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A systematic review and meta-analysis looks at ketamine infusions for the reductio of suicidal and depressive symptoms.
Prof Rupert McShane, Consultant Psychiatrist at Oxford Health NHS Trust and Associate Professor of Psychiatry at University of Oxford, said:
“This is a high-quality systematic review and meta-analysis by a group of well-regarded researchers, published in a high impact journal. It includes recent negative studies – and includes an ‘end of treatment’ time point, as well as shorter time points. It includes appropriate caveats about the long-term nature of depression and the need for data on longer term outcomes.
“This study confirms that ketamine can have a useful clinical place in the treatment of suicidality and depression.
“The French national regulator has recently approved 2 doses for acute suicidality. The Norwegian equivalent of NICE has said that ketamine is cost effective compared to ECT and it is now funded nationally.
“NICE has recently turned down ketamine as an option for those who might otherwise need ECT. Its analysis made no mention of the difference in cognitive side effects between ECT and ketamine: ECT causes enduring cognitive side-effects but ketamine does not. NICE dismissed from consideration a large US study which used the type of ECT which is used in most US ECT clinics, on the grounds that this version was weaker than the version used in the UK.”
Comments from our friends at SMC Spain:
Dr Gerard Anmella, a psychiatrist and researcher at the Unit for Depressive and Bipolar Disorders at Hospital Clínic in Barcelona, says:
“This meta-analysis evaluates treatment with intravenous ketamine infusions in people with a major depressive episode. It brings together 26 randomized, placebo-controlled clinical trials conducted in different parts of the world, involving a total of 1,166 participants.
Each individual study has its own characteristics: different doses, different participant profiles, and different follow-up periods. A meta-analysis combines the results of several trials to estimate the average effect of the treatment (some studies will show a greater effect, others a lesser one, but this allows for comparison). That is why it is considered one of the strongest sources of evidence: it integrates multiple studies and increases the statistical power to detect real effects.
Compared to placebo, people who received intravenous ketamine showed a significant reduction in suicidal ideation and other depressive symptoms. The effect was already apparent four hours after the infusion and persisted at 24 hours, three days, one week, and even one month.
“The magnitude of the change was approximately SMD = 0.7, which is considered a large effect size. To understand this intuitively: at 24 hours, the typical person in the ketamine group had fewer suicidal thoughts than about 75% of the placebo group. And if we randomly pair one person from each group, in approximately seven out of every 10 pairs, the person in the ketamine group shows fewer symptoms.
“This effect was observed in both suicidal ideation and other depressive symptoms: sadness, difficulty experiencing pleasure, sluggishness, anxiety, insomnia, lack of appetite, pessimism, and difficulty concentrating, among others.
“When response rates were analyzed (a 50% reduction in depressive symptoms from baseline), ketamine outperformed the placebo during the first week, but not thereafter. And no differences were found in terms of remission, that is, becoming virtually symptom-free.
Most studies reported no significant adverse effects, and those described were mostly unrelated to ketamine. Even so, caution is warranted: participants in clinical trials are typically selected (for example, those without other associated conditions), so when this treatment is applied to the general population, the frequency of adverse effects is likely to be higher. Furthermore, in depression, it is difficult to distinguish whether a specific symptom stems from the illness itself or from the treatment.
“Some people improved with a single administration, but most relapsed and required repeated infusions. People with bipolar depression showed worse outcomes than those with unipolar depression; while there are few studies, this is an interesting hypothesis to investigate. When comparing intravenous ketamine with esketamine, no significant differences were found, although only two studies were included.
“Limitations
“Intravenous ketamine produces a rapid and intense improvement in depressive symptoms and, particularly importantly, in suicidal ideation, as early as the first few hours after the infusion. This is an important finding, especially when considering clinical situations where time is of the essence—such as high suicide risk—and in which classic antidepressants take weeks to take effect.
”That said, the data also call for caution. The effect on response rates wanes beyond the first week, does not translate into higher remission rates, most people relapse and require repeated infusions, and we do not know what happens in the medium and long term. Added to this are the methodological limitations discussed (difficult blinding, selected populations, heterogeneity among studies), which likely mean that the actual effect in clinical practice is somewhat smaller than that observed in these trials.
“Intravenous ketamine is therefore not a cure for depression, but it is a promising tool that expands the available options, especially in severe cases or those at risk of suicide. More studies are needed—with long-term follow-ups, more representative populations, and well-defined maintenance regimens—to determine for whom, when, and for how long this treatment should be offered.”
Dr Juan Antonio García Carmona, a neurologist at Santa Lucía General Hospital in Cartagena, an associate professor of pharmacology at the Catholic University of Murcia (UCAM), and a researcher in neuropsychiatry at the Murcian Institute for Biomedical Research (IMIB), says:
“This is a significant study that also employs a robust methodology: a systematic review and meta-analysis of 26 randomized clinical trials involving a total of 1,166 patients with major depression. This type of analysis is considered one of the highest levels of clinical evidence because it combines results from multiple studies and provides a more accurate picture of the treatment’s actual effect. In this case, the data reasonably support the conclusions: intravenous ketamine infusions showed a rapid and significant reduction in both depressive symptoms and suicidal ideation, with effects detectable in as little as four hours and, in some cases, lasting up to a month.
