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 DOI: 10.1016/j.psychres.2026.117184 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Longitudinal Peer reviewed |
|---|---|
| Sample size | 97 |
| Population | Adult patients with treatment-resistant unipolar or bipolar depression |
| Intervention | Intravenous ketamine |
| Duration | Up to three months |
| Topics | Depression Ketamine Esketamine |
| Keywords | Mood disorders Precision medicine |
| Key findings | Intravenous ketamine produced faster and greater antidepressant effects in bipolar depression compared with unipolar depression, with no sex differences in efficacy. |
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.
Comparable studies
Other observational and cohort studies on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
| Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... | 2017 | Observational cohort | n = 59 |
| Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... | 2014 | Post hoc analysis of pooled data from four studies | n = 108 |
| An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder | 2011 | Observational cohort | n = 14 |
| Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... | 2019 | Observational cohort | n = 25 |