled with an approximate 2% reduction in overall brain volume, primarily in the grey matter, is seen in schizophrenia.” (opens the source at this quote in a new tab)

DSM-5 diagnostic criteria for schizophrenia

Criterion	Quoted text
A: characteristic symptoms	“Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be (1), (2), or (3):”
A1	“delusions”
A2	“hallucinations”
A3	“disorganized speech (e.g., frequent derailment or incoherence)”
A4	“grossly disorganized or catatonic behavior”
A5	“Negative symptoms (i.e., diminished emotional expression or avolition).”
B: functioning	“For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or self-care, is markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational functioning).”
C: duration	“Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms.”
D: mood disorder exclusion	“Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either (1) no major depressive or manic episodes have occurred concurrently with the active-phase symptoms, or (2) if mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.”
E: substance and medical exclusion	“The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.”
F: developmental disorder	“If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).”

DSM-5-TR and ICD-10 as the diagnostic systems in use

“The 2 systems used in diagnosing schizophrenia are DSM-5-TR and ICD-10, which have slight variations.” (opens the source at this quote in a new tab)
“Continuous signs must persist for at least 6 months, including at least 1 month of active-phase symptoms, which might be less if treated.” (opens the source at this quote in a new tab)
“Schizoaffective, depressive, or bipolar disorders with psychotic features must be excluded. The symptoms should not be due to substance use, medication, or another medical condition.” (opens the source at this quote in a new tab)

Clinical diagnosis with no confirmatory test

“No laboratory, psychometric, or radiologic studies currently exist for diagnosing schizophrenia.” (opens the source at this quote in a new tab)
“Schizophrenia is primarily a clinical diagnosis and necessitates specific laboratory and radiographic investigations to exclude other potential causes.” (opens the source at this quote in a new tab)
“The clinical diagnosis of schizophrenia is made after obtaining a detailed psychiatric history and mental status examination and after ruling out other psychiatric and medical causes of psychosis.” (opens the source at this quote in a new tab)

Initial assessment: American Psychiatric Association guideline statements 1 and 2

“APA recommends (1C) that the initial assessment of a patient with a possible psychotic disorder include the reason the individual is presenting for evaluation; the patient's goals and preferences for treatment; a review of psychiatric symptoms and trauma history; an assessment of tobacco use and other substance use; a psychiatric treatment history; an assessment of physical health; an assessment of psychosocial and cultural factors; a mental status examination, including cognitive assessment; and an assessment of risk of suicide and aggressive behaviors, as outlined in APA's Practice Guidelines for the Psychiatric Evaluation of Adults (3rd edition).” (opens the source at this quote in a new tab)
“APA recommends (1C) that the initial psychiatric evaluation of a patient with a possible psychotic disorder include a quantitative measure to identify and determine the severity of symptoms and impairments of functioning that may be a focus of treatment.” (opens the source at this quote in a new tab)

Assessment in secondary care: NICE guideline

“Carry out a comprehensive multidisciplinary assessment of people with psychotic symptoms in secondary care. This should include assessment by a psychiatrist, a psychologist or a professional with expertise in the psychological treatment of people with psychosis or schizophrenia.” (opens the source at this quote in a new tab)

Differential diagnosis

“Examples of conditions that can mimic schizophrenia in their initial presentation include neurosyphilis, Huntington’s disease, Wilson’s disease, and anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (Lieberman and First 2018).” (opens the source at this quote in a new tab)
“Psychotic symptoms can also occur in the context of other neurological and systemic illnesses, with or without delirium, and such acute states can at times be mistaken for an acute exacerbation of schizophrenia.” (opens the source at this quote in a new tab)

“Major depressive or bipolar disorder with psychotic or catatonic features: If hallucinations or delusions occur only during major depressive or manic episodes, the diagnosis is a depressive or bipolar disorder with psychotic features, depending on the timing and severity of mood disturbances.” (opens the source at this quote in a new tab)
“Schizoaffective disorder: This diagnosis requires concurrent depressive or manic episodes with active-phase schizophrenia symptoms, with mood symptoms prevalent for most of the active phase.” (opens the source at this quote in a new tab)

Laboratory and imaging evaluation to exclude other causes

“Drug toxicology screen: This screen may be clinically indicated to detect substance use that could cause psychotic symptoms.” (opens the source at this quote in a new tab)
“Imaging: Brain imaging, either CT or MRI (with MRI preferred), may be indicated based on the neurological examination or history.” (opens the source at this quote in a new tab)

Rating scales used in practice and research

“A 6-item version of the Positive and Negative Syndrome Scale (PANSS-6; Bech et al. 2018; Østergaard et al. 2018b) consists of the PANSS items for delusions, conceptual disorganization, hallucinations, blunted affect, social withdrawal, and lack of spontaneity and flow of conversation (Kay et al. 1987).” (opens the source at this quote in a new tab)
“Other clinician-rated scales are commonly used for monitoring psychopathology in research but are likely to be too lengthy for routine clinical use. These include the PANSS-30 (Kay et al. 1987), the Scale for the Assessment of Negative Symptoms (SANS; Andreasen 1984a), the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen 1984b), and the Brief Psychiatric Rating Scale” (opens the source at this quote in a new tab)

“The PANSS-30 is a comprehensive tool that includes 30 items, subdivided into positive symptoms, negative symptoms, and general psychopathology.” (opens the source at this quote in a new tab)

“Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology.” (opens the source at this quote in a new tab)

Duration of untreated psychosis in United States community settings

“Participants were 404 individuals (ages 15-40) who presented for treatment for first-episode psychosis at 34 nonacademic clinics in 21 states.” (opens the source at this quote in a new tab)
“Median DUP was 74 weeks (mean=193.5±262.2 weeks; 68% of participants had DUP of greater than six months).” (opens the source at this quote in a new tab)

“Long DUP correlated statistically significantly with poor general symptomatic outcome, more severe positive and negative symptoms, lesser likelihood of remission and poor social functioning and global outcome (correlations 0.13-0.18). Long DUP was not associated with employment, quality of life or hospital treatment.” (opens the source at this quote in a new tab)

Positive symptoms: delusions, hallucinations, and disorganized thought

“Delusions (fixed false beliefs) may be present and bizarre (extremely implausible). Thought broadcasting, thought insertion, or withdrawal may also be reported.” (opens the source at this quote in a new tab)
“Hallucinations, mainly auditory, are common but may be in any sensory modality. Patients may report hearing voices commenting on their actions or conversing with each other.” (opens the source at this quote in a new tab)
“Thought processes (inferred from the patient's speech) may be disorganized, leading to illogical connections, loose associations, or thought blocking when the patient suddenly stops speaking mid-sentence.” (opens the source at this quote in a new tab)

“Symptoms of schizophrenia include psychotic symptoms such as hallucinations, delusions, and thought disorder (unusual ways of thinking), as well as reduced expression of emotions, reduced motivation to accomplish goals, difficulty in social relationships, motor impairment, and cognitive impairment.” (opens the source at this quote in a new tab)

Negative symptoms: blunted affect, alogia, avolition, asociality, and anhedonia

“The negative symptom domain consists of five key constructs: blunted affect, alogia (reduction in quantity of words spoken), avolition (reduced goal-directed activity due to decreased motivation), asociality, and anhedonia (reduced experience of pleasure). Negative symptoms are common in schizophrenia; up to 60% of patients may have prominent clinically relevant negative symptoms that require treatment.” (opens the source at this quote in a new tab)
“Negative symptoms can be primary symptoms, which are intrinsic to the underlying pathophysiology of schizophrenia, or secondary symptoms that are related to psychiatric or medical comorbidities, adverse effects of treatment, or environmental factors.” (opens the source at this quote in a new tab)

“Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition-apathy and expressive deficit.” (opens the source at this quote in a new tab)

Negative symptoms: prevalence of any and of primary negative symptoms in treated outpatients

“A total of 1,452 evaluable patients (863 men, 60.9%), 40.7 +/- 12.2 (mean +/- SD) years of age, were included. One or more negative symptoms were present in 57.6% of patients, with primary negative symptoms in 12.9% of subjects. The most frequent negative symptom items were social withdrawal (45.8%), emotional withdrawal (39.1%), poor rapport (35.8%), and blunted affect (33.1%).” (opens the source at this quote in a new tab)

Cognitive impairment: magnitude relative to healthy controls

“Individuals with schizophrenia show a substantial impairment in overall cognitive performance, which, on average, is around two standard deviations below that in healthy controls” (opens the source at this quote in a new tab)
“Moreover, this deficit contributes to poor clinical outcomes such as unemployment and an inability to live independently” (opens the source at this quote in a new tab)

“Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero.” (opens the source at this quote in a new tab)

“Results evidence that in all domains and in all different analyses performed within each domain, patients show a significant reduction of cognitive efficiency with respect to normal subjects.” (opens the source at this quote in a new tab)

Cognitive impairment: first-episode schizophrenia

“The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20).” (opens the source at this quote in a new tab)

Mood symptoms: comorbid depression

“Of the 5633 potentially eligible studies identified, 18 studies (n = 6140 SZ stabilized outpatients) were retrieved in the systematic review and included in the meta-analysis. The pooled estimate of the prevalence of SZ-MDD was 32.6% (95% CI: 27.9–37.6)” (opens the source at this quote in a new tab)

“Among adults with SSDs, the most common comorbidities were major depressive episode (51.7%, CI 34.0–69.4), alcohol use disorder (23.0%, CI 2.6–43.3), cannabis use disorder (20.0%, CI 1.2–38.7) and post-traumatic stress disorder (17.3%, CI 4.7–30.0).” (opens the source at this quote in a new tab)

Suicidality: suicidal ideation and suicide plans

“Twenty-six studies covering 5079 people with schizophrenia were included for meta-analysis. The lifetime and point prevalence of SI were 34.5% (95% CI: 28.2−40.9%), and 29.9% (95% CI: 24.2−35.6%), respectively. The lifetime prevalence of SP was 44.3% and the point prevalence of SP ranged between 6.4 and 13%.” (opens the source at this quote in a new tab)

“Suicide is the most common cause of premature death in schizophrenia, with two-thirds of patients reporting at least one episode of suicidal ideation.” (opens the source at this quote in a new tab)

Acute exacerbation: return of psychotic symptoms at relapse

“once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode” (opens the source at this quote in a new tab)

“The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants.” (opens the source at this quote in a new tab)
“Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27).” (opens the source at this quote in a new tab)

Agitation: frequency in psychiatric emergency settings

“Agitation is a common problem in many patients with schizophrenia, bipolar mania, or dementia.” (opens the source at this quote in a new tab)

“The reported prevalence of agitation in psychiatric emergency services is between 4–10%” (opens the source at this quote in a new tab)

“A total of 334 agitation episodes out of 7295 psychiatric emergencies were recorded, giving a prevalence rate of 4.6% (95% CI: 4.12-5.08).” (opens the source at this quote in a new tab)
“The most common psychiatric conditions associated with agitation were schizophrenia, bipolar disorder and personality disorder.” (opens the source at this quote in a new tab)

Agitation: episodes reported by people with schizophrenia or bipolar disorder

“Patients experienced an average of 22.4 (SD 57.2) mild, 15.4 (SD 61.2) moderate, 6.8 (SD 63.3) moderate-intense and 2.9 (SD 24.4) severe episodes within the last 12 months; on average 2.7 (SD 6.8) required hospital attendance.” (opens the source at this quote in a new tab)

Psychomotor and behavioral signs on examination

“Behavior may range from psychomotor retardation to agitation, and patient responses can vary from being cooperative to being unpredictable, withdrawn, or hostile.” (opens the source at this quote in a new tab)
“Some patients may exhibit grossly disorganized or abnormal motor behavior, including catatonic behaviors, such as stupor, mutism, odd gestures, or posturing.” (opens the source at this quote in a new tab)

Proportion of people with schizophrenia who experience agitation during an acute exacerbation

No evidence found.

