The anti-anhedonic effects of ketamine in the treatment of resistant unipolar and bipolar depression: A systematic review and meta-analysis of current data

Abstract

Introduction: Anhedonia is a core symptom in depressive episodes, predicting the occurrence of treatment resistance, suicidality, and poor responses to conventional treatments. Ketamine has shown potent antidepressant properties and appears to be a promising antianhedonic agent. Methods: A systematic review and meta-analysis were performed for interventional studies published between 2013 and April 2023. Additionally, an active search was conducted on April 10, 2024. Sixteen studies, with an initial total sample of 1048 participants with treatment-resistant major depressive disorder (MDD) and bipolar depression (BD), were included in the meta-analysis. The ROBINS-I and ROB-2 tools assessed the risk of bias. Results: Compared to baseline levels, ketamine showed a significant antianhedonic effect 24 h after the first infusion (MD -0.73, 95 % CI -0.93, -0.52, p < 0.01; Z= -7.07, Tau2= 0.0643, I²= 53 %, p = 0.02), for the general analysis considering the last infusion defined by each study protocol (MD -1.42, 95 % CI -1.79, -1.05, p < 0.01; Z= -7.46, Tau2= 0.6208, I² = 92 %, p < 0.01). Subanalysis revealed a significant effect for ketamine both in MDD patients (MD -1.13, 95 % CI -1.56, -0.70, p < 0.01; Z= -5.11, Tau2= 0.4116, I²= 88 %, p < 0.01) and those with BD (MD -1.21, 95 % CI -1.80, -0.62, p < 0.001; Z=-4.02, Tau2= 0.2142, I² = 66 %, p = 0.05). Limitations: most included studies were non-randomized trials and post-hoc analyses. In addition, consistent heterogeneity was identified in the analysis. Conclusion: The growing current evidence suggests that ketamine is a promising treatment for anhedonia.

Keywords

• Anhedonia
• Ketamine
• Treatment-resistant depression
• Major depressive disorder
• Bipolar depression