Antimanic Efficacy, Tolerability, and Acceptability of Clonazepam: A Systematic Review and Meta-Analysis

Abstract

(1) Background: The use of benzodiazepines for the treatment of acute mania remains prevalent. This systematic review and meta-analysis provides an updated assessment of Clonazepam's antimanic efficacy, tolerability, and acceptability. (2) Methods: A systematic search of multiple databases and clinical trial registries was conducted, aiming to identify any controlled studies of Clonazepam vs. placebo or any other pharmacotherapy for the treatment of acute mania. Pairwise meta-analytic evaluations were performed. (3) Results: Six studies were included with a total number of 192 participants, all of which were randomized controlled trials. Clonazepam may be superior to a placebo in the acute phase of treatment and no different to Lithium and Haloperidol in terms of efficacy, both acutely and in the medium to long term. Clonazepam may be an acceptable and well-tolerated treatment for acute mania, especially when used as an augmentation strategy. Comparisons were underpowered, with minimal sample sizes and only one study per comparison in many cases, thus limiting the generalizability of our findings and hindering firm clinical conclusions. (4) Conclusions: Given the prevalence of benzodiazepine use in current practice, more and larger studies are urgently needed.

Keywords: benzodiazepines; bipolar disorder; clonazepam; mania; meta-analysis; systematic review.

Figure 1

Summary of risk of bias assessment.

Figure 2

Response to treatment: Clonazepam vs. Lithium. (a): acute effects (up to 3 weeks). Clark 1997a [49]: endpoint: 3 weeks. (b): long-term effects (more than 3 weeks of continuous treatment). Clark 1997b [49]: endpoint: 4 weeks.

Figure 3

Response to treatment: Clonazepam vs. Haloperidol. (a): acute effects (up to 3 weeks). Yang 2009a [50]: endpoint: 3 weeks. (b): long-term effects (more than 3 weeks of continuous treatment). Yang 2009b [50]: endpoint: 16 weeks.

Figure 4

Tolerability (discontinuation due to adverse effects, measured as the proportion of patients who dropped out due to adverse effects): Clonazepam vs. any other pharmacotherapy, including placebo. (a): acute effects (up to 3 weeks). Bradwejn 1990a [47], Clark 1997a [49] and Yang 2009a [50] present the acute effects (endpoint up to 3 weeks). (b): Bradwejn 1990b [47], Clark 1997b [49] and Yang 2009b [50] present the long-term effects (endpoint more than 3 weeks of continuous treatment).

Figure 5

Acceptability (all cause discontinuation, measured as the proportion of patients who dropped out due to any reason): Clonazepam vs. any other pharmacotherapy, including placebo. (a): acute effects (up to 3 weeks). Bradwejn 1990a [47], Clark 1997a [49] and Yang 2009a [50] present the acute effects (endpoint up to 3 weeks). (b): long-term effects (more than 3 weeks of continuous treatment). Bradwejn 1990b [47], Clark 1997b [49] and Yang 2009b [50] present the medium and long-term effects (endpoint more than 3 weeks of continuous treatment).

Figure 6

Severity of extrapyramidal adverse effects in the short-term (up to 3 weeks of treatment): Clonazepam vs. any other pharmacotherapy, including placebo. Clark 1997a [49]: acute effects (endpoint up to 3 weeks).