Augmentation Strategies in Clozapine-Resistant Schizophrenia

Abstract

The introduction of antipsychotics in the 1950s revolutionised the treatment of schizophrenia, but it soon became apparent that a substantial number of patients demonstrated a suboptimal response to these antipsychotics. Clozapine proved to be beneficial in patients whose symptoms were treatment resistant, but it too had limitations, with as many as 40-70% of those treated with clozapine demonstrating inadequate response to this drug as well. The availability of other 'atypical' antipsychotics offers options, but clozapine appears to remain the most effective option in treatment-resistant schizophrenia. This, of course, raises the question of what to do when clozapine is only partially effective. To address the issue of treatment in patients who have demonstrated a suboptimal response to clozapine, efforts have focused on a variety of augmentation strategies, including numerous medications and electroconvulsive therapy. The current body of evidence consists largely of data from smaller open trials and case series/reports, although data from a limited number of controlled studies are now available. Not surprisingly, the evidence drawn from the former is more supportive of augmentation strategies, although the controlled trials are not without positive findings. The available information is certainly not so overwhelming as to endorse any single augmentation approach. Indeed, it argues for more controlled data and cautions us regarding the cost-benefit ratio in adopting this strategy. Over and above the added adverse effects of another treatment, there is evidence to indicate that actual clinical worsening can occur. Without compelling evidence, clinicians must resort to guiding principles. The potential benefits of augmentation cannot be ruled out, but it should be approached with caution and in a systematic fashion. Factors compromising clozapine response should first be ruled out, and any augmentation trials should be guided by existing evidence and a treatment plan that incorporates a clear understanding of target symptoms. A means of evaluating outcome effectively needs to be in place, and the trial should be circumscribed to prevent needless polypharmacy. A priori, an endpoint needs to be established and the trial discontinued unless results firmly support added benefits.

Where to Position Clozapine: Re-Examining the Evidence

“…16,17 The widespread use of SGAs has provided a rapidly growing body of evidence by which to assess them against the FGAs and clozapine itself. Most notably, the purported advantages of the SGAs, compared with FGAs, have been tempered, 18,19 while clozapine has more clearly distinguished itself among other SGAs.…”

Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

“…Such studies tend to produce a strong bias for positive results because negative reports in a case or a small sample are unlikely to be reported and/or published. 37,38 In addition, the specific therapeutic response cannot be distinguished from placebo effects in uncontrolled studies. Meanwhile, there are only few randomized controlled trials (RCTs) available.…”

“…38,39 For example, the 2009 Schizophrenia Patient Outcomes Research Team has discussed adjunctive treatment strategies but argued that studies have failed to document sufficient efficacy to support a recommendation in patients with clozapine-resistant schizophrenia. 40 Therefore, this study aims to review all double-blind randomized controlled studies available regarding the efficacy of pharmacological augmentation in clozapineresistant patients, and perform meta-analyses on the efficacy of individual clozapine adjuncts when sufficient studies are available.…”

Augmentation of Clozapine with Aripiprazole in Severe Psychotic Bipolar and Schizoaffective Disorders: A Pilot Study

“…Psychotic bipolar and schizoaffective patients resistant to mood stabilizers may need long-term treatment with atypical antipsychotics, including clozapine. Not withstanding the clinical efficacy of clozapine due to its serotoninergic and dopaminergic activity leads to significant clinical improvement [23], the drug does not provide a complete remission of positive or negative symptoms in a substantial percentage of patients [24,25,26,6,27,28], and augmentation strategies are required.…”