Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: A systematic review and meta-analysis of randomized-controlled trials
Introduction
Although treatment-resistant schizophrenia causes a huge social and economic burden, only clozapine is widely accepted as the treatment of choice. However, its efficacy and safety are still unsatisfactory. Many patients with schizophrenia have poor or partial response to clozapine. For the responders, most of them have to suffer from cardiometabolic abnormalities related with clozapine, e.g., weight gain, dyslipidemia.
Clozapine is a highly effective antipsychotic medication with serotonin/dopamine antagonism. Its efficacy is superior to many antipsychotic agents (Davis et al., 2003), both the first- and the second-generation antipsychotics (Essali et al., 2009, McEvoy et al., 2006). In addition, it reduces the suicide risk and possibly extends the lifespan of patients with schizophrenia (Meltzer et al., 2003, Tiihonen et al., 2009). However, at least 50% of patients with refractory schizophrenia have poor response to clozapine (Conley and Kelly, 2001), which has been a challenge since those patients need huge assistance for living (Kennedy et al., 2014).
Given that the efficacy of clozapine is superior to other antipsychotic medications, clozapine augmentation by other agents appears to be a common strategy for clozapine-resistant or -intolerant schizophrenia (e.g., severe weight gain). Of 15 augmentation strategies reviewed by Sommer et al. (2012), a fair amount of evidence suggests the limited benefits of antipsychotic, lamotrigine, and citalopram augmentation (Miyamoto et al., 2014). Adjunct an antipsychotic medication to clozapine may result in a small benefit (Taylor et al., 2012). Although a meta-analysis found the modest efficacy of lamotrigine augmentation (Sommer et al., 2012), negative findings of a recent RCT caused this add-on strategy more doubtful (Vayisoglu et al., 2013). The benefit of citalopram augmentation was reported in a single RCT (n = 61) and has never been replicated (Lancon et al., 2006). The evidence supporting clozapine augmentation by any pharmacological agent was, therefore, very limited (Porcelli et al., 2012, Sommer et al., 2012).
Another concern of clozapine treatment is its adverse effects, in particular weight gain that is relevant to cardiometabolic risk. Among all antipsychotic medication, clozapine has the highest propensity to cause severe weight gain that can lead to an intolerability of this medication yet after a very short period of treatment (Davis et al., 2014, Mitchell et al., 2013). Limited options are available to mitigate these metabolic problems. Metformin and exercise, commonly used options, may have only modest benefits for clozapine-induced weight gain or metabolic abnormalities (Caemmerer et al., 2012, Maayan et al., 2010).
Together with other antipsychotic agents, aripiprazole is a first-line treatment for schizophrenia (Osser et al., 2013). It differs from others by stabilizing dopamine function through dopamine D2 receptor partial agonism, not D2 antagonism (Croxtall, 2012). Other pharmacodynamic actions include partial serotonin 5-HT1A agonism and serotonin 5-HT2A antagonism. Although agitation, anxiety, headache, and insomnia are its common adverse effects (Marder et al., 2003, Swainston Harrison and Perry, 2004), aripiprazole is unlikely to cause weight gain or dyslipidemia (Stip and Tourjman, 2010). Little has been known about aripiprazole monotherapy and the combination of aripiprazole with psychotropic medications for clozapine-resistant schizophrenia (Mossaheb and Kaufmann, 2012). However, some open trials of aripiprazole augmentation of clozapine reported the benefits of this regimen in attenuating psychotic symptoms and/or minimizing weight gain (Henderson et al., 2006, Mitsonis et al., 2007, Ziegenbein et al., 2006).
As treatment options for clozapine-resistant schizophrenia are limited and adverse events are an issue of concern, we proposed to carry out a systematic review of randomized-controlled trials to determine the efficacy and safety of aripiprazole augmentation for patients with clozapine-resistant schizophrenia or clozapine-related cardiometabolic risk.
Section snippets
Methods
This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Statement (Moher et al., 2009).
Literature search
The number of records identified through database search and other sources were 1909 and 14, respectively. Records after the duplication removed and filtered were 1551 and 163, respectively. After the 25 full-text articles were assessed, six articles of five RCTs were included in this review (see Fig. 1).
Main characteristics of included RCTs
Four RCTs were short-term (8–24 weeks) comparison of aripiprazole and placebo in combination with clozapine (Chang et al., 2008, Fan et al., 2013, Fleischhacker et al., 2010, Muscatello et al.,
Discussion
The short-term meta-analytic results suggested that aripiprazole augmentation of clozapine had trends of benefits on psychotic symptoms. The effect sizes for overall, positive, and negative psychotic symptoms were medium to large (SMDs between 0.36 and 1.05), but their trends (p's for the Z tests between 0.08 and 0.12) suggested the uncertainty of these benefits. It could minimize some cardiometabolic risks by reducing body weight for a mean of 1.36 kg and LDL for a mean of 11.06 mg/dL.
Acknowledgment
None.
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