Meta-Analysis Conundrums

For patients whose psychosis doesn’t adequately respond to antipsychotics, especially clozapine, treatment options include electroconvulsive therapy, cognitive-behavior therapy, and augmentation with another medication. Investigators have done cotreatment trials with other antipsychotics, anticonvulsant/mood stabilizers, and even the antibiotic minocycline and anti-inflammatory agents such as aspirin. The trials are small in many cases, so meta-analyses allow various trials to be pooled. Two recent publications give some new guidance but also may sow confusion.

One team examined clinical trials of the anticonvulsants lamotrigine, topirimate and valproate added to clozapine. They included 22 randomized controlled trials (RCTs) comprising 1227 subjects; 613 received clozapine alone, whereas the others received, in order of frequency, valproate, lamotrigine or topirimate. The primary outcome was change in Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. The analysis showed no significant effect for lamotrigine, confirming a previous meta-analysis, but also confirming a prior analysis, topirimate was superior to clozapine alone for reduction in total, positive and negative psychotic symptoms ratings. Sodium valproate, but not magnesium valproate, was superior to clozapine alone in reducing total and positive psychotic symptom scores; it was not effective for negative symptoms. In terms of tolerability, topirimate but not valproate had a significant all-cause discontinuation rate compared to clozapine monotherapy.

One of the limitations of this pooled data set was that many of the patients were not clearly designated as having clozapine resistance; for instance, clozapine serum levels were not recorded. Another concern was that all the trials for valproate augmentation were done in China, and the generalizability to other settings and ethnic groups is uncertain.

The anticonvulsant meta-analysis is one of many that has examined antipsychotic augmentation, which prompted a group led by Christoph Correll to do a meta-meta-analysis. Summarizing this article will not do it justice, so I recommend reading it in its entirety. The investigators looked at 29 existing meta-analyses of trials of augmentation of any antipsychotic with any of 42 medications including, mood stabilizers, anticonvulsants, antidepressants, minocycline, a second antipsychotic, or various hormones such as estrogenic agents. They applied a novel method to assess the quality of the meta-analyses, AMSTAR-Plus Content. Five of the meta-analyses looked at augmentation of clozapine.

In combination with clozapine for positive symptoms of psychosis, only glycine, an amino acid which modulates the NMDA glutamate receptor, had a significant effect size. No treatments showed efficacy in combination with clozapine for total psychopathology or negative symptom scores. In combination with non-clozapine antipsychotics, lamotrigine, estrogenic agents, mirtazapine and a few others showed efficacy.

An important finding is buried in the discussion: “When all this metanalytic literature was compared regarding the quality of its meta-analyzed content, the effect sizes were inversely correlated with the study quality, reducing confidence in these affirmative recommendations.” In other words, many of the studies in this uber-study were small or contained biases, and those studies tended to overrate the effects of the adjunctive treatments. They point out that individual patients may benefit from specific interventions, but the evidence to guide treatment selection is lacking. This leaves the clinician without clear direction for the most difficult-to-treat patients. In an accompanying editorial, however, Wolfgang Fleishhacker suggests that this meta-analysis does not necessarily invalidate all preceding analyses.


Zheng W, Xiang YT, Yang XH, Xiang YQ, de Leon J. Clozapine Augmentation with Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. J Clin Psychiatry. 2017;78(5):e498-e505. Abstract

Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-Analytic Evidence. JAMA Psychiatry. 2017;74(7):675-684. Astract

Topirimate as augmentation for antipsychotic treatment

With modulating dopamine as the primary pharmacotherapeutic option to treat schizophrenia, we are left unable to adequately treat at least 30% of our patients, Dr. Christoph Correll told the audience at the 2016 Pacific Psychopharmacology Conference in Vancouver. The evidence for combining dopamine antagonists, whether first- or second-generation antipsychotics, is not favorable according to a meta-analysis he described which is in review for publication. When only high-quality studies were included, which involved 14 trials with 938 subjects, the evidence for combining antipsychotics melted to nothing. Although it makes sense that using two medications with the essentially the same mechanism of action would not be synergistic, many practitioners nevertheless do just that.

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Correll, who is Professor of Psychiatry at Hofstra Northwell School of Medicine and Medical Director of the Recognition and Prevention Program at the Zucker Hillside Hospital in Queens, New York, said that adding agents with a different mechanism of action may be more promising. Topirimate acts to inhibit activity in the glutamate-NMDA receptor complex and is approved as an anticonvulsant. It also counters the weight gain of psychotropic medications by reducing appetite and enhancing insulin sensitivity. He and six coauthors have recently published a meta-analysis of 16 randomized, controlled trials including a total of 934 patients who received topirimate adjunctive to antipsychotic therapy; outcome data included PANSS or BPRS total scores and body weight, and secondary outcomes included positive and negative symptoms and various metabolic measures including waist circumference and serum glucose.

