On 2017 Dec 22, Peter Gøtzsche commented:

Leucht et al. conclude that “approximately twice as many patients improved with antipsychotics as with placebo” (1). However, no reliable conclusion can be made, as all the 167 double-blind trials were flawed. None of the trials exclusively examined first-episode patients and when patients who already receive antipsychotic drugs are randomised to placebo, serious withdrawal symptoms will occur. Yet, this withdrawal group is mischaracterized as a placebo group. Even trials with a long tapering period before randomization are unreliable. Antipsychotics cause permanent brain damage, e.g. about 5% a year develop tardive dyskinesia but the drugs may mask this, so that it appears for the first time when the drugs are stopped.

My conclusion is that 60 years of “placebo”-controlled trials of antipsychotics have been wasted. We need to do trials in drug-naïve patients with their first episode of psychosis if we want to know what these drugs to do people. We also need to ensure that the trials are adequately blinded by adding a substance to the placebo that gives side effects. Leucht et al. praise the NIMH study from 1964, but in this trial, the psychiatrists reported the exact opposite of what happens when people get antipsychotics. The drugs were said to reduce apathy, improve motor movement and make patients less indifferent (2).

1. Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017;174:927-942.

2. Cole JO. Phenothiazine treatment in acute schizophrenia; effectiveness: the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Arch Gen Psychiatry 1964;10:246-61.

On 2017 Dec 22, Peter Gøtzsche commented:

Leucht et al. conclude that “approximately twice as many patients improved with antipsychotics as with placebo” (1). However, no reliable conclusion can be made, as all the 167 double-blind trials were flawed. None of the trials exclusively examined first-episode patients and when patients who already receive antipsychotic drugs are randomised to placebo, serious withdrawal symptoms will occur. Yet, this withdrawal group is mischaracterized as a placebo group. Even trials with a long tapering period before randomization are unreliable. Antipsychotics cause permanent brain damage, e.g. about 5% a year develop tardive dyskinesia but the drugs may mask this, so that it appears for the first time when the drugs are stopped.

My conclusion is that 60 years of “placebo”-controlled trials of antipsychotics have been wasted. We need to do trials in drug-naïve patients with their first episode of psychosis if we want to know what these drugs to do people. We also need to ensure that the trials are adequately blinded by adding a substance to the placebo that gives side effects. Leucht et al. praise the NIMH study from 1964, but in this trial, the psychiatrists reported the exact opposite of what happens when people get antipsychotics. The drugs were said to reduce apathy, improve motor movement and make patients less indifferent (2).

1. Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017;174:927-942.

2. Cole JO. Phenothiazine treatment in acute schizophrenia; effectiveness: the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Arch Gen Psychiatry 1964;10:246-61.