Off-Label Prescribing: Rational Practice in the Psychopharmacology Landscape

BRAIN TRUST: CONVERSATIONS IN PSYCHOPHARMACOLOGY

-Series Editor Joseph F. Goldberg, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Henry Nasrallah, MD, to discuss off-label prescribing and polypharmacy.

Nasrallah grounded the discussion in his landmark analysis demonstrating that 88% of DSM psychiatric diagnoses have no US Food and Drug Administration (FDA)-approved pharmacotherapy, leaving clinicians with no choice but to prescribe off-label for many patients they encounter.¹ He argued that the FDA's diagnosis-centric approval framework, rather than a symptom- or circuit-based model, is a primary driver of this gap, noting that a shift toward symptom-level indications could render irrelevant much of current off-label practice.

Both clinicians emphasized that off-label prescribing, when rationale-based and neuroscientifically informed, constitutes responsible clinical care rather than reckless deviation. Nasrallah described examples like using valproate for impulsive aggression in traumatic brain injury, clozapine augmentation for treatment-resistant suicidality, and high-dose modafinil for refractory depression—each grounded in mechanistic reasoning.^2,3 Goldberg observed that "off-label practices are legitimate…good for patients and save a lot of lives," while cautioning that prescribers must understand what a drug does in the brain, not merely follow or ignore labeling.

The conversation also addressed the transdiagnostic model, polypharmacy, insurance barriers to off-label coverage, and the underutilization of clozapine. Nasrallah closed by characterizing off-label discovery as "a creative process, the cutting edge of scientific advances," urging clinicians to publish case reports and share serendipitous findings to catalyze future trials.

Dr Goldberg is a clinical professor of psychiatry at The Icahn School of Medicine at Mount Sinai in New York, NY and the immediate-past president of the American Society of Clinical Psychopharmacology.

Dr Nasrallah is professor of psychiatry, neurology, and neuroscience, as well as vice chair for Faculty Development and Mentorship, at the University of Cincinnati College of Medicine.

References

1. Devulapalli KK, Nasrallah HA. An analysis of the high psychotropic off-label use in psychiatric disorders. The majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr. 2009;2(1):29-36.

2. Robert S. Traumatic brain injury and mood disorders. Ment Health Clin. 2020;10(6):335-345.

3. Meltzer HY, Alphs L, Green AI, et al; International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.