Therapygenetics: Serotonin transporter gene polymorphism (5-HTTLPR) is associated with behavioral treatment response to virtual exposure therapy in patients with spider phobia

Abstract Identifying biomarkers predicting therapy outcomes before treatment holds great promise for advancing precision medicine. Genetic variants such as the serotonin transporter gene linked polymorphic region (5-HTTLPR) may be associated with response to cognitive behavioral therapy in anxiety disorders, albeit results so far are controversial. Contributing to the ongoing debate, we investigated whether treatment response to a highly standardized one-session virtual reality exposure therapy (VRET) was predicted by 5-HTTLPR genotype. N=194 patients with arachnophobia (spider phobia) were genotyped for 5-HTTLPR and the functionally related single nucleotide polymorphism rs25531 and grouped into high-(LA/LA), and low-expression (S/S, S/LG, LG/LG, S/LA, LG/LA) genotype. At baseline, after VRET, and at a 6-month follow-up, participants underwent a standardized behavioral avoidance task (BAT) and the spider phobia questionnaire (SPQ) to assess symptom severity. Chi-square tests revealed a significant association between 5-HTTLPR/rs25531 and behavioral treatment outcome, that remained significant at the 6-month follow-up. No association was found between genotype and self-reported symptom severity measured with the SPQ. Our results support the idea that while LA/LAgenotype carriers might benefit from highly standardized treatment, lower 5-HTT expression may convey risk to poorer treatment response, likely necessitating more tailored psychotherapeutic interventions to promote sufficient response. Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT03208400 Clinical Protocols https://onlinelibrary.wiley.com/doi/pdf/10.1002/mpr.1812 Funding Statement This work was funded by the Deutsche Forschungsgemeinschaft (DFG), Projektnummer 44541416-TRR 58 (CRC-TRR58, Project C08 to M.J. and T.S., Project C09 to U.D. and U.L., Project C07 to T.S. and M.H., Project Z02 to K.D., J.D., U.D., and U.L.) and the Interdisci-plinary Center for Clinical Research (IZKF) of the medical faculty of Munster (Grant Dan3/012/17 to U.D.), as well as the Innovative Medizinische Forschung (IMF) of the Medical Faculty, University of Munster (EJL, grant number LE121904 and LE112403). The work was further supported by the Else Kroner-Fresenius Stiftung (EJL, grant number 2022_EKEA.193). None of the funders had a further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 1. Ethics committee of "Arztekammer Westfalen-Lippe und der Westfalischen Wilhelms-Universitat Munster" gave ethical approval for this work. 2. Ethics committee of "Medizinische Fakultat Universtiat Wurzburg" gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Due to the sensitive nature of the data, which includes genetic information, individual-level data cannot be shared in order to protect participant privacy. However, aggregated data are available from the corresponding author upon reasonable request.