Intended for healthcare professionals

Rapid response to:


Esketamine for treatment resistant depression

BMJ 2019; 366 doi: (Published 23 September 2019) Cite this as: BMJ 2019;366:l5572


A drug not a miracle—why we need a new system for monitoring ketamine

Rapid Response:

Re: Esketamine for treatment resistant depression

Esketamine for depression? No thanks, please

Sameer Jauhar’s and Paul Morrison’s praise of esketamine (1) is not deserved. Common sense tells us that a drug cannot possibly have a dramatic effect on depression within the first day of treatment unless something is terribly wrong.

Ketamine seems to work mainly through stimulation of opioid receptors. In a cross-over trial of 12 very severely depressed patients (Hamilton score of 27.4), a colossal “effect” was observed the first day post-infusion of ketamine + placebo, a reduction of 22.3, which corresponds to an effect size of 7.0 (2). With ketamine + naltrexone (an opioid antagonist), the reduction was only 5.6, and the difference to the other condition was 16.7, or an effect size of 2.5. As prolonged opioid use can cause depression (3), long-term use of esketamine might increase the risk of chronic depression.

In comparison, meta-analyses of depression pills have shown effect sizes of only 0.2 to 0.3, and not after one day, but after weeks (4,5).

Jauhar and Morrison mention dissociation as a harm of esketamine. Dissociative drugs are hallucinogens, which produce feelings of detachment from the environment and self. No wonder they write that ketamine was initially used in psychiatry as a drug model of psychosis!

Jauhar and Morrison write that the effects of ketamine and esketamine fit with “modern theory that depression emerges from an impoverished neural network rather than serotonin deficiency.” It is not clear what they mean by this, and newness does not make a theory any more reliable than the discarded hypothesis about a chemical imbalance causing depression. Further, there is no scientific support for long term use, yet such use is now common in US private clinics following FDA approval.

We are convinced it could be demonstrated that alcohol, morphine, cocaine, ecstasy and MDMA also exert an “effect” on depression within the first day, but that does not make these substances acceptable. They may have acute euphoric effects, but frequent and long-term use often results in dysphoric mood states.

Jauhar and Morrison write that ketamine is widely used as a street drug, but that the risk of esketamine being so used seems low, given its high cost. We do not agree. Ketamine ranks highly on the list of commonly abused substances (2), and the price of a narcotic cannot prevent widespread abuse.

The dream of a quick fix for depression must stop.

1 Jauhar S, Morrison P. Esketamine for treatment resistant depression. We should cautiously welcome this new therapeutic option. BMJ 2019;366:l5572.

2 Williams NR, Heifets BD, Blasey B, et al. Opioid receptor antagonism attenuates antidepressant effects of ketamine. Am J Psychiatry 2018;175(12):1205–15.

3 Mazereeuw G, Sullivan MD, Juurlink DN. Depression in chronic pain: might opioids be responsible? Pain 2018;159(11):2142-5.

4 Jakobsen JC, Katakam KK, Schou A, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry 2017;17:58.

5 Munkholm K, Paludan-Müller AS, Boesen K. Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis. BMJ Open 2019;9(6):e024886.

Competing interests: No competing interests

03 October 2019
Peter C Gøtzsche
Michael P Hengartner, James Davies, John Read, Anne Guy, Sami Timimi and Peter Kinderman, all from the Council for Evidence-based Psychiatry
Institute for Scientific Freedom, Copenhagen