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Child Psychiatrist /Adult Psychiatrist

Combination Therapy of SSRIs and SGAs Is Optimal for Psychotic Depression

Keypoint: These findings provide specific recommendations for the most efficacious psychotic depression treatment options.


Psychotic Depression

The combination of a selective serotonin reuptake inhibitor (SSRI) and a second-generation antipsychotic (SGA) may be the most effective psychotic depression treatment approach, according to results from a systematic review and meta-analysis published in Lancet Psychiatry.


Psychotic depression, characterized by hallucinations or delusions occurring during a major depressive episode, is associated with greater symptom severity and duration than non-psychotic depression. While current psychotic depression treatment guidelines recommend polytherapy with an antidepressant and antipsychotic, there is limited research regarding the most efficacious options and combinations for specific medications. The current study aimed to address this research gap through a network meta-analysis to determine the efficacy of pharmacological treatments for psychotic depression, contributing to a more comprehensive understanding of treatment options.


The investigators searched publication databases from inception to November 23, 2023 for randomized controlled trials evaluating the efficacy and safety of pharmacological treatments for acute major depressive episodes with psychotic features. The primary endpoints were treatment response rate and treatment acceptability, with secondary outcomes including changes in depressive symptom severity, remission rates, tolerability, and frequency of adverse events.


The investigators included a total of 15 studies in the systematic review, for a pooled sample size of 1161 individuals with psychotic depression. On average, participants were 50.5 years of age, 44.4% were women, and 42.1% identified as White. The meta-analysis included 13 reports, encompassing 14 randomized controlled trials. Overall, 2 trials assessed depressive symptom severity using the Montgomery-Asberg Depression Rating Scale while the remaining studies used the Hamilton Rating Scale for depression.


Relative to placebo, the investigators found that only the combination of SSRIs plus SGAs was associated with a higher proportion of participants with a treatment response (risk ratio [RR] 1.89; 95% CI, 1.17-3.04). By specific medications, only the combination of fluoxetine and olanzapine outperformed placebo (RR, 1.91; 95% CI, 1.27-2.85) for the proportion of patients with a treatment response.


Additionally, the investigators found that antipsychotic plus antidepressant combinations were consistently more efficacious than monotherapy alone with either drug class. Among monotherapies, tricyclic antidepressants (TCAs) were associated with the most favorable response profile.


These findings suggest that the combination of an SSRI plus an SGA may be the most optimal and effective treatment option for patients with psychotic depression. The study authors concluded, “This expansion of evidence for the pharmacological treatment of psychotic depression should improve clinical care, facilitate the development of treatment guidelines, and provide valuable insights for future clinical research, which remains insufficiently developed.”


Limitations of the study include its reliance on data from randomized controlled trials published between 1985 and 2013, which excludes recent medications like ketamine or esketamine. Additionally, small sample sizes and the limited number of trials may affect the precision of effect estimates, while the inclusion of both major depressive disorder and bipolar disorder patients challenges the transitivity assumption and complicates the assessment of treatment effectiveness across the spectrum of psychotic depression.


Note: This article originally appeared on Psychiatry Advisor

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