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

Carmellini and colleagues situate the study within growing interest in intravenous ketamine as a rapid-acting treatment for treatment-resistant depression, but note that the evidence base is still heterogeneous, particularly across diagnostic subtypes. They also highlight that real-world data comparing unipolar and bipolar depression, and exploring sex-related differences, remain limited. The extracted text presents ketamine as promising for both conditions, yet uncertainty remains about whether response differs by diagnosis or sex in routine clinical practice. The study aimed to evaluate the antidepressant efficacy, tolerability, and dissociative effects of intravenous racemic ketamine in treatment-resistant unipolar depression and treatment-resistant bipolar depression in a naturalistic setting. The authors also sought to determine whether diagnostic subtype or gender influenced treatment trajectories, with the broader goal of identifying clinically relevant patterns that might support more personalised treatment decisions. The primary outcome was change in depressive symptom severity over time, with clinical severity and dissociative symptoms as secondary outcomes.

This was a retrospective observational study conducted at a university psychiatric centre in Siena, Italy, using clinical records from April 2016 to April 2025. The sample included adults aged 18 to 75 years with DSM-5 diagnoses of either treatment-resistant unipolar depression or treatment-resistant bipolar depression. Diagnostic assessment was performed with the Structured Clinical Interview for DSM-5 after comprehensive clinical evaluation. The paper states that the study followed STROBE guidance and had regional ethics committee approval, with written informed consent obtained from participants. Eligibility criteria excluded patients with aneurysmal vascular disease, a history of cerebral haemorrhage, known ketamine or esketamine hypersensitivity, a recent cardiovascular or cerebrovascular event, a positive pregnancy test, inability to provide consent, premature discontinuation of ketamine within the first three months, or any adverse event after ketamine administration during the first three months. The extracted text indicates that the cohort reflected routine clinical practice, and data came from verified clinical documentation and medical records. Participants received racemic intravenous ketamine under an individually adjusted infusion plan developed with anaesthesia colleagues. Dosing generally started at 0.2-0.3 mg/kg and was titrated towards a target range of 0.4-1.0 mg/kg, with many patients treated in the 0.6-0.8 mg/kg range. Infusions were typically given twice weekly for the first four weeks, then weekly or fortnightly depending on response and tolerability. Outcomes were measured at baseline, week 1, week 2, week 3, week 4, and month 3. Depressive symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), global severity with the Clinical Global Impression-Severity scale (CGI-S), and dissociative symptoms with the Clinician-Administered Dissociative States Scale (CADSS), administered about 40 minutes after infusion. Adverse events were recorded during infusion, at 40 minutes, and again at 24 hours post-infusion. The main analyses used mixed-effects models with random intercepts to account for repeated measures, treating time as continuous because the visits were not equally spaced. Separate models examined MADRS, CGI-S, and CADSS, including time-by-diagnosis interactions, and additional models added sex and a three-way time-by-diagnosis-by-sex interaction. Analyses were run in R, with statistical significance set at p<0.05.

The final sample included 97 patients: 46 with unipolar depression and 51 with bipolar depression. The two groups were broadly similar in demographic and clinical characteristics, including age, gender distribution, marital status, occupation, episode counts, hospitalisations, comorbidity burden, and baseline ketamine dose. BMI was higher in the bipolar group, and manic episodes were, as expected, more frequent in bipolar depression. Baseline depressive severity was high in both groups, with mean MADRS scores of 36.5 in unipolar depression and 37.7 in bipolar depression, and mean CGI-S scores of 5.5 and 5.6 respectively. CADSS scores were relatively stable over time in both groups. MADRS scores fell significantly over time overall, by about 1.2 points per week (β = -1.19, 95% CI -1.41 to -0.98, p<0.001). Although baseline differences between diagnoses were not significant, the time-by-diagnosis interaction was significant (β = -0.57, 95% CI -0.87 to -0.28, p<0.001), indicating faster improvement in bipolar depression. The contrasts showed that bipolar and unipolar groups did not differ at baseline, but bipolar depression had significantly lower MADRS scores from week 2 onwards, with the largest difference at week 12 (estimate = 9.21, p<0.001). By week 12, mean MADRS scores were 13.0 in bipolar depression and 19.7 in unipolar depression. CGI-S scores also improved over time, decreasing by 0.13 points per week (β = -0.13, 95% CI -0.16 to -0.10, p<0.001). Again, the diagnosis-by-time interaction was significant (β = -0.09, 95% CI -0.13 to -0.04, p<0.001), with bipolar depression improving more rapidly. The between-group difference emerged from week 4 and was largest at week 12 (estimate = 1.13, p<0.001). By the end of follow-up, CGI-S scores were 2.6 in the bipolar group and 3.6 in the unipolar group. CADSS scores did not change significantly over time (β = 0.04, 95% CI -0.03 to 0.11, p = 0.295), and there were no baseline diagnostic differences or time-by-diagnosis effects. In the sex-stratified models, sex did not modify antidepressant response on MADRS or CGI-S. For CADSS, there was a significant time-by-sex interaction overall, but diagnostic subgroup contrasts showed no male-female difference in bipolar depression. In unipolar depression, females had higher predicted CADSS scores at week 12 (estimate = -5.72, p = 0.003), suggesting greater dissociative symptoms at that point.

Carmellini and colleagues interpret the findings as real-world evidence that repeated intravenous ketamine produces a rapid and sustained antidepressant effect in treatment-resistant depression, with greater benefit in bipolar than in unipolar depression. They emphasise that improvement was already visible by week 2 and remained present at three months, which they suggest may reflect longer-lasting neuroadaptive and neuroplastic changes rather than only an acute drug effect. The authors relate the diagnostic difference to underlying glutamatergic biology, arguing that bipolar and unipolar depression may differ in baseline glutamate-glutamine levels and therefore respond differently to ketamine, which acts through NMDA receptor antagonism and AMPA-related signalling. They also propose that BDNF-mTOR-mediated synaptogenesis could be more strongly engaged in bipolar depression. In their interpretation, this may help explain the larger and more sustained response in the bipolar group. Regarding sex effects, the authors describe more complex patterns. They report a trend towards greater antidepressant improvement in males with bipolar depression, whereas females with unipolar depression had more persistent dissociative symptoms over time. They attribute possible sex differences to hormonal influences on NMDA receptor expression, ketamine metabolism, inflammatory signalling, and BDNF responses. The authors present these as potential mechanisms rather than proven explanations. The discussion also acknowledges important limitations. The study was retrospective and uncontrolled, so causal conclusions cannot be made. The sample only included patients who completed at least three months of treatment without adverse events, which may bias tolerability findings towards favourable outcomes. The absence of placebo or active comparator limits estimation of ketamine’s specific effect size, the sample may have been underpowered to detect smaller predictors or sex effects, and the 12-week follow-up does not address longer-term maintenance or late adverse events. The authors conclude that larger prospective controlled studies are needed to confirm these observations and better define the comparative clinical course of bipolar and unipolar patients treated with ketamine.

The authors conclude that intravenous ketamine appears particularly effective for treatment-resistant bipolar depression, with stronger and longer-lasting antidepressant effects than in treatment-resistant unipolar depression. They further conclude that sex-related biological factors may help refine prediction of response and tolerability, and that incorporating diagnostic and gender considerations into treatment decisions could improve the precision, efficacy, and cost-effectiveness of ketamine therapy.