Distinct trajectories of antidepressant response to intravenous ketamine

The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response.

We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations.

GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01).

This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available.

Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.