Comparative efficacy of antidepressant augmentation with amantadine vs pramipexole in treatment-resistant unipolar depression: A randomised controlled trial.

Background: Augmentation strategies for treatment-resistant depression (TRD) are limited, with strongest evidence for atypical antipsychotics. Given emerging insights into the neurobiology of TRD, new drug classes merit investigation. We hypothesised that augmentation with amantadine (NMDA antagonist) and pramipexole (dopamine agonist) would show comparable efficacy and safety to quetiapine in TRD.

Methods: In this open-label trial, 150 patients with TRD were equally randomised to receive amantadine 200 mg/day, pramipexole 37.5 mg/day, or quetiapine 100 mg/day, as augmentation to ongoing sertraline. The Hamilton Depression Rating Scale (HAM-D21) and Clinical Global Impression (CGI)-Severity and CGI-Improvement scales were assessed and compared within and between the groups at baseline, four, and eight weeks. Serum Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) were measured at baseline, four and eight weeks to evaluate and compare neurotrophic changes between the groups alongside clinical response.

Results: Mixed-model ANOVA revealed significant HAM-D and CGI-S reductions in all three groups over eight weeks (p < 0.001). Between-group analysis revealed pramipexole was significantly better compared to both amantadine and quetiapine on all clinical measures at weeks four and eight (p < 0.001). Amantadine and quetiapine showed comparable efficacy (p > 0.05). BDNF and NGF levels increased significantly within each group (p < 0.001), but between-group differences were non-significant (p > 0.05). The three groups reported similar occurence of adverse events (p = 0.184).

Conclusion: Augmentation with amantadine and pramipexole were safe and effective in TRD. Additionally, pramipexole showed better efficacy to amantadine and quetiapine. Clinical improvements corroborated with improved BDNF and NGF levels. However, larger multi-centric studies are warranted for generalisability. (ClinicalTrials.gov: NCT04936126).