Toward Precision Psychiatry: Using Clinical and Pharmacokinetic Data to Increase Antidepressant Dose or Change Treatment in Late-Life Depression.

Creator(s)

• Helena K. Kim
• Xiaoyu Men
• Samar S M Elsheikh
• Daniel J. Müller
• Daniel M. Blumberger
• Jordan F. Karp
• Eric J. Lenze
• Laura Ramsey, Children's Mercy Kansas CityFollow
• Charles F. Reynolds
• Zachary L. Taylor
• Benoit H. Mulsant

Document Type

Article

Publication Date

9-2026

Identifier

DOI: 10.1097/JCP.0000000000002182

Abstract

PURPOSE: Decision trees can use clinical predictors to determine whether to continue the same antidepressant or switch to a different treatment in older patients with major depressive disorder (MDD). We examined whether pharmacogenetic and pharmacokinetic variables could improve their performance.

PROCEDURES: We analyzed 191 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-Grey) trial who had not responded fully after 4 weeks of venlafaxine XR (150 mg/d) and for whom venlafaxine up to 300 mg/d was continued for 8 additional weeks. CYP2D6 genotypes were determined; venlafaxine, o-desmethylvenlafaxine (ODV), and active moiety (AM) exposures at week 4 were calculated using population pharmacokinetic modeling. Decision tree analysis was performed using 5 early clinical predictors of eventual nonresponse identified in previous research and 4 pharmacogenetic and pharmacokinetic potential predictors. One decision tree was designed to optimize specificity (k=0.3), and another to optimize sensitivity (k=0.7).

RESULTS: Longer episode duration and lack of partial response at week 4 were retained as clinical predictors, and lower AM and ODV exposures were identified as additional predictors. Negative predictive values (NPVs) of the high-specificity and high-sensitivity trees (77.7% and 73.0%, respectively) were similar to NPVs in trees based solely on clinical predictors.

IMPLICATIONS: Our methods can guide future studies combining clinical and biomarker data to address applied pharmacological questions relevant to day-to-day practice.

Journal Title

Journal of clinical psychopharmacology

Volume

46

Issue

5

First Page

556

Last Page

563

MeSH Keywords

Humans; Major Depressive Disorder; Venlafaxine Hydrochloride; Female; Decision Trees; Male; Cytochrome P-450 CYP2D6; Aged; Antidepressive Agents; Precision Medicine; Pharmacogenetics; Dose-Response Relationship, Drug; Desvenlafaxine Succinate

PubMed ID

42047285

Keywords

antidepressant; decision tree; major depression; pharmacogenetic; pharmacokinetic; predictors

Comments

Grants and funding

• R01 MH083660 University of Pittsburgh/National Institute of Mental Health and Neurosciences
• P30 MH90333 University of Pittsburgh/National Institute of Mental Health and Neurosciences
• R01 MH083648 Washington University/National Institute of Mental Health and Neurosciences
• R01 MH083643 University of Toronto/National Institute of Mental Health and Neurosciences

Recommended Citation

Kim HK, Men X, Elsheikh SSM, et al. Toward Precision Psychiatry: Using Clinical and Pharmacokinetic Data to Increase Antidepressant Dose or Change Treatment in Late-Life Depression. J Clin Psychopharmacol. 2026;46(5):556-563. doi:10.1097/JCP.0000000000002182