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LB-102

Schizophrenia

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345 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatmentCurrent treatment options and standard of care

Limitations of current therapies

13 evidence topics · 25 sources

Summary

Treatment discontinuation is frequent. In CATIE, 1,061 of 1,432 participants (74%) stopped the assigned antipsychotic before 18 months, from 64% with olanzapine to 82% with quetiapine. In a Swedish cohort of 29,823 individuals with schizophrenia followed from 2006 to 2013, 43.7% were rehospitalized and 71.7% of 28,189 had treatment failure. A meta-analysis pooled psychotropic medication nonadherence in schizophrenia at 56%, and an earlier review reported mean nonadherence rates of 41.2% and 49.5% under two sets of inclusion criteria.

Response is incomplete. Across 167 placebo-controlled trials with 28,102 participants, at least a minimal response occurred in 51% of participants receiving an antipsychotic and 30% receiving placebo, and a good response in 23% and 14%. Treatment resistance developed in 22.8% of first-episode cohorts (12 studies, 11,958 participants) and in 24.4% of first-episode schizophrenia cohorts. Clozapine, the agent guidelines recommend for treatment resistance, produced response in 40.1% of treated participants, which the authors translate into 12% to 20% of people with schizophrenia being ultra-resistant. Clozapine carries a boxed warning for severe neutropenia, orthostatic hypotension, seizure, and myocarditis.

Negative and cognitive symptoms remain. Up to 60% of people with schizophrenia have prominent, clinically relevant negative symptoms, and a meta-analysis of 168 placebo-controlled trials found that no treatment reached the threshold for clinically significant improvement in negative symptoms. The VA/DoD guideline found insufficient evidence to recommend for or against augmentation with any non-antipsychotic medication for cognitive or negative symptoms.

Adverse effects differ by agent. Metabolic syndrome was present in 32.5% of people with schizophrenia and related disorders. Mean weight gain against placebo ranged up to 3.01 kg for clozapine in one network meta-analysis and up to 3.21 kg for zotepine in another. Rating scale-based tardive dyskinesia prevalence was 25.3% across 41 studies (20.7% with current second-generation and 30.0% with current first-generation treatment), and risk ratios for antiparkinson medication use against placebo ranged from 1.61 for paliperidone to 6.14 for pimozide among the 21 agents with a significant increase. Prolactin change against placebo ranged from a decrease of 77.05 ng/mL with clozapine to an increase of 48.51 ng/mL with paliperidone, and the highest rates of hyperprolactinemia are reported with amisulpride, risperidone, and paliperidone.

Relapse occurs during treatment. Maintenance antipsychotic treatment reduced relapse at 1 year from 64% to 27% in one meta-analysis and from 61% to 24% in a Cochrane review, and pooled relapse incidence during long-acting injectable treatment was 22.97 per 100 participant-years. The median proportion of people meeting recovery criteria was 13.5% across 50 studies. Among agents with a mechanism other than dopamine receptor blockade, adjunctive xanomeline and trospium chloride did not reach statistical significance on its primary endpoint in ARISE (2.0-point PANSS difference, P = 0.11), and emraclidine did not meet the primary endpoint in two phase 2 trials.

All-cause discontinuation in CATIE

“The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons.” (opens the source at this quote in a new tab)

Medication nonadherence

“Overall, 49% of major psychiatric disorder patients were non-adherent to their psychotropic medication.” (opens the source at this quote in a new tab)

“Of these, psychotropic medication non-adherence for schizophrenia, major depressive disorders, and bipolar disorders were 56%, 50%, and 44%, respectively.” (opens the source at this quote in a new tab)

“Among the 10 reports that met a strict set of study inclusion criteria, we found a mean rate of nonadherence of 41.2%; the 5 reports that met a stricter set of inclusion criteria had a mean nonadherence rate of 49.5%.” (opens the source at this quote in a new tab)

Incomplete response in placebo-controlled trials

“At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response.” (opens the source at this quote in a new tab)

Treatment resistance in first-episode cohorts

“Twelve studies were included, totalling 11 958 participants; six studies were of high quality.” (opens the source at this quote in a new tab)

“The rate of TRS was 22.8% (95% CI 19.1-27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5-30.0%, P < 0.001) among first-episode schizophrenia cohorts.” (opens the source at this quote in a new tab)

“When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third.” (opens the source at this quote in a new tab)

Definition of treatment resistance

“The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence.” (opens the source at this quote in a new tab)

“There is considerable variation in current approaches to defining treatment resistance in schizophrenia.” (opens the source at this quote in a new tab)

Residual negative symptoms

“Negative symptoms are common in schizophrenia; up to 60% of patients may have prominent clinically relevant negative symptoms that require treatment.” (opens the source at this quote in a new tab)

“Negative symptoms clearly constitute an unmet medical need in schizophrenia, and new and effective treatments are urgently needed.” (opens the source at this quote in a new tab)

“Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale.” (opens the source at this quote in a new tab)

“Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.” (opens the source at this quote in a new tab)

Cognitive and negative symptoms: no recommended augmentation and no approved therapy

“There is insufficient evidence to recommend for or against augmentation with any non-antipsychotic medication for treatment of cognitive and/or negative symptoms for individuals with schizophrenia.” (opens the source at this quote in a new tab)

“There are no approved therapies in the U.S. for the treatment of predominantly negative symptoms of schizophrenia or cognitive impairment associated with schizophrenia.” (opens the source at this quote in a new tab)

Metabolic syndrome prevalence

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

Extrapyramidal symptoms and tardive dyskinesia

“Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment.” (opens the source at this quote in a new tab)

“Antipsychotic drugs (as a group and irrespective of duration) were associated with more participants experiencing movement disorders (e.g. at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI 1.25 to 1.85, number needed to treat for an additional harmful outcome (NNTH) 20, 95% CI 14 to 50), sedation (drug 8% versus placebo 5%, 18 RCTs, n = 4078, RR 1.52, 95% CI 1.24 to 1.86, NNTH 50, 95% CI not significant), and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR 1.69, 95% CI 1.21 to 2.35, NNTH 25, 95% CI 20 to 50).” (opens the source at this quote in a new tab)

Hyperprolactinemia

“Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL.” (opens the source at this quote in a new tab)

“The highest rates of HPRL are reported in association with risperidone, amisulpride and sulpiride, often in as high as 80–90 % of all female subjects” (opens the source at this quote in a new tab)

“FGAs and SGAs that bind strongly to the dopamine D2 receptor might also cause prolactin elevation, which can lead to galactorrhea, dysmenorrhea, and sexual dysfunction.” (opens the source at this quote in a new tab)

Relapse despite maintenance treatment

“Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3).” (opens the source at this quote in a new tab)

“Antipsychotic drugs were more effective than placebo in preventing relapse at seven to 12 months (primary outcome; drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR 0.38, 95% CI 0.32 to 0.45, number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 3; high‐certainty evidence).” (opens the source at this quote in a new tab)

“Relapse was associated with functional decline” (opens the source at this quote in a new tab)

Recovery

“The median proportion (25%–75% quantiles) who met our recovery criteria was 13.5% (8.1%–20.0%).” (opens the source at this quote in a new tab)

“Based on the best available data, approximately, 1 in 7 individuals with schizophrenia met our criteria for recovery.” (opens the source at this quote in a new tab)