Treatment resistance: consensus criteria

“The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) ≥moderate functional impairment; 3) prior treatment consisting of ≥2 different antipsychotic trials, each for a minimum duration and dose” (opens the source at this quote in a new tab)

“More specifically, the TRRIP Working Group recommended that symptoms be of at least 12 weeks’ duration in total, be of at least moderate severity, and be associated with at least moderate functional impairment as determined by validated rating scales (e.g., PANSS, BPRS, or SANS and SAPS for symptoms and a score < 60 on the SOFAS as a measure of functioning). If a prospective medication trial of at least 6 weeks at adequate dose has not led to symptom reduction of more than 20%, this provides additional evidence of treatment resistance.” (opens the source at this quote in a new tab)

Treatment resistance: proportion of first-episode cohorts

“Twelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1-27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5-30.0%, P < 0.001) among first-episode schizophrenia cohorts.” (opens the source at this quote in a new tab)

“Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset.” (opens the source at this quote in a new tab)

Rehospitalization and readmission

“During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure.” (opens the source at this quote in a new tab)

“Among patients with an initial hospital stay for schizophrenia, the 30-day readmission rate was over four times higher than for a non-M/SUD condition (15.7 vs. 3.8 percent), when only stays with a principal diagnosis of schizophrenia are counted. When the definition of readmissions was expanded to include stays with schizophrenia as a principal or secondary diagnosis, 18.6 percent of patients experienced a 30-day readmission—115 percent higher than for non-M/SUD stays (8.7 percent).” (opens the source at this quote in a new tab)

Metabolic syndrome: CATIE baseline and meta-analysis

“Of 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males.” (opens the source at this quote in a new tab)
“In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts.” (opens the source at this quote in a new tab)

“The overall rate of MetS was 32.5% (95% CI = 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females.” (opens the source at this quote in a new tab)

“The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%-34.4%; N = 198; n = 52,678).” (opens the source at this quote in a new tab)

Cardiovascular disease in severe mental illness

“The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4‐13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross‐sectional studies (odds ratio, OR=1.53, 95% CI: 1.27‐1.83; 11 studies), and higher odds of coronary heart disease (OR=1.51, 95% CI: 1.47‐1.55) and cerebrovascular disease (OR=1.42, 95% CI: 1.21‐1.66).” (opens the source at this quote in a new tab)

Tardive dyskinesia prevalence

“The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002).” (opens the source at this quote in a new tab)

Substance use comorbidity

“The prevalence of any SUD was 41.7%, followed by illicit drugs (27.5%), cannabis (26.2%), alcohol (24.3%) and stimulant use (7.3%).” (opens the source at this quote in a new tab)

“Relative to the general population, individuals with severe psychotic disorders have increased risk of smoking (OR 4.6, 95% CI 4.3-4.9), heavy alcohol use (OR 4.0, 95% CI 3.6-4.4), heavy marijuana use (OR 3.5, 95% CI 3.2-3.7), and recreational drug use (OR 4.6, 95% CI 4.3-5.0).” (opens the source at this quote in a new tab)

Tobacco smoking

“Forty-two studies across 20 nations consistently demonstrated an association between schizophrenia and current smoking (weighted average odds ratio, OR=5.9; 95% confidence interval, CI 4.9--5.7).” (opens the source at this quote in a new tab)

“Overall, 64% of individuals with schizophrenia, 44% with bipolar disorder, and 19% without psychiatric illness reported that they were current smokers.” (opens the source at this quote in a new tab)

Employment

“People with SSDs were less likely to be employed (16.9% vs. 61.0%; AOR 0.1, CI=0.1–0.3).” (opens the source at this quote in a new tab)

“Altogether, 14.5% of the patients reported participating in competitive employment in the month before the baseline assessment, 12.6% reported other (noncompetitive) employment activity, and 72.9% reported no employment activity.” (opens the source at this quote in a new tab)

“Most recent European studies report rates between 10 % and 20%, while the rate in the US is less clear.” (opens the source at this quote in a new tab)

“An employment rate of 10.24% and societal costs of USD 890 million (NOK 7.9 billion) was also found for this patient group using comprehensive healthcare and welfare registers.” (opens the source at this quote in a new tab)

Educational attainment and global functioning: United States adults

“Compared to people without SSDs, those with SSDs were more likely to have no more than a high school degree (63.9% vs. 36.3%; AOR 3.5, CI=1.6–7.7) and less likely to have completed college (3.6% vs. 32.2%; AOR 0.1, CI=0.0–0.1).” (opens the source at this quote in a new tab)
“Mean Global Assessment of Functioning scores were lower among people with than without schizophrenia (44.8 [standard error 2.0] vs. 77.2 [0.5], p<0.01).” (opens the source at this quote in a new tab)

Social functioning over 20 years

“Functioning in the preserved group did not differ from that of never psychotic individuals at 20-years, but the other groups functioned worse (all p < 0.001). Differences among trajectories were already evident in childhood.” (opens the source at this quote in a new tab)

Homelessness

“The study included 10,340 persons treated for schizophrenia, bipolar disorder, or major depression in the San Diego County Adult Mental Health Services over a 1-year period (1999-2000).” (opens the source at this quote in a new tab)
“The prevalence of homelessness was 15%. Homelessness was associated with male gender, African American ethnicity, presence of a substance use disorder, lack of Medicaid, a diagnosis of schizophrenia or bipolar disorder, and poorer functioning.” (opens the source at this quote in a new tab)

“Thirty-one studies involving 51,925 homeless people were included in the final analysis.” (opens the source at this quote in a new tab)
“The meta-analysis showed a remarkably higher prevalence of psychosis [21.21% (95% CI:13.73, 31.29), I2 = 99.43%], schizophrenia [10.29% (95%, CI: 6.44, 16.02), I2 = 98.76%]” (opens the source at this quote in a new tab)

Incarceration

“During the year, 11.5% of patients (N=4,544) were incarcerated. Risk factors for incarceration included prior incarcerations; co-occurring substance-related diagnoses; homelessness; schizophrenia, bipolar, or other psychotic disorder diagnoses; male gender; no Medicaid insurance; and being African American.” (opens the source at this quote in a new tab)

“Forty-seven respondents (9%) were incarcerated over the follow-up period.” (opens the source at this quote in a new tab)

“We identified 109 samples including 33 588 prisoners in 24 countries. Data were meta-analysed using random-effects models, and we found a pooled prevalence of psychosis of 3.6% (95% CI 3.1-4.2) in male prisoners and 3.9% (95% CI 2.7-5.0) in female prisoners.” (opens the source at this quote in a new tab)

Violence and comorbid substance abuse

“We identified 20 individual studies reporting data from 18,423 individuals with schizophrenia and other psychoses.” (opens the source at this quote in a new tab)
“The effect of comorbid substance abuse was marked with the random-effects ORs of 2.1 (95% confidence interval [CI] 1.7–2.7) without comorbidity, and an OR of 8.9 (95% CI 5.4–14.7) with comorbidity” (opens the source at this quote in a new tab)

Health state utilities for stable schizophrenia, relapse, and antipsychotic adverse events: time trade-off in patients and laypersons

“The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable schizophrenia patients and 75 laypersons.” (opens the source at this quote in a new tab)
“Stable schizophrenia had the highest mean utility (0.87 and 0.92 for laypersons and patients respectively), while relapse (0.48 and 0.60) had the lowest mean utility.” (opens the source at this quote in a new tab)
“Of the treatment-related adverse events, EPS had the lowest mean utility (0.57 and 0.72, respectively).” (opens the source at this quote in a new tab)
“On average, patient utilities are 0.077 points higher than utilities derived from laypersons, although the ranking was similar between the two groups.” (opens the source at this quote in a new tab)

Health state	Patient sample, mean utility (standard error)	Lay sample, mean utility (standard error)
Stable schizophrenia	“0.919 (0.023)”	“0.865 (0.021)”
Weight gain	“0.825 (0.028)”	“0.779 (0.024)”
Hyperprolactinemia	“0.815 (0.030)”	“0.783 (0.025)”
Diabetes	“0.769 (0.036)”	“0.712 (0.028)”
Extrapyramidal symptoms	“0.722 (0.037)”	“0.574 (0.032)”
Relapse	“0.604 (0.042)”	“0.479 (0.033)”

Health state utilities by symptom severity and adverse effect: standard gamble in the United States general public

“Subjects: 620 well-educated, ethnically diverse volunteers (54% Caucasian), who spanned a broad range of age groups and geographical regions of the US participated in this study.” (opens the source at this quote in a new tab)
“In the remaining 441 subjects, SG utilities, re-weighted to match US population demographic profiles, ranged from 0.88 for mild schizophrenia to 0.47 extremely severe schizophrenia.” (opens the source at this quote in a new tab)
“Modest reductions in symptoms (for example, from severe to moderate or moderate to mild) were associated with relatively large changes in utility (0.12-0.19).” (opens the source at this quote in a new tab)
“Adverse effects decreased utilities for states by amounts ranging from 0.09 (pseudo-parkinsonism) to 0.05 (obesity).” (opens the source at this quote in a new tab)

Health state utility values by symptom severity and instrument: systematic review and meta-analysis

“A total of 54 studies involving 87 335 participants were included.” (opens the source at this quote in a new tab)
“The pooled estimate using direct elicitation was a mean HSUV of 0.79 (95% CI: 0.70-0.88) for mild symptomatic states, 0.69 (95% CI: 0.54-0.85) in moderate states, and 0.34 (95% CI: 0.13-0.56) in severe states.” (opens the source at this quote in a new tab)
“Studies using indirect techniques resulted in a pooled mean HSUV of 0.73 (95% CI: 0.67-0.78) applying the EuroQol 5-dimension, 0.66 (95% CI: 0.62-0.71) in the Short-Form 6-dimension, and 0.59 (95% CI: 0.57-0.61) using the Quality of Well-Being scale.” (opens the source at this quote in a new tab)

EQ-5D utility decrements for extrapyramidal symptoms, weight gain, sexual dysfunction, and sedation: European Schizophrenia Cohort

“This sample consisted of 1208 patients with schizophrenia.” (opens the source at this quote in a new tab)
“Patients reporting none of the studied side-effects had an average EQ-5D index score of 0.81, found to be higher than scores of patients reporting EPS (0.70), sexual dysfunction (0.67), sedation (0.70), or weight gain (0.72).” (opens the source at this quote in a new tab)
“The random effects model reported a utility decrement of 0.042 for EPS, 0.022 for weight gain, 0.022 for sexual dysfunction, and 0.019 for sedation.” (opens the source at this quote in a new tab)

Disability weights and years lived with disability: Global Burden of Disease Study 2016

“The estimated disability weights for acute and residual states of schizophrenia were 0.778 (0.606–0.900) and 0.588 (0.411–0.754), respectively.” (opens the source at this quote in a new tab)
“Acute schizophrenia carries the highest disability weight of all disorders in GBD.” (opens the source at this quote in a new tab)
“Overall, 62.7% (28.8%–91.4%) of schizophrenia cases fell within an acute state and 37.3% (8.6%–71.2%) fell within a residual state.” (opens the source at this quote in a new tab)
“Schizophrenia contributes 13.4 (95% UI: 9.9–16.7) million YLDs to burden of disease globally, equivalent to 1.7% of total YLDs globally in 2016.” (opens the source at this quote in a new tab)

Share of mental disorder disability-adjusted life-years: Global Burden of Disease Study 2019

“Depressive disorders accounted for the largest proportion of mental disorder DALYs in 2019 (37·3% [32·3–43·0]), followed by anxiety disorders (22·9% [18·6–27·5]) and schizophrenia (12·2% [9·6–15·2]; figure 1 ; appendix p 38 ).” (opens the source at this quote in a new tab)

Functional outcomes: employment at baseline in the CATIE trial

“Baseline data on more than 1,400 patients with a diagnosis of schizophrenia were collected before their entry into the CATIE study.” (opens the source at this quote in a new tab)
“Altogether, 14.5% of the patients reported participating in competitive employment in the month before the baseline assessment, 12.6% reported other (noncompetitive) employment activity, and 72.9% reported no employment activity.” (opens the source at this quote in a new tab)

Psychosocial functioning on the Quality of Life Scale during antipsychotic treatment in the CATIE trial

“Psychosocial functioning was assessed using the Quality of Life Scale.” (opens the source at this quote in a new tab)
“Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units).” (opens the source at this quote in a new tab)
“There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months.” (opens the source at this quote in a new tab)
“More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions.” (opens the source at this quote in a new tab)

Functional and social outcomes associated with relapse: United States physician and patient survey

“Of these, 469 patients (mean age, 39.6 years; 56.5% male) had known hospitalisation history for the last 12 months and completed a PSC; 116 (24.7%) patients had ≥1 relapse.” (opens the source at this quote in a new tab)
“Compared to patients without relapses, patients who relapsed were more likely to be homeless, unemployed, previously incarcerated, and currently have difficulties living independently (all p < 0.05).” (opens the source at this quote in a new tab)
“Patients who experience a relapse also had greater working impairment and poorer quality of life compared with those who did not relapse.” (opens the source at this quote in a new tab)

Stigma: prevalence of perceived stigma, experienced stigma, and self-stigma

“Of 54 studies (n=5,871), published from 1994 to 2011, 23 (42.6%) reported on prevalence rates, and 44 (81.5%) reported on correlates and/or consequences of perceived or experienced stigmatization or self-stigma.” (opens the source at this quote in a new tab)
“On average, 64.5% (range: 45.0–80.0%) of patients perceived stigma, 55.9% (range: 22.5–96.0%) actually experienced stigma, and 49.2% (range: 27.9–77.0%) reported alienation (shame) as the most common aspect of self-stigma.” (opens the source at this quote in a new tab)

Patient-reported burden of second-generation antipsychotic side effects: seven-country web survey

“In total, 435 participants (mean age: 38 years, 53.8% female) were included.” (opens the source at this quote in a new tab)
“Key side effects impacted physical, social, occupational and psychological aspects of functioning.” (opens the source at this quote in a new tab)
“Total Q-LES-Q-SF score showed a significant inverse correlation with the score of pre-defined groups of side effects indicating worse QoL in association with more severe key side effects in these patients.” (opens the source at this quote in a new tab)

Side effects, adherence, and resource use: United States nationwide patient survey

