This study compared the efficacy and tolerability of the 5 second-generation antipsychotics that are currently FDA approved as adjunctive treatments for adults with MDD.
TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A monthly column dedicated to reviewing the literature and sharing clinical implications.
In this study, McIntyre et al conducted a systematic review and network meta-analysis (NMA) including trials using atypical antipsychotics as adjunctive treatment for adults with MDD.2 Although other atypical antipsychotics have shown some efficacy in alleviating MDD symptoms, such as risperidone and olanzapine (especially in combination with fluoxetine),3 the authors of this current study only included the 5 atypical antipsychotics that have been specifically approved by the FDA for antidepressant augmentation in MDD.
McIntyre RS, Stahl SM, Shim SR, et al.
No direct funding was reported. Several authors disclosed receiving speaker or consultant fees from numerous pharmaceutical companies, including those with active interests in medications compared in this study.
This study compared the efficacy and tolerability of the 5 second-generation antipsychotics that are currently FDA approved as adjunctive treatments for adults with MDD.
This systematic review and NMA included double-blind randomized controlled trials comparing atypical antipsychotics that are currently FDA approved for adjunctive treatment in adults with MDD (antidepressant plus either brexpiprazole, aripiprazole, cariprazine, lumateperone, or quetiapine extended release [XR]) with placebo. The literature search was conducted using PubMed/Medline, PsycINFO, the Cochrane Library, and Embase databases; both the US and European Union clinical trials registries; and Google Scholar.
Included studies had adults aged 18 and older with an MDD diagnosis, according to DSM-IV, DSM-IV-TR, DSM-5, or DSM-5-TR criteria, and prior inadequate response to antidepressant trials. There was no language exclusion for identifying the studies. Studies involving atypical antipsychotic monotherapy or antipsychotics not FDA approved for MDD adjunctive treatment (eg, risperidone, olanzapine-fluoxetine) were excluded. Heterogeneity concerns prompted the exclusion of 1 study from the main analysis because it enrolled only older participants.
The primary outcomes measured were efficacy (≥ 50% improvement in depressive symptoms at week 6, as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS]) and acceptability (all-cause discontinuation rate). Secondary outcomes evaluated at week 6 included remission rates (MADRS, ≤ 8 or ≤ 10, depending on the study), rate of discontinuation due to adverse events, change in depressive symptoms’ overall severity, extrapyramidal symptoms (EPS), weight gain rate, and improvement in Clinical Global Impressions scale. Network meta-analyses were conducted to allow comparison of multiple treatments across studies. Finally, subgroup and sensitivity analyses were conducted: (1) including the geriatric trial that was excluded from the main analysis, (2) excluding studies published prior to 2010, and (3) stratifying antipsychotics by individual dosages for pairwise comparisons.
Twenty-two studies totaling 10,962 participants were included in the main analysis. The number of participants within each treatment group was as follows: aripiprazole (n = 2297), brexpiprazole (n = 1973), cariprazine (n = 1894), quetiapine XR (n = 719), lumateperone (n = 483), and placebo (n = 3596). Twenty-one of the 22 trials were industry sponsored. All studies were conducted in the outpatient setting.
Lumateperone demonstrated the greatest efficacy among the treatment groups (RR, 1.72). Efficacy outcomes decreased for the other treatments as follows: aripiprazole (RR, 1.53), brexpiprazole (RR, 1.38), cariprazine (RR, 1.20), and quetiapine XR (RR, 1.15; 95% CI, 0.96-1.35; the only CI of these groups that indicated a statistically insignificant difference from placebo). Aripiprazole demonstrated the highest acceptability (RR, 1.16), followed by cariprazine (RR, 1.44), brexpiprazole (RR, 1.47), quetiapine XR (RR, 1.56), and lumateperone (RR, 2.30). These results remained consistent across multiple sensitivity and subgroup analyses. In the dose-stratified primary outcome analysis, 42 mg of lumateperone demonstrated the highest efficacy of all treatment dose subgroups (RR, 1.73). Higher doses analyzed for each treatment group showed a significant difference in efficacy compared with placebo, but aripiprazole 2 mg, brexpiprazole 2.5 mg, and quetiapine XR 150 and 225 mg did not differ from placebo in this regard.
The secondary outcome analysis found that lumateperone demonstrated the greatest benefit for achieving remission (RR, 1.87) and produced the largest reduction in depressive symptom severity (mean difference, –4.83) among the evaluated agents. However, lumateperone was also associated with the highest rate of treatment discontinuation due to adverse events (RR, 16.50), followed by quetiapine XR (RR, 6.70). In contrast, aripiprazole demonstrated the lowest rate of discontinuation due to adverse events (RR, 2.21). Dose-stratified analyses yielded similar results, and the findings remained consistent across sensitivity and subgroup analyses. Except for cariprazine, each treatment showed significant improvement on the CGI scale compared with placebo. Although akathisia was significantly associated with each treatment (RR, 3.71-4.40) except quetiapine, overall EPS did not differ significantly from placebo in any treatment group. Finally, all treatments except lumateperone were associated with a significantly higher incidence of 7% or more weight gain, with aripiprazole and quetiapine showing the strongest associations.
This systematic review and NMA demonstrated that the atypical antipsychotics currently approved for adult MDD augmentation are overall effective for this indication. These treatments vary in efficacy and tolerability, with lumateperone demonstrating the greatest efficacy and aripiprazole demonstrating the greatest acceptability over a relatively short (6 weeks) time frame.
These findings may help inform the treatment of adults with MDD. Clinicians should be mindful of the variable efficacy and tolerability of MDD augmentation agents, as well as the relatively small sample sizes in the included lumateperone trials and the lack of longer-term/maintenance treatment trials with lumateperone. Additionally, although lumateperone ranked first for efficacy, it ranked last for tolerability. Patients should be engaged in shared decision-making, and some patients may prefer a better-tolerated but less efficacious agent. It is also worth noting that aripiprazole ranked second in efficacy and first in tolerability.
Among FDA-approved antipsychotics for MDD adjunctive treatment, lumateperone demonstrated the highest efficacy but lowest tolerability. Aripiprazole was the best-tolerated and second-most efficacious agent studied.
Dr Palakollu is a third-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Kubista is a fourth-year psychiatry resident at Creighton University. Dr Dickan is a consultation-liaison psychiatrist at PeaceHealth Southwest Medical Center in Vancouver, Washington. Dr Schuster is an assistant professor of psychiatry at Creighton University School of Medicine. Dr Mullen is an assistant professor of psychiatry at Saint Louis University School of Medicine in St. Louis, Missouri. Dr Tampi is a professor and chair of the Department of Psychiatry at Creighton University School of Medicine and CHI (Catholic Health Initiatives) Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.
References
1. GBD 2023 Mental Disorder Collaborators.
2. McIntyre RS, Stahl SM, Shim SR, et al.
3. Yan Y, Yang X, Wang M, et al.
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