Maintenance treatment with antipsychotic drugs for schizophrenia

Anna Ceraso, Jessie Jingxia Lin, Johannes Schneider-Thoma, Spyridon Siafis, Magdolna Tardy, Katja Komossa, Stephan Heres, Werner Kissling, John M Davis, Stefan Leucht, Anna Ceraso, Jessie Jingxia Lin, Johannes Schneider-Thoma, Spyridon Siafis, Magdolna Tardy, Katja Komossa, Stephan Heres, Werner Kissling, John M Davis, Stefan Leucht

Abstract

Background: The symptoms and signs of schizophrenia have been linked to high levels of dopamine in specific areas of the brain (limbic system). Antipsychotic drugs block the transmission of dopamine in the brain and reduce the acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotic drugs are also effective for relapse prevention. This is the updated version of the aforesaid review.

Objectives: To review the effects of maintaining antipsychotic drugs for people with schizophrenia compared to withdrawing these agents.

Search methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (12 November 2008, 10 October 2017, 3 July 2018, 11 September 2019).

Selection criteria: We included all randomised trials comparing maintenance treatment with antipsychotic drugs and placebo for people with schizophrenia or schizophrenia-like psychoses.

Data collection and analysis: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) or standardised mean differences (SMD), again based on a random-effects model.

Main results: The review currently includes 75 randomised controlled trials (RCTs) involving 9145 participants comparing antipsychotic medication with placebo. The trials were published from 1959 to 2017 and their size ranged between 14 and 420 participants. In many studies the methods of randomisation, allocation and blinding were poorly reported. However, restricting the analysis to studies at low risk of bias gave similar results. Although this and other potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear. 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). Hospitalisation was also reduced, however, the baseline risk was lower (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR 0.43, 95% CI 0.32 to 0.57, NNTB 8, 95% CI 6 to 14; high-certainty evidence). More participants in the placebo group than in the antipsychotic drug group left the studies early due to any reason (at seven to 12 months: drug 36% versus placebo 62%, 24 RCTs, n = 3951, RR 0.56, 95% CI 0.48 to 0.65, NNTB 4, 95% CI 3 to 5; high-certainty evidence) and due to inefficacy of treatment (at seven to 12 months: drug 18% versus placebo 46%, 24 RCTs, n = 3951, RR 0.37, 95% CI 0.31 to 0.44, NNTB 3, 95% CI 3 to 4). Quality of life might be better in drug-treated participants (7 RCTs, n = 1573 SMD -0.32, 95% CI to -0.57 to -0.07; low-certainty evidence); probably the same for social functioning (15 RCTs, n = 3588, SMD -0.43, 95% CI -0.53 to -0.34; moderate-certainty evidence). Underpowered data revealed no evidence of a difference between groups for the outcome 'Death due to suicide' (drug 0.04% versus placebo 0.1%, 19 RCTs, n = 4634, RR 0.60, 95% CI 0.12 to 2.97,low-certainty evidence) and for the number of participants in employment (at 9 to 15 months, drug 39% versus placebo 34%, 3 RCTs, n = 593, RR 1.08, 95% CI 0.82 to 1.41, low certainty evidence). 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).

Authors' conclusions: For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs prevents relapse to a much greater extent than placebo for approximately up to two years of follow-up. This effect must be weighed against the adverse effects of antipsychotic drugs. Future studies should better clarify the long-term morbidity and mortality associated with these drugs.

Trial registration: ClinicalTrials.gov NCT00111189 NCT00658645 NCT00704509.

Conflict of interest statement

Anna Ceraso: none to declare. Jessie Lin: none to declare. Johannes Schneider‐Thoma: none to declare. Spyridon Siafis: none to declare. Magdolna Tardy: none to declare. Katja Komossa: none to declare. Stephan Heres: received speaker honoraria from Janssen‐Cilag, Eli Lilly, Sanofi‐Aventis, Otsuka, Lundbeck and Johnson & Johnson; accepted travel or hospitality payment from Janssen‐Cilag, Sanofi‐Aventis, Johnson & Johnson, Pfizer, Bristol‐Myers‐Squibb, AstraZeneca, Lundbeck, Novartis and Eli Lilly; participated in clinical trials sponsored or supported by Eli Lilly, Janssen Cilag, Johnson & Johnson, Bristol‐Myers‐Squibb, AstraZeneca, Lundbeck, Novartis, Servier, Pierre Fabre, Pfizer, Organon, Roche and Merck; and received honoraria for participation in advisory‐boards or activities as a consultant from Lundbeck, Otsuka, Eli Lilly, Roche, Teva, Janssen and Johnson & Johnson. Werner Kissling: has received honoraria for board memberships, consulting and lectures from Janssen and Eli Lilly; honoraria for development of educational materials from Janssen; grant support from Janssen and AstraZeneca; and travel/accommodation expenses from AstraZeneca, Eli Lilly and Janssen. John M Davis: none to declare. Stefan Leucht: In the last three years Stefan Leucht has received honoraria for lectures or consulting from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini, Recordati, Sunovion, Geodon Richter.