Clozapine resistance: Augmentation strategies

Abstract

Background: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy. Objectives: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis. Methods: A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5). Results: 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. Conclusion: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.

Introduction

Schizophrenia represents one of the most disabling psychiatric disorders: it is the 8th leading causes of disability in the age group of 15–44 (Rossler et al., 2005), with a worldwide prevalence around the 1% (Perala et al., 2007). Overall, the disease reduces the individual's lifespan by on average 15–20 years (Tandon et al., 2009), and causes a variable degree of functional impairment and social disability. Although antipsychotics are effective in the majority of patients with schizophrenia, between 5 and 25% of patients have little or no benefit from them (Brenner et al., 1990, Kane, 1996). So far, clozapine (CLZ) — the first atypical antipsychotic drug (or second generation antipsychotics, SGAs) — is the most important pharmacological advance for such patients (Grunder et al., 2009). Nevertheless, it has been estimated that between 40% and 70% of patients, defined as treatment resistant according to Kane's criteria (Kane et al., 1988), do not respond to CLZ as well (Chakos et al., 2001, Lieberman et al., 1994, Meltzer et al., 1990). These patients are known as CLZ-resistant or affected by Super Refractory Schizophrenia (SRS) (Buckley et al., 2001, Williams et al., 2002). We could hypothesize that these patients might represent a particular subgroup of schizophrenic patients, united by the same biological substrate. Indeed, the pathophysiology of schizophrenia remains largely unknown and some researcher hypothesized schizophrenia as the common phenotype of several pathophysiological mechanisms (Kirkpatrick et al., 2001). In order to optimize CLZ therapy, several studies evaluated the relationship between CLZ blood levels and therapeutic response showing that CLZ plasma concentrations over of 350–420 ng/mL predict a favorable therapeutic outcome (Kronig et al., 1995, Nielsen et al., 2011, Perry et al., 1991, Potkin et al., 1994). Several studies suggested that CLZ oral dosage should be determined in order to reach these plasma concentrations, avoiding useless CLZ high dosages. Indeed, evidence suggests that a lower dose of CLZ may be as effective as a higher dose and may cause fewer side effects, as demonstrated also by the different clinical experiences in the U.S. and in the European countries (Fleischhacker et al., 1994). Furthermore, the duration of an adequate CLZ clinical trial is not yet clear: two different studies suggested that the optimal trial should be from 3 to 6 months (Carpenter et al., 1995, Lieberman et al., 1994), as supported by other studies that reported no added advantage in extending CLZ trial beyond 6 months (Conley et al., 1997, Fabrazzo et al., 2002, Schulte, 2003, Wilson, 1996). On the other hand, some authors identified a group of “late responders” who showed delayed responses occurring after 6 months to one year of treatment (Meltzer et al., 1989, Rosenheck et al., 1999). In any case, there is an overall consensus that CLZ trials should be longer than those characteristically employed with other antipsychotics, i.e. 4–8 weeks. Consistently, in a recent review, Nielsen et al. (2011) pointed out that augmentation should not be tried before the first 3–6 months of treatment with CLZ to avoid the risk of confusing the effects of the augmenting drug with late-onset effects of CLZ (Nielsen et al., 2011). When an adequate trial with CLZ fails to lead to a clinical improvement, augmentation of CLZ with a second antipsychotic is relatively common in clinical practice, with a reported prevalence ranging from 18% to 44% (Buckley et al., 2001, Potter et al., 1989). Other CLZ augmentation strategies, although less common, are adding antidepressants, mood stabilizers or ECT. Many other augmentation strategies have been investigated so far, but for most of these, clinical practice seems to be highly driven by case reports or case series, without any evidence supporting these CLZ augmentations (Remington et al., 2005). Meanwhile, there are only few randomized controlled trials (RCTs) available.

Overall, the scenario that emerge from these papers seems to be almost various, without any clear information that could be translated into clinical practice.

Given these considerations, our study was carried out with three main aims: 1) to summarize literature about CLZ augmentation strategies, evaluating the efficacy of each strategy; 2) to perform, when possible, a meta-analysis including all the randomized, placebo-controlled trials regarding CLZ augmentation; 3) to give reliable suggestions for the choice of the best augmentation strategy in patient resistant to CLZ, since guidelines are not informative about this difficult therapeutic challenge.