Faster and greater antidepressant response to intravenous ketamine in bipolar compared with unipolar treatment-resistant depression: Diagnostic and sex-related findings from a naturalistic study

Apr 27, 2026Psychiatry research

Faster and stronger antidepressant response to intravenous ketamine in bipolar versus unipolar treatment-resistant depression, with differences by diagnosis and sex

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Abstract

Ninety-seven adult patients with treatment-resistant depression received intravenous ketamine, showing significant reductions in depressive symptoms over time.

Patients with bipolar depression experienced faster and greater improvements in depressive symptoms compared to those with unipolar depression.
Differences in symptom improvement emerged from week 2 and persisted through three months.
Dissociative symptoms remained unchanged throughout the study across all diagnostic categories.
No differences in antidepressant efficacy were found between sexes, although women with unipolar depression reported higher dissociative symptoms at three months.

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BACKGROUND: Intravenous ketamine has emerged as a rapid-acting antidepressant intervention that has shown promising effects in patients with treatment-resistant depression, although evidence remains heterogeneous and less well established across diagnostic subtypes. Nevertheless, real-world data comparing diagnostic subtypes and sex-related differences remain limited. This observational study examined the antidepressant efficacy, tolerability, and dissociative effects of intravenous ketamine in patients with treatment-resistant unipolar depression (TRD) and treatment-resistant bipolar depression (TRBD) in a naturalistic clinical setting.

METHODS: Ninety-seven adult patients meeting DSM-5 criteria for unipolar or bipolar depression received racemic intravenous ketamine at a university psychiatric center. Depressive symptoms and global clinical severity were assessed at baseline and up to three months using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Severity scale (CGI-S). Dissociative symptoms were measured with the Clinician-Administered Dissociative States Scale (CADSS). Longitudinal outcomes were analyzed using mixed-effects models.

RESULTS: Both groups experienced significant reductions in depressive symptoms over time. Patients with bipolar depression demonstrated a faster and greater improvement than those with unipolar depression, with differences emerging from week 2 and persisting through three months. CGI-S scores showed a comparable pattern. The dissociative symptoms showed no change throughout the study and they appeared at the same level in all diagnostic categories. Sex-stratified analyses revealed no differences in antidepressant efficacy, although women with unipolar depression exhibited higher dissociative symptoms at three months.

CONCLUSIONS: Intravenous ketamine is effective in real-world treatment-resistant depression, with superior and more sustained antidepressant effects in bipolar compared with unipolar depression.

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Faster and greater antidepressant response to intravenous ketamine in bipolar compared with unipolar treatment-resistant depression: Diagnostic and sex-related findings from a naturalistic study

Abstract

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