Ketamine-Induced Dissociative Symptoms Predict Antidepressant Response

Patient in hospital bed
Patient in hospital bed
Investigators hypothesize that increased dissociative symptoms may improve depressive symptom scores after ketamine infusion.

Increased dissociative symptoms associated with ketamine infusion treatment can predict a greater antidepressant effect in individuals with major depressive disorder or bipolar disorder. In fact, specific properties of ketamine-induced dissociation (such as depersonalization and derealization) can uniquely predict the antidepressant response, according to a study published in the Journal of Affective Disorders.

This follow-up study expanded on previous research that explored the relationship between ketamine’s dissociative side-effects and the antidepressant response in individuals with treatment-resistant depression. Furthermore, it validated the subdimensions of dissociation as unique predictors of depression improvement. Data were obtained for 126 patients from 3 previous studies and participants were identified as ketamine-bipolar (n=39), ketamine-riluzole (n=52), and ketamine-MOA (n=35); all patients experienced a major depressive episode lasting at least 2 weeks at screening and had failed to respond to other antidepressants.

Dissociative symptoms were assessed at baseline and again 40 minutes after the subanesthetic-dose of ketamine was administered. The 19-item Clinician-Administered Dissociative States Scale (CADSS) was used to evaluate dissociative symptoms, and study researchers proposed 3 subdimensions of dissociation: amnesia (2 items), depersonalization (5 items), and derealization (12 items). The depressive response was evaluated using the 17-item Hamilton Depression Rating Scale (HAM-D), in which a percent change in score was measured at 230 minutes, 1 day, and 7 days after ketamine infusion.

The antidepressant response (shown by a negative change in HAM-D scores) was predicted by a greater CADSS total score, along with the derealization and depersonalization subscales. Specifically, a relationship between the CADSS total score and a significant percent change in HAM-D score at Day 7 in the ketamine-MOA study was observed. The relationship was non-significant for both the ketamine-bipolar and ketamine-riluzole groups, and for all studies at the 230-minute time point. Similarly, the derealization subscale showed a significant effect on the Day-7 HAM-D score, but only in the ketamine-MOA group. However, across all studies and all time points, a greater depersonalization subscale predicted a significant percent change in HAM-D score. The amnesia subscale was non-significant.

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Limitations of the study included possible inadequate blinding as participants can often discern ketamine from placebo, as well as increased dissociation symptoms may unblind researchers. Another limitation may be the use of combined data sets for both major depressive disorder and bipolar disorder, in which ketamine is less efficacious in individuals with bipolar depression.

These results suggest that depersonalization as a differential symptom cluster of ketamine-induced dissociation is uniquely related to the antidepressant response, and may be used as a reliable predictor of improvement for treatment-resistant depression.


Niciu MJ, Shovestul BJ, Jaso BA, et al. Features of dissociation differently predict antidepressant response to ketamine in treatment-resistant depression. J Affect Disord. 2018; 232:310-315.