In their reply, “Lost in translation (al neuroscience)?,” Sameer Jauhar and Paul Morrison use straw men, such as alleging, incorrectly, that we believe morphine, alcohol and MDMA constitute one drug class (1). They also falsely state that we are driven by ideology; that, oddly, we argue that depression doesn’t exist; and that we have expressed “organised antipathy” towards various psychiatric treatments including antipsychotics and ECT. Some of us have explained, based on randomised trials and observational studies, why antipsychotics and ECT seem to do more harm than good (2,3). The general public agrees with us (4). This is not ideology or antipathy but simple fact.
Jauhar and Morrison cite a study where seven patients randomised to intravenous ketamine or saline were followed up for 72 hours (5). Another study they cite was a mess (6). It involved 24 patients who got up to 6 intravenous infusions of ketamine administered open-label three times a week over a 12-day period. Only participants meeting response criteria were monitored for relapse. At the same time, some participants took part in a placebo-controlled study of venlafaxine. Seventeen of the 24 patients responded to ketamine with a rapid decline in depressive symptoms. However, 13 of the 17 responding patients relapsed a median of 18 days after the last infusion. We do not know which other treatments the 4 patients who did not relapse had received. A third study they cite compared depressive symptoms only 24 hours after treatment with esketamine or midazolam infusions (7).
In a 2018 study they did not cite, where 68 patients were randomised to intranasal esketamine or placebo, there was no difference between the two groups by day 25 in either depression scores or suicidal risk (8). The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.
Based on the references Jauhar and Morrison provide it seems that they think results after a few days or a couple of weeks are sufficient evidence and that results beyond this should be ignored. However, short-term results cannot provide a rational basis for treatment recommendations for depression. As we do not know whether esketamine is more likely to benefit than to harm those with resistant depression, this drug should not be used in clinical practice but only as an experimental drug in randomised trials of adequate length, with long-term follow up, and with patient relevant outcomes. It is not enough to simply render the patients acutely euphoric with a hallucinogenic substance.
3 Read J, Bentall R. The effectiveness of electroconvulsive therapy: a literature review. Epidemiol Psichiatr Soc 2010;19:333-47.
4 Jorm AF, Korten AE, Jacomb PA, et al. ”Mental health literacy”: a survey of the public’s ability to recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aus 1997;166:182-6.
5 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–4.
6 Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013;74:250–6.
7 Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134–42.
8 Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018;175:620-30.
Competing interests:
No competing interests
11 October 2019
Peter C Gøtzsche
Professor
Michael P Hengartner, James Davies, John Read, Anne Guy, Sami Timimi and Peter Kinderman, all from the Council for Evidence-based Psychiatry
Rapid Response:
Re: Esketamine for treatment resistant depression
In their reply, “Lost in translation (al neuroscience)?,” Sameer Jauhar and Paul Morrison use straw men, such as alleging, incorrectly, that we believe morphine, alcohol and MDMA constitute one drug class (1). They also falsely state that we are driven by ideology; that, oddly, we argue that depression doesn’t exist; and that we have expressed “organised antipathy” towards various psychiatric treatments including antipsychotics and ECT. Some of us have explained, based on randomised trials and observational studies, why antipsychotics and ECT seem to do more harm than good (2,3). The general public agrees with us (4). This is not ideology or antipathy but simple fact.
Jauhar and Morrison cite a study where seven patients randomised to intravenous ketamine or saline were followed up for 72 hours (5). Another study they cite was a mess (6). It involved 24 patients who got up to 6 intravenous infusions of ketamine administered open-label three times a week over a 12-day period. Only participants meeting response criteria were monitored for relapse. At the same time, some participants took part in a placebo-controlled study of venlafaxine. Seventeen of the 24 patients responded to ketamine with a rapid decline in depressive symptoms. However, 13 of the 17 responding patients relapsed a median of 18 days after the last infusion. We do not know which other treatments the 4 patients who did not relapse had received. A third study they cite compared depressive symptoms only 24 hours after treatment with esketamine or midazolam infusions (7).
In a 2018 study they did not cite, where 68 patients were randomised to intranasal esketamine or placebo, there was no difference between the two groups by day 25 in either depression scores or suicidal risk (8). The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.
Based on the references Jauhar and Morrison provide it seems that they think results after a few days or a couple of weeks are sufficient evidence and that results beyond this should be ignored. However, short-term results cannot provide a rational basis for treatment recommendations for depression. As we do not know whether esketamine is more likely to benefit than to harm those with resistant depression, this drug should not be used in clinical practice but only as an experimental drug in randomised trials of adequate length, with long-term follow up, and with patient relevant outcomes. It is not enough to simply render the patients acutely euphoric with a hallucinogenic substance.
1 Jauhar S, Morrison P. Lost in translation(al neuroscience)? BMJ 2019 Oct 6. https://www.bmj.com/content/366/bmj.l5572/rapid-responses.
2 Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.
3 Read J, Bentall R. The effectiveness of electroconvulsive therapy: a literature review. Epidemiol Psichiatr Soc 2010;19:333-47.
4 Jorm AF, Korten AE, Jacomb PA, et al. ”Mental health literacy”: a survey of the public’s ability to recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aus 1997;166:182-6.
5 Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351–4.
6 Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013;74:250–6.
7 Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134–42.
8 Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018;175:620-30.
Competing interests: No competing interests