The benefit for augmentation was significant as measured by total PANSS or BPRS for the entire group, and sensitivity analyses showed it held true with a dose of 150 mg per day or less, in first and multi-episode patients, and either with clozapine or non-clozapine antipsychotics. The effect was independently significant for positive and for negative symptoms. Topirimate was associated with a significant reduction in weight with a mean reduction of 2.75 kg; other metabolic measures were unchanged except for significant reduction in serum triglycerides and fasting insulin. Although discontinuation for adverse effects or inefficacy did not differ with topirimate or placebo, notable adverse effects of topirimate included concentration problems and paresthesias.

These studies were all short-term with a mean duration of 11.8 weeks, a problem with many clinical trials in psychiatry  given that schizophrenia is a chronic disorder and patients remain on  medication for months to years. Cognitive problems including word-finding difficulty are a known effect of topirimate, and in an illness in which cognitive impairment is inherent, this could be a major liability. Longer-term effects on cognition, metabolic outcomes and psychosis are needed. Will topirimate be the NMDA-modulating treatment that makes a difference or end up like lamotrigine, abandoned after a brief dalliance?


Zheng W, Xiang Y-T, Xiang Y-Q, Li X-B, Ungvari GS, Chiu HFK, Correll CU. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2016:1–14. Published online 1 Sep 2016. Abstract

Clozapine-induced seizures: prophylaxis or not?

Clozapine is associated with an elevated risk of seizures, especially with doses of 600 mg or greater. At such doses and with elevated serum levels, many psychiatrists consider adding a prophylactic antiepileptic, which was first recommended in the journal Neurology in 1991 (1). Caetano has reviewed available studies in an effort to determine if this is sound practice, and he concludes it is not (2). According to him, the risk of clozapine-induced seizures is greatest when the serum level is 1300 ng/ml or more, the equivalent of 4000 nmol/L. The evidence for this finding is skimpy, however, and consists of case reports: one from 1994, two from 1978, and one from 2001. To accurately determine the dose-response relationship between seizures and clozapine serum levels, prospective studies would be necessary.

Despite this shortcoming, Caetano’s recommendation against prophylaxis makes sense, at least if the serum level is not approaching 4000 nmol/L and the patient doesn’t have other risk factors such as coarse brain disease. The risk of pharmacokinetic interactions and additional adverse effects with anticonvulsants is high; for instance, phenytoin can decrease and lamotrigine can increase clozapine levels. He recommends other measures for managing seizure risk and what to do if a patient does have a seizure.


1. Devinsky O, Honigfeld G and Patin J. Clozapine-related seizures. Neurology. 1991;41:369–371. Abstract

2. Caetano D. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine. Australas Psychiatry. 2014;22:78-82. Abstract

Does lamotrigine augment clozapine?

Many of the patients referred to B.C psychosis Program are on clozapine or have received it in the past, and many have had a limited response. Clozapine-resistance is a big challenge for psychiatrists who manage chronic psychosis, and a recent quantitative review of clozapine augmentation strategies provides little guidance or solace. Stefan Leucht and colleagues examined randomized, masked, placebo-controlled studies

of at least two weeks duration in which another drug was added following at least four weeks of  clozapine therapy. Whenever possible, they used intention-to-treat data to calculate effect size.

The studies involved a range of medications including antidepressants, antipsychotics, glutamatergic agents, and antiepileptics. Lamotrigine is particularly of interest because Tiihonen’s group performed a meta-analysis in 2009 based on five studies that showed a significant effect for augmentation of clozapine. This group obtained unpublished data from studies that looked at lamotrigine added to a variety of antipsychotics, and intention-to-treat outcomes from the trial by Zocali, the largest study to date with 30 subjects on active therapy. Based on the 2009 meta-analysis, Goff commented that “the addition of lamotrigine in patients who remain symptomatic despite adequate clozapine treatment represents the most promising treatment option currently available.”

Although Tiihonen et al. found insignificant heterogeneity, Leucht et al. did find heterogeneity and concluded that the Zocali study was an outlier. They therefore excluded it from their final analysis. This is the crucial difference between the two meta-analyses and the reason for the sharply divergent conclusions. Four studies of lamotrigine augmentation are negative and one is positive. A closer look reveals that the Zocali trial was 24 weeks in duration, whereas the other trials were 10 to 14 weeks; could this be a crucial difference? Goff is still correct, and rather than throw lamotrigine overboard, we need a replication trial lasting 24 or 30 weeks. We know that the benefits of clozapine may take many months to be fully evident, so we should not expect that clozapine augmentation to be a quick affair.

As for other findings of the Leucht meta-analysis, sulpiride augmentation showed significant impact on both positive and negative symptoms, and citalopram showed significant impact on negative symptoms, but the findings are based on one trial each. A trial of an experimental glutamatergic agent showed a signal. This leaves us with few clear optins but some direction for further research.


Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. Mar 21 2011; Epub ahead of print; doi:10.1093/schbul/sbr004

Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2009;109:10–14.

Goff DC. Review: lamotrigine may be an effective treatment for clozapine resistant schizophrenia. Evid Based Mental Health. 2009;12:111.

Zoccali R,Muscatello MR,Bruno A, Cambria R, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res. 2007;93:109–116.