Comparative effectiveness of repeated ketamine infusions in treating anhedonia in bipolar and unipolar depression

Anhedonia, defined as a reduced capacity to experience or anticipate pleasure, is a core symptom of both major depressive disorder (MDD) and bipolar depression (BD). The extracted text notes that clinically significant anhedonia affects a substantial minority of patients (up to 37% in MDD and 52% in BD) and is associated with poorer treatment outcomes. Conventional antidepressant treatments have limited efficacy for anhedonia and can produce emotional blunting or sexual side effects. Non‑pharmacological approaches such as electroconvulsive therapy and transcranial magnetic stimulation have shown some benefit, but no approved medication specifically targets anhedonia. Zheng and colleagues frame ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, as a promising rapid‑acting treatment that has previously reduced depressive symptoms and suicidal ideation in MDD and BD and shown antianhedonic effects after single infusions. Biological mechanisms discussed by the authors include brain-derived neurotrophic factor (BDNF), inflammatory and kynurenine pathways, and reversal of anhedonic phenotypes in animal models. The primary aim of this single-arm, open-label study was to evaluate the antianhedonic effects of six intravenous ketamine infusions (0.5 mg/kg) in a sample of Chinese patients with MDD and BD, and to compare outcomes between the diagnostic groups.

The study used an open-label, single-arm design drawing on a clinical trial registered as ChicCTR-OOC-17012239 and conducted from November 2016 to December 2017. Eligible participants were adults aged 18–65 years experiencing a major depressive episode of MDD or BD without psychotic features, diagnosed according to DSM-5 criteria. Inclusion required a score of ≥17 on the 17-item Hamilton Rating Scale for Depression at screening, and either suicidal ideation (Beck Scale for Suicide Ideation part I score ≥2) or failure to respond to at least two pharmacological treatments for the current episode. Exclusion criteria included other primary psychiatric disorders such as schizophrenia or substance/alcohol use disorder; comorbid eating disorders, anxiety disorders or obsessive–compulsive disorder were permitted if not judged primary. Intervention comprised six subanaesthetic intravenous infusions of ketamine at 0.5 mg/kg given over 40 minutes across a 12-day period. Participants continued their existing psychotropic medications throughout the study. Anhedonia was assessed using the Montgomery‑Åsberg Depression Rating Scale (MADRS) 5-item anhedonia factor (items 1, 2, 6, 7 and 8). Assessments occurred before each infusion, at 40 minutes and 1 day after each infusion, and at 14 days after the final infusion. Antianhedonic response and remission were predefined as ≥50% and ≥75% reductions in MADRS anhedonia subscale score on day 13 (one day after the sixth infusion), respectively. An intention-to-treat (ITT) analysis was performed on MADRS anhedonia subscale scores for all participants. Between-group comparisons (MDD versus BD) of baseline characteristics used chi-square or Fisher’s exact tests for categorical variables and t-tests or Mann–Whitney U tests for continuous variables as appropriate. Longitudinal changes in anhedonia were analysed with linear mixed models; an additional model included the total MADRS score minus the anhedonia subscale as a covariate to test whether antianhedonic effects were independent of other depressive symptoms. Statistical significance was set at P < 0.05 and analyses were conducted in SPSS 24.0.

Ninety-seven participants received the repeated ketamine infusions: 77 with MDD and 20 with BD. Baseline characteristics were similar between groups for body mass index, age, age at onset, sex, education level, total MADRS score and MADRS anhedonia subscale score (all P > 0.05). The BD group had a significantly higher family history of psychiatric disorders and a longer illness duration than the MDD group (both P < 0.05). One day after the sixth infusion (day 13), 47 participants met the predefined antianhedonic response criterion (48.5%, 95% confidence interval 38.3%–58.6%) and 30 met the remission criterion (30.9%, 95% confidence interval 21.6%–40.3%). Response and remission rates did not differ significantly between the MDD and BD groups (all P > 0.05). The linear mixed model for MADRS anhedonia scores showed a significant main effect of time (F = 39.9, P < 0.05) but no significant effect of diagnosis (F = 1.9, P > 0.05) and no significant time-by-diagnosis interaction (F = 1.7, P > 0.05). A between-group difference was observed only at 4 hours after the third infusion (P < 0.05). Compared with baseline, a significant reduction in anhedonia scores was evident at 4 hours after the first infusion and was maintained at all subsequent time points (all P < 0.05). When the total MADRS score minus the anhedonia subscale was entered as a covariate, the antianhedonic effects of ketamine remained statistically significant (P < 0.05), indicating effects independent of changes in other depressive symptoms.

Zheng and colleagues interpret their findings as evidence that repeated intravenous ketamine infusions rapidly reduce anhedonia severity in patients with MDD and BD, with comparable efficacy across diagnoses. The reduction in anhedonia began within 4 hours of the first infusion and persisted throughout the five additional infusions. The authors highlight that effects on anhedonia remained after controlling for non‑anhedonic depressive symptoms, supporting a degree of specificity. The Discussion situates these results within prior work showing rapid antianhedonic effects after a single ketamine infusion and aligns them with recent reports of subcutaneous esketamine producing similar improvements in anhedonia for both MDD and BD. Route-of-administration considerations are noted: subcutaneous administration was described as a practical alternative associated with smaller blood pressure increases and fewer psychotomimetic effects compared with intravenous dosing, according to cited studies. The authors also mention other agents with potential antianhedonic effects (for example agomelatine, bupropion, acetyl-L-carnitine) but state that no head-to-head trials have compared these drugs directly with ketamine or esketamine for anhedonia. Key limitations acknowledged by the authors include the use of the MADRS 5-item anhedonia factor rather than a specific anhedonia instrument (such as the Snaith–Hamilton Pleasure Scale), the absence of a placebo or control group, continuation of participants’ existing psychotropic medications which could confound effects, and incomplete reporting of possible comorbid diagnoses. The authors therefore characterise the findings as preliminary and call for randomized, placebo-controlled, double-blind trials to verify and extend these results.

This preliminary, open-label study found that six subanaesthetic intravenous ketamine infusions appeared to produce rapid and sustained reductions in anhedonia in Chinese patients with MDD and BD, with similar effect sizes across diagnoses. The authors conclude that randomized, placebo-controlled, double-blind trials are needed to confirm these findings.