Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: A systematic review and meta-analysis of randomized-controlled trials

https://doi.org/10.1016/j.jpsychires.2015.01.004Get rights and content

Highlights

  • Options are limited for clozapine-resistant/-intolerant schizophrenia.

  • Aripiprazole augmentation of clozapine can minimize the cardiometabolic risk.

  • This combination may attenuate psychotic symptoms.

  • This combination causes agitation/akathesia, and may cause anxiety and insomnia.

Abstract

Limited options are available for clozapine-resistant schizophrenia and intolerable side effects of clozapine. We conducted a systematic review of randomized-controlled trials (RCTs) to determine the efficacy and safety of aripiprazole augmentation of clozapine for schizophrenia. Electronic databases searched included PubMed, Scopus, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. This review synthesized the data of four short-term (8–24 weeks), placebo-controlled trials (N = 347). The overall relative risk (RR, 95% confidence interval) of discontinuation rates was not significantly different between groups (RR = 1.41, 95% CI = 0.78 to 2.56). The pooled standardized mean differences (SMDs, 95% CIs) (Z-test; number of study; I2-index) suggested trends of aripiprazole augmentation benefits on overall psychotic [−0.40 (−0.87 to 0.07) (n = 3; Z = 1.68, p = 0.09; I2 = 68%)], positive [−1.05 (−2.39 to 0.29) (n = 3; Z = 1.54, p = 0.12; I2 = 94%)], and negative [−0.36 (−0.77 to 0.05) (n = 3; Z = 1.74, p = 0.08; I2 = 54%)] symptoms. Despite of no benefit on three cardiometabolic indices (i.e., fasting plasma glucose, triglyceride, and high-density lipoprotein), aripiprazole augmentation was superior for weight change with a mean difference (95% CI) of −1.36 kg (−2.35 to −0.36) (n = 3; Z = 2.67, p = 0.008; I2 = 39%) and LDL-cholesterol with a mean difference of −11.06 mg/dL (−18.25 to −3.87) (n = 3; Z = 3.02, p = 0.003; I2 = 31%). Aripiprazole augmentation was not correlated with headache and insomnia but significantly associated with agitation/akathesia (RR = 7.59, 95% CI = 1.43 to 40.18) (n = 3; Z = 2.38, p = 0.02; I2 = 0%) and anxiety (RR = 2.70, 95% CI = 1.02 to 7.15) (n = 1; Z = 2.00, p = 0.05). The limited short-term data suggested that aripiprazole augmentation of clozapine can minimize the cardiometabolic risk, causes agitation/akathesia, and may be effective in attenuating psychotic symptoms.

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.

References (43)

  • J. Tiihonen et al.

    11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)

    Lancet

    (2009)
  • S. Vayisoglu et al.

    Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment

    Schizophr Res

    (2013)
  • American Diabetes A et al.

    Consensus development conference on antipsychotic drugs and obesity and diabetes

    J Clin Psychiatry

    (2004)
  • C. Barbui et al.

    Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial

    J Clin Psychopharmacol

    (2011)
  • J.S. Chang et al.

    Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial

    J Clin Psychiatry

    (2008)
  • A. Cipriani et al.

    Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial

    J Clin Psychopharmacol

    (2013)
  • J.D. Croxtall

    Aripiprazole: a review of its use in the management of schizophrenia in adults

    CNS Drugs

    (2012)
  • J.M. Davis et al.

    A meta-analysis of the efficacy of second-generation antipsychotics

    Arch Gen Psychiatry

    (2003)
  • M.C. Davis et al.

    Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients

    Acta Psychiatr Scand

    (2014)
  • M. De Hert et al.

    Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level

    World Psychiatry

    (2011)
  • A. Essali et al.

    Clozapine versus typical neuroleptic medication for schizophrenia

    Cochrane Database Syst Rev

    (2009)
  • Cited by (40)

    • Cardio-metabolic risk and its management in a cohort of clozapine-treated outpatients

      2018, Schizophrenia Research
      Citation Excerpt :

      Meta-analyses of clozapine augmentation with a second antipsychotic have concluded that there are at best modest clinical benefits (Taylor et al., 2012) or that there is insufficient evidence to support the practice (Barbui et al., 2009). One possible exception is aripiprazole, for which there is meta-analytic evidence of significant reductions of positive and negative symptoms, weight and LDL cholesterol when used in clozapine augmentation (Srisurapanont et al., 2015). As this was a cross-sectional study it is not possible to make inferences about whether use of polypharmacy did or did not contribute to detrimental metabolic effects in this population.

    • Treatment resistant schizophrenia - Review and a call to action

      2019, Irish Journal of Psychological Medicine
    View all citing articles on Scopus
    View full text