Reacción a "A meta-analysis concludes that intravenous ketamine is effective in reducing depressive and suicidal symptoms in patients with major depression"

This meta-analysis evaluates treatment with intravenous ketamine infusions in people with major depressive episodes. It includes 26 randomized, placebo-controlled clinical trials conducted in various 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

• Short follow-up. There is little data available several months later, so the long-term effect is unknown. More longitudinal studies are needed.

• Heterogeneity among studies. They differ in the profiles of the participants, doses, regimens (single or serial), and duration of follow-up. This makes comparison difficult, although the meta-analysis provides a good approximation.

• Difficulty maintaining blinding. In a clinical trial, it is essential that the participant not know whether they are receiving a placebo or active treatment, as believing they are receiving the treatment can magnify the perceived benefit (placebo effect). With ketamine, this is particularly complicated: the substance often causes noticeable effects—relaxation or dissociative symptoms such as a sense of strangeness or difficulty recognizing body parts—that make it easy to guess that it has been administered. To mitigate this, some studies used an active comparator (midazolam, a benzodiazepine with a sedative effect), while others used an inactive placebo (saline solution), which adds variability to the results.

• Study population. Trials typically exclude individuals with comorbidities, both psychiatric (anxiety, OCD, etc.) and non-psychiatric (diabetes, etc.), and the presence of more than one diagnosis is the norm, not the exception. The greater the number of comorbid conditions, the more difficult it is to treat depression, so the results may be somewhat inflated compared to what would be seen in routine clinical practice.

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.