“Data were analyzed from a 2007-2008 nationwide survey of adults who self-reported a diagnosis of schizophrenia and were currently using an antipsychotic medication (N = 876).” (opens the source at this quote in a new tab)
“A majority of patients reported experiencing at least one side effect due to their medication (86.19%).” (opens the source at this quote in a new tab)
“When grouped as side effect clusters in a single model, extra pyramidal symptoms (EPS)/agitation (odds ratio (OR) = 0.57, p = 0.0007), sedation/cognition (OR = 0.70, p = 0.033), prolactin/endocrine (OR = 0.69, p = 0.0342), and metabolic side effects (OR = 0.64, p = 0.0079) were all significantly related with lower rates of adherence.” (opens the source at this quote in a new tab)
“Those who reported complete adherence to their medication were significantly less likely to report a hospitalization for a mental health reason (OR = 0.51, p = 0.0006), a hospitalization for a non-mental health reason (OR = 0.43, p = 0.0002), and an emergency room (ER) visit for a mental health reason (OR = 0.60, p = 0.008).” (opens the source at this quote in a new tab)

Tolerability ranking of antipsychotic side effects: patients and caregiver proxies

“A cross-sectional survey was conducted with 200 people living with schizophrenia and 100 caregiver proxies for those with severe disease presentation.” (opens the source at this quote in a new tab)
“Results indicated that extrapyramidal side effects such as pseudoparkinsonism and tardive dyskinesia, as well as feeling detached and memory and cognitive issues were ranked as the least tolerable.” (opens the source at this quote in a new tab)
“Side effects such as pseudoparkinsonism, memory and cognitive problems, and weight gain were associated with unwillingness to initiate or continue an effective antipsychotic medication.” (opens the source at this quote in a new tab)

Patient preferences: anticipated weight gain and willingness to change antipsychotic medication

“When asked about willingness to change antipsychotic medication, anticipated weight gain had a negative influence on willingness to try the new treatment, with 22.0% declining to try a medication that would lead to weight gain of 2.7–4.5 kg (6–10 lb), 34.0% declining for anticipated weight gain of 5.0–9.1 kg (11–20 lb), and 52.4% declining for anticipated weight gain greater than 9 kg (20 lbs).” (opens the source at this quote in a new tab)

Patient preferences: discrete-choice experiment on benefits, risks, and formulation in the United States

“The final sample consisted of 271 patients.” (opens the source at this quote in a new tab)
“Complete improvement in positive symptoms was the most preferred outcome (relative importance score of 10.0), followed by elimination of hyperglycemia (3.6, 95% confidence interval [CI]=2.6-4.6), improvement in negative symptoms (3.0, CI=1.6-4.3), reduced weight gain (2.6, CI=1.2-4.0), avoidance of hyperprolactinemia (1.7, CI=.9-2.6), improved social functioning (1.5, CI=.4-2.5), and avoidance of EPS (1.0, CI=.3-1.8).” (opens the source at this quote in a new tab)
“Patients judged a daily pill superior to monthly injections (p<.01) and monthly injections superior to injections every three months (p<.01) for adherent patients and monthly injections superior to a daily pill for nonadherent patients (p=.01).” (opens the source at this quote in a new tab)

Patient preferences: discrete-choice experiment on attributes of oral antipsychotics

“In total, 144 respondents with SZ and 152 with BD-I completed the DCE.” (opens the source at this quote in a new tab)
“Treatment efficacy was the most important attribute, with a conditional relative importance (CRI) of 31.4% for respondents with SZ and 31.0% for those with BD-I.” (opens the source at this quote in a new tab)
“Weight gain (CRI = 21.3% and 23.1%, respectively) and sexual dysfunction (CRI = 23.4% and 19.2%, respectively) were adverse effects in this study that respondents most wanted to avoid.” (opens the source at this quote in a new tab)
“Respondents with SZ were willing to accept 9.8 lb of weight gain or > 25% risk of sedation for symptom improvement; those with BD-I were willing to accept 8.5 lb of weight gain or a > 25% risk of sedation.” (opens the source at this quote in a new tab)

Sexual dysfunction: pooled prevalence in a systematic review and meta-analysis

“A total of 72 of 1119 studies from 33 countries on 6 continents published from inception to June 2022 were included with a total of 21 076 participants with schizophrenia.” (opens the source at this quote in a new tab)
“The pooled global prevalence of sexual dysfunctions was 56.4% (95% CI, 50.5-62.2), with a prevalence of 55.7% (95% CI, 48.1-63.1) for men and 60.0% (95% CI, 48.0-70.8) for women.” (opens the source at this quote in a new tab)
“The most frequent sexual dysfunction was erectile dysfunction in men (44%; 95% CI, 33.5-55.2), followed by loss of libido in men (41%; 95% CI, 30.7-51.4), ejaculation dysfunction in men (39%; 95% CI, 26.8-51.8), orgasm dysfunction in women (28%; 95% CI, 18.4-40.2), and amenorrhea in women (25%; 95% CI, 17.3-35.0).” (opens the source at this quote in a new tab)

Sexual dysfunction and quality of life in men treated with antipsychotics

“Sexual dysfunction occurred in 45.3% of patients.” (opens the source at this quote in a new tab)
“However, as compared with patients without sexual dysfunction, patients with sexual dysfunction reported significantly lower ratings on global quality of life (t = 2.4, df = 136, p = .02) and the level of enjoyment in their life (t = 2.5, df = 136, p = .01).” (opens the source at this quote in a new tab)
“Patients with sexual dysfunction were significantly less likely than those without sexual dysfunction to report having a romantic partner (17.5% vs. 43.4%; chi(2) = 10.7, df = 1, p = .001), though they were not significantly less likely to report difficulty making friends (27.0% vs. 32.9%; chi(2) = 0.57, df = 1, p = .45).” (opens the source at this quote in a new tab)

United States economic burden in 2019: total and per-person excess costs

“Given a prevalence estimate of 1.19%, the schizophrenia population in the US in 2019 was estimated to be 3,906,050, contributing to an excess economic burden of $343.2 billion (Figure 1, Table 2), which corresponded to an annual excess cost per person with schizophrenia of $87,856.” (opens the source at this quote in a new tab)
“The excess direct health care costs were $62.3 billion ($15,957 per person with schizophrenia), the excess direct non–health care costs were $35.0 billion ($8,956 per person with schizophrenia), and the excess indirect costs were $251.9 billion ($64,479 per person with schizophrenia) (Figure 1).” (opens the source at this quote in a new tab)
“Using a lifetime prevalence rate of 0.72%,3 the schizophrenia population in the US in 2019 was estimated to be 2,363,325, contributing to an excess economic burden of $215.1 billion (Table 2).” (opens the source at this quote in a new tab)

United States economic burden in 2019: direct health care costs by service category and by payer

“Excess direct health care costs were estimated to be $62.3 billion and included costs associated with pharmacy ($12.1 billion), outpatient care ($12.9 billion), inpatient care ($30.2 billion), emergency department visits ($5.6 billion), long-term care ($1.5 billion), and other medical services ($120.6 million) (Table 2).” (opens the source at this quote in a new tab)
“Among these patients, 24,881 (19.0%) were commercially insured, 2,779 (2.1%) were Medicare-insured, and 103,465 (78.9%) were Medicaid-insured (Table 3).” (opens the source at this quote in a new tab)
“Mean total health care costs were similar across the commercially insured and Medicaid-insured cohorts but were higher for Medicare-insured patients ($26,904, $26,095, and $34,391, respectively) (Table 4).” (opens the source at this quote in a new tab)
“Mean excess health care costs varied across cohorts, with the greatest excess among commercially insured patients ($19,293), followed by Medicaid- and Medicare-insured patients at $15,347 and $11,963, respectively.” (opens the source at this quote in a new tab)

United States economic burden in 2019: law enforcement, incarceration, homeless shelter, and disability income costs

“Excess law enforcement costs were estimated to be $26.1 billion, including $8.2 billion in police protection, $4.6 billion in judicial and legal services, and $13.3 billion in incarceration costs.” (opens the source at this quote in a new tab)
“Excess homeless shelter costs were estimated to be $2.1 billion, corresponding to homeless shelter costs for 139,410 excess sheltered homeless individuals with schizophrenia.” (opens the source at this quote in a new tab)
“Excess costs related to SSI and SSDI were estimated to be $6.5 billion, accounting for mean annual SSI and SSDI payments of, respectively, $7,317 and $11,234 per schizophrenia patient.” (opens the source at this quote in a new tab)

United States economic burden in 2019: indirect costs and change since 2013

“Excess indirect costs accounted for 73.4% ($251.9 billion) of the total economic burden of schizophrenia (Figure 1, Table 2).” (opens the source at this quote in a new tab)
“Costs due to premature mortality, unemployment, and productivity loss totaled $77.9 billion, $54.2 billion, and $7.4 billion, respectively.” (opens the source at this quote in a new tab)
“These findings suggest that the total estimated burden of schizophrenia doubled (+100.9%) between 2013 and 2019 (after adjusting for inflation).” (opens the source at this quote in a new tab)
“The increase in direct health care costs (+50.7%) was primarily driven by a $13.5 billion increase in inpatient costs (+80.9%) and a $4.8 billion increase in outpatient costs (+58.8%).” (opens the source at this quote in a new tab)

United States economic burden in 2013

“The economic burden of schizophrenia was estimated at $155.7 billion ($134.4 billion-$174.3 billion based on sensitivity analyses) for 2013 and included excess direct health care costs of $37.7 billion (24%), direct non-health care costs of $9.3 billion (6%), and indirect costs of $117.3 billion (76%) compared to individuals without schizophrenia.” (opens the source at this quote in a new tab)
“The largest components were excess costs associated with unemployment (38%), productivity loss due to caregiving (34%), and direct health care costs (24%).” (opens the source at this quote in a new tab)

Medicaid: national utilization and per-patient costs in 2018

“The AP utilization rate was 51% (state range: 24-77%), while the LAI utilization rate was 13% (range: 4-26%).” (opens the source at this quote in a new tab)
“The proportion of patients with ≥1 inpatient admission and ≥1 emergency room visit was 34% (range: 19-82%) and 45% (range: 20-70%).” (opens the source at this quote in a new tab)
“Per-patient-per-year total healthcare costs averaged $32,920 (range: $717-$93,972).” (opens the source at this quote in a new tab)

Medicare fee-for-service: national utilization and per-patient costs in 2019

“About 91% used any AP; 20% used any long-acting injectable antipsychotic (LAI); and 14% used atypical LAIs.” (opens the source at this quote in a new tab)
“About 28% of beneficiaries had ≥1 hospitalization and 47% had ≥1 emergency room (ER) visits, the vast majority of which were related to mental health (MH).” (opens the source at this quote in a new tab)
“Total annual all-cause, MH, and schizophrenia-related costs were $23,662, $15,000 and $12,109, respectively.” (opens the source at this quote in a new tab)

Medicare fee-for-service: costs relative to the general Medicare population, 2003 to 2009

“Although adults with schizophrenia make up approximately 1% of the US adult population, they represent about 1.5% of Medicare beneficiaries.” (opens the source at this quote in a new tab)
“The cost of care for MBSs in 2009 was, on average, 80% higher than for the average GMB per patient year (2010 dollars), and more than 50% of these costs are attributable to a combination of psychiatric and medical hospitalizations, concentrated in about 30% of MBSs with 1 or more hospitalizations per year.” (opens the source at this quote in a new tab)
“From 2004-2009, total estimated Medicare fee-for-service payments for MBSs increased from $9.4 billion to $11.5 billion, excluding Part D prescription drugs and payments for services to MBSs in Medicare for less than 1 year.” (opens the source at this quote in a new tab)

Medicare Part D: out-of-pocket costs for oral and long-acting injectable antipsychotics by low-income subsidy status

“In the final sample, 90.3% of beneficiaries had full LIS status, paying minimal copayments (29.6% institutionalized full LIS, paying $0; 42.2% noninstitutionalized full LIS, ≤100% federal poverty level [FPL], paying $1.25-$3.80; and 18.5% noninstitutionalized full LIS, >100% FPL, paying $3.40-$8.50).” (opens the source at this quote in a new tab)
“Before entering catastrophic coverage, median OOP costs per prescription for generic OAPs, brand-name OAPs, FGA-LAIs, and SGA-LAIs were $10.85, $171.97, $26.09, and $394.28, respectively, for non-LIS beneficiaries and $3.69, $105.82, $9.35, and $229.20, respectively, for partial LIS beneficiaries.” (opens the source at this quote in a new tab)
“The annual total OOP costs varied substantially by LIS status (full LIS, $0-$130.79; partial LIS, $458.96; non-LIS, $998.81).” (opens the source at this quote in a new tab)

Commercial insurance: per-patient costs, cost shares by service category, and utilization

“A total of 8985 patients with schizophrenia met the inclusion criteria for the snapshot analysis.” (opens the source at this quote in a new tab)
“The mean cost per patient per month (PPPM) for a patient with schizophrenia was $1806 versus $419 per member per month for the demographically adjusted nonschizophrenic (ie, matched for age and sex) population.” (opens the source at this quote in a new tab)
“The PPPM cost of $1806 for patients with schizophrenia was 42% for inpatient expenditures, 33% for outpatient, and 25% for prescription drug costs.” (opens the source at this quote in a new tab)
“The annual inpatient admission rates were 636 per 1000 patients with schizophrenia and 48 per 1000 persons for the demographically adjusted population without schizophrenia.” (opens the source at this quote in a new tab)
“The annual emergency department visits for patients with schizophrenia were 2270 per 1000 patients and 158 per 1000 persons without schizophrenia for the demographically adjusted population.” (opens the source at this quote in a new tab)
“The highest costs occurred in the month of diagnosis (designated as the index month; mean cost, $6601).” (opens the source at this quote in a new tab)

