Pharmacogenomic-informed antidepressant prescribing for moderate-to-severe depressive symptoms in Australian general practice (PRESIDE): a double-blind, randomised controlled trial

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Background Depression affects over 280 million people worldwide and is a leading contributor to disease burden in Australia, where most patients are managed in primary care. Although antidepressants are recommended for moderate-to-severe depression, up to half of patients do not respond to their first medication. Pharmacogenomic testing of CYP2C19 and CYP2D6 genotypes has been proposed to guide antidepressant prescribing, but evidence of their effectiveness from primary care settings is scarce. The aim of this trial was to test the effect of a pharmacogenomic-informed antidepressant-prescribing report on depressive symptoms at 12 weeks in primary care. Methods This double-blind, two-arm, stratified, randomised controlled trial was conducted in 19 general practices in Victoria, Australia. Adults aged 18–65 years with moderate-to-severe depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) and an upcoming appointment with a participating general practitioner (GP) within 2 days of being approached for participation in the trial were eligible. Participants were randomly assigned (1:1) to have their GP receive a prescribing report with four to six recommended antidepressants and respective dosage based either on the Australian Therapeutic Guidelines (control intervention) or CYP2C19 and CYP2D6 genotype-predicted phenotypes (experimental intervention). In the intervention reports, if there were no pharmacogenomic-specific recommendations for a patient, guidance was also based on Australian Therapeutic Guidelines. The primary outcome was the between-group difference in mean change in PHQ-9 score from baseline to 12 weeks. Analyses were conducted by intention-to-treat. This trial was registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12621000181808) and is completed. Findings Between May 26, 2021, and Sept 28, 2023, 552 participants were randomly assigned. Two participants withdrew after randomisation (one in each group), leaving a final intention-to-treat cohort of 550 participants (275 in each group); 168 men, 368 women, and 14 non-binary or gender diverse participants who were predominantly of European (n=452; 82%) or Asian ethnicity (n=56; 10%). At 12 weeks, 479 (87%; n=235 intervention, n=244 control) reported their PHQ-9 for the primary outcome. Both groups improved compared with baseline, but the control group showed a slightly greater reduction in PHQ-9 scores (mean change from baseline: intervention group –3·45, control group –4·63; between-group difference 0·90, 95% CI 0·06–1·75; standardised mean between-group difference 0·23, 0·02–0·45; p=0·036). There were no serious adverse events or deaths, and one grade 1 adverse event related to mishandling of a prescribing report by a general practice. Interpretation Pharmacogenomic-guided antidepressant prescribing did not improve depression severity compared with prescribing reports based on national clinical guidelines in Australian primary care, and cannot be recommended for implementation. Better approaches are needed to ensure pharmacogenomic results are accessible at the point of prescribing, and to identify if particular subgroups of patients with depression treated in primary care could benefit. Funding Australian Medical Research Futures Fund.

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