KETAMINE’S POTENTIAL FOR TREATING LONELINESS IN TREATMENT RESISTANT BIPOLAR DEPRESSION

Introduction

Loneliness is a subjective feeling characterized by decreased social connectedness and dissatisfaction with the quality of relationships. Replicated observational studies have demonstrated a strong association between loneliness with depression, suicidality and numerous other psychiatric and physical disorders making this a potential trans-diagnostic target for treatment. Loneliness has a high prevalence in bipolar disorders and is associated with poorer outcomes to treatments and increased risk of suicidality. Psychedelics, including ketamine, have been shown to potentially enhance one’s connectedness to their surroundings, social engagement and feelings of empathy. In addition to ketamine’s rapid antidepressant properties, replicated clinical trials and real-world effectiveness studies have demonstrated its robust anti-suicidal effects. Taken together, further research into ketamine’s therapeutic potential for reducing loneliness specifically in individuals with treatment resistant bipolar depression (TRBD) is needed.

Methods

We completed the world’s first randomized clinical trial (RCT) to evaluate the efficacy, safety and tolerability of an acute course of intravenous (IV) ketamine for TRBD. While the primary outcome was antidepressant efficacy, we also evaluated the effects of ketamine on secondary outcomes of interest for exploratory analysis, including the effects on loneliness. The University of California Los Angeles (UCLA) Loneliness Scale, a self-report assessment evaluating one’s subjective feelings of loneliness, was administered at baseline, Day 14 and Day 28. An independent samples t-test was completed comparing the mean change in UCLA score from baseline to Day 14 and baseline to Day 28 in the ketamine arm to the midazolam arm.

Results

This exploratory analysis included 57 participants with a diagnosis of moderate to severe TRBD. We observed significant reductions in the UCLA mean scores in both groups, indicative of clinically significant reductions in symptoms of loneliness. However, no significant difference (p=0.319) in mean UCLA Loneliness score from baseline to Day 14 was identified when comparing the ketamine group (mean [SD]= -4.81 [9.39]) to the midazolam group (mean [SD] = -6.00[9.36]). Similarly, when evaluating mean change in UCLA scores from baseline to Day 28, both groups had significant improvements with no significant difference observed between groups (p=0.077, mean [SD]: ketamine = -8.23 [8.43], midazolam = -4.84 [9.08]).

Discussion

In this exploratory analysis of individuals with TRBD, ketamine was not statistically superior compared to midazolam in reducing loneliness scores at either Day 14 or Day 28. Although both groups displayed decreases in UCLA Loneliness scores over time, the magnitude of change was comparable at Day 14 with greater reduction in the ketamine arm only at Day 28. The possibility of delayed effects warrants further investigation. This exploratory analysis is limited as it is inadequately powered to detect small differences between groups. As well, reductions in feelings of loneliness observed in both arms may be better explained by nonspecific effects such as therapeutic engagement, consistent studyrelated support throughout the 19 total study visits in approximately one month, expectancy, or natural fluctuations in social connectedness. Continued research of the relationship of ketamine and loneliness is encouraged in future adequately powered RCTs.

References

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