Commercial insurance: adherence and costs in a systematic literature review of privately insured patients

“A total of 25 studies were reviewed; 10 included only privately insured patients; and 15 included a mix of different types of insurance.” (opens the source at this quote in a new tab)
“Antipsychotic (AP) adherence was low, ranging from 31.5% to 68.7%.” (opens the source at this quote in a new tab)
“patients with a recent (vs. chronic) diagnosis of schizophrenia had significantly higher frequencies of emergency department visits and hospitalizations and greater length of stay (LOS) and total annual per-capita costs.” (opens the source at this quote in a new tab)

Integrated health system: hospitalization, readmission, and emergency room use

“The study cohort included 2,941 patients (mean age, 48.3 years; 54.5% male, 51.8% black, 45.8% with Medicare).” (opens the source at this quote in a new tab)
“During the follow-up period (mean, 4.6 years), inpatient hospital stays were common, with at least one all-cause, mental health-related, or schizophrenia-related inpatient visit occurring for 48.7%, 47.3%, and 38.8% of patients, respectively.” (opens the source at this quote in a new tab)
“Hospital readmissions within 30 days of an all-cause inpatient visit occurred in 20.4% of patients, with 14.5% of patients readmitted within 30 days of a schizophrenia-related inpatient visit.” (opens the source at this quote in a new tab)

Cost of relapse: Medicaid beneficiaries with recent relapse or with nonadherence and uncontrolled symptoms

“Among 158,763 patients with schizophrenia, 18,771 (11.8%) had a recent relapse (mean age 50.5 years; 48.6% female, 51.4% male) and 13,697 (8.6%) were not adherent to APs and had uncontrolled symptoms of schizophrenia (mean age 47.1 years; 48.0% female, 52.0% male).” (opens the source at this quote in a new tab)
“Patients with recently relapsed schizophrenia had mean total healthcare costs $21,862 higher relative to their controls ($37,424 vs $15,563), driven by $8,486 higher mean long-term care costs (all P < 0.001).” (opens the source at this quote in a new tab)
“Patients non-adherent to APs with uncontrolled symptoms of schizophrenia had adjusted mean total healthcare costs $20,787 higher relative to their controls ($38,337 vs $15,241), driven by $8,019 higher adjusted mean inpatient costs (all P < 0.001).” (opens the source at this quote in a new tab)
“Additional total healthcare costs incurred by patients with recently relapsed schizophrenia and those of patients non-adherent to APs with uncontrolled symptoms of schizophrenia exceeded by 55.2% and 47.6%, respectively, incremental total healthcare costs incurred by all patients with schizophrenia ($14,087).” (opens the source at this quote in a new tab)

Cost of relapse: United States prospective observational study

“Of 1,557 participants with eligible data, 310 (20%) relapsed during the 6 months prior to the 1-year study period.” (opens the source at this quote in a new tab)
“Compared to patients who did not experience prior relapse, patients with prior relapse incurred significantly higher total annual direct mental health care costs during the 1-year study period, which were nearly 3 times higher for the relapsed ($33,187 ± $47,616) compared with those who did not ($11,771 ± $10,611, p < .01).” (opens the source at this quote in a new tab)
“Inpatient costs for patients with a relapse during both the prior 6 months and the follow-up year were 5 times the costs for patients with relapse during the follow-up year only.” (opens the source at this quote in a new tab)

Cost of relapse: range across studies in a systematic review

“We found 16 studies reporting costs associated with relapse over a defined period of time and identified a cost associated with hospitalisation for relapse in 43 studies.” (opens the source at this quote in a new tab)
“Studies from the US report excess costs of relapse of $6033-$32,753 (2015 Purchasing Power Parity dollars [PPP$]) over periods of 12-15 months.” (opens the source at this quote in a new tab)

Inpatient stays: cost per stay and length of stay, United States, 2016

“Alcohol-related disorders and schizophrenia each constituted nearly one in five MSUD stays.” (opens the source at this quote in a new tab)
“Inpatient stays for schizophrenia were the second costliest ($8,900 per stay) and second longest (11 days on average) MSUD stay.” (opens the source at this quote in a new tab)
“Schizophrenia was the most common reason for MSUD stays for males aged 18-44 years.” (opens the source at this quote in a new tab)

Readmissions: 30-day all-cause readmissions after Medicaid index admissions for schizophrenia spectrum and other psychotic disorders, 2018

Metric	Value
Number of index admissions	“166,100”
Rank among Medicaid principal diagnoses by number of readmissions	“2”
Number of 30-day readmissions	“39,300”
Readmission rate, percent	“23.7”
Percent of total Medicaid readmissions	“5.4”

“For both Medicaid and self-pay/no charge, two of the five diagnoses with the most readmissions were mental and/or substance use disorders: alcohol-related disorders (Medicaid and self-pay/no charge), schizophrenia (Medicaid), and depressive disorders (self-pay/no charge).” (opens the source at this quote in a new tab)

Readmissions: incidence and cost in the 2014 Nationwide Readmissions Database

“A total of 77 625 of 343 579 (22%) index hospital discharges for SPDs resulted in readmissions.” (opens the source at this quote in a new tab)
“The average index and readmission costs were $9285 and $8593, respectively.” (opens the source at this quote in a new tab)

Emergency department visits related to schizophrenia: United States, 2009 to 2011

“During 2009–2011, an estimated 382,000 emergency department (ED) visits related to schizophrenia occurred each year among adults aged 18–64, with an overall ED visit rate of 20.1 per 10,000 adults.” (opens the source at this quote in a new tab)
“Public insurance (Medicaid, Medicare, or dual Medicare and Medicaid) was used more frequently at ED visits related to schizophrenia compared with ED visits not related to schizophrenia.” (opens the source at this quote in a new tab)
“About one-half of ED visits related to schizophrenia led to either a hospital admission (32.7%) or a transfer to a psychiatric hospital (16.7%); these percentages were higher than for ED visits not related to schizophrenia.” (opens the source at this quote in a new tab)

Treatment-resistant schizophrenia: costs relative to schizophrenia overall

“Sixty-five studies were identified.” (opens the source at this quote in a new tab)
“Annual costs for patients with schizophrenia are $15 500-$22 300 and are 3-11-fold higher for patients with TRS.” (opens the source at this quote in a new tab)
“Although estimates in the literature vary greatly, TRS conservatively adds more than $34 billion in annual direct medical costs in the USA.” (opens the source at this quote in a new tab)

Nonadherence: national rehospitalization costs

“Seven studies were identified and reviewed based on the study design, measurement of medication nonadherence, study setting, and cost outcome results.” (opens the source at this quote in a new tab)
“We also estimated that the national rehospitalization costs related to antipsychotic nonadherence was $1479 million, ranging from $1392 million to $1826 million in the US in 2005.” (opens the source at this quote in a new tab)
“The estimate of rehospitalization costs was restricted to schizophrenia patients from the Medicaid program.” (opens the source at this quote in a new tab)

Antipsychotic adverse effects: hospitalization and costs associated with extrapyramidal symptoms in Medicaid

“A total of 11,642 patients with schizophrenia filled a prescription for an SGA; of which, 2,468 (21.2%) experienced EPS in the first year.” (opens the source at this quote in a new tab)
“Multivariate analyses confirmed that EPS patients had 25% higher odds of all-cause (OR = 1.25; 95% CI = 1.11-1.40) and 75% increased odds of schizophrenia-related (OR = 1.75; 95% CI = 1.53-2.00) inpatient admissions compared to non-EPS patients.” (opens the source at this quote in a new tab)
“Multivariate adjustment of post-period costs between groups also found significant differences in both all-cause (EPS: $27,408 vs. non-EPS: $22,489, p < 0.001) and schizophrenia-related (EPS:$12,833 vs. non-EPS:$8,077, p < 0.0001) costs between the EPS and non-EPS cohorts.” (opens the source at this quote in a new tab)

Antipsychotic adverse effects: healthcare costs after new-onset metabolic disorders following oral antipsychotic initiation

“A total of 45,528 individuals with schizophrenia qualified for the study, and 34.7% developed metabolic disorders within 6 years after initiating OAPs.” (opens the source at this quote in a new tab)
“Compared to a matched cohort of individuals without metabolic disorders, individuals with a metabolic disorder incurred significantly greater all-cause annual healthcare costs (mean [standard deviation] in 2023 US dollars, $27,520 [$44,200] vs. $19,044 [$34,352]; p < 0.0001) during the 12-month post-index period.” (opens the source at this quote in a new tab)

Negative symptoms: healthcare resource utilization and costs in linked records and claims

“A total of 79,326 patients were enrolled in the EHR cohort and 14,992 (18.9%) had documented negative symptoms.” (opens the source at this quote in a new tab)
“Patients with documented negative symptoms had more HCRU including days hospitalized, outpatient visits, and all-cause healthcare claims than patients without documented negative symptoms (all P < .001).” (opens the source at this quote in a new tab)

Criminal justice system involvement: prevalence and per-patient cost

“Overall, 278 (46%) of 609 participants reported at least 1 criminal justice system encounter.” (opens the source at this quote in a new tab)
“The 2 most prevalent types of encounters were being a victim of a crime (67%) and being on parole or probation (26%).” (opens the source at this quote in a new tab)
“The mean annual per-patient cost of involvement was $1,429, translating to 6% of total annual direct health care costs for those with involvement (11% when excluding crime victims).” (opens the source at this quote in a new tab)

Share of antipsychotic pharmacy spending attributable to branded oral atypical antipsychotics and long-acting injectables

No evidence found.

Caregiving costs in the United States economic burden estimate for 2019

“Costs associated with caregiving were the greatest contributor to excess indirect costs at $112.3 billion ($28,761 per person with schizophrenia), accounting for about a third of the total excess costs (Figure 1).” (opens the source at this quote in a new tab)
“Indirect costs accounted for over 73% of total costs and were largely driven by caregiving costs ($112.3 billion), which accounted for about one-third (32.7%) of the total excess economic burden.” (opens the source at this quote in a new tab)

Caregiving productivity loss in the United States economic burden estimate for 2013

“Indirect costs were estimated for productivity loss from unemployment, reduced work productivity among the employed, premature mortality (ie, suicide), and caregiving.” (opens the source at this quote in a new tab)
“The largest components were excess costs associated with unemployment (38%), productivity loss due to caregiving (34%), and direct health care costs (24%).” (opens the source at this quote in a new tab)

United States caregiver survey: hours of care and out-of-pocket costs

“Unpaid caregivers ( n = 200) of adults with schizophrenia or schizoaffective disorder completed an online survey.” (opens the source at this quote in a new tab)
“Caregivers reported providing 36.1 ± 33 h of care per week.” (opens the source at this quote in a new tab)
“Caregivers reported paying OOP to support SLEs (average annual costs ranged from $1068 to $2395 across categories).” (opens the source at this quote in a new tab)
“Caregivers also reported additional monthly OOP costs of $1809 for everyday needs.” (opens the source at this quote in a new tab)
“The highest monthly costs included mental health treatment ($767), property damage ($728), housing ($670), and medication ($664).” (opens the source at this quote in a new tab)

United States caregiver survey: employment, wage, and career effects

“Most caregivers (80.0%) reported current employment, with 32.5% of those at the same job as before they became a caregiver.” (opens the source at this quote in a new tab)
“Caregivers reported lost wages (58.0%), reducing hours at work (38.5%), taking a leave of absence (30.0%), switching jobs for fewer/more predicable hours (16.0%), early retirement (6.0%), and leaving the workforce (9.5%) due to their caregiving responsibilities.” (opens the source at this quote in a new tab)
“Humanistic impacts are high, with 79% of caregivers meeting criteria on the Burden Assessment Scale.” (opens the source at this quote in a new tab)

Hours of care by caregivers of people with treatment-resistant schizophrenia

“Non-professional adult caregivers providing ≥20 h/week of care to individuals with schizophrenia completed an online survey.” (opens the source at this quote in a new tab)
“One hundred seventy seven caregivers (n = 100 TRS group, n = 77 comparator group) completed the online survey.” (opens the source at this quote in a new tab)
“Relevant differences between caregiver groups were also noted for mean number of hours spent per week on direct care (TRS group vs . comparator group: 61.1 h/week vs . 39.7 h/week, respectively) and time spent “on call” (162.8 h/week vs . 121.6 h/week).” (opens the source at this quote in a new tab)

Caregiver psychological distress: United States online survey

“Of 2,338 Web site "hits," 1,708 individuals consented, 1,398 were eligible, and 1,142 had complete data.” (opens the source at this quote in a new tab)
“Compared with U.S. norms on the PSS (13.4±6.5), mean caregiver distress was high (18.9±7.1).” (opens the source at this quote in a new tab)
“Contributing most to greater distress were caregiver health problems, providing frequent caregiving assistance, monitoring medication, having limited social support, and appraising caregiving negatively.” (opens the source at this quote in a new tab)

Caregiver-reported burdens: United States national survey

“A survey instrument was developed and fielded to 96 caregivers of patients with schizophrenia in the United States (September–October 2019) via online communities and caregiver newsletters.” (opens the source at this quote in a new tab)
“Caregivers report that a schizophrenia diagnosis has strained their own emotional health, reduced their ability to have a satisfying personal life, and disrupted their family life.” (opens the source at this quote in a new tab)

Caregiver health utility and health status compared with non-caregivers and other caregivers: five European countries

“After matching, schizophrenia caregivers reported lower MCS (40.3 vs. 45.9), PCS (46.8 vs. 49.0), and health utilities (0.64 vs. 0.71) compared with non-caregivers (all p < 0.001).” (opens the source at this quote in a new tab)
“Comparing schizophrenia caregivers and other caregivers, schizophrenia caregivers reported lower MCS (40.3 vs. 42.7, p < 0.001), and health utilities (0.64 vs. 0.67, p < 0.001).” (opens the source at this quote in a new tab)
“Almost 60 % of schizophrenia caregivers agree/strongly agree that caring for the patient is important to them, but only 31.9 % agree/strongly agree that they have the financial resources to provide adequate care.” (opens the source at this quote in a new tab)

Financial and health effects of caregiving: review

“Financial impacts of caregiving include treatment costs for care recipients, providing financial support, and lost productivity and income.” (opens the source at this quote in a new tab)
“Depression and anxiety are common health impacts for caregivers, who also have increased physical healthcare resource use relative to healthy controls.” (opens the source at this quote in a new tab)

Diagnostic or companion diagnostic testing required for LB-102 eligibility

Not applicable.

