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ABSTRACT FROM: Zheng W, Xiang YT, Xiang YQ, et al. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016;134:385–98.
What is already known on this topic
Although a previous meta-analysis showed that topiramate-antipsychotic cotreatment improved the psychopathology and prevented/reduced weight gain in patients with schizophrenia,1 the number of patients and studies included in the analysis were small (8 randomised controlled trials (RCTs), 439 patients). Therefore, Zheng et al conducted a systematic review and meta-analysis to achieve more robust evidence with respect to the efficacy for psychopathology and body weight of topiramate adjunctive therapy in antipsychotic-treated schizophrenia (16 RCTs, 934 patients).
Methods of the study
This study included RCTs of antipsychotic cotreatment with topiramate in patients with schizophrenia-spectrum disorders (schizophrenia, schizophreniform disorder, schizoaffective disorder). PubMed, PsycINFO, Embase, Cochrane Library databases, the Cochrane Controlled Trials Register and Chinese databases (WanFang Database, Chinese Biomedical database and China Journal Net) were searched until June 2015, without language restriction. Moreover, reference lists from the RCTs, meta-analyses and systematic reviews were reviewed to identify additional studies. The primary outcome measures were improvement of total symptoms (change/end point difference in Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale total score) and in body weight. Secondary outcomes were improvement of PANSS positive, negative and general subscale scores, body mass index (BMI), waist and hip circumference, waist-to-hip ratio, glucose and lipid parameters, all-cause and specific-cause discontinuation, and adverse effect frequencies. Dichotomous outcomes were presented as risk ratios (RRs) with 95% CIs. When RRs were significant, the number needed to harm (NNH) was calculated as the inverse of the risk difference. Continuous outcomes were analysed using the mean difference (MD) or, when different studies used different scales (psychopathology), standardised MD (SMD). Heterogeneity was assessed using the I2 statistics, with I2≥50% considered substantial heterogeneity. A random-effects model was used for all cases.
What does this paper add
Topiramate adjunctive therapy was superior to control (placebo and antipsychotic alone) in the psychopathology (total symptoms (SMD −0.58, 95% CI −0.82 to −0.35, I2=53%), PANSS positive (SMD −0.37, −0.61 to −0.14), negative (SMD −0.58, −0.87 to −0.29) and general subscale scores (SMD −0.68, −0.95 to −0.40)) as well as body weight (MD −2.75 kg, −4.03 to −1.47, I2=84%), BMI (MD −1.77, −2.38 to −1.15), serum triglycerides (MD −0.22, −0.38 to −0.06) and fasting insulin (MD −2.04, −2.66 to −1.41).
The researchers performed the sensitivity/subgroup analyses and a meta-regression analysis to determine the reasons for the heterogeneity. Although meta-regression analysis showed that only shorter illness duration (p=0.047) was significantly related to greater total symptoms change, they did not detect apparent confounding factors.
Topiramate was associated with a higher incidence of concentration/attention difficulties (RR 8.97, 1.17 to 68.63; NNH 8, 4 to 25), psychomotor slowing (RR 1.81, 1.11 to 2.96; NNH 7, 4 to 25) and paraesthesia (RR 2.03, 0.99 to 4.18; NNH 2, 4 to 33) compared with control. Conversely, topiramate was associated with a less incidence of constipation (RR 0.17, 0.03 to 0.94, NNH 9, 5 to 100), increased appetite (RR 0.26, 0.10 to 0.66; NNH 4, 3 to 9) and weight gain (RR 0.31, 0.15 to 0.65; NNH 2, 1 to 2).
Since the study duration was short (mean=11.8±5.6, range=2–24 weeks), the researchers could not determine whether topiramate adjunctive therapy has long-term effects on psychopathology and metabolic parameter.
The study did not evaluate the association between topiramate dose and the results of treatment outcomes (psychopathology, metabolic parameter and individual adverse events).
Although there was difference in risk of weight gain among the antipsychotics,2 because the meta-analysis included various antipsychotics trials, it remains unclear which antipsychotic should be used in association with topiramate.
What next in research
Further research is required to examine the long-term (at least 6 months, eg, a trial which examine relapse rate is considered to need duration of this period3) efficacy and safety/acceptability of topiramate adjunctive therapy in antipsychotic-treated schizophrenia patients.
Since antipsychotics differ in their characteristics in terms of efficacy and safety (eg, olanzapine and clozapine have been demonstrated to have a higher risk of weight gain compared with other second-generation antipsychotics),2 further study is required to determine which antipsychotic should be used in association with topiramate.
Do these results change your practices and why?
Yes and no. The use of topiramate for treatment of schizophrenia and for control antipsychotic-induced metabolic adverse events is off-label. However, this study suggests that topiramate adjunctive therapy is a useful agent for patients with schizophrenia to improve psychopathology and prevent/reduce weight gain, triglycerides and insulin resistance.
Competing interests TK has received speaker's honoraria from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, Janssen, Yoshitomi, Otsuka, Meiji, MSD and Tanabe-Mitsubishi, and has a Fujita Health University School of Medicine research grant.
Provenance and peer review Commissioned; internally peer reviewed.