INTRAVENOUS KETAMINE IMPROVES SOCIAL ANHEDONIA IN PATIENTS WITH TREATMENT-RESISTANT DEPRESSION AND SUICIDAL IDEATION

Social anhedonia—reduced pleasure from social interaction—has long been examined in schizophrenia-spectrum disorders but is increasingly recognized as a transdiagnostic phenotype linked to mood disorders and suicide risk. Yet no evidence-based treatments directly target social anhedonia in depression. Emerging work suggests entactogens may enhance social connection, and ketamine has shown putative entactogenic effects, including transient changes in self/other-perception, enhanced social reward sensitivity, and increased prosocial motivation. To test these effects empirically, we examined ketamine-related changes in social anhedonia among patients with mood disorders and suicidal ideation receiving open-label treatment. We hypothesized that 1) ketamine will improve social anhedonia in a dose-dependent manner, 2) that the improvement in social anhedonia would be independent from the general antidepressant effect, and 3) mediated by ketamine’s transient dissociative effects altering self-and other-perception. Participants were enrolled in the Neurobiology of Suicide clinical trial (NCT02543983) from 2015–2025 and received up to five intravenous infusions of racemic ketamine (0.5 mg/kg) twice weekly. The Snaith-Hamilton Pleasure Scale (SHAPS) was administered at –60 and +230 minutes relative to each infusion; four SHAPS items indexing enjoyment of social connection and altruism were used to derive a social anhedonia score. Depressive symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Dissociation was measured with the Clinician-Administered Dissociative States Scale (CADSS) at +40 minutes; ten items reflecting altered self/other-perception were combined into a “Self-Other” score. Linear mixed models tested changes in social anhedonia across time and infusions, adjusting for age and sex with a random intercept for subjects. Mediation analysis tested whether dissociation explained ketamine’s effects. Alpha was .05. Data from 282 observations across 28 participants (mean age = 40 ± 14 years; 54% female) were included. Social anhedonia significantly decreased after the first ketamine infusion (mean change = –1.0 points, 95% CI: –1.8 to –0.2; t = –2.5, p = .01). This improvement was maintained but did not significantly increase with repeated infusions. When adjusting for MADRS total score, the effect of ketamine on social anhedonia was no longer statistically significant. CADSS Self-Other scores were significantly associated with lower social anhedonia (B = –0.1, 95% CI: –0.2 to – 0.02; p = .02) but did not mediate ketamine’s effect. Intravenous ketamine improved social anhedonia, though the additional improvements with repeat doses was non-significant. Contrary to our hypotheses, ketamine’s effect on social anhedonia was not independent from its general antidepressant effect, nor was it mediated by ketamine’s dissociative properties pertaining to perception of self and others. This, however, does not rule out that ketamine’s effect on social anhedonia is pharmacologically distinct from the antidepressant mechanisms. Future studies should also replicate analyses using double-blinded studies to overcome the limitation of an open-label study design and incorporate multimodal outcomes. These may include but not limited to neuroimaging correlates; behavioral tasks measuring social anhedonia or prosocial behavior; a more extensive panel of self-report questionnaires measuring social anhedonia, empathy, and self-other relationships; and peripheral markers tied to social affiliative behavior (e.g. oxytocin, vasopressin).

References

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