After 20 years of research, we still can’t predict it, but one clue stands out
STUDY: Syed OA et al, CNS Drugs 2026;
STUDY TYPE: Systematic review
FUNDING: Independent
Background
Ketamine and esketamine (Spravato) work fast for treatment-resistant depression. This review looks at who is most likely to respond.
The Study
- 122 studies, 12,674 patients with unipolar or bipolar treatment-resistant depression
- Randomized controlled trials, open-label studies, and retrospective analyses
- Researchers extracted the direction of effect (positive, negative, or no association) for 77 clinical and demographic predictor variables.
Results
Most variables did not predict response, including age, sex, depression severity, anxiety comorbidity, prior hospitalizations, psychiatric diagnoses, number of failed antidepressants, and concurrent medications.
Two signals emerged as consistently positive predictors:
- Early response to (es)ketamine. In 13 studies, patients who improved early in a treatment course went on to respond by the end of treatment.
- Family history of substance use disorder. This predicted better response in 5 of 8 studies examining this variable, a counterintuitive finding with a plausible biological basis, given ketamine’s effects on the same reward circuitry implicated in addiction.
Dissociation during infusion, measured by the Clinician-Administered Dissociative States Scale (CADSS), showed no association with outcomes in 15 of 20 studies. Unlike psilocybin, where mystical experiences generally predict response, ketamine’s antidepressant effect appears independent of its psychedelic-esque effects.
Practice Implications
- The ketamines help all kinds of patients with treatment-resistant depression, especially those with early response to the drug or a family history of substance use disorder.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
