Interest has been growing in ketamine as a treatment of depression (Aan Het Rot, et al 2012; Diamond et al., 2014) and there is some genuine excitement among some of the elvish bloggers.

Mainly used in veterinary surgery, ketamine has been discovered to rapidly improve even the most severe cases of unipolar and bipolar depression. However, as yet there are still many questions left unanswered before ketamine can become a licensed treatment alternative.

For one, there needs to be more clarity about the safety and effectiveness of the drug before an informed weighing of pros and cons is feasible. In addition, in order to stay on top of the immense interest ketamine has spurred, it is essential to have an updated overview of all studies out there. To this end McGirr et al have provided the most recent systematic review of methodologically sound studies (McGirr et al, 2014).

Methods

The authors scanned major medical databases for double-blind, placebo-controlled and randomised studies conducted with depressed patients. Response and remission after one day, three days and seven days was assessed by independent raters.

Results

Overall, six studies using intravenous and one using intranasal administration satisfied criteria, including 34 patients with bipolar depression and 149 with unipolar depression. 110 subjects were assessed in a cross-over design, while the remainder were enrolled in a more “traditional” parallel study. Odd’s ratios (OR) and number needed to treat (NNT) were calculated to provide illustrative statistics. In addition, the authors report the standardised mean difference (SMD), a composite statistic often used in meta-analyses that is useful when studies have different outcome measures (e.g. depression scales):

• Compared to placebo, a single ketamine injection led to more remissions after:
  • 24 hours (OR 7.06, NNT=5)
  • 3 days (OR 3.86, NNT=6)
  • 1 week (OR 4.00, NTT=6)
• A similar picture emerged for clinical response after:
  • 24 hours (OR 9.10, NNT=3)
  • 3 days (OR 6.77, NNT=3)
  • 1 week (OR 4.87, NNT=4)
• When looking at “raw” depression scores, an SMD of 0.90 in favour of ketamine compared to placebo was noted (p<0.001)
• Overall, there was evidence of higher efficacy in unipolar compared to bipolar depression
• Short-term psychosis-like experiences were relatively common, but no treatment-induced mania or other serious adverse events were reported in patients taking ketamine
• Looking at study completion as a proxy measure of tolerability:
  • 13.3% of patients scheduled to receive ketamine and
  • 7.4% scheduled to receive placebo did not finish the protocol, which was not significantly different (p=0.11)

Discussion

The authors concluded:

[…] meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Limitations

• Unfortunately, most of the studies this meta-analysis aggregates had small sample sizes and/or cross-over designs, which reduces their overall methodological strength.
• More crucially, to date no adequate placebo control has been identified (the short-acting benzodiazepine midazolam was used in one study – however, it is far from ideal). Because of the strong dissociative experiences associated with ketamine, it seems unlikely that saline offers a reliable placebo check (or possibility of double-blind designs, for that matter).
• Also, duration of follow-up was usually short and administration restricted to a single dosage. Thus, it remains unclear how it fares with a remitting disorder like depression that likely requires more than “one hit”.

Conclusions

Ketamine remains one of the most promising “pipeline drugs” for depressive disorders. However, there is still a long way to go before it can be made available to a larger patient population.

More knowledge about safety, tolerability and the best route of administration is necessary to allow for a balanced view of ketamine’s antidepressant potential.

As suggested previously by my colleague Alex Langford (Langford, 2014), the next step still remains:

A well controlled, randomised and blinded trial of a series of ketamine infusions versus an active placebo in patients maintained on other antidepressants.

Links

McGirr, A., Berlim, M. T., Bond, D. J., Fleck, M. P., Yatham, L. N., & Lam, R. W. (2014). A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychological Medicine, 1–12. doi:10.1017/S0033291714001603

Aan Het Rot, M., Zarate, C. a, Charney, D. S., & Mathew, S. J. (2012). Ketamine for depression: where do we go from here? Biological Psychiatry, 72(7), 537–47. doi:10.1016/j.biopsych.2012.05.003

Diamond, P. R., Farmery, A. D., Atkinson, S., Haldar, J., Williams, N., Cowen, P. J., … McShane, R. (2014). Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. Journal of Psychopharmacology, 28(6), 536–544. doi:10.1177/0269881114527361

Langford A. (2014) Ketamine for severe depression: what can we conclude from a small open label study? The Mental Elf, 8 Apr 2014.