Major depressive disorder (MDD) exhibits significant heterogeneity in treatment responses, necessitating multiple pharmacological trials to achieve therapeutic success. Pharmacogenetic (PGx) testing has emerged as a promising tool to personalize antidepressant (AD) treatments, though its clinical utility remains controversial.

This study assessed the efficacy of PGx-guided treatment in improving clinical outcomes among 287 MDD patients within the PANDORA trial, a prospective randomized, participant- and rater-blinded, controlled trial conducted in Italy. A total of 268 adults with moderate-to-severe MDD were randomized into Treated as Usual (TAU) or Treated with Genetic Test Guide (TGTG). Patients were assessed using the Hamilton Depression Rating Scale (HAM-D17), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory, MINI-ICF-APP for psychosocial functioning, and the UKU Side Effects Rating Scale, at baseline and at 4, 8, and 12 weeks.

Both groups demonstrated significant symptom improvement over the 12-week period. No significant differences were observed between the groups in terms of response and remission rates, measured by HAM-D17 and BDI-II, at weeks 8 and 12. Notably, in the BDI-II symptom cluster analysis, significant differences were found only in neurovegetative symptoms, with TGTG patients showing greater improvement at the 4-week and 8-week follow-up visits. Among patients with severe baseline symptoms, those in the TGTG group exhibited greater symptom reduction and higher response rates at week 8.

These findings suggest that while PGx testing did not significantly improve overall treatment efficacy in MDD compared to TAU, it may offer benefits in managing patients with severe symptoms and specific symptom domains.