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.
Pietro Carmellini, Andrea Fagiolini, Mario Pinzi, Marta Magno, Donato Martella, Lorenzo Nicchi, Maria Beatrice Rescalli, Francesca Tarantino, Rebecca Tinturini, Simona Scheggi, Giacomo Gualtieri, Alessandro Cuomo
Psychiatry research August 1, 2026 Peer reviewed DOI: 10.1016/j.psychres.2026.117184 via PubMed
Summary
Intravenous ketamine is effective in treating treatment-resistant depression, showing significant reductions in depressive symptoms over time for both unipolar and bipolar depression patients. Those with bipolar depression experienced faster and greater improvements starting from week 2 and lasting up to three months. Dissociative symptoms remained unchanged across all diagnostic categories, although women with unipolar depression reported higher dissociative symptoms after three months.
Study at a glance
| Design | observational study |
|---|---|
| Sample size | 97 |
| Population | adult patients with treatment-resistant unipolar or bipolar depression |
| Key finding | Patients with bipolar depression demonstrated a faster and greater improvement in depressive symptoms compared to those with unipolar depression. |
Abstract
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. 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. 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. Intravenous ketamine is effective in real-world treatment-resistant depression, with superior and more sustained antidepressant effects in bipolar compared with unipolar depression.