Cost of laboratory, prolactin, and electrocardiographic monitoring during antipsychotic treatment

No evidence found.

APA practice guideline: antipsychotic treatment and continuation

“APA recommends (1A) that patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects.” (opens the source at this quote in a new tab)
“APA recommends (1A) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with an antipsychotic medication.” (opens the source at this quote in a new tab)
“APA suggests (2B) that patients with schizophrenia whose symptoms have improved with an antipsychotic medication continue to be treated with the same antipsychotic medication.” (opens the source at this quote in a new tab)

APA practice guideline: no ranking of agents and no preference between generations

“An evidence-based ranking of FGAs and SGAs or an algorithmic approach to antipsychotic selection is not possible because of the significant heterogeneity in clinical trial designs, the limited numbers of head-to-head comparisons of antipsychotic medications, and the limited clinical trial data for a number of the antipsychotic medications.” (opens the source at this quote in a new tab)
“By the same token, it is not possible to note a preference for either SGAs or FGAs.” (opens the source at this quote in a new tab)
“there is no definitive evidence that one antipsychotic will have consistently superior efficacy compared with another, with the possible exception of clozapine.” (opens the source at this quote in a new tab)
“Furthermore, there is no reliable strategy to predict response or risk of side effects with one agent compared with another.” (opens the source at this quote in a new tab)

VA/DoD guideline: acute treatment, maintenance treatment, and switching

“We recommend the use of an antipsychotic medication other than clozapine for the treatment of an acute episode in individuals with schizophrenia or first-episode psychosis who have previously responded to antipsychotic medications.” (opens the source at this quote in a new tab)
“We recommend the use of an antipsychotic medication for the maintenance treatment of schizophrenia to prevent relapse and hospitalization in individuals with schizophrenia who have responded to treatment.” (opens the source at this quote in a new tab)
“Choice of antipsychotic medication should be based on an individualized evaluation that considers patient-specific characteristics and side effect profiles of the different antipsychotic medications.” (opens the source at this quote in a new tab)
“We suggest a trial of another antipsychotic medication for individuals with schizophrenia who do not respond to (or tolerate) an adequate trial of an antipsychotic medication.” (opens the source at this quote in a new tab)

VA/DoD guideline: adverse effect profile of second-generation agents

“In contrast, second-generation antipsychotic medications (SGA) (e.g., olanzapine, quetiapine, risperidone) are less likely than FGAs to cause EPS but might be associated with increased risk of weight gain and other metabolic abnormalities, including hyperlipidemias and type 2 diabetes mellitus.” (opens the source at this quote in a new tab)
“Finally, both FGAs and SGAs might cause cardiovascular side effects, including dysrhythmias and QT prolongation, and, rarely, seizures.” (opens the source at this quote in a new tab)

NICE guideline: oral antipsychotic medication with psychological interventions

“For people with an acute exacerbation or recurrence of psychosis or schizophrenia, offer: oral antipsychotic medication (see the section on how to use antipsychotic medication) in conjunction with psychological interventions (family intervention and individual CBT, delivered as described in the section on how to deliver psychological interventions).” (opens the source at this quote in a new tab)
“The choice of antipsychotic medication should be made by the service user and healthcare professional together, taking into account the views of the carer if the service user agrees.” (opens the source at this quote in a new tab)
“Do not initiate regular combined antipsychotic medication, except for short periods (for example, when changing medication).” (opens the source at this quote in a new tab)

INTEGRATE international algorithm: development and key recommendations

“From May 1, 2023, to Jan 1, 2025, International Guidelines for Algorithmic Treatment (INTEGRATE) authors from all UN regions collaborated to develop a consensus guideline focused on the pharmacological treatment of schizophrenia.” (opens the source at this quote in a new tab)
“Key recommendations include a focus on metabolic health from treatment initiation, timely assessment and management of non-response, symptom domain-specific interventions, mitigation of side-effects, and the prompt use of clozapine in cases of treatment resistance.” (opens the source at this quote in a new tab)

Australian and New Zealand GRADE guideline: first-line and second-line agents

“We recommend that people with schizophrenia should be given oral second-generation antipsychotic medications with a favourable cardiometabolic side effect (including hyperprolactinemia) profile as the first-line treatment (i.e. aripiprazole, brexiprazole, cariprazine, lurasidone).” (opens the source at this quote in a new tab)
“Combined, we recommend choosing the second antipsychotic medication from the remaining agents from the first-line treatment options (aripiprazole, brexpiprazole, cariprazine, or lurasidone) with additional consideration for agents with different receptor profiles such as amisulpride and risperidone” (opens the source at this quote in a new tab)

Acute efficacy against placebo: 167 trials over sixty years

“The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants.” (opens the source at this quote in a new tab)
“The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38.” (opens the source at this quote in a new tab)
“Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27).” (opens the source at this quote in a new tab)
“Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response.” (opens the source at this quote in a new tab)

Comparative acute efficacy of 32 oral antipsychotics: network meta-analysis

“We identified 54 417 citations and included 402 studies with data for 53 463 participants.” (opens the source at this quote in a new tab)
“Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants).” (opens the source at this quote in a new tab)
“Clozapine, amisulpride, zotepine, olanzapine, and risperidone reduced overall symptoms significantly more than many other drugs” (opens the source at this quote in a new tab)
“There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete.” (opens the source at this quote in a new tab)

Comparative adverse effects of 32 oral antipsychotics: network meta-analysis

“Mean differences compared to placebo for weight gain (28 317 participants) ranged from −0·16 kg (−0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from −77·05 ng/mL (−120·23 to −33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from −2·21 ms (−4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole).” (opens the source at this quote in a new tab)
“Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide).” (opens the source at this quote in a new tab)
“Olanzapine, asenapine, lurasidone, sertindole, haloperidol, amisulpride, risperidone, and paliperidone were associated with significantly elevated prolactin levels (mean difference range 4·47–48·51 ng/mL).” (opens the source at this quote in a new tab)

Metabolic effects of 18 antipsychotics: network meta-analysis

“Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients.” (opens the source at this quote in a new tab)
“Mean differences for weight gain compared with placebo ranged from −0·23 kg (95% CI −0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine” (opens the source at this quote in a new tab)
“Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles.” (opens the source at this quote in a new tab)

Maintenance treatment: network meta-analysis of 32 oral and long-acting injectable antipsychotics

“All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect.” (opens the source at this quote in a new tab)
“As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability.” (opens the source at this quote in a new tab)

Long-term head-to-head comparisons of oral second-generation antipsychotics

“Across 59 studies (N=45,787), lasting 47.4±32.1 weeks (range 24‐186), no consistent superiority of any SGA emerged across efficacy and tolerability outcomes.” (opens the source at this quote in a new tab)
“Concerning weight gain, olanzapine was worse than all other compared non‐clozapine SGAs, and risperidone was significantly worse than several other SGAs.” (opens the source at this quote in a new tab)

CATIE: all-cause discontinuation over 18 months by assigned agent

“A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months.” (opens the source at this quote in a new tab)
“Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone.” (opens the source at this quote in a new tab)
“Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.” (opens the source at this quote in a new tab)

Class labeling: boxed warning and metabolic warning in the olanzapine label

“Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.” (opens the source at this quote in a new tab)
“Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain.” (opens the source at this quote in a new tab)

APA practice guideline: no preference between first-generation and second-generation agents

“By the same token, it is not possible to note a preference for either SGAs or FGAs.” (opens the source at this quote in a new tab)

VA/DoD guideline: adverse effect profile of first-generation agents

“First-generation antipsychotics (FGA) (e.g., fluphenazine, haloperidol) are more prone to produce persistent extrapyramidal symptoms (EPS), including pseudoparkinsonian symptoms, akathisia, dystonias, tardive dyskinesia (TD), and neuroleptic malignant syndrome, especially when used at higher doses.” (opens the source at this quote in a new tab)

CATIE: perphenazine compared with second-generation agents

“We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.” (opens the source at this quote in a new tab)
“olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.” (opens the source at this quote in a new tab)
“Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone.” (opens the source at this quote in a new tab)

CUtLASS: quality of life with first-generation compared with second-generation agents

“Participants in the FGA arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores.” (opens the source at this quote in a new tab)
“In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs.” (opens the source at this quote in a new tab)

EUFEST: haloperidol compared with second-generation agents in first-episode schizophrenia

“The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone.” (opens the source at this quote in a new tab)
“However, symptom reductions were virtually the same in all the groups, at around 60%.” (opens the source at this quote in a new tab)

Extrapyramidal adverse effects and weight gain: network meta-analysis

“Risk ratios for the 21 (66%) of 32 antipsychotics that were associated with significantly increased use of antiparkinson medication compared with placebo ranged from 1·61 (95% CrI 1·17–2·10) for paliperidone to 6·14 (4·81–6·55) for pimozide” (opens the source at this quote in a new tab)
“12 (46%) of 26 antipsychotics caused significantly more weight gain than placebo with mean differences ranging from 0·54 kg (95% CrI 0·15–0·95) for haloperidol to 3·21 kg (2·10–4·31) for zotepine” (opens the source at this quote in a new tab)

Tardive dyskinesia prevalence by antipsychotic class

“The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies” (opens the source at this quote in a new tab)
“Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002).” (opens the source at this quote in a new tab)

Relapse prevention: second-generation compared with first-generation agents as classes

“comparing second‐generation antipsychotics (SGAs) with first‐generation antipsychotics (FGAs), found that the former as a class were superior to the latter regarding relapse prevention, all‐cause discontinuation and other relapse‐related outcomes” (opens the source at this quote in a new tab)

APA practice guideline: long-acting injectable antipsychotic medication

“APA suggests (2B) that patients receive treatment with a long-acting injectable antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence.” (opens the source at this quote in a new tab)

“LAI formulations of antipsychotic medications can provide a number of benefits for patients, families, and clinicians, yet they are often underutilized” (opens the source at this quote in a new tab)

VA/DoD guideline: long-acting injectable antipsychotics for adherence

“We suggest offering long-acting injectable antipsychotics to improve medication adherence in individuals with schizophrenia.” (opens the source at this quote in a new tab)

NICE guideline: initiating depot or long-acting injectable medication

“take into account the service user's preferences and attitudes towards the mode of administration (regular intramuscular injections) and organisational procedures (for example, home visits and location of clinics)” (opens the source at this quote in a new tab)

Australian and New Zealand GRADE guideline: long-acting injectables by stage of illness

“We suggest that people with schizophrenia in the early stages of the illness may be offered long-acting injectable antipsychotic medications.” (opens the source at this quote in a new tab)
“We recommend that people with schizophrenia in the maintenance stages of the illness should be offered long-acting injectable antipsychotic medications as a treatment option.” (opens the source at this quote in a new tab)

Long-acting injectable compared with oral antipsychotics: meta-analysis across three study designs

“We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria” (opens the source at this quote in a new tab)
“LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79-0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88-0·98], p=0·0044; pre-post studies: 28 studies, 17 876 patients, RR 0·44 [0·39-0·51], p<0·0001).” (opens the source at this quote in a new tab)
“In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design.” (opens the source at this quote in a new tab)

Real-world rehospitalization: Swedish nationwide cohort of 29,823 patients

“During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure.” (opens the source at this quote in a new tab)
“Long-acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort).” (opens the source at this quote in a new tab)
“Clozapine and long-acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia.” (opens the source at this quote in a new tab)

PRELAPSE: long-acting injectable aripiprazole in early-phase schizophrenia

“Fifty-two AOM (22%) and 91 CC participants (36%) had at least 1 hospitalization.” (opens the source at this quote in a new tab)
“The number needed to treat to prevent 1 additional hospitalization was 7 participants treated with AOM compared with CC.” (opens the source at this quote in a new tab)

Relapse during long-acting injectable treatment

“Pooled incidence of relapse was 22·97 per 100 participant-years” (opens the source at this quote in a new tab)
“Despite the established efficacy of antipsychotics in preventing relapse, these data indicate that these drugs might not prevent subsequent exacerbations for a proportion of individuals whose illness is stabilised on continuous antipsychotic treatment.” (opens the source at this quote in a new tab)

APA practice guideline: clozapine for treatment resistance, suicide risk, and aggression

