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.