“The study aligns well with the evidence accumulated over the past decade, which already pointed to ketamine as one of the few psychiatric treatments with an almost immediate antidepressant and antisuicidal effect. The main novelty of this meta-analysis is that it updates and reinforces that evidence by incorporating more recent trials, including studies with repeated infusions, and offers a more comprehensive synthesis of both efficacy and safety. It also comes at an important time, following the recent approval in France of intravenous ketamine for adults with severe suicidal symptoms, which increases its clinical and regulatory relevance.
“The authors have made a reasonable effort to control for confounding factors. They included only randomized trials, assessed the risk of bias using standard tools, and employed appropriate statistical models to address heterogeneity across studies. Nevertheless, there are significant limitations. Many of the included trials have relatively small sample sizes, short durations, and strict selection criteria, so the results may not be generalizable to all patients seen in routine clinical practice. Furthermore, although the short-term effects are consistent, uncertainty remains regarding the duration of the benefit, the need for maintenance doses, and potential risks associated with prolonged use, such as tolerance or cognitive effects.
“In practical terms, the implications are significant. This study reinforces the idea that intravenous ketamine can be a valuable tool for urgent clinical situations, especially in patients with treatment-resistant depression or high suicide risk, where conventional antidepressants often take weeks to take effect. However, it should not be interpreted as a definitive solution or a substitute for other treatments. Rather, it suggests that it could become established as a rapid rescue intervention within specialized settings, while longer-term therapeutic strategies are established.”
Dr Elisabet Domínguez Clavé, president of the Spanish Society of Psychedelic Medicine (SEMPsi), says:
“This is a systematic review and meta-analysis of high methodological quality, published in JAMA Psychiatry, which analyzes 26 randomized clinical trials involving more than 1,100 patients. Overall, the conclusions are well supported by the data: intravenous ketamine shows a rapid reduction (within hours) in depressive and suicidal symptoms, with moderate to high effect sizes, especially in the first 24 hours. This is clinically very relevant, as no currently available treatment acts that quickly in situations of acute suicide risk.
“The study aligns well with the evidence accumulated in recent years and reinforces it. It confirms that ketamine can produce rapid improvements in depressive distress that conventional antidepressants fail to achieve in such a short timeframe. In fact, this body of evidence is already beginning to have a regulatory impact: France recently approved its use in certain clinical contexts for severe suicidal symptoms.
“Even so, there are important limitations that should be taken into account. There is some heterogeneity among the included studies, and in some cases ketamine’s dissociative effect may have compromised blinding, as patients may have sensed which treatment they received. Furthermore, most trials have small sample sizes, and, above all, there is very little data on long-term safety and efficacy, as the studies focus on the acute effect.
“In terms of their implications, these results are particularly relevant for patients with treatment-resistant depression and for suicidal crisis situations requiring urgent intervention. However, it is not a general treatment for depression, and its use raises key questions about how, where, and under what supervision it should be administered. It is also important to consider the potential for abuse and possible long-term adverse effects before considering an expansion of its use.
“Overall, this meta-analysis reinforces the idea that we are dealing with a potentially very valuable therapeutic tool in specific clinical contexts, especially due to its rapid onset of action. However, it also highlights that we are still at a relatively early stage, and that the real challenge is not only to demonstrate short-term efficacy but to define how to integrate it safely, sustainably, and in an evidence-based manner within health systems.”
‘Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode A Systematic Review and Meta-Analysis’ by Sung Ryul Shim et al. was published in JAMA Psychiatry at 16:00 UK time on Wednesday 6th May.
DOI: 10.1001/jamapsychiatry.2026.0612
Declared interests
Prof Rupert McShane: Rupert McShane is past chair of the RCPsych Committee for ECT and related treatments. He has run an ECT service for 30 years and a ketamine clinic https://oxfordhealth.nhs.uk/ips/ketamine-trd/ for 15 years. He represented the RCPsych in its appeal against NICE’s rejection of esketamine nasal spray. About 10 years ago he once attended a conference paid for by Janssen. His department has received his fees for lectures about ketamine.
He is a consultant psychiatrist at Oxford Health NHS Trust and associate professor of psychiatry at University of Oxford
Dr Gerard Anmella: Gerard Anmella has received fees for continuing medical education (FMC) activities or consulting services from Abartis Pharma, Adamed, Abbott, Angelini, Casen Recordati, Esteve, Johnson & Johnson, Lundbeck, Lundbeck/Otsuka, Rovi and Viatris, without any financial or other relationship relevant to the subject of this article.
Juan Antonio García Carmona: No conflicts of interest declared.
Elisabet Domínguez Clavé: She declares that she has no conflicts of interest.