A groundbreaking randomized and blinded clinical trial published today in JAMA Psychiatry challenges the prevailing optimism surrounding repeated ketamine infusions as an adjunctive treatment for depression in hospitalized patients. The KARMA-Dep 2 trial, a collaborative effort among St Patrick’s Mental Health Services, Trinity College Dublin, and Queens University Belfast, reveals that ketamine offers no discernible advantage over standard inpatient care augmented with midazolam, a psychoactive comparator. This landmark study calls for a critical reassessment of ketamine’s role in contemporary depression treatment protocols.
Depression continues to impose a staggering global health burden, recognized by the World Health Organization as one of the leading causes of disability worldwide. Within Ireland alone, psychiatric inpatient admissions reached over fifteen thousand in 2023, with depressive disorders topping the chart as the predominant diagnosis. Despite the widespread use of conventional antidepressants targeting monoaminergic pathways—including serotonin, dopamine, and noradrenaline—approximately 30% of patients demonstrate treatment-resistant profiles. This therapeutic gap has galvanized research into novel mechanisms and agents.
Ketamine, traditionally known as a dissociative anesthetic, has emerged as a candidate promising rapid antidepressant effects distinct from monoamine modulation. Its putative mechanism involves modulation of the glutamatergic system, specifically via antagonism of NMDA receptors, subsequently enhancing synaptic plasticity and connectivity within critical mood-regulating circuits. Initial investigations observed transient mood improvements following single ketamine infusions, fostering hope for its application in refractory depression.
However, the ephemeral nature of ketamine’s benefits—often fading within days—has prompted clinicians to explore repeated dosing regimens as a strategy to sustain therapeutic gains. The KARMA-Dep 2 trial rigorously evaluated this approach in an inpatient setting, administering up to eight intravenous infusions over four weeks alongside standard care. Employing midazolam as an active control, the study endeavored to maintain blinding despite ketamine’s distinctive dissociative side effects known to compromise masking in clinical trials.
Primary endpoints focused on changes in depressive symptoms measured objectively via the Montgomery-Åsberg Depression Rating Scale (MADRS), complemented by patient-reported outcomes using the Quick Inventory of Depressive Symptoms, Self-Report scale (QIDS-SR-16). Secondary analyses encompassed cognitive performance, health economic assessments, and quality-of-life indices to holistically appraise treatment impact.
Remarkably, the study’s findings demonstrated no statistically significant difference in depression scores between the ketamine and midazolam groups at treatment completion. Subjective assessments mirrored this outcome, refuting the hypothesis that repeated ketamine infusions provide superior mood amelioration when appended to routine inpatient mechanisms. Furthermore, cognitive and economic evaluations revealed parity between the two cohorts, underscoring a lack of ancillary benefits attributable to ketamine.
A notable methodological insight emerged from the difficulty in maintaining effective blinding, as most patients and raters accurately identified treatment assignments, likely influenced by ketamine’s pronounced psychoactive effects. This revelation accentuates the potential for enhanced placebo responses, a factor that may have contributed to inflated efficacy signals in earlier, less rigorously controlled studies.
Declan McLoughlin, the principal investigator and Research Professor of Psychiatry at Trinity College Dublin, emphasized the study’s profound implications: “Contrary to our initial hypothesis, adjunctive repeated ketamine infusions did not improve mood outcomes under stringent trial conditions. This challenges existing perceptions and underscores the necessity to temper expectations regarding ketamine’s antidepressant efficacy in clinical practice.” His reflections call attention to the imperative for evidence-based recalibration of treatment strategies within psychiatric inpatient care contexts.
Co-lead author Dr. Ana Jelovac further stressed the critical importance of assessing and reporting blinding success in trials involving pharmacodynamic agents with discernible effects. She remarked, “Our findings highlight how compromised masking can potentiate placebo artifacts, skewing results and obscuring true therapeutic impact. This serves as an essential consideration for future investigations of ketamine and analogous modalities such as psychedelics or neuromodulation therapies.”
The KARMA-Dep 2 trial thereby advances the discourse on ketamine’s clinical utility and safeguards against premature widespread adoption of off-label practices. Its robust design and comprehensive evaluation parameters set a benchmark for future efforts aiming to unravel the complexities of depression treatment beyond monoaminergic paradigms.
As depression continues to challenge healthcare systems internationally, these findings inject a sobering perspective into the excitement surrounding novel pharmacotherapies. They reiterate that rigorous scientific validation must precede integration into standard therapeutic arsenals to ensure patient benefit, cost-effectiveness, and optimization of mental health resources.
This pivotal research not only refines our understanding of ketamine’s mechanistic actions and clinical profile but also exemplifies the critical role of methodological rigor in psychiatry’s evolving landscape. It invites a renewed focus on innovative avenues, potentially combining pharmacology with targeted psychotherapeutic interventions and personalized medicine to elevate depression care.
For clinicians, patients, and policymakers, the KARMA-Dep 2 trial prompts a reevaluation of ketamine’s positioning, emphasizing caution and continued investigation rather than unbridled enthusiasm. Its transparent dissemination empowers evidence-informed decisions in confronting one of modern medicine’s most formidable challenges—treatment-resistant depression.
Subject of Research: People
Article Title: Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression
News Publication Date: 22-Oct-2025
Web References: http://dx.doi.org/10.1001/jamapsychiatry.2025.3019
Keywords: Depression; Mental Health; Psychiatric Disorders; Psychiatry; Psychotic Disorders; Psychological Science; Neuroscience
