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MIXED AMPHETAMINE SALTS AND LISDEXAMFETAMINE AS ADJUNCTIVE TREATMENT FOR BIPOLAR DEPRESSION: POOLED ANALYSIS OF TWO RANDOMIZED CONTROLLED TRIALS

Mark Frye — Jorge Sanchez-Ruiz1, Nicolas Nunez1, Karin Lindstrom1, Vanessa Pazdernik1, Nicole Mori2, Balwinder Singh1, Aysegul Ozerdem1, Georgi Georgiev1, Joshua Baruth1, Katherine Moore1, Hannah Betcher61 Dina N. Al11, Joanna Biernacka1, Susan McElroy2 1Mayo Clinic, 2Lindner Center of HOPE, University of Cincinnati College of Medicine Mark Frye, Mayo Clinic

2026 ASCP Annual Meeting

Objective

Depression is the predominant mood state in bipolar disorder (BD) and is often accompanied by significant attentional deficits. Adjunctive amphetamine derivatives may effectively target both mood and cognitive symptoms in this patient population. In this analysis, we aim to evaluate the efficacy and safety of adjunctive mixed amphetamine salts (MAS) Mydayis® and lisdexamfetamine (LDX) Vyvanse® in bipolar depression.

Methods

This pooled analysis combined two 8-week, randomized, placebo-controlled clinical trials of adjunctive amphetamine treatment (MAS and LDX) in bipolar depression. The primary outcome was baseline-to-endpoint change in Montgomery-Asberg Depression Rating Scale (MADRS) score. Secondary outcomes included response (≥50% MADRS reduction), remission (MADRS < 10), and baseline-to-endpoint change in the Digit Symbol Substitution Test (DSST). The primary safety measure was the change in Young Mania Rating Scale (YMRS) score.

Results

In this pooled sample of 57 participants (amphetamine n=26; placebo n=31), adjunctive amphetamine treatment demonstrated superior antidepressant efficacy versus placebo, with greater MADRS reduction (52.8% vs 27.1%), higher response rates (61.5% vs 19.4%), and higher remission rates (46.2% vs 16.1%) (all p ≤ 0.02). Effect sizes were medium-to-large for depression outcomes (MADRS: d = 0.69; response: φ = 0.43; remission: φ = 0.33), with no evidence of increased manic symptoms (YMRS: d = −0.16). Treatment effects were consistent regardless of concomitant antidepressant or antipsychotic use (all interaction p ≥ 0.18). There was no statistically significant between-group difference in DSST percent change (amphetamine 22.7% vs placebo 11.5%; p=0.11).

Conclusions

Adjunctive amphetamine treatment demonstrates robust antidepressant efficacy in bipolar depression with medium-to-large effect sizes and minimal manic switch risk. These findings challenge traditional concerns about stimulant use in BD and suggest amphetamine derivatives represent a valuable therapeutic option for patients with inadequate response to standard treatments, warranting further investigation in larger trials.

Learning Objective 1: Assess the efficacy of adjunctive amphetamine derivatives for bipolar depression by interpreting MADRS change, response, and remission outcomes from pooled randomized clinical trial data.

Learning Objective 2: Evaluate clinical safety of stimulant augmentation in BD— particularly manic switch risk (YMRS) and cognitive effects (DSST), to inform treatment decisions in patients with inadequate response to standard therapies.

References

  1. McElroy, S.L., et al., Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial. International Clinical Psychopharmacology, 2015. 30(1): p. 6-13.
  2. Miskowiak, K.W., et al., Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force. Bipolar Disord, 2024. 26(3): p. 216-239.