Maintenance treatment with antipsychotic drugs for schizophrenia

Antipsychotic drugs are the mainstay of treatment of schizophrenia, not only in the event of acute episodes, but also in the long-term perspective. While people might want to stop their treatment at some stage, recurrences of psychotic symptoms are known to occur after treatment discontinuation. Relapses can lead to risk of harm, loss of autonomy and substantial distress for individuals and their families.

The current report presents the update version of a systematic review previously published in 2012, and is based on 75 randomised controlled trials (RCTs) published over a long period since the 1950s and including more than 9000 participants. The effects of all antipsychotic drugs are here compared to those of placebo - namely drug discontinuation - for maintenance treatment, that is prevention of relapses. The aim is to explore the benefits and risks of each of the two options.

The results of this review show very consistently that antipsychotic drugs effectively reduce relapses and need for hospitalisation. Indeed, in case of treatment discontinuation, the risk of relapse at one year is almost three times higher. Antipsychotic drugs appear to have a positive effect on the ability to engage in activities and relationships, and on the possibility to fulfil remission from symptoms, although less evidence is available in this regard. Though based again on a lower number of reports, people continuing their treatment tend to experience higher satisfaction with their life, which confirms the negative consequences on well-being of being at higher risk for recurrence. Conversely, antipsychotic drugs are, as a group, associated with a number of side effects such as movement disorders, weight gain and sedation. However, this review allows more understanding of the fact that stopping treatment is far more harmful than thoughtfully maintaining it.

Unfortunately, studies included in this review do generally last up to one year, and this makes difficult to clarify the longer-term effect of these drugs. It is however true that the longer the study the more likely that other factors - e.g. environmental – may accumulate and complicate the interpretation of results. Most of all, this review supports the advantages of antipsychotic drugs among many different types of participants. The best strategy would be therefore to continue treatment with antipsychotics, eventually discussing and adapting it if any adverse effect occurs.

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.

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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 strategy: 

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).

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