What next when clozapine fails?


Schizophrenia is an extremely challenging disorder to treat. Between one-fifth and one-third of patients have little, if any, benefit from antipsychotics.The landmark trial of Kane et al demonstrated superior efficacy for clozapine over other antipsychotic agents for  medication-resistant patients. However,40%–70% of  patients on clozapine achieve only poor or partial response with it, even with adequate blood levels of clozapine. Augmenting these partial responders is a tricky business.Expert guidelines have generally been conservative about augmentation strategies due to want of clear documented evidence.

This meta-analysis looked at RCT evidence for  augmentation medications for patients with schizophrenia spectrum disorder on a stable dose of clozapine for at least one month. 29 RCTs met the inclusion criteria.The primary outcome measure was the mean change in total score on the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS).

Findings:  All results are based on small number of studies.  29 RCTS had 1066 patients in total. Altogether 15 different agents were used to augment.

Lamotrigine:  Superior than placebo. but, once the outlier study was excluded,no difference with placebo.

Topiramate:  A trend towards benefit. Studies differ widely ( ie heterogeneity is high) and once outlier study is excluded there is no benefit.

Citolapram: superior to placebo  on total symptom severity. Superior for negative symptoms, not for positive symptoms.

Flouxetine- No benefit

Mirtazapine- A trend towards benefit.High heterogeneity among studies, some studies show large effect and others none.

Amisulpiride- 1 study- no benefit

Aripiprazole.- 2 studies- no benefit

Haloperidol- No benefit

Risperiodne-  5 studies-no benefit

Sulpiride- 1 study- Benefit over placebo.

d cycloserine- no benefit, D serine- no benefit,Glycine- 3 studies ,no benefit

CX516. (glutamatergic drug): superior to placebo

Sarcosine- no benefit

Better improvement of total symptom severity than placebo was found for lamotrigine, sulpiride, citalopram, and CX516. The superior efficacy of lamotrigine was only present if an outlier remained included in the meta-analysis. Sulpiride, citalopram, and CX516 results were based on single RCT.Significant better efficacy on positive symptom severity was found for topiramate and sulpiride. After outlier removal the significant effect for topiramate disappeared. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Previous meta analysis:

1. Taylor and Smith: (Augmentation of clozapine with a second antipsychotic—a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand. 2009;119: 419–425): Marginally superior effect compared with placebo for total symptom severity if augmented with a second antipsychotic agent.

2.Barbui et al : (Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull. 2009;35:458–468): Only modest or absent effect for  second antipsychotic for augmentation.

3. Kontaxakis et al. (Risperidone augmentation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006;256:350–35):Qualitatively reviewed all studies on risperidone addition to clozapine. Risperidone augmentation is an effective strategy for clozapine-resistant patients. They included case reports and open case series and this might explain the positive conclusion.

4.Tiihonen et al  (The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109: 10–14): Lamotrigine is beneficial. They did not consider one of the studies highlighted as an outlier  in this review and this accounts for the different conclusion.

Authors conclude that there is currently no replicated evidence for any pharmacological augmentation strategy to combat resistant total, positive, or negative symptoms in clozapine-treated patients. All positive effects were either based on one outlying study or derived from a single RCT.

However, psychiatrists would have to try different options when there is only partial response to clozapine. Any augmentation would need to be part of a broader plan. Trials need to be adequate in dose and duration.Monitoring should be robust. Benefits need to be assessed objectively.

summary of the article:

Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Sommer IE, Begemann MJ, Temmerman A, Leucht S. Schizophr Bull. 2012 Sep;38(5):1003-11.

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