Journal of affective disorders · 2026
Efficacy and safety of adjunctive orexin receptor antagonist therapy in major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.
СтатьяСистематический обзорМетаанализНазвание и аннотация: Перевод в очереди
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Pereira Samuel Izaias Dos Santos, Kotochinsky Martin, Amador Wellgner Fernandes Oliveira, Alessi Mateus Rodrigues, Fonseca Pandora Eloa Oliveira, Fidelis Alice Maria Freire, Barroso Douglas, Sherpa Nima Norbu, Lezana Andrea Gonzalez
Аннотация
BACKGROUND: A substantial proportion of adults with major depressive disorder (MDD) exhibit an inadequate response to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) and experience persistent insomnia. Orexin receptor antagonists (ORAs) have emerged as a potential adjunctive treatment targeting hyperarousal mechanisms; however, their efficacy and safety remain uncertain.
METHODS: A systematic search of PubMed (including MEDLINE), Web of Science, Cochrane CENTRAL, Scopus, Europe PMC, and CINAHL (via EBSCO), as well as ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), was conducted from inception to August 2025. Randomized controlled trials (RCTs) evaluating adjunctive ORAs in adults with MDD and inadequate response to SSRIs/SNRIs were included. Outcomes included depressive severity (Montgomery-Åsberg Depression Rating Scale [MADRS], MADRS without sleep item [MADRS-WOSI], 17-item Hamilton Depression Rating Scale [HAMD17], Patient Health Questionnaire-9 [PHQ-9]), sleep disturbance (Patient-Reported Outcomes Measurement Information System-Sleep Disturbance [PROMIS-SD]), and safety (adverse events [AEs], serious adverse events [SAEs], and discontinuations).
RESULTS: ORA therapy was associated with statistically significant improvements in depressive symptoms on MADRS (MD -1.96, 95% CI -3.29 to -0.63), MADRS-WOSI (MD -1.40, 95% CI -2.70 to -0.11), and PHQ-9 (MD -1.15, 95% CI -2.13 to -0.18), while no significant effect was observed for HAMD17. An exploratory pooled analysis combining MADRS and HAM-D17 suggested a small effect favoring ORA therapy; however, this finding should be interpreted with caution (SMD -0.15, 95% CI -0.27 to -0.03). Sleep improved on PROMIS-SD (MD -3.39, 95% CI -4.78 to -2.00). Safety outcomes did not differ significantly from placebo, and no drug-related deaths were reported.
CONCLUSIONS: Adjunctive ORA therapy is associated with modest improvements in depressive symptoms and sleep disturbance, with no clear signal of increased adverse events; however, the available evidence is insufficient to establish comparative tolerability in SSRI/SNRI partial responders. These findings should be interpreted with caution given the limited number of studies. Larger, longer-duration, and more diverse RCTs are needed to define clinical relevance and long-term safety.
METHODS: A systematic search of PubMed (including MEDLINE), Web of Science, Cochrane CENTRAL, Scopus, Europe PMC, and CINAHL (via EBSCO), as well as ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), was conducted from inception to August 2025. Randomized controlled trials (RCTs) evaluating adjunctive ORAs in adults with MDD and inadequate response to SSRIs/SNRIs were included. Outcomes included depressive severity (Montgomery-Åsberg Depression Rating Scale [MADRS], MADRS without sleep item [MADRS-WOSI], 17-item Hamilton Depression Rating Scale [HAMD17], Patient Health Questionnaire-9 [PHQ-9]), sleep disturbance (Patient-Reported Outcomes Measurement Information System-Sleep Disturbance [PROMIS-SD]), and safety (adverse events [AEs], serious adverse events [SAEs], and discontinuations).
RESULTS: ORA therapy was associated with statistically significant improvements in depressive symptoms on MADRS (MD -1.96, 95% CI -3.29 to -0.63), MADRS-WOSI (MD -1.40, 95% CI -2.70 to -0.11), and PHQ-9 (MD -1.15, 95% CI -2.13 to -0.18), while no significant effect was observed for HAMD17. An exploratory pooled analysis combining MADRS and HAM-D17 suggested a small effect favoring ORA therapy; however, this finding should be interpreted with caution (SMD -0.15, 95% CI -0.27 to -0.03). Sleep improved on PROMIS-SD (MD -3.39, 95% CI -4.78 to -2.00). Safety outcomes did not differ significantly from placebo, and no drug-related deaths were reported.
CONCLUSIONS: Adjunctive ORA therapy is associated with modest improvements in depressive symptoms and sleep disturbance, with no clear signal of increased adverse events; however, the available evidence is insufficient to establish comparative tolerability in SSRI/SNRI partial responders. These findings should be interpreted with caution given the limited number of studies. Larger, longer-duration, and more diverse RCTs are needed to define clinical relevance and long-term safety.