‘Equal-unblinding’ meta-analysis of psychedelic therapy vs. antidepressants for the treatment of depression
Barnett, H., Szigeti, B., Williams, Z. J.
This pre-print pre-registered meta-analysis (s=24) comparing psychedelic-assisted therapy (PAT) and open-label traditional antidepressants (tAD) for major depression found no significant difference in effectiveness between the two approaches, with both producing clinically meaningful improvements, challenging previous assumptions about PAT's superiority when accounting for the unblinding effect present in psychedelic trials.
Abstract
Importance: Psychedelic-assisted therapy (PAT) trials have high levels of functional unblinding. This effect positively biases results when PAT trials are compared against truly blinded trials.Objective: This pre-registered meta-analysis investigated the comparative efficacy of PAT and open-label traditional antidepressants (tAD; such as SSRIs and SNRIs) for the treatment of major depression. The rationale is that PAT is effectively always open-label, thus, it is only fair to compare results against open-label tAD trials, so both interventions equally benefit from effects associated with patients knowing the treatment.Data Sources: PubMed was systematically searched for trials of PAT and open-label tAD for the treatment of major depression without comorbidity in outpatient, non-psychotic adults. Twenty-four of the initially retrieved 619 records met inclusion.Data Extraction and Synthesis: Depression scores were extracted by two independent reviewers; estimates were pooled with both Bayesian and frequentist mixed-effects models. The reporting follows the PRISMA guideline.Main Outcome(s) and Measure(s): Following pre-defined hypotheses, we compared the mean within-arm effect size from baseline to primary endpoint, i.e. the patient improvement, between PAT and open-label tAD trials on the 17-item Hamilton Depression Rating Scale. We also compared the within-arm effect size of blinded vs. open-label trials in both PAT and tAD, to assess the influence of blinding.Results: In total, eight PAT trials involving 548 patients and sixteen open-label tAD studies involving 9751 patients were included. Contrary to prior hypothesis, PAT was no more effective than open-label tAD treatment (estimated difference: 0.3 favouring open-label tAD; 95% confidence interval: −1.39 to 1.98; p = 0.730). Open-label tAD was associated with better outcomes than blinded treatment (1.3 [0.07, 2.51]; p = 0.038), but the same difference was not observed in PAT (0.4 [−2.20, 3.11]; p = 0.738).Conclusions and Relevance: Both tAD and PAT were associated with robust, statistically and clinically meaningful improvements. However, PAT’s lack of superiority compared to tADs under equal-unblinding conditions highlights the influence of blinding integrity and presents a sobering viewpoint on the treatment’s potential.