“APA recommends (1B) that patients with treatment-resistant schizophrenia be treated with clozapine.” (opens the source at this quote in a new tab)
“APA recommends (1B) that patients with schizophrenia be treated with clozapine if the risk for suicide attempts or suicide remains substantial despite other treatments.” (opens the source at this quote in a new tab)
“APA suggests (2C) that patients with schizophrenia be treated with clozapine if the risk for aggressive behavior remains substantial despite other treatments.” (opens the source at this quote in a new tab)

“many patients would benefit from earlier consideration of clozapine initiation.” (opens the source at this quote in a new tab)

VA/DoD guideline: clozapine for treatment-resistant schizophrenia

“We recommend the use of clozapine for individuals with treatment-resistant schizophrenia.” (opens the source at this quote in a new tab)

NICE guideline: clozapine after two antipsychotic drugs

“Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs. At least 1 of the drugs should be a non-clozapine second-generation antipsychotic.” (opens the source at this quote in a new tab)

Australian and New Zealand GRADE guideline: clozapine and electroconvulsive therapy in treatment resistance

“We recommend that people with treatment-resistant schizophrenia should be offered clozapine.” (opens the source at this quote in a new tab)
“We suggest that people with treatment-resistant schizophrenia may be offered electroconvulsive therapy.” (opens the source at this quote in a new tab)

FDA-approved indications and restriction of use

“Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.” (opens the source at this quote in a new tab)
“Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.” (opens the source at this quote in a new tab)
“Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior.” (opens the source at this quote in a new tab)

Boxed warning

“WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS” (opens the source at this quote in a new tab)
“CLOZARIL has caused severe neutropenia, which is associated with an increased risk of serious and fatal infections.” (opens the source at this quote in a new tab)

Efficacy in treatment-refractory schizophrenia: meta-analysis of randomized trials

“Twenty-one papers with 25 comparisons were included. The number needed to treat was 9.” (opens the source at this quote in a new tab)
“Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered.” (opens the source at this quote in a new tab)

Response rate in treatment-resistant schizophrenia

“Overall, 40.1% (95% confidence interval [CI], 36.8%-43.4%) responded, with a mean reduction in PANSS of 22.0 points (95% CI, 20.9-23.1), a reduction of 25.8% (95% CI, 24.7%-26.9%) from baseline.” (opens the source at this quote in a new tab)
“A 40% response rate to clozapine suggests that 12% to 20% of people with schizophrenia will be ultra-resistant.” (opens the source at this quote in a new tab)

Real-world rehospitalization and treatment failure

“Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine.” (opens the source at this quote in a new tab)

OPTiMiSE: clozapine after non-remission on amisulpride and olanzapine

“Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission.” (opens the source at this quote in a new tab)

Underuse of clozapine

“Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers.” (opens the source at this quote in a new tab)

FDA approval of xanomeline and trospium chloride

“It is the first antipsychotic drug approved to treat schizophrenia that targets cholinergic receptors as opposed to dopamine receptors, which has long been the standard of care.” (opens the source at this quote in a new tab)
“The prescribing information includes warnings that Cobenfy can cause urinary retention, increased heart rate, decreased gastric movement or angioedema (swelling beneath the skin) of the face and lips.” (opens the source at this quote in a new tab)

Xanomeline and trospium chloride: indication and dosing

“COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, indicated for the treatment of schizophrenia in adults.” (opens the source at this quote in a new tab)
“Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily for at least two days, then increase the dosage to 100 mg/20 mg twice daily for at least five days.” (opens the source at this quote in a new tab)

Xanomeline and trospium chloride: warnings and precautions

“Risk of Urinary Retention: COBENFY can cause urinary retention.” (opens the source at this quote in a new tab)
“Risk of Use in Patients with Hepatic Impairment: COBENFY is contraindicated in patients with moderate to severe hepatic impairment and is not recommended in patients with mild hepatic impairment.” (opens the source at this quote in a new tab)
“Risk of Use in Patients with Biliary Disease: Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated.” (opens the source at this quote in a new tab)

Xanomeline and trospium chloride: adverse reactions in the pooled 5-week trials

“The adverse reaction findings are based on two pooled 5-week, placebo-controlled, flexible-dose studies in 504 adult patients with schizophrenia” (opens the source at this quote in a new tab)

“The most common side effects of Cobenfy are nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness and gastroesophageal reflux disease.” (opens the source at this quote in a new tab)

EMERGENT-2: primary endpoint and tolerability

“EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia.” (opens the source at this quote in a new tab)
“The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61).” (opens the source at this quote in a new tab)
“Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).” (opens the source at this quote in a new tab)

EMERGENT-3: primary endpoint and tolerability

“At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , −20.6; placebo, −12.2; least squares mean difference, −8.4; 95% CI, −12.4 to −4.3; P < .001; Cohen d effect size, 0.60).” (opens the source at this quote in a new tab)
“The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]).” (opens the source at this quote in a new tab)

ARISE: adjunctive xanomeline and trospium chloride with an atypical antipsychotic

“In the Phase 3 trial, adjunctive Cobenfy treatment demonstrated a 2.0-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo with an atypical antipsychotic at Week 6, which did not reach the threshold for statistical significance for the primary endpoint (P = 0.11).” (opens the source at this quote in a new tab)
“In a post-hoc subgroup analysis there was a notable difference in response between subjects treated with risperidone as a background therapy compared with the remaining subjects treated with other background antipsychotics (non-risperidone).” (opens the source at this quote in a new tab)

Emraclidine: phase 1b and phase 2 EMPOWER results

“These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile.” (opens the source at this quote in a new tab)

“EMPOWER-1 and EMPOWER-2 Phase 2 clinical trials did not meet their primary endpoint” (opens the source at this quote in a new tab)
“In the EMPOWER trials, emraclidine was well-tolerated with a safety profile comparable to that observed in the Phase 1b trial.” (opens the source at this quote in a new tab)

Consensus panel report on clinical use of xanomeline and trospium chloride

“In July 2025, a consensus panel of clinicians with expertise in treating schizophrenia and real-world experience using XT convened to discuss practical strategies for its use across treatment settings.” (opens the source at this quote in a new tab)
“The panel concluded that XT should be considered early in the course of illness, particularly in first-episode psychosis, because it may alter long-term outcomes while reducing reliance on high-dose dopamine antagonists.” (opens the source at this quote in a new tab)

NICE technology appraisal of xanomeline tartrate and trospium chloride: status

“Expected publication date: 14 July 2027” (opens the source at this quote in a new tab)
“Status: In progress” (opens the source at this quote in a new tab)

Recommendations on muscarinic receptor agonists in the APA, VA/DoD, NICE, and Australian and New Zealand guidelines

No evidence found.

APA practice guideline: recommended psychosocial interventions

“APA recommends (1B) that patients with schizophrenia who are experiencing a first episode of psychosis be treated in a coordinated specialty care program.” (opens the source at this quote in a new tab)
“APA recommends (1B) that patients with schizophrenia be treated with cognitive-behavioral therapy for psychosis (CBTp).” (opens the source at this quote in a new tab)
“APA recommends (1B) that patients with schizophrenia receive psychoeducation.” (opens the source at this quote in a new tab)
“APA recommends (1B) that patients with schizophrenia receive supported employment services.” (opens the source at this quote in a new tab)
“APA recommends (1B) that patients with schizophrenia receive assertive community treatment if there is a history of poor engagement with services leading to frequent relapse or social disruption (e.g., homelessness; legal difficulties, including imprisonment).” (opens the source at this quote in a new tab)

APA practice guideline: suggested psychosocial interventions

“APA suggests (2B) that patients with schizophrenia who have ongoing contact with family receive family interventions.” (opens the source at this quote in a new tab)
“APA suggests (2C) that patients with schizophrenia receive interventions aimed at developing self-management skills and enhancing person-oriented recovery.” (opens the source at this quote in a new tab)
“APA suggests (2C) that patients with schizophrenia receive cognitive remediation.” (opens the source at this quote in a new tab)
“APA suggests (2C) that patients with schizophrenia who have a therapeutic goal of enhanced social functioning receive social skills training.” (opens the source at this quote in a new tab)
“APA suggests (2C) that patients with schizophrenia be treated with supportive psychotherapy.” (opens the source at this quote in a new tab)

VA/DoD guideline: psychosocial and service recommendations

“We recommend treatment/management with early intervention services for individuals with first-episode psychosis.” (opens the source at this quote in a new tab)
“We recommend the use of psychosocial interventions provided to a primary support person or family member to decrease the risk of relapse and hospitalization for individuals with schizophrenia.” (opens the source at this quote in a new tab)
“We recommend the use of the Individual Placement and Support model of supported employment for individuals with schizophrenia with a goal of employment.” (opens the source at this quote in a new tab)
“We suggest cognitive training programs for the treatment of cognitive impairment and negative symptoms for individuals with schizophrenia.” (opens the source at this quote in a new tab)

NICE guideline: psychological interventions in first-episode psychosis

“For people with first episode psychosis offer: oral antipsychotic medication (see the section on how to use antipsychotic medication) in conjunction with psychological interventions (family intervention and individual CBT, delivered as described in the section on how to deliver psychological interventions).” (opens the source at this quote in a new tab)
“Advise people who want to try psychological interventions alone that these are more effective when delivered in conjunction with antipsychotic medication.” (opens the source at this quote in a new tab)

Australian and New Zealand GRADE guideline: psychological interventions

“We recommend that people with schizophrenia should be offered cognitive behavioural therapy for psychosis.” (opens the source at this quote in a new tab)
“We recommend that people with schizophrenia should be offered cognitive remediation therapy, particularly those who have cognitive deficits/difficulties or poor functioning.” (opens the source at this quote in a new tab)

Psychological interventions for positive symptoms: network meta-analysis

“We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add‐on to antipsychotics.” (opens the source at this quote in a new tab)
“cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=−0.29; 95% CI: –0.55 to −0.03), treatment as usual (SMD=−0.30; 95% CI: –0.45 to −0.14) and supportive therapy (SMD=−0.47; 95% CI: –0.91 to −0.03).” (opens the source at this quote in a new tab)

RAISE Early Treatment Program: comprehensive care for first-episode psychosis

“223 NAVIGATE recipients remained in treatment longer, experienced greater improvement in quality of life, psychopathology and involvement in work/school compared to 181 Community Care participants.” (opens the source at this quote in a new tab)
“Rates of hospitalization were relatively low compared to other first episode psychosis clinical trials and did not differ between groups.” (opens the source at this quote in a new tab)

Summary

Treatment discontinuation is frequent. In CATIE, 1,061 of 1,432 participants (74%) stopped the assigned antipsychotic before 18 months, from 64% with olanzapine to 82% with quetiapine. In a Swedish cohort of 29,823 individuals with schizophrenia followed from 2006 to 2013, 43.7% were rehospitalized and 71.7% of 28,189 had treatment failure. A meta-analysis pooled psychotropic medication nonadherence in schizophrenia at 56%, and an earlier review reported mean nonadherence rates of 41.2% and 49.5% under two sets of inclusion criteria.

Response is incomplete. Across 167 placebo-controlled trials with 28,102 participants, at least a minimal response occurred in 51% of participants receiving an antipsychotic and 30% receiving placebo, and a good response in 23% and 14%. Treatment resistance developed in 22.8% of first-episode cohorts (12 studies, 11,958 participants) and in 24.4% of first-episode schizophrenia cohorts. Clozapine, the agent guidelines recommend for treatment resistance, produced response in 40.1% of treated participants, which the authors translate into 12% to 20% of people with schizophrenia being ultra-resistant. Clozapine carries a boxed warning for severe neutropenia, orthostatic hypotension, seizure, and myocarditis.

Negative and cognitive symptoms remain. Up to 60% of people with schizophrenia have prominent, clinically relevant negative symptoms, and a meta-analysis of 168 placebo-controlled trials found that no treatment reached the threshold for clinically significant improvement in negative symptoms. The VA/DoD guideline found insufficient evidence to recommend for or against augmentation with any non-antipsychotic medication for cognitive or negative symptoms.

Adverse effects differ by agent. Metabolic syndrome was present in 32.5% of people with schizophrenia and related disorders. Mean weight gain against placebo ranged up to 3.01 kg for clozapine in one network meta-analysis and up to 3.21 kg for zotepine in another. Rating scale-based tardive dyskinesia prevalence was 25.3% across 41 studies (20.7% with current second-generation and 30.0% with current first-generation treatment), and risk ratios for antiparkinson medication use against placebo ranged from 1.61 for paliperidone to 6.14 for pimozide among the 21 agents with a significant increase. Prolactin change against placebo ranged from a decrease of 77.05 ng/mL with clozapine to an increase of 48.51 ng/mL with paliperidone, and the highest rates of hyperprolactinemia are reported with amisulpride, risperidone, and paliperidone.

Relapse occurs during treatment. Maintenance antipsychotic treatment reduced relapse at 1 year from 64% to 27% in one meta-analysis and from 61% to 24% in a Cochrane review, and pooled relapse incidence during long-acting injectable treatment was 22.97 per 100 participant-years. The median proportion of people meeting recovery criteria was 13.5% across 50 studies. Among agents with a mechanism other than dopamine receptor blockade, adjunctive xanomeline and trospium chloride did not reach statistical significance on its primary endpoint in ARISE (2.0-point PANSS difference, P = 0.11), and emraclidine did not meet the primary endpoint in two phase 2 trials.

