2026 ECNP Congress

PS02-2190

Clinical and genetic characteristics of patients exposed to high-dose selective serotonin reuptake inhibitors (SSRIs) in UK Biobank

Chris Wai Hang Lo — D. Handley, M. Singh, C. Fabbri, A.C. Gillett, C.J. Watson, M. Kamp, D. Li, A.H. Young, C.M. Lewis · King's College London, Social- Genetic and Developmental Psychiatry Centre, London, United Kingdom

2026 ECNP Congress

Introduction

In clinical trials, only one-third of patients respond clinically to antidepressants, the first-line pharmacotherapy in the treatment of MDD [1]. In cases of non-response, clinical guidelines recommend dosage increment alongside drug switching [2]. However, meta-analyses of clinical trials for selective serotonin reuptake inhibitors (SSRIs) do not show a consistent dose-response relationship. Using real-world evidence from UK Biobank (UKB), we identified individuals with MDD exposed to high-dose SSRIs and examined their clinical and genetic characteristics.

Aims

Using primary care records in UKB, we aim to:

(1) describe antidepressant prescribing patterns by dosage;

(2) identify patients exposed to high-dose SSRIs;

(3) study the clinical and genetic characteristics of patients exposed to high-dose SSRIs.

Methods

Using antidepressant prescriptions in UKB primary care records (nprescriptions = 2,323,393), dosage of SSRI prescriptions was ascertained by the R package, T-Rx using product strength information and dosing instructions imputed from prescribed quantities.

A “high-dose” SSRI exposure group (n=10,780) was identified when patients received any SSRI prescriptions for >1 consecutive prescriptions, with dosage above the minimum effective dose listed in British National Formulary (BNF). This is compared to a “standard-dose” group (n=19,618), where patients received SSRIs at or below the BNF minimum effective doses.

To characterise the clinical profiles of patients exposed to high-dose SSRIs, we tested for associations with MDD symptoms reported by Composite International Diagnostic Interview short form (CIDI-SF) and 1,130 UKB-ascertained health outcomes. Association testing was also performed with proxy antidepressant response outcomes, including treatment-resistant depression, switching from SSRIs and self-reported SSRI response. We tested for association of dosage with polygenic scores (PGSs) of antidepressant response (from clinical trials) and eight mental health phenotypes, calculated by SBayesRC. Associations were controlled for drug (SSRI), sex, duration of SSRI exposure, assessment centre, and 10 principal components for population stratification, and corrected for multiple testing.

Results

High-dose SSRI exposure was associated with six of the nine depressive symptoms from CIDI-SF (p<4.38E-4). Patients on high-dose SSRIs were more likely to be treatment-resistant (OR=4.06 [95% CI 3.68-4.49], p=1.11E-166) and to be an SSRI switcher (OR=1.55 [1.41-1.71], p=3.01E-18). High-dose SSRI exposure was also associated with health outcomes including alternative indications for high-dose SSRIs prescriptions (obsessive-compulsive disorders, recurrent MDD), metabolic conditions (obesity, type 2 diabetes mellitus) and other physical health disorders (hypotension, anaemia, gastroesophageal reflux disorders).

PGS of percentage improvement from antidepressants in clinical trials were associated with a lower likelihood of high-dose SSRI exposure (OR=0.96, 95% CI [0.94-0.98], p=0.004), and PGS for non-remission from antidepressants was nominally associated with higher likelihood of being exposed to high-dose SSRI (OR=1.02 [1.01-1.03], p=0.03). PGSs of mental health traits were also associated with high-dose antidepressants: MDD (OR=1.13 [1.10-1.16], p=1.30E-18), ADHD (OR=1.04 [1.02-1.05], p=5.6E-6) and bipolar disorder (p= 0.003).

Conclusions

SSRI dosage information is useful to identify clinical and genetic characteristics of non-responders to medications. High-dose SSRI exposure also captured specific clinical characteristics of MDD patients, including MDD severity and physical health conditions.

References

  1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
  2. Depression in adults: treatment and management. London: National Institute for Health and Care Excellence (NICE); 2022.