Major depression is a serious mental illness that often does not respond to mainstream drug treatment (antidepressants). In addition, there is usually a delay of 2-6 weeks before mood improves significantly. In situations like this, when at least two conventional antidepressants have been tried without success, depression is considered treatment-resistant. While multiple different strategies to deal with treatment-resistant depression have been suggested, “silver bullet” treatments are still lacking.

Ketamine has been shown to lead to rapid and sustained antidepressant relief even in treatment-resistant patients (Zarate et al., 2006).  However, methodological limitations in the research have made it impossible to determine whether ketamine really is an antidepressant drug. For instance, most studies used an inactive placebo (i.e. a saline injection), which is problematic as ketamine produces strong dissociative side effects. As a consequence, it is likely that participants were able to infer whether they had been given ketamine or the placebo, which raises concerns regarding blinding. In addition, sample sizes have generally been very small which makes generalizability difficult.

A new ground-breaking study published in the American Journal of Psychiatry has gone some way to addressing these shortcomings (Murrough et al, 2013).

Methods

The authors randomised a total of 72 patients to receive either a single intravenous infusion of ketamine (n = 47) or midazolam (n = 25) under double-blind conditions.

Patients had previously failed on at least three conventional antidepressants, such as selective serotonin-reuptake inhibitors, to be eligible. Psychotic forms of depression were excluded and sufficient drug washout was ensured.

Midazolam is a short-acting benzodiazepine with side effects similar to ketamine but without any antidepressant effects, making it an ideal active placebo.

As the primary study endpoint, depression severity was assessed 24 hours after injection with the Montgomery-Asberg Depression Rating Scale (MADRS).

Results

• MADRS scores were 7.95 points lower in the ketamine group (95% CI, 3.2 to 12.71, Cohen’s d = 0.81, large effect)
• Odds of response (at least 50% reduction in MADRS scores) to ketamine was 2.18 higher than of response to midazolam (95% CI, 1.21 to 41.4)
• Response rate to ketamine was 64% versus 28% for midazolam
• Reported side effects (most commonly dizziness and headache) were similar across both groups and usually resolved within four hours
• There were no severe psychotic symptoms in any patient, although 17% experienced dissociative effects under ketamine
• After one week, differences between the treatment groups had vanished

Conclusions

The authors conclude that:

In this two-site trial in treatment-resistant patients with moderate-to-severe and persistent depressive symptoms, we found that a single low dose of ketamine, as compared with a psychoactive placebo control medication, was associated with a rapid-onset antidepressant effect.

Limitations

Unfortunately, this study only assessed the effects of a single injection of ketamine. While effective in acute intervention, another main problem with current treatment is how to maintain mood improvement. From this perspective, it would have been interesting to study the effects of consecutive treatments, for instance on a weekly basis. Evidence from other studies (e.g. aan het Rot et al., 2010) suggest that this is feasible and highly efficacious. However, this point also highlights how little is known about the long-term effects of ketamine treatment. Also, it should be kept in mind that due to possible dissociative effects, ketamine will be restricted to non-psychotic forms of depression. While making sense clinically speaking, this is somewhat unfortunate, as psychotic depression is usually more severe and difficult to treat, making such patients more likely to be treatment-resistant.

From a methodological perspective, this study raises some doubts concerning the appropriateness of midazolam as an active control. While 17% of patients reported dissociative symptoms with ketamine, this was not found for midazolam. It would have been interesting to assess directly (i.e. via questionnaires) if participants were aware of their experimental condition after the infusion to rule out these concerns.

Summary

Ketamine seems to be an acutely safe and effective antidepressant. Yet, its application (i.e. intravenous infusion), ignorance of long-term health outcomes and dissociative properties highly restrain usage. In very severe cases and after careful screening, however, it could prove to be a useful tool for clinicians.

Links

Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M. et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression; a two-site randomized controlled trial. Am J Psychiatry, 170, 1134-1142. [PubMed abstract]

aan het Rot, M.; Collins, K.A.; Murrough, J.W.; Perez, A.M.; Reich, D.L.; Charney, D.S. et al. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression (PDF). Biol Psychiatry, 67, 139-145. [PubMed abstract]

Zarate, C.A.; Singh, J.B.; Carlson, P.J.; Brutsche, N.E.; Ameli, R.; Luckenbaugh, D.A.; Charney, D.S., & Manji, H.K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression (PDF). Arch Gen Psychiatry, 63, 856-864. [PubMed abstract]