Letter to the Editor
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Sep 19, 2025; 15(9): 108222
Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.108222
Unmet needs in precision psychiatry
Philipp G Sand, Timm B Poeppl, Vera Roessler
Philipp G Sand, Department of Psychiatry, University of Regensburg, Regensburg 93053, Bavaria, Germany
Philipp G Sand, Vera Roessler, Centre of Psychiatry, Psychotherapy and Special Education, Bezirkskrankenhaus Kaufbeuren, Kaufbeuren 87600, Bavaria, Germany
Timm B Poeppl, Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg 93053, Bavaria, Germany
Timm B Poeppl, Department of Psychiatry, Psychotherapy, and Psychosomatics, RWTH Aachen University, Aachen 52074, North Rhine-Westphalia, Germany
Author contributions: Sand PG and Roessler V assessed the index study and drafted the manuscript; Poeppl TB provided a critical review for important intellectual content and assisted with interpretation of data; and all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Philipp G Sand, MD, Associate Professor, Department of Psychiatry, University of Regensburg, Universitätsstr. 84, Regensburg 93053, Bavaria, Germany. philipp.sand@ukr.de
Received: April 8, 2025
Revised: May 13, 2025
Accepted: July 23, 2025
Published online: September 19, 2025
Processing time: 140 Days and 10.3 Hours
Abstract

A recent meta-analysis has suggested a 5-HTR1A promoter variant may predict antidepressant response. The present review comments on the claims made in view of sensitivity issues and issues pertaining to genetic exposure. We also alert to errors in the original data that had been carried over. Specifically, primers meant to amplify the HTR1A gene aligned to the BDNF gene sequence. Alleles had been confounded owing to DNA strand ambiguities and demographic information proved inaccurate. In the light of these findings, adherence to PRISMA guidelines and use of the Newcastle-Ottawa Scale did not safeguard against bias. More after action reviews are encouraged to identify factors likely to interfere with estimates of genetic risk in large data sets. These may result from pooling of ethnic groups, the use of binary data or other formats that are not human-readable, the introduction of surrogate identifiers and a failure to reverse-engineer previously published experimental protocols. Unless the above challenges are met, sequence variants are unlikely to inform personalized medicine strategies in psychiatry.

Keywords: Major depressive disorder; Antidepressant efficacy; Meta-analysis; 5-HTR1A gene; C-1019G polymorphism

Core Tip: A recent meta-analysis has suggested a 5-HTR1A promoter variant may predict antidepressant response. However, re-analysis of the original data unveiled numerous shortcomings pertaining to genetic exposure and interpretation of genetic findings. We alert to ambiguities that are likely to have introduced bias in the calculation of overall effects by muddling of alleles or entire genes, and by demographic inaccuracies. In part, these may be explained by specific features of genetic information that are not encoded in the DNA sequence, such as transcriptional orientation.