Re: Esketamine for treatment resistant depression: Putting drug company interests over the public good
We were surprised to see a BMJ editorial endorsing the latest pharmaceutical industry project to profit from the epidemic of modern misery 1. Esketamine has been licenced for Treatment Resistant Depression in the United States on the basis of flimsy evidence. Yet, the very existence of Treatment Resistant Depression is a testimony to the ineffectiveness of the pharmacological approach to depression. The scientific community should instead be calling on the European Medicines Agency to resist the proposal to unleash another chemical on the unsuspecting public that has unproven benefits and untested harms.
Interest in ketamine arose in part from the use of psychedelics as an adjunct to psychotherapy. The idea behind this movement is that undergoing an altered state of consciousness in a supported and therapeutic setting might provide a ‘healing experience’ 2. The administration of a limited number of intravenous ketamine injections has become popular in private practice, and is advertised as helping to break the cycle of depression 3. This approach may seem simplistic, but at least there is a transparent logic to it.
The idea behind esketamine is different; it is packaged as a new antidepressive agent for regular and long-term use. This is what makes it potentially profitable, because we know that people who start antidepressants often get stuck on them for years on end. Like other antidepressants, it is suggested to work by acting on some hypothetical neural mechanism of depression, yet it is more likely that its characteristic mind-altering effects simply mask or over-ride depressed feelings, in the same way that alcohol can temporarily ‘drown your sorrows’.
Despite this, evidence for the benefits of esketamine is very weak. Only one of the three trials of acute treatment presented to the FDA was positive, and the difference between esketamine and placebo was not large, especially compared to the large placebo response observed 4, and in view of the fact that blinding is unlikely to have been maintained. The acute trials lasted only 28 days; there is almost no data on the adverse effects of long-term treatment, yet we know from the recreational drug scene that ketamine use is associated with severe bladder problems and that prolonged use of euphoriant drugs like ecstasy can cause depression in itself 5. We also know that serious adverse effects may take time to come to light, as with tardive dyskinesia following long-term antipsychotic treatment, and serious and prolonged withdrawal and persistent sexual dysfunction following cessation of SSRIs 6. Leaving this crucial research until after the drug is licenced, as the FDA has done in the United States, and Juahar and Morrison propose for Europe, puts the public at risk and sets depressed patients up as unwitting guinea pigs in a huge and unregulated pharmaceutical experiment.
1. Jauhar S, Morrison P. Esketamine for treatment resistant depression. BMJ 2019;366:l5572. doi: 10.1136/bmj.l5572 [published Online First: 2019/09/25]
2. Tupper KW, Wood E, Yensen R, et al. Psychedelic medicine: a re-emerging therapeutic paradigm. CMAJ 2015;187(14):1054-59. doi: 10.1503/cmaj.141124 [published Online First: 2015/09/10]
3. Collie M. Ketamine for depression divdes experts: 'I've seen these drugs come and go'. Global News, 2019.
4. Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry 2019;176(6):428-38. doi: 10.1176/appi.ajp.2019.19020172 [published Online First: 2019/05/22]
5. Taurah L, Chandler C, Sanders G. Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Psychopharmacology (Berl) 2014;231(4):737-51. doi: 10.1007/s00213-013-3288-1 [published Online First: 2013/10/12]
6. Moncrieff J. Persistent adverse effects of antidepressants. Epidemiol Psychiatr Sci 2019:1-2. doi: 10.1017/S2045796019000520 [published Online First: 2019/09/24]
Competing interests:
No competing interests
08 October 2019
Joanna Moncrieff
medical doctor
Dr Mark Horowitz
Division of Psychiatry, University College London
University College London, Gower street, London WC1E 6BT
Rapid Response:
Re: Esketamine for treatment resistant depression: Putting drug company interests over the public good
We were surprised to see a BMJ editorial endorsing the latest pharmaceutical industry project to profit from the epidemic of modern misery 1. Esketamine has been licenced for Treatment Resistant Depression in the United States on the basis of flimsy evidence. Yet, the very existence of Treatment Resistant Depression is a testimony to the ineffectiveness of the pharmacological approach to depression. The scientific community should instead be calling on the European Medicines Agency to resist the proposal to unleash another chemical on the unsuspecting public that has unproven benefits and untested harms.
Interest in ketamine arose in part from the use of psychedelics as an adjunct to psychotherapy. The idea behind this movement is that undergoing an altered state of consciousness in a supported and therapeutic setting might provide a ‘healing experience’ 2. The administration of a limited number of intravenous ketamine injections has become popular in private practice, and is advertised as helping to break the cycle of depression 3. This approach may seem simplistic, but at least there is a transparent logic to it.
The idea behind esketamine is different; it is packaged as a new antidepressive agent for regular and long-term use. This is what makes it potentially profitable, because we know that people who start antidepressants often get stuck on them for years on end. Like other antidepressants, it is suggested to work by acting on some hypothetical neural mechanism of depression, yet it is more likely that its characteristic mind-altering effects simply mask or over-ride depressed feelings, in the same way that alcohol can temporarily ‘drown your sorrows’.
Despite this, evidence for the benefits of esketamine is very weak. Only one of the three trials of acute treatment presented to the FDA was positive, and the difference between esketamine and placebo was not large, especially compared to the large placebo response observed 4, and in view of the fact that blinding is unlikely to have been maintained. The acute trials lasted only 28 days; there is almost no data on the adverse effects of long-term treatment, yet we know from the recreational drug scene that ketamine use is associated with severe bladder problems and that prolonged use of euphoriant drugs like ecstasy can cause depression in itself 5. We also know that serious adverse effects may take time to come to light, as with tardive dyskinesia following long-term antipsychotic treatment, and serious and prolonged withdrawal and persistent sexual dysfunction following cessation of SSRIs 6. Leaving this crucial research until after the drug is licenced, as the FDA has done in the United States, and Juahar and Morrison propose for Europe, puts the public at risk and sets depressed patients up as unwitting guinea pigs in a huge and unregulated pharmaceutical experiment.
1. Jauhar S, Morrison P. Esketamine for treatment resistant depression. BMJ 2019;366:l5572. doi: 10.1136/bmj.l5572 [published Online First: 2019/09/25]
2. Tupper KW, Wood E, Yensen R, et al. Psychedelic medicine: a re-emerging therapeutic paradigm. CMAJ 2015;187(14):1054-59. doi: 10.1503/cmaj.141124 [published Online First: 2015/09/10]
3. Collie M. Ketamine for depression divdes experts: 'I've seen these drugs come and go'. Global News, 2019.
4. Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry 2019;176(6):428-38. doi: 10.1176/appi.ajp.2019.19020172 [published Online First: 2019/05/22]
5. Taurah L, Chandler C, Sanders G. Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Psychopharmacology (Berl) 2014;231(4):737-51. doi: 10.1007/s00213-013-3288-1 [published Online First: 2013/10/12]
6. Moncrieff J. Persistent adverse effects of antidepressants. Epidemiol Psychiatr Sci 2019:1-2. doi: 10.1017/S2045796019000520 [published Online First: 2019/09/24]
Competing interests: No competing interests