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Child Psychiatrist /Adult Psychiatrist

Revisiting Modafinil/Armodafinil for the Treatment of Bipolar Disorder

Keypoint: An expert shares some lessons learned from prior research on the treatment and suggestions for a way forward at the 2024 ASCP Annual Meeting.


“The pharmacopoeia on the depressive phase of bipolar disorder, from a regulatory standpoint, is really quite limited in comparison to other phases of illnesses and other mental illnesses. Antidepressants for use in bipolar disorder have a very limited evidence base, and concern always remains for associated destabilization. I would argue that our studies need to develop more narrow precision.”

Bipolar Disorder

Mark A. Frye, MD, served as chair of a panel of experts who discussed the potential of modafinil/armodafinil as a treatment for bipolar disorder targeting cognition, depression, and sleep circadian rhythm at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting. Frye is a consultant in the Department of Psychiatry & Psychology and a professor of psychiatry at Mayo Clinic College of Medicine.

In his individual presentation, titled “Modafinil / armodafinil in bipolar disorder: lesson learned, roadmap forward,”1 Frye shared that, despite mixed results in clinical trials, recent meta-analyses suggest that armodafinil (R-modafinil), which is currently approved for managing excessive sleepiness in conditions like shift work disorder and narcolepsy,2 may still hold potential as a treatment option for bipolar 1 depression.1

According to Frye, mrmodafinil works as a wakefulness-promoting agent by inhibiting dopamine transport at low affinity. This mechanism of action is different from the typical treatments for bipolar depression involving mood stabilizers and antipsychotics. Existing treatments, such as quetiapine and cariprazine, have traditionally been used for both acute mania and depression (bimodal mood stabilization) or in combination with antimanic agents, like the olanzapine-fluoxetine combination.1

However, Frye said, the development of armodafinil as a treatment for bipolar 1 depression faced significant challenges. Two out of 3 phase 3 clinical trials did not demonstrate a clear benefit over placebo, leading to the discontinuation of the development program. Despite these setbacks, a meta-analysis reported that both modafinil and armodafinil could be efficacious and safe for treating bipolar 1 depression.1

Frye stated that 1 of the key issues in these trials was the heterogeneity of the patient population, particularly regarding the use of mood stabilizers. The varied composition of mood stabilizers among participants might have affected the trials’ ability to detect a significant difference between armodafinil and placebo. According to Frye, this variability, which was initially seen as a strength for generalizability and community translation, may have inadvertently limited the studies’ sensitivity to armodafinil’s effects.1

Given these findings, Frye reported that researchers are advocating for a fully powered clinical trial with a more targeted approach. Such a trial would focus on identifying patient characteristics that predict a favorable response to armodafinil. Factors like atypical depressive symptoms, circadian rhythm disruptions, cognitive issues, and specific therapeutic combinations need to be considered to better tailor treatment to individual patient needs.1

“A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with armodafinil,” Frye concluded. “Additional research is warranted and necessary to better identify clinical predictors…that would provide optimized, individualized therapeutics for bipolar depression and or cognitive enhancement in bipolar disorder.”

Frye was joined in this panel by Katherine E. Burdick, PhD, and Ellen Frank, PhD. Burdick is Jonathan F. Borus, MD, Distinguished Chair in Psychiatry and vice chair for research in the Department of Psychiatry at Brigham and Women’s Hospital, and a professor at Harvard Medical School. Frank is a distinguished professor emeritus in the Department of Psychiatry at the University of Pittsburgh School of Medicine and chief scientific officer at Health Rhythms Inc.

In the overall panel presentation, Frye, Burdick, and Frank reviewed the methodological limitations associated with developing modafinil/armodafinil for bipolar depression and discussed cognitive impairment and circadian rhythm issues in bipolar disorder as targets for modafinil/armodafinil.

Note: This article originally appeared on Psychiatric Times

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