Antidepressant discontinuation during screening does not confound efficacy in treatment-resistant depression: a Phase 2b evaluation of intranasal mebufotenin benzoate (BPL-003)

Introduction

Patients with treatment-resistant depression (TRD) bear a major unmet medical need and, by definition, do not obtain adequate symptom improvement despite ongoing antidepressant treatment. Clinical trials evaluating novel therapeutics for TRD therefore typically require participants to discontinue existing antidepressant therapy to assess investigational medicines as monotherapy. This design feature raises a practical concern, as antidepressant tapering and washout may exacerbate depressive symptoms or produce discontinuation effects that could influence baseline severity and subsequent efficacy outcomes. Determining whether antidepressant withdrawal during screening influences these outcomes is therefore critical for interpreting treatment efficacy and for informing future trial design in TRD. Here, we examined the potential role of antidepressant discontinuation during screening on treatment response in a Phase 2b international, multicenter, randomized, double-blind, low-dose controlled study of a single administration of a novel intranasal formulation of the serotonergic 5-HT₁A/5-HT₂A psychedelic agonist 5-MeO-DMT (mebufotenin benzoate; BPL-003), under development for TRD.

Aims

To evaluate whether antidepressant washout during screening affected efficacy of BPL-003 in adults with TRD.

Methods

We enrolled adults with TRD, having failed 2–5 adequate trials of approved antidepressants (per MGH-ATRQ) and moderate to severe depression (Hamilton Depression Rating Scale ≥19). Participants were required to be antidepressant-free at baseline; investigators supervised tapering and discontinuation of ongoing antidepressants during screening. Participants were randomized (3:2:3) to receive a single intranasal dose of 0.3 mg (subperceptual low-dose comparator), 8 mg, or 12 mg BPL-003, with 8 weeks of follow-up. The primary endpoint was change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) Total score at Day 29 for 12 mg versus 0.3 mg. Secondary endpoints included MADRS change at Day 8 (12 mg and 8 mg vs 0.3 mg) and Day 29 (8 mg vs 0.3 mg). In a prespecified analysis, we used a mixed effects model for repeated measures (MMRM) that included antidepressant washout status (yes/no) as a model term.

Results

The study randomized 193 participants (0.3 mg: n=74; 8 mg: n=46; 12 mg: n=73). Baseline demographics and clinical characteristics were similar across groups. Mean age was 41 years; 59% were female and 89% were White. During screening, 126/193 (65%) participants discontinued antidepressant therapy, including bupropion (15%) and venlafaxine (13.5%). Mean baseline MADRS score was 31.8. At Day 29, the 12 mg dose produced a statistically significant improvement versus 0.3 mg (LS mean difference −5.3 [1.80]; p=0.0033). Both the 8 mg and 12 mg doses produced significant and sustained reductions in MADRS scores versus 0.3 mg from Day 2 through Day 57. BPL-003 was generally safe and well tolerated; adverse events were mostly mild-to-moderate. When antidepressant washout status (yes/no) was included as a covariate in the MMRM for the primary endpoint, washout status was not associated with the efficacy outcome (p=0.9527).

Conclusions

In this Phase 2b trial in TRD, antidepressant discontinuation during screening did not influence antidepressant efficacy outcomes. These findings support the interpretability of BPL-003 treatment effects and suggest that supervised antidepressant washout did not confound efficacy assessment.

References

No references