A comparison of the antianhedonic effects of repeated ketamine infusions in melancholic and non-melancholic depression

This study is a post hoc analysis of data drawn from an ongoing real-world, open-label study of adjunctive multiple ketamine infusions for people with depression who had treatment-resistant depression (TRD) and/or suicidal ideation. The parent study began in November 2016 and is registered in the Chinese Clinical Trial Registry (ChicCTR-OOC-17012239). All participants provided written informed consent and the protocol received Institutional Review Board approval from the Affiliated Brain Hospital of Guangzhou Medical University. The analysis compared individuals classified as having melancholic versus non-melancholic depression. Melancholic status was determined at baseline using depression scale items mapped to DSM criteria. The intervention consisted of six intravenous infusions of ketamine at 0.5 mg/kg administered over 40 minutes (reported in the extracted text). Anhedonic symptoms were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia items. Statistical analysis was performed with SPSS v24.0 using an intention-to-treat approach. Between-group comparisons for continuous variables used Student’s t-tests and categorical variables used Chi-square tests. Rates of antianhedonic response and remission were compared with Chi-square tests and further examined using logistic regression to derive odds ratios adjusted for sociodemographic confounders. A linear mixed-effects model assessed change in anhedonic symptoms over time, with covariates including baseline demographic and clinical variables that differed between groups. Bonferroni correction was applied for multiple comparisons and the significance level was set at α = 0.05.

The extracted text reports that the total sample comprised 135 participants, of whom 30 (22.2%) met DSM criteria for melancholic depression. L-M. and colleagues report that both melancholic and non-melancholic groups showed rapid improvements in anhedonic symptoms following six ketamine infusions. Comparisons of antianhedonic response and remission rates after six infusions indicated no statistically significant differences between the melancholic and non-melancholic groups. The extracted text states that the melancholic group had a non-significantly lower antianhedonic response and remission than the non-melancholic group, but the specific response and remission percentages and exact p-values are not clearly reported in the extracted material. The melancholic group had significantly lower MADRS anhedonia subscale scores than the non-melancholic group at an early post-treatment time point referenced in the text, and the reduction in anhedonic symptoms was greater in the melancholic group at day 26 compared with the non-melancholic group. The exact p-values and some numerical details for these time-point comparisons are missing in the extraction. The authors used adjusted logistic regression and linear mixed-effects models to account for covariates, but further subgroup or adverse-event data are not provided in the extracted sections.

L-M. and colleagues conclude that this is the first study to compare antianhedonic effects of repeated ketamine infusions between patients with melancholic and non-melancholic depression. The principal findings reported are: (1) 22.2% (30/135) of the sample met DSM-criteria for melancholic depression; (2) antianhedonic response and remission rates after six 0.5 mg/kg ketamine infusions were similar in individuals with and without melancholic depression; and (3) the reduction in anhedonic symptoms among patients with melancholic depression was greater at day 26 than in patients without melancholic depression. The authors note that the observed prevalence of melancholic depression (22%) is lower than some prior reports and attribute differences across studies mainly to varying diagnostic criteria for melancholia. They report rapid improvements in anhedonia in both melancholic and non-melancholic patients following multiple ketamine infusions and that overall antianhedonic efficacy was comparable between groups. The lack of a statistically significant difference in response/remission rates may reflect the relatively small melancholic subgroup, and the authors recommend further research with larger samples to explore a potential superior effect in melancholic patients and to investigate effects following a single infusion. The authors identify several strengths and limitations. Strengths include being the first study to make this particular comparison. Limitations reported are the open-label design; a relatively small melancholic group (n = 30); pooling of participants with major depressive disorder and bipolar disorder, which increases sample heterogeneity; use of the MADRS anhedonia items rather than a dedicated anhedonia scale such as the Snaith–Hamilton Pleasure Scale (SHAPS); and the fact that melancholic classification was derived in a secondary/post hoc manner from scale items rather than by a primary diagnostic instrument. These caveats are highlighted as reasons for cautious interpretation and for the need for further, more definitive studies.