Narrative review of TRD epidemiology and CYP2C19 genotypes in Pakistan

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medRxiv Published April 19, 2026 Medically reviewed April 25, 2026 Study authors: Umar, M.; Hussain, F.; Khizar, B.; Khan, I.; Khan, F.; Cotic, M.; Chan, L.; Hussain, A.; Ali, M. N.;… DOI ↗ By Dr. Ji-eun Park, MD · Brain, Mind & Pain

Key Takeaway

Consider that CYP2C19 poor and ultra-rapid metabolizers may have higher TRD risk, but findings are observational and not causal.

This narrative review summarizes findings from an observational genetic epidemiological study conducted at psychiatric care facilities across Pakistan. The analysis included 3677 eligible adult patients with major depressive disorder, with CYP enzyme data available for 1085 patients. Treatment-resistant depression (TRD) was defined as minimal to no improvement after at least 12 weeks of adherent antidepressant therapy.

The authors report a TRD prevalence of 34% (95% CI: 32–36%). Compared with normal CYP2C19 metabolizers, poor metabolizers had increased odds of TRD (OR 1.85; 95% CI 1.11–3.07; p=0.01), and ultra-rapid metabolizers also had increased odds (OR 3.11; 95% CI 1.59–6.12; p=0.0009). The TRD group had more psychotic symptoms (OR 1.39; 95% CI 1.04–1.84; p=0.02) and more suicidal behavior (OR 1.03; 95% CI 1.01–1.05; p=0.005). Social support was associated with lower odds of TRD (OR 0.55; 95% CI 0.44–0.69; p=1.4×10−7), as were parents being first cousins (OR 0.81; 95% CI 0.69–0.96; p=0.01).

The authors acknowledge key limitations: the observational design cannot establish causality; data come from a single country and may not be generalizable; and pharmacogenetic analysis was limited to 1085 patients with CYP enzyme data. No safety or adverse event data were reported.

Practice relevance is cautious: the review highlights the potential of pharmacogenetic markers to predict TRD in low-income settings and the importance of culture-specific social support, while emphasizing evidence-based practice and the need for confirmatory research.

Study Details

Sample sizen = 1,085

EvidenceLevel 5

PublishedApr 2026

View Original Abstract ↓

BackgroundMajor depressive disorder (MDD), a leading cause of disability worldwide, exhibits substantial heterogeneity in treatment outcomes. Patients who do not respond to standard antidepressant therapy account for the majority of MDDs disease burden. Risk factors have been implicated in treatment response, including genes impacting on how antidepressants are metabolised. Yet, despite its clinical importance, risk factors for treatment-resistant depression (TRD) remain unexplored in low- and middle-income countries (LMIC). We used data from the DIVERGE study on MDD to investigate the risk factors of TRD in Pakistan. MethodsDIVERGE is a genetic epidemiological study that recruited adult MDD patients ([≥]18 years) between Sep 27,2021 to Jun 30, 2025, from psychiatric care facilities across Pakistan. Detailed phenotypic information was collected by trained interviewers and blood samples taken. Infinium Global Diversity Array with Enhanced PGx-8 from Illumina was used for genotyping followed by DRAGEN calling to infer metaboliser phenotypes for Cytochrome P450 (CYP) enzyme genes. We defined TRD as minimal to no improvement after [≥]12 weeks of adherent antidepressant therapy. We conducted multi-level logistic regression to test the association of demographic, clinical and pharmacogenetic variables with TRD. FindingsAmong 3,677 eligible patients, polypharmacy was rampant; 86% were prescribed another psychotropic drug along with an antidepressant. Psychological therapies were uncommon (6%) while 49% of patients had previously visited to a religious leader/faith healer in relation to their mental health problems. TRD was experienced by 34% (95%CI: 32-36%) patients. The TRD group was characterised by more psychotic symptoms and suicidal behaviour (OR=1.39, 95%CI=1.04-1.84, p=0.02; OR=1.03, 95%CI=1.01-1.05, p=0.005). Social support (OR=0.55, 95%CI=0.44-0.69, p=1.4x10-7) and parents being first cousins (OR=0.81, 95%CI=0.69-0.96, p=0.01) were associated with lower odds of TRD. In 1,085 patients with CYP enzyme data, poor (OR=1.85, 95%CI=1.11-3.07, p=0.01) and ultra-rapid (OR=3.11, 95%CI=1.59-6.12, p=0.0009) metabolizers for CYP2C19 had increased risk of TRD compared with normal metabolisers. InterpretationThere was an excessive use of polypharmacy in the treatment of depression while psychological therapies were uncommon highlighting the need for more evidence-based practice. This first large study of MDD from Pakistan uncovered the importance of culture-specific forms of social support in preventing TRD, highlighting opportunities for interventions in low-income settings. Pharmacogenetic markers can be leveraged to predict TRD.