All-cause discontinuation in CATIE

“The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons.” (opens the source at this quote in a new tab)

Medication nonadherence

“Overall, 49% of major psychiatric disorder patients were non-adherent to their psychotropic medication.” (opens the source at this quote in a new tab)
“Of these, psychotropic medication non-adherence for schizophrenia, major depressive disorders, and bipolar disorders were 56%, 50%, and 44%, respectively.” (opens the source at this quote in a new tab)

“Among the 10 reports that met a strict set of study inclusion criteria, we found a mean rate of nonadherence of 41.2%; the 5 reports that met a stricter set of inclusion criteria had a mean nonadherence rate of 49.5%.” (opens the source at this quote in a new tab)

Incomplete response in placebo-controlled trials

“At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response.” (opens the source at this quote in a new tab)

Treatment resistance in first-episode cohorts

“Twelve studies were included, totalling 11 958 participants; six studies were of high quality.” (opens the source at this quote in a new tab)
“The rate of TRS was 22.8% (95% CI 19.1-27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5-30.0%, P < 0.001) among first-episode schizophrenia cohorts.” (opens the source at this quote in a new tab)
“When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third.” (opens the source at this quote in a new tab)

Definition of treatment resistance

“The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence.” (opens the source at this quote in a new tab)

“There is considerable variation in current approaches to defining treatment resistance in schizophrenia.” (opens the source at this quote in a new tab)

Residual negative symptoms

“Negative symptoms are common in schizophrenia; up to 60% of patients may have prominent clinically relevant negative symptoms that require treatment.” (opens the source at this quote in a new tab)
“Negative symptoms clearly constitute an unmet medical need in schizophrenia, and new and effective treatments are urgently needed.” (opens the source at this quote in a new tab)

“Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale.” (opens the source at this quote in a new tab)
“Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.” (opens the source at this quote in a new tab)

Cognitive and negative symptoms: no recommended augmentation and no approved therapy

“There is insufficient evidence to recommend for or against augmentation with any non-antipsychotic medication for treatment of cognitive and/or negative symptoms for individuals with schizophrenia.” (opens the source at this quote in a new tab)

“There are no approved therapies in the U.S. for the treatment of predominantly negative symptoms of schizophrenia or cognitive impairment associated with schizophrenia.” (opens the source at this quote in a new tab)

Metabolic syndrome prevalence

“The overall rate of MetS was 32.5% (95% CI = 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females.” (opens the source at this quote in a new tab)

Extrapyramidal symptoms and tardive dyskinesia

“Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment.” (opens the source at this quote in a new tab)

“Antipsychotic drugs (as a group and irrespective of duration) were associated with more participants experiencing movement disorders (e.g. at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI 1.25 to 1.85, number needed to treat for an additional harmful outcome (NNTH) 20, 95% CI 14 to 50), sedation (drug 8% versus placebo 5%, 18 RCTs, n = 4078, RR 1.52, 95% CI 1.24 to 1.86, NNTH 50, 95% CI not significant), and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR 1.69, 95% CI 1.21 to 2.35, NNTH 25, 95% CI 20 to 50).” (opens the source at this quote in a new tab)

Hyperprolactinemia

“Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL.” (opens the source at this quote in a new tab)
“The highest rates of HPRL are reported in association with risperidone, amisulpride and sulpiride, often in as high as 80–90 % of all female subjects” (opens the source at this quote in a new tab)

“FGAs and SGAs that bind strongly to the dopamine D2 receptor might also cause prolactin elevation, which can lead to galactorrhea, dysmenorrhea, and sexual dysfunction.” (opens the source at this quote in a new tab)

Relapse despite maintenance treatment

“Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3).” (opens the source at this quote in a new tab)

“Antipsychotic drugs were more effective than placebo in preventing relapse at seven to 12 months (primary outcome; drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR 0.38, 95% CI 0.32 to 0.45, number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 3; high‐certainty evidence).” (opens the source at this quote in a new tab)

“Relapse was associated with functional decline” (opens the source at this quote in a new tab)

Recovery

“The median proportion (25%–75% quantiles) who met our recovery criteria was 13.5% (8.1%–20.0%).” (opens the source at this quote in a new tab)
“Based on the best available data, approximately, 1 in 7 individuals with schizophrenia met our criteria for recovery.” (opens the source at this quote in a new tab)

Summary

LB-102 is investigational and has no established place in therapy. LB Pharmaceuticals states that LB-102 has the potential to be the first benzamide antipsychotic approved for neuropsychiatric disorders in the United States and describes it as a potential alternative to branded and generic therapeutics for schizophrenia. The parent compound, amisulpride, is approved in more than 50 countries excluding the United States; the company reports that Sanofi announced in 2000 that it would not pursue U.S. approval for schizophrenia. The company expects to commercialize the oral formulation where amisulpride is unavailable as a generic and a long-acting injectable formulation worldwide.

The studied setting is acute inpatient care. NOVA-1 randomized 359 participants at 25 U.S. inpatient sites to 28 days of inpatient treatment, and its authors state that further studies are needed to assess whether the findings generalize to outpatients and that the trial was not designed to evaluate long-term durability. The company describes NOVA-2 as the pivotal phase 3 trial and NOVA-3 as an outpatient open-label trial that accrues the safety population for the NDA. Long-term outpatient maintenance use is therefore anticipated and has no controlled evidence yet.

Guidelines do not rank agents. The APA guideline states that an evidence-based ranking of antipsychotics is not possible and notes no preference between generations, the VA/DoD guideline bases the choice on patient characteristics and side effect profiles, and a 2026 Australian and New Zealand guideline names aripiprazole, brexpiprazole, cariprazine, and lurasidone as first-line agents and lists amisulpride among agents to consider second. Evidence for amisulpride comes from European trials and network meta-analysis: amisulpride had the largest standardized mean difference against placebo for positive symptoms (−0.69) among the 17 agents with a significant reduction, and the authors note that no placebo-controlled amisulpride study was available, which makes that evidence indirect; in EUFEST, 12-month all-cause discontinuation was 40% with amisulpride and 72% with haloperidol; in OPTiMiSE, 250 of 446 participants (56%) achieved remission on open-label amisulpride; and in BeSt InTro, the 52-week PANSS reduction was 32.7 points with amisulpride, 21.9 with aripiprazole, and 23.3 with olanzapine. The company reports at least two million monthly amisulpride prescriptions in 2023 in 16 continental European countries. Amisulpride is among the agents with the highest reported rates of hyperprolactinemia.

Company positioning: first benzamide antipsychotic in the United States

“We are building a pipeline that leverages the broad therapeutic potential of our lead product candidate, LB-102, which we believe has the potential to be the first benzamide antipsychotic drug approved for neuropsychiatric disorders in the United States.” (opens the source at this quote in a new tab)
“We believe that LB-102, if approved, can become a mainstay of psychiatric practice by offering a potentially attractive alternative to branded and generic therapeutics for the treatment of schizophrenia, bipolar depression, adjunctive MDD and other neuropsychiatric diseases, given the compelling balance of clinical activity and tolerability observed to date.” (opens the source at this quote in a new tab)

Company positioning in the 2025 initial public offering prospectus

“We believe that LB-102, if approved, can become a mainstay of psychiatric practice by offering a potentially attractive alternative to branded and generic therapeutics for the treatment of schizophrenia, bipolar depression, and other neuropsychiatric diseases.” (opens the source at this quote in a new tab)

Agents the company describes as first-line treatments in the United States

“This analysis also found that amisulpride was 20% more effective at reducing overall symptoms of schizophrenia compared to risperidone, which is a first-line treatment for schizophrenia in the United States.” (opens the source at this quote in a new tab)
“A 2020 Lancet Psychiatry report of a head-to-head long-term study showed amisulpride to have greater reduction in PANSS total score from baseline compared to first-line treatments of aripiprazole and olanzapine.” (opens the source at this quote in a new tab)

Company-stated target profile

“We believe a treatment that is effective, tolerable, supports adherence in a fragile population and can address negative and residual symptoms could become a mainstay of schizophrenia treatment.” (opens the source at this quote in a new tab)
“We believe LB-102 has the potential to meet this profile.” (opens the source at this quote in a new tab)

Amisulpride: approval outside the United States

“Amisulpride is a dopamine receptor antagonist originally developed in France in the 1980s and is approved in more than 50 countries worldwide (not including the United States) for the treatment of schizophrenia and, in certain countries outside of the United States, for the treatment of dysthymia, a form of depression, and predominantly negative symptoms of schizophrenia.” (opens the source at this quote in a new tab)
“In 2000, Sanofi S.A., the manufacturer of Solian, the branded version of amisulpride, announced it would not pursue approval for schizophrenia in the United States because the development and regulatory requirements of the FDA were incompatible with its patent coverage on the drug.” (opens the source at this quote in a new tab)

Amisulpride: company-reported use in Europe

“Amisulpride is a generic drug that has been extensively used in clinical practice following its initial approval in France in the 1980s, generating at least two million monthly prescriptions in 2023 in a subset of 16 continental European countries.” (opens the source at this quote in a new tab)
“Among these European prescriptions for amisulpride, our data suggest that approximately 60% are for schizophrenia and schizoaffective disorders, approximately 20% are for mood disorders, approximately 14% are for anxiety, and the remainder are for a variety of other indications.” (opens the source at this quote in a new tab)

Planned commercialization by formulation

“If approved for schizophrenia, we expect to commercialize the oral formulation of LB-102 in jurisdictions where amisulpride is unavailable as a generic, and we expect to commercialize an LAI form of LB-102 worldwide.” (opens the source at this quote in a new tab)

Studied setting: inpatient acute treatment in NOVA-1

“conducted at 25 inpatient sites in the US between December 2023 and August 2024.” (opens the source at this quote in a new tab)
“The inpatient setting minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications; further studies are needed to assess whether these findings are generalizable to an outpatient population.” (opens the source at this quote in a new tab)
“was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment.” (opens the source at this quote in a new tab)

Phase 3 and outpatient open-label trials

“LB-102 is currently in late-stage clinical development for schizophrenia (pivotal Phase 3 NOVA-2 trial) and bipolar depression (Phase 2 ILLUMINATE-1 trial).” (opens the source at this quote in a new tab)
“we are enrolling an outpatient, open label trial (NOVA-3) to accrue the requisite safety population required to support NDA submission” (opens the source at this quote in a new tab)

“Doses selected to inform use in commercial setting” (opens the source at this quote in a new tab)
“~900 patients – rollover from Phase 3 trial + new patients” (opens the source at this quote in a new tab)

Amisulpride in European randomized trials

“Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57])” (opens the source at this quote in a new tab)

“Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1.” (opens the source at this quote in a new tab)

“After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025).” (opens the source at this quote in a new tab)
“We observed weight gain and increases of serum lipids and prolactin in all groups.” (opens the source at this quote in a new tab)

Amisulpride in the network meta-analysis of 32 antipsychotics

“Amisulpride was among the most efficacious antipsychotics, but no placebo-controlled study was available, making this evidence entirely indirect.” (opens the source at this quote in a new tab)
“The SMDs for the 17 (81%) drugs that significantly reduced positive symptoms compared with placebo ranged between −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole” (opens the source at this quote in a new tab)

Amisulpride in a 2026 guideline

“Certain medications, such as cariprazine, aripiprazole and low-dose amisulpride, may offer greater efficacy for negative symptoms and antidepressant augmentation may be helpful for some” (opens the source at this quote in a new tab)

Recommendations on benzamide antipsychotics in United States guidelines

No evidence found.

