• Koen Demyttenaere, Johan Detraux, Giorgio Racagni, and Kristof Vansteelandt.
• Department of Neurosciences, Research Group Psychiatry, Department of Psychiatry, Faculty of Medicine, University Psychiatric Center KU Leuven and University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000, Louvain, Belgium. koen.demyttenaere@uzleuven.be.
• CNS Drugs. 2019 Jun 1; 33 (6): 549-566.

BackgroundAkathisia is a common and distressing movement disorder that can be associated with the use of antipsychotics. It is characterized by a subjective (inner restlessness) and an objective (excessive movements) component. Akathisia can have a negative impact on clinical outcome and even lead to treatment discontinuation. Although medication-induced akathisia is more commonly associated with the use of first-generation antipsychotics (FGAs), it also occurs with second-generation antipsychotics (SGAs), including the newly approved antipsychotics (NAPs) asenapine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Until now, no meta-analysis has been published on the risk of akathisia for all NAPs, as monotherapy or adjunctive treatment, in patients with a severe mental illness.ObjectiveThe primary objectives of this systematic review and meta-analysis were to (i) compare akathisia incidence rates of the NAPs, as monotherapy or adjunctive treatment, in adult patients with a severe mental illness (i.e., schizophrenia, bipolar disorder, or major depressive disorder), using data from published and unpublished randomized controlled trials; and (ii) examine the role of several study characteristics explaining differences in akathisia incidence rates between studies.MethodsA systematic literature search, using the PubMed, EMBASE, and Cochrane Library databases (until October 2018), was conducted for English-language placebo- as well as active-controlled clinical trials, including subjective (percentage of patients reporting akathisia) and/or scale-defined medication-induced akathisia incidence rates with NAPs (as monotherapy or as adjunctive treatment) in adult patients with schizophrenia, bipolar disorder, or major depressive disorder. Additional unpublished clinical trials were identified through the ClinicalTrials.gov electronic database. Two meta-analyses (incidence rates and odds ratio [OR] [placebo vs. active] of medication-induced akathisia with NAPs) were performed to obtain an optimal estimation of akathisia risks of adult patients with a severe mental illness under these treatment conditions and to assess the role of study characteristics.ResultsTwo hundred and thirteen reports were selected as potentially eligible for our meta-analysis. Of these, 48 met the inclusion criteria. Eight records, identified through the ClinicalTrials.gov database and cross-referencing, and which fulfilled the inclusion criteria, were added, resulting in a total of 56 records (iloperidone = 5, asenapine = 11, lurasidone = 15, brexpiprazole = 13, cariprazine = 12). The estimated weighted mean incidence rate of akathisia was 7.7% (95% confidence interval [CI] 6.5-9.1), with estimates being 3.9% (95% CI 2.4-6.3) for iloperidone, 6.8% (95% CI 5.1-9.0) for asenapine, 10.0% (95% CI 7.4-13.5) for brexpiprazole, 12.7% (95% CI 10.1-16.1) for lurasidone, and 17.2% (95% CI 13.4-22.1) for cariprazine. After Tukey-adjustment for multiple testing, the incidence rate of akathisia was significantly (p < 0.05) lower for iloperidone than for brexpiprazole, lurasidone, and cariprazine. In addition, the incidence rate of akathisia was significantly (p < 0.05) lower for asenapine than for lurasidone and cariprazine. Finally, the incidence rate of akathisia was significantly (p < 0.05) lower for brexpiprazole than for cariprazine. Type of medication (p < 0.0001), diagnosis (p = 0.02), and race (p = 0.0003) significantly explained part of the heterogeneity of the incidence estimates of akathisia between studies. The estimated weighted OR of akathisia under medication, compared with placebo, was 2.43 (95% CI 1.91-3.10). The OR was smallest for iloperidone (OR 1.20; 95% CI 0.42-3.45) and increased for brexpiprazole (OR 2.04; 95% CI 1.09-3.83), asenapine (OR 2.37; 95% CI 1.32-4.27), lurasidone (OR 3.74; 95% CI 2.32-6.02), and cariprazine (OR 4.35; 95% CI 2.80-6.75). Only type of medication (p = 0.03) explained systematic differences in the OR for akathisia between placebo versus active treatment across studies. After Tukey-adjustment for multiple testing, no significant differences between these ORs were found. The severity of akathisia with NAPs generally is mild to moderate, only leading to treatment discontinuation in a minority of cases (< 5%).ConclusionsThe use of a NAP raises the akathisia risk more than two-fold when compared with patients receiving placebo. Although distinctions between the different NAPs were not clear in placebo-controlled trials, the results of our meta-analyses and systematic review generally indicate that these differences more than likely reflect real differences, with iloperidone showing the most and cariprazine showing the least benign akathisia profile. Moreover, due to patient characteristics and methodological issues, incidence rates of akathisia with NAPs found in this meta-analysis may even be an underestimation of true incidence rates.

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