Dextromethorphan combined with bupropion, fluoxetine, or paroxetine in real-world unipolar and bipolar depression: effectiveness, tolerability, and switch risk

Background

Dextromethorphan (DXM) is a non-competitive NMDA antagonist and sigma-1 agonist with rapid antidepressant potential. As it is rapidly metabolised by CYP2D6 to dextrorphan, co-administration with a CYP2D6 inhibitor is required. While the DXM–bupropion combination is approved for MDD [1], real-world data — especially in bipolar depression and with alternative CYP2D6 inhibitors — remain limited.

Aims

To evaluate the effectiveness, tolerability, manic-switch risk and impact on suicidal ideation of DXM combined with CYP2D6 inhibitors in a real-world cohort of adults with unipolar and bipolar depression.

Methods

Prospective single-centre observational study (University of Siena, 2025–2026). Sixty-eight adults (52.9 ± 15.4 years) with a DSM-5 major depressive episode (unipolar or bipolar) were assessed at baseline and at weeks 2, 4, 6 and 12. All received DXM (38–76 mg/day) on top of a stable CYP2D6 inhibitor (bupropion, paroxetine or fluoxetine). Outcomes included MADRS, HAM-A, YMRS and CGI-S. Response was defined as ≥50% MADRS reduction and remission as MADRS ≤10. Adverse events, manic switch, suicidal ideation and discontinuation were recorded. Within-subject changes were tested with paired Wilcoxon tests.Outcomes were analysed on observed cases at each timepoint.

Results

Most patients had bipolar-spectrum disorders (74%); psychiatric comorbidity and polypharmacy were frequent (median 3 concomitant drugs). CYP2D6 inhibitors used were bupropion (51%), paroxetine (28%) and fluoxetine (25%). MADRS decreased from 30 to 12 at week 12 (p < 0.001), and HAM-A scores improved progressively in parallel. Symptomatic improvement was already detectable at week 2 (median MADRS 30→25, mean reduction ~17%), with response rates rising from 14% at week 4 to 74.4% at week 12; remission reached 48.8%. Non-responders showed an approximately two-fold higher rate of psychiatric comorbidity than responders (50% vs 27%), most commonly obsessive–compulsive disorder and borderline personality disorder. Anxiety was the most common adverse event (28%; often transient and not requiring drug discontinuation), peaking early and associated with higher SSRI doses. Discontinuation rate was 22.1%, mainly due to inefficacy or adverse events.Serotonergic-like symptoms were rare (2 patients), mild, and self-limiting; no case required hospitalisation or specific medical intervention . No manic switch occurred and active suicidal ideation improved from 10 to 2 patients at week 12.

Conclusions

In a heterogeneous real-world cohort with prevalent bipolar depression and polypharmacy, DXM combined with CYP2D6 inhibitors showed robust antidepressant effects, with parallel improvement in HAM-A anxiety scores and a clear reduction in active suicidal ideation. Tolerability was acceptable: anxiety/activation was the main early adverse event, particularly with higher SSRI doses, while no manic switch occurred — supporting the use of DXM-based augmentation in bipolar depression. Non-response was more frequent in patients with comorbid personality disorders or obsessive–compulsive disorder, suggesting subgroups in which closer monitoring or alternative strategies may be warranted.

Limitations

Uncontrolled observational design, single-centre recruitment, non-randomised CYP2D6 inhibitor selection, heterogeneous concomitant medications, absence of DXM plasma levels or CYP2D6 genotyping, and incomplete 12-week follow-up.

References

1. Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry 2022;179(7):490-499.