A new study in BMJ Mental Health found that antipsychotic drug researchers rarely bother to assess whether they successfully blinded participants and researchers in their studies. Worse, in all four trials in which blinding was assessed—out of 188 total studies—the blind was broken.
According to the researchers, “There remains suspicion that treatment effects of antipsychotics for schizophrenia may be overestimated unless the trials are properly blinded.”
The study was led by Aran Tajika at Kyoto University Graduate School of Medicine.
The double-blind, placebo-controlled trial is the mainstay of evidence-based drug assessment. In this type of study, a drug is compared to a placebo, and neither the researcher nor the research participant knows whether the participant is receiving the drug or the placebo. If the blind is broken—meaning that the researcher or the participant (or both) have guessed whether the participant received the active drug—this can lead to overestimating the power of the drug. Researchers and participants are more likely to note an improvement if they believe the participant received the active drug.
“Blinding of randomized controlled trials (RCTs) is very important for the accurate assessment of drug efficacy. Without proper blinding, the effect of the intervention may be overestimated,” Tajika et al. write.
Just conducting a supposed “double-blind” trial is not enough, according to Tajika et al. It is also important that the blind is actually successful. One of the easiest ways to break the blind is when researchers and participants notice that they have experienced drug side effects—a big clue that they are receiving the active drug.
For this reason, it’s crucial for researchers to assess whether the blind was broken in their study. It’s easy to do so—at the end of the study, you ask the researchers and participants whether they received the drug or the placebo. If they all guess correctly, you know the blind was broken—which means the drug’s effect could be tremendously overestimated.
However, Tajika et al. note that there is no consensus on how to interpret blinding success, and the 2010 Consolidated Standards of Reporting Trials (CONSORT) statement no longer recommends that researchers test the success of their blinding process.
For antipsychotics, which have powerful sedating effects (among other harms), it can be pretty easy to tell whether you’re getting the drug or a placebo. Yet Tajika et al. observed that in trials of antipsychotic drugs for schizophrenia, the success of the blind was rarely, if ever, assessed. So, they decided to do a thorough study on this question, gathering all of the placebo-controlled trials of antipsychotics that featured a double (or more) blind.
They identified 188 such studies published between 1955 and 2021. However, only three of them had actually assessed whether the blinding process had worked—all studies of the oldest antipsychotics, chlorpromazine, haloperidol, and promazine, from the 1950s and ’60s.
After one more search, Tajika et al. found one more study from 2007 that assessed the blinding process, a drug development study of an injectable antipsychotic that is not on the market, dihydrexidine.
In all four of the studies that checked the blind, the blind was broken.
“Blinding was broken in all the four studies that we had identified. The proportion of correctly guessed allocation ranged between 70% and 91%,” they write.
It is unclear whether this has actually led to an overestimation of the effects of the drugs—the current study was not designed to examine that question. However, we do know that, in general, breaking the blind leads to an overestimation of drug effects. The researchers also note that it’s unclear to what degree the blind was actually broken in most studies.
This is particularly true for newer antipsychotic drugs, as there are no studies that assessed the blind for these, the most commonly prescribed antipsychotics today. However, it is telling that in all four studies that did assess the blind, it was broken to a significant degree.
According to Tajika et al., “Researchers should therefore be encouraged to conduct blinding assessment and report the results in each RCT. We then need to integrate the results of more studies to examine the exact rate at which blinding is broken and how they may or may not affect the effect size estimates.”
Stefan Leucht, one of the study’s co-authors, has also published research finding that only 23% of patients respond well to antipsychotic drugs, challenging the notion that these drugs are an effective treatment for psychosis.
Long-term research has found that those who used antipsychotic drugs for a more extended period had worse outcomes than those who did not—including higher rates of premature death, worse cognitive functioning, lower work functioning, and more psychotic symptoms. This was true even after accounting for baseline severity and diagnosis.
Tajika A., Furukawa, T. A., Shinohara, K., Kikuchi, S., Toyomoto, R., Furukawa, Y., . . . & Leucht, S. (2023). Blinding successfulness in antipsychotic trials of acute treatment for schizophrenia: A systematic review. BMJ Mental Health, 26(1). http://dx.doi.org/10.1136/bmjment-2023-300654 (Link)