Z-drug for schizophrenia: A systematic review and meta-analysis

Highlights

• Systematic review and meta-analysis of Z-drug for schizophrenia were performed.

• Pooled Z-drug did not outperform placebo in all outcomes pertaining to efficacy and safety/acceptability.

• One study showed that eszopiclone was superior to placebo in improving the Insomnia Severity Index scores.

Abstract

No systematic reviews and meta-analyses on the use of Z-drug for schizophrenia are available. Randomized, placebo-controlled, or non-pharmacological intervention-controlled trials published before 03/20/2017 were retrieved from major healthcare databases and clinical trial registries. A meta-analysis including only randomized, placebo-controlled trials was performed. Efficacy outcomes were measured as improvement in overall schizophrenia symptoms, total sleep time, and wake after sleep onset. Safety/acceptability outcomes were discontinuation rate and individual adverse events. Four trials [1 alpidem placebo-controlled study (n=66), 2 eszopiclone placebo-controlled studies (n=60), and 1 eszopiclone, shallow needling-controlled study (n=96)] were identified. The meta-analysis showed no significant differences in any outcome between pooled Z-drug and placebo treatment groups. For individual studies, alpidem was superior to placebo in improving the overall schizophrenia symptoms. One of the eszopiclone studies showed that eszopiclone was superior to placebo in improving the Insomnia Severity Index scores. Another eszopiclone study showed that eszopiclone did not differ from shallow needling therapy in improving both schizophrenia- and insomnia-related symptoms. Although this study failed to show significant benefits for the use of Z-drug in the treatment of schizophrenia, it showed that short-term use of eszopiclone is an acceptable method for treating persistent insomnia among these patients.

Introduction

Approximately 44% patients with schizophrenia suffer from sleep disturbance (Palmese et al., 2011). Insomnia is associated with psychiatric symptoms, including depression, decreased quality of life, and metabolic abnormality (Hung et al., 2014, Ritsner et al., 2004, Ritsner et al., 2002).

The World Federation of Societies of Biological Psychiatry guideline stated that “liberal doses of benzodiazepines may be essential to relieve distress, insomnia, and behavioral disturbances secondary to psychosis, whereas antipsychotic medication takes effect. However, the combination of long half-life benzodiazepines with antipsychotics only has little evidence and is also associated with an increased mortality in patients with schizophrenia (Hasan et al., 2012).” Benzodiazepines were reported to be associated with drowsiness, abuse potential, withdrawal symptoms, rebound insomnia (Lader, 2011), hip fracture (Saarelainen et al., 2017), fall (Woolcott et al., 2009), impairment of cognitive function, and motor vehicle accidents/violations (Rapoport et al., 2009). They produce a sedative effect by binding to the γ-aminobutyric acid type A receptor (GABA_AR) α subunit, enhancing the GABA_AR-associated chloride channel conductance and simultaneously inhibiting neuronal excitability (Rudolph and Knoflach, 2011). Although binding to the α1 subunit specifically produces sedative effects, binding to the α2, α3, and α5 subunits produces the anxiolytic effect, addiction, analgesia, memory impairment, and myorelaxation (Rudolph and Knoflach, 2011). Although Z-drugs are considered safer than benzodiazepines (Rudolph and Knoflach, 2011) because they selectively bind to the α1 subunit rather than the α2, α3, and α5 subunits, they are not addressed in most schizophrenia treatment guidelines (Hasan et al., 2012, NICE, 2014) for patients with schizophrenia. Z-drugs are also called nonbenzodiazepines and include alpidem, eszopiclone, zaleplon, zolpidem, and zopiclone.

To date, there have been three randomized controlled trials on Z-drugs for the treatment of schizophrenia (Minervini et al., 1990, Tek et al., 2014, Wamsley et al., 2013). However, the results have been inconsistent. Although one study showed that eszopiclone was superior to placebo for the treatment of severe insomnia (Tek et al., 2014), another study showed no difference in this outcome between eszopiclone and placebo treatment groups (Wamsley et al., 2013). The discrepancy among the stated results may be due to the small sample size of the trials (21–39 participants in total) and different outcome measures. A meta-analysis can increase the statistical power for group comparisons and can overcome the limitation of sample size in underpowered studies (Cohn and Becker, 2003). Moreover, using standardized mean difference (SMD) analysis, outcomes with different metrics can be combined (DerSimonian and Laird, 1986). Therefore, to overcome the limitations of the small sample sizes of individual studies, inform clinical practice regarding the efficacy and safety/acceptability of Z-drugs for schizophrenia, and provide input for future research directions in this area, we performed a meta-analysis on the effects of Z-drugs in patients with schizophrenia.