For most antipsychotics used to treat schizophrenia, many differences are relatively small, but there are marked differences in their side effects, new research suggests.
Results of a network meta-analysis of 402 randomized controlled trials (RCTs) that compared 32 older and newer oral antipsychotics either to each other or to placebo showed that with few exceptions, only clozapine, amisulpride, zotepine, olanzapine, and risperidone were significantly more effective for reducing symptoms.
In general, older antipsychotics were more frequently associated with extrapyramidal motor side effects (EPS) and elevations in prolactin levels. Many newer antipsychotics were associated with more weight gain and sedation.
"We hope that doctors can use the efficacy and side effects panels presented in the publication to choose the best-suited drug for the individual patient," Maximilian Huhn, PhD, of the Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Germany, toldMedscape Medical News.
"The side effect profile should be weighed against the comparably smaller efficacy differences between the individual drugs," he said.
The study was published online July 11 inLancet.
Newer vs Older Agents
Although antipsychotics are the "mainstay of treatment" for schizophrenia, they are associated with important side effects, the authors write.
For this reason, a clear understanding of the relative risks and benefits of these agents is "essential for informed decision making," the investigators state.
Newer antipsychotics are often the treatment of choice, but older antipsychotics are less expensive and are still used worldwide, especially in low-income countries, the authors note.
In addition, neither the older antipsychotics nor brexpiprazole and cariprazine — both recently approved agents — have been compared in a network meta-analysis.
"There are many antipsychotic treatment options for acute treatment of schizophrenia and many different side effects, so we conducted a network meta-analysis. This is an attempt to summarize the data in a quantitative way," said Huhn.
Of 54,417 studies, the researchers included 402 RCTs of antipsychotics used to treat patients with acute symptoms of schizophrenia or related disorders (n = 53,463 participants; mean [SD] age, 37.40 [5.96] years; 56.02% male; mean duration of illness, 11.9 [5.19] years).
Studies were double-blind and were either placebo controlled or head-to-head comparisons.
Studies of treatment-resistant patients, as well as studies of first episode, predominantly negative or depressive symptoms, concomitant medical illness, and relapse prevention, were excluded, as were trials in which antipsychotics were used as an adjunctive or combination treatment.
The researchers included all oral second-generation ("atypical") antipsychotics available in Europe or the United States, as well as a selection of oral first-generation ("typical" or "conventional") antipsychotics.
The primary outcome was change in overall symptoms of schizophrenia, as measured by published rating scales, such as the Positive and Negative Syndrome Scale or the the Brief Psychiatric Rating Scale.
Secondary outcomes were all-cause discontinuation; discontinuation due to inefficacy; and study-defined responder rates.
Additional secondary outcomes were change in positive, negative, and depressive symptoms; quality of life; and social functioning, as measured by means of published rating scales.
Side effects examined were EPS (assessed on the basis of use of antiparkinson drugs), akathisia, weight gain, prolactin levels, sedation or somnolence, QTc prolongation, and ≥1 anticholinergic side effects.
The network meta-analysis combined direct and indirect comparisons using a Bayesian hierarchical model.
Effect sizes were risk ratios (RRs) for dichotomous outcomes and standardized mean differences (SMDs) for efficacy-related continuous outcomes. These were selected because the study involved use of different rating scales.
Efficacy, Response Rates
All antipsychotics produced greater reductions in overall symptoms than placebo. SMDs ranged from –.89 (95% credible interval [Crl], –1.08 to –.71) for clozapine to –.03 (–.59 to .52) for levomepromazine (n = 218 studies; 40,815 participants; 32 antipsychotics).
Clozapine, amisulpride, zotepine, olanzapine, and risperidone reduced overall symptoms the most. For the remaining drugs, differences were "small or very uncertain."
Compared with placebo, amisulpride, risperidone, olanzapine, paliperidone, and haloperidol were found to be more effective than other drugs in reducing positive symptoms (n = 117 studies; 31,179 participants; 21 antipsychotic). Clozapine, amisulpride, olanzapine, and (to a lesser extent) zotepine and risperidone reduced negative symptoms significantly more than many other drugs (n = 132 studies; 32,015 participants; 21 antipsychotics).
Sulpiride, clozapine, amisulpride, and olanzapine were associated with significantly greater reduction of depressive symptoms; aripiprazole was associated with the greatest improvement in quality of life, and thioridazine with improvement in social functioning (n = 89 studies, 19,683 participants, n = 10 studies, 3341 participants; and n = 16 studies, 4370 participants, respectively).
Although 192 studies (n = 35,115 participants) used very different cutoffs for defining response rates, 29 of 31 antipsychotics included were found to have significantly higher response rates compared with placebo, with RRs ranging from 2.16 (95% CrI, 1.53 – 3.55) for thioridazine to 1.11 (95% CrI, 1.01 – 1.19) for brexpiprazole.
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