Antipsychotic drugs v. barbiturates or benzodiazepines used as active placebos for schizophrenia: a systematic review and meta-analysis

Abstract

BackgroundComparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos.MethodsRandomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263).ResultsSeven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a ‘good’ response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36–3.41; I2 = 48.9) and ‘any’ response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35–3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on ‘any’ response (74.7% v. 65%; RR 1.15; 95% CI 0.82–1.62).ConclusionsAntipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants.

Antipsychotics as particular types of sedatives

“…We did not suggest that antipsychotics are merely active placebos, nor that they are identical in their effects to other sedatives. In line with Siafis et al (2019), we pointed out that some trials found that antipsychotics were superior to barbiturates for the treatment of schizophrenia, but that current evidence has not established that they are different from benzodiazepines in their effectiveness. What we also suggested was that there is no evidence that antipsychotics, or any other drug prescribed for a mental disorder, produce their therapeutic effects by reversing an underlying brain-based abnormality.…”

“…We agree that it is important to establish whether antipsychotics are superior to other sedative drugs for the treatment of acute psychotic symptoms, and hence appreciate the review by Siafis et al (2019). We would like to correct a misperception of our work, however (Moncrieff & Cohen, 2005).…”

Antipsychotic drugs: from ‘major tranquilizers’ to Neuroscience-based-Nomenclature

“…Nevertheless, the public debate about psychotropic agents is often ideological rather than evidence-based. Therefore, although Professor Moncrieff did not explicitly write that antipsychotics are just unspecific sedatives, such arguments are often used making our systematic review important (Siafis et al, 2019).…”

“…We believe that our review further elucidated this discussion. We found sufficient evidence that antipsychotic drugs were superior to phenobarbital for acute schizophrenia, yet evidence on the comparison with benzodiazepines was inconclusive because it was based on a single small trial (80 participants including the inert placebo arm) with large response rates in all arms (65% in inert placebo and benzodiazepines, 75% in chlorpromazine), small doses of chlorpromazine (about 150 mg/day), and the trial being sponsored by the company manufacturing the benzodiazepines (Merlis, Turner, & Krumholz, 1962; Siafis et al, 2019). We also want to add that in a small trial (not meeting the inclusion criteria of our review because it was conducted in stable patients) in 53 patients with schizophrenia, diazepam was comparable to fluphenazine and superior to placebo in preventing progression to a full relapse when used for early signs of exacerbation after the abrupt discontinuation of antipsychotics (Carpenter, Buchanan, Kirkpatrick, & Breier, 1999).…”

Kaleidoscope

“…A meta-analysis of RCTs comparing antipsychotics with barbiturates or benzodiazepines in the acute treatment of schizophrenia demonstrated that antipsychotics were significantly more effective than barbiturates, but there were inadequate data on benzodiazepines to draw any firm conclusions. 5 The findings rebut the challenge that effectiveness is a result of sedation or unmasking, although it is notable that the studies included are somewhat dated; a large contemporary RCT comparing antipsychotics with benzodiazepines would be interesting.…”