Genetically Informed Triangulation Can Strengthen Counseling About Gestational Antidepressant Exposure

See article by Andrade

To the Editor: We read with great interest the article “Gestational Exposure to Antidepressants and Neurodevelopmental Disorders in Offspring” by Chittaranjan Andrade.¹ Dr Andrade’s clinically balanced review of gestational antidepressant exposure and neurodevelopmental disorders (NDDs) in offspring is valuable because it separates “real-world risk” from causal interpretation and emphasizes shared decision-making. The discussion of attenuation after adjustment, exposure outside the pregnancy window, paternal exposure, and discordant sibling comparisons correctly highlights the central problem: The apparent association may reflect maternal illness, familial liability, and shared environment rather than a direct intrauterine drug effect.

One additional point may further strengthen clinical interpretation. Future reviews and counseling frameworks could explicitly distinguish 3 estimands: (1) the total prognostic risk observed among pregnancies in which antidepressants are used, (2) the direct pharmacologic effect of fetal drug exposure, and (3) the effect of untreated or undertreated maternal psychiatric illness. These estimands have different implications. The first is useful for risk communication; the second is relevant to medication safety; the third is central to treatment decisions. Mixing them can unintentionally make antidepressant discontinuation appear safer than it is.

Genetically informed triangulation may be useful here. Discordant sibling analyses reduce many stable familial confounders, but they can still be affected by time-varying illness severity, treatment indication, measurement error, and carryover from previous pregnancies. Paternal exposure and prepregnancy exposure are informative negative controls, but they do not fully quantify inherited liability to autism spectrum disorder or attention-deficit/hyperactivity disorder. When large biobanks allow linkage of parental genotypes, offspring outcomes, medication exposure, and psychiatric diagnoses, polygenic risk scores, within-family designs, negative-control exposure windows, and Mendelian-randomization-informed sensitivity analyses could be used as complementary—not definitive—evidence. Concordance across these approaches would be more persuasive than any single observational design.

This distinction also matters for counseling. A clinician can acknowledge that children exposed to antidepressants in utero may show higher unadjusted rates of NDDs while explaining that much of this excess risk may reflect familial and illness-related factors. The practical message is not that fetal exposure is proven harmless, but that decisions should compare medication continuation with the risks of relapse, functional impairment, suicidality, substance use, poor prenatal care, and other consequences of undertreated maternal illness. Framing the evidence around explicit estimands and triangulated causal inference may make shared decision-making both scientifically clearer and less alarming for patients.

Article Information

Published Online: August 19, 2026. https://doi.org/10.4088/JCP.26lr16590
© 2026 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2026;87(3):26lr16590
To Cite: Ye Z, Ye Y, Zhu Y. Genetically informed triangulation can strengthen counseling about gestational antidepressant exposure. J Clin Psychiatry 2026;87(3):26lr16590.
Author Affiliations: The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Corresponding Author: Yusheng Zhu, MD, The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China ([email protected]).
Drs Z. Ye and Y. Ye share first authorship.
Financial Disclosure: None.
Funding/Support: None.