Dose-response across antipsychotics, including amisulpride

“Sixty-eight studies met the inclusion criteria.” (opens the source at this quote in a new tab)
“The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg” (opens the source at this quote in a new tab)
“In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy.” (opens the source at this quote in a new tab)

LB-102 dose groups in NOVA-1

“LB-102 50 mg and 75 mg, were statistically superior to placebo in change from baseline to week 4 in PANSS total score (mean [SE], placebo, −9.3 [1.08]; 50 mg, −14.3 [1.10], P < .001; Hedges g = 0.61; 75 mg, −14.0 [1.11], P = .002; Hedges g = 0.41); LB-102 100 mg, also showed significance (mean [SE], −16.1 [1.91]; nominal P = .002; Hedges g = 0.83).” (opens the source at this quote in a new tab)
“LB-102 100 mg prespecified to have a lower randomized enrollment, demonstrated a nominally significant treatment effect compared with placebo on the primary endpoint, with a numerically larger effect size (Hedges g = 0.83) when compared with the 50-mg (Hedges g = 0.61) or 75-mg (Hedges g = 0.41) doses.” (opens the source at this quote in a new tab)

Baseline symptom severity

“The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo.” (opens the source at this quote in a new tab)
“In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116).” (opens the source at this quote in a new tab)
“Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics.” (opens the source at this quote in a new tab)

First-episode compared with multi-episode schizophrenia

“We included 17 studies with a total of 3156 participants.” (opens the source at this quote in a new tab)
“On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively.” (opens the source at this quote in a new tab)
“Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naïve patients, in patients with a shorter illness duration and in open studies.” (opens the source at this quote in a new tab)

Early non-response as a predictor of later non-response

“In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%.” (opens the source at this quote in a new tab)
“Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change.” (opens the source at this quote in a new tab)

Sex: registration trials of antipsychotics

“The number needed to treat (NNT) for a response in women was 6.9, in men 9.4.” (opens the source at this quote in a new tab)
“Despite the impact of gender and age on effect size in acute antipsychotic treatment, efficacy was clinically relevant in all subgroups.” (opens the source at this quote in a new tab)

Sex: individual participant data from fixed-dose trials

“There was no evidence of sex differences in drug effects on overall symptoms (difference of standardised mean difference [DoSMD] 0·04, 95% CI -0·09 to 0·18).” (opens the source at this quote in a new tab)
“Prolactin increase was greater in females (DoSMD 0·83, 0·67-0·99; high credibility)” (opens the source at this quote in a new tab)

Race and ethnicity

“In the complete data-set, 61% of patients were White, 25.6% of patients were Black and 13.4% of patients were of other ethnicities.” (opens the source at this quote in a new tab)
“Atypical antipsychotic medication is equally effective in both Black and White patients with schizophrenia.” (opens the source at this quote in a new tab)

“Many sites had a trial population that was predominantly Black, reflecting the urban US clinical settings in which recruitment for many sites occurred.” (opens the source at this quote in a new tab)

Age and predominant negative symptoms: amisulpride

“Nevertheless, amisulpride was significantly superior to placebo in older patients (≥60 years of age; SMD 0·86) and in patients with predominant negative symptoms (SMD 0·47).” (opens the source at this quote in a new tab)

Moderators of metabolic adverse effects

“Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082).” (opens the source at this quote in a new tab)
“Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity.” (opens the source at this quote in a new tab)

Sex and treatment resistance

“Men were 1.57 times more likely to develop TRS than women (95% CI 1.11-2.21, P = 0.010).” (opens the source at this quote in a new tab)

Trial-level moderators of drug-placebo differences

“However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes.” (opens the source at this quote in a new tab)

NOVA-1 subgroup analyses by sex, race, age, or baseline severity

No evidence found.

Coordinated specialty care for first-episode psychosis

“APA recommends (1B) that patients with schizophrenia who are experiencing a first episode of psychosis be treated in a coordinated specialty care program.” (opens the source at this quote in a new tab)

“Participants (mean age 23) with schizophrenia and related disorders and ≤6 months antipsychotic treatment (N=404) were enrolled and followed for ≥2 years.” (opens the source at this quote in a new tab)
“NAVIGATE participants with duration of untreated psychosis <74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in Community Care.” (opens the source at this quote in a new tab)

Assertive community treatment and intensive case management

“We recommend the use of service models based on standard Assertive Community Treatment in individuals with schizophrenia evidencing severe functional impairments and/or risk for repeated hospitalizations.” (opens the source at this quote in a new tab)

“When ICM was compared with standard care for the outcome service use, ICM slightly reduced the number of days in hospital per month (n = 3595, 24 RCTs, MD ‐0.86, 95% CI ‐1.37 to ‐0.34,low‐quality evidence).” (opens the source at this quote in a new tab)

Long-acting injectable programs in early-phase illness

“In this cluster randomized trial of 489 participants, use of long-acting injectable aripiprazole monohydrate was associated with a significant delay in time to first hospitalization, with the number needed to treat to prevent 1 hospitalization of 7.” (opens the source at this quote in a new tab)

Clozapine: removal of the risk evaluation and mitigation strategy in 2025

“Food and Drug Administration (FDA) removed the risk evaluation and mitigation strategy (REMS) for clozapine (currently marketed as Clozaril, Versacloz, and generics), effective June 13, 2025.” (opens the source at this quote in a new tab)
“The removed REMS required enrollment of prescribers, pharmacies, and patients in a restricted distribution program and reporting of the level of certain white blood cells (i.e., the absolute neutrophil count (ANC)) to mitigate the risk of severe neutropenia.” (opens the source at this quote in a new tab)
“the Agency determined that the REMS was no longer necessary to ensure the benefits of clozapine outweigh the risk of severe neutropenia.” (opens the source at this quote in a new tab)
“Eliminating the REMS is expected to improve access to clozapine and decrease the burden on the health care delivery system.” (opens the source at this quote in a new tab)

Clozapine: neutrophil monitoring retained in labeling

“Prior to initiating CLOZARIL treatment, obtain baseline ANC(s).” (opens the source at this quote in a new tab)

“Frequent absolute neutrophil count (ANC) monitoring is necessary to identify neutropenia early so that health care professionals can intervene.” (opens the source at this quote in a new tab)

Metabolic monitoring during antipsychotic treatment

“Fasting blood glucose or HbA1c four months after initiating a new treatment and at least annually thereafter” (opens the source at this quote in a new tab)
“Lipid panel four months after initiating a new antipsychotic medication and at least annually thereafter” (opens the source at this quote in a new tab)

Management of antipsychotic-induced weight gain

“We suggest using metformin, topiramate, or aripiprazole augmentation for treatment of metabolic side effects of antipsychotic medication and weight loss for individuals with schizophrenia.” (opens the source at this quote in a new tab)

“We recommend that people with schizophrenia should be offered adjunctive metformin for the management of antipsychotic-induced weight gain.” (opens the source at this quote in a new tab)

Prior authorization of atypical antipsychotics: Maine Medicaid

“More than one-third of Medicaid programs and Medicare Part D plans use prior authorization (PA) policies to control the use of atypical antipsychotics (AAs).” (opens the source at this quote in a new tab)
“Patients initiating AAs during Maine's policy experienced a 29 percent greater risk of treatment discontinuity than patients initiating AAs before the policy took effect; no change occurred in a comparison state.” (opens the source at this quote in a new tab)

Formulary restrictions on atypical antipsychotics: 24 state Medicaid programs

“Patients with schizophrenia subject to formulary restrictions were more likely to be hospitalized (odds ratio 1.13, P <.001), had 23% higher inpatient costs (P <.001), and 16% higher total costs (P <.001).” (opens the source at this quote in a new tab)

Prior authorization and antipsychotic utilization in Medicaid

“We find that prior authorization requirements on atypical antipsychotics and other psychotherapeutics greatly reduced the utilization of these drugs and this reduction is not offset by substitution to other drugs in the same drug classes” (opens the source at this quote in a new tab)
“with the adverse consequence that fewer patients are receiving pharmacotherapy.” (opens the source at this quote in a new tab)

Step therapy for atypical antipsychotics: Georgia Medicaid

“Among patients with schizophrenia, the PA policy was associated with a USD 19.62 per member per month (PMPM) decrease in atypical antipsychotic expenditures and a USD 2.20 PMPM increase in typical antipsychotic expenditures (both, P < 0.001).” (opens the source at this quote in a new tab)
“the reduction in atypical antipsychotic expenditures was accompanied by a USD 31.59 PMPM increase in expenditures for outpatient services (P < 0.001).” (opens the source at this quote in a new tab)

State law limiting step therapy for serious mental illness: Colorado

“Effective January 1, 2025, with respect to step-therapy protocols (protocols) for health insurance, section 1 of the act defines "serious mental illness" and prohibits the protocols from requiring a person to try more than one prescription drug prior to receiving coverage for the drug prescribed by the person's health-care provider.” (opens the source at this quote in a new tab)
“The act requires the medical services board to require a review for coverage of a new drug approved by the federal food and drug administration for a serious mental illness within 90 days after the drug is approved.” (opens the source at this quote in a new tab)

Trials the company expects to support approval

“Based on the design of this clinical trial, the results discussed below, and positive feedback from FDA as part of our end-of-Phase 2 interaction, we believe this Phase 2 trial may serve as one of two adequate well-controlled clinical trials of LB-102 required for approval.” (opens the source at this quote in a new tab)

Safety database the company anticipates the FDA will require

“In addition to our 6-week Phase 3 trial, the design of which we shared with the FDA as part of our end-of-Phase 2 interaction, we anticipate the FDA will require 1,500 patient exposures to support an approval in schizophrenia.” (opens the source at this quote in a new tab)
“We expect to accrue these patient exposures through the Phase 3 and long-term OLE trials, the supportive Phase 1 trials and trials in other indications.” (opens the source at this quote in a new tab)

“Concurrently with the Phase 3 NOVA-2 trial, we are enrolling an outpatient, open label trial (NOVA-3) to accrue the requisite safety population required to support NDA submission as well as other clinical trials and non-clinical studies typically required by FDA for an NDA approval.” (opens the source at this quote in a new tab)

Post-marketing requirements or commitments

Not applicable.

Post-approval monitoring requirements

Not applicable.

Summary

Guidelines state three aims of treatment planning: to promote and maintain recovery, to maximize quality of life and adaptive functioning, and to reduce or eliminate symptoms. In trials, symptom outcomes are measured on the PANSS (range 30 to 210). A CGI rating of minimally improved corresponds to a PANSS reduction of 19% to 28% and a rating of much improved to 40% to 53%, which is the basis for the 20% and 50% response thresholds; the authors recommend at least a 50% reduction as the response criterion in acute trials and note that a 25% cut-off might be appropriate in treatment-resistant populations. An absolute reduction of about 15 PANSS points corresponds to minimal improvement on the CGI, and an anchor-based analysis of CATIE data estimated the minimum clinically important difference at 15.3 points (34.0%) with the clinician-rated CGI and 11.2 points (24.6%) with the patient-rated CGI.

Against these thresholds, 51% of participants receiving antipsychotics and 30% receiving placebo had at least a minimal response in placebo-controlled trials of mainly chronic participants, and 23% and 14% had a good response. In first-episode trials, 81.3% reached a 20% reduction and 51.9% a 50% reduction. Absence of a 20% reduction at week 2 predicted nonresponse at endpoint with a positive predictive value of 90%. The mean drug-placebo difference in PANSS change rises with baseline severity, from 9.5 points at a baseline score of 58 to 24.0 points at a baseline score of 116. In NOVA-1, the week 4 change in PANSS total score was −14.3 points with LB-102 50 mg, −14.0 with 75 mg, and −9.3 with placebo.

Remission is defined by consensus criteria as no more than mild positive and negative symptoms sustained for at least 6 months. With maintenance treatment, relapse at 1 year occurred in 24% to 27% of participants receiving antipsychotics and 61% to 64% receiving placebo, and hospitalization in 7% and 18%. The median proportion meeting recovery criteria that combine clinical and social outcomes was 13.5%.

Aims of treatment planning: APA practice guideline

“The overarching aims of treatment planning are 1) to promote and maintain recovery, 2) to maximize quality of life and adaptive functioning, and 3) to reduce or eliminate symptoms.” (opens the source at this quote in a new tab)

Response thresholds on the PANSS linked to clinical global impressions

“To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively.” (opens the source at this quote in a new tab)
“The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%.” (opens the source at this quote in a new tab)
“Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds.” (opens the source at this quote in a new tab)
“In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.” (opens the source at this quote in a new tab)

Absolute PANSS change linked to clinical global impressions

“An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of ‘minimally improved’ and to a change of the CGI severity score by one severity step.” (opens the source at this quote in a new tab)
“Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients.” (opens the source at this quote in a new tab)

Minimum clinically important difference on the PANSS

“The MCID for PANSS scores using this scale equaled a 15.3 point (34.0%) change from baseline.” (opens the source at this quote in a new tab)
“With the patient-rated CGI as the anchor, PANSS scores were higher for CGI scores of 1 through 4 and the MCID was lower, 11.2 points (24.6%).” (opens the source at this quote in a new tab)

Early response as the expected course

“Available evidence suggests that patients who have not exhibited at least a 20% reduction in symptoms (or minimal improvement) by about 2 weeks on a therapeutic dose are unlikely to be much improved at 4–6 weeks as reflected by at least a 50% reduction in symptoms” (opens the source at this quote in a new tab)

Remission criteria

“The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness.” (opens the source at this quote in a new tab)

“remission, consisting of no more than mild positive and negative symptoms for ≥6 months” (opens the source at this quote in a new tab)

Relapse prevention and hospitalization on maintenance treatment

“Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted.” (opens the source at this quote in a new tab)

“Hospitalisation was also reduced, however, the baseline risk was lower (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR 0.43, 95% CI 0.32 to 0.57, NNTB 8, 95% CI 6 to 14; high‐certainty evidence).” (opens the source at this quote in a new tab)
“For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs prevents relapse to a much greater extent than placebo for approximately up to two years of follow‐up.” (opens the source at this quote in a new tab)

Quality of life and functioning

“Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term.” (opens the source at this quote in a new tab)

“Quality of life might be better in drug‐treated participants (7 RCTs, n = 1573 SMD ‐0.32, 95% CI to ‐0.57 to ‐0.07; low‐certainty evidence)” (opens the source at this quote in a new tab)

Functional recovery

“Based on the best available data, the median proportion of individuals with schizophrenia who met our recovery criteria was 13.5%.” (opens the source at this quote in a new tab)

LB-102 primary outcome in NOVA-1

“The primary end point of the change from baseline to week 4 in PANSS total score showed statistical superiority with LB-102 50 mg and 75 mg compared with placebo using the Hochberg correction” (opens the source at this quote in a new tab)
“Additionally, although LB-102 demonstrated broad symptomatic efficacy, it is possible that, in an acute 4-week trial, improvements in negative symptoms may be secondary to the resolution of positive symptoms (pseudospecificity); further studies are required to disentangle these effects.” (opens the source at this quote in a new tab)