The PRESIDE TRIAL

The PRESIDE (PhaRmacogEnomicS In Depression) Trial is a double-blind RCT of pharmacogenomically-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care. In other words, participants who have depressive symptoms will be randomly allocated to one of two groups and neither they, nor their GP, nor the researchers will be aware of which group they are in. One group (intervention) will receive recommendations for which antidepressant drugs may be most effective for them based on how their DNA impacts how they break these drugs down. The other group (control) will receive recommendations for antidepressant drugs based on current Australian guidelines. All participants, regardless of which group they are in, will decide with their GP which antidepressant, if any, is best for them. This trial addresses significant knowledge gaps related to how clinically useful this type of pharmacogenomic (DNA) test may be in managing patients with major depressive disorder in primary care. It will create evidence about the efficacy, safety, and costeffectiveness of this approach, working with health service delivery partners and research end-users to ensure the findings can be implemented into practice as quickly as possible. Participants will be recruited (informed consent) from participating Australian General Practices. For those in the intervention arm, the DNA will be used to generate a recommendation for antidepressant prescribing guided by the participants' pharmacogenomic profile. For those in the control arm, the recommendation for prescribing will be based on the TGA guidelines. Each participant's General Practitioner will be provided with the relevant test report and will be blinded to which group the participant has been allocated into. Neither report will refer to specific genomic variants, only a prescription recommendation. Before recruitment, participants will be informed of the randomised nature of the study and that neither they, nor their GP, nor the study team can allocate them to a particular group. The researcher will ensure they understand as part of the consent process. After 6 months, all participants' GPs, regardless of the participant's arm, will receive their full clinical pharmacogenomic report. The intervention consists of a pharmacogenomic test with resulting recommendations for which antidepressants may work best for that participant. The DNA sample will be obtained using the Oragene-DNA buccal kit, which we have used successfully in our previous genotyping studies in primary care. The Sonic Pathology PGx panel will be used for genotyping, with specific focus on two genes: CYP2D6 (alleles *2, *3, *4, *4M, *6, *7, *8, *9, *10, *11, *12, *14A, *14B, *13, *15, *17, *18, *19, *20, *29, *36, *38, *41, *5 (gene deletion), XN (gene duplication) (VeriDose® Core and CYP2D6 CNV Panels) and CYP2C19 (alleles *2, *3, *4, *4B, *5, *6, *7, *8, *17). The allele that each participant carries can predict how they metabolise certain drugs. This is used to create actionable recommendations about antidepressant class and dose, based on Clinical Pharmacogenetics Implementation Consortium (CPIC) and Royal Dutch Pharmacogenetics Working Group (DPWG) international guidelines.(10, 11) Sonic Genetics has an established pharmacogenomic genotyping and interpretive service in conjunction with Translational Software (https://www.translationalsoftware.com/), which will generate the patient-specific prescribing advice. The recommendations will take into account concurrent medication use, in particular accounting for CYP2D6 and CYP2C19 inducers and inhibitors, by applying an evidence-based algorithm created by CI Bousman (Sequence2Script). The GPs of those in both the intervention arm and the control arm will receive a specific prescribing recommendation within 2 weeks of entry into the trial. For those in the intervention arm, this report will be based on the participant’s genotype, predicted metaboliser phenotype, concomitant medication use and the Australian Therapeutic Guidelines. For those in the control arm, this will be based on the Australian Therapeutic Guidelines. To ensure blinding, the report will not refer to the participant’s genotype or phenotype but only provide prescribing recommendations. All participants will be advised to see their GP to discuss this prescribing report and determine clinical management. They will also be advised to see their GP for review at 2, 4, 8 and 12 weeks after the initial consultation to discuss the prescribing report. This is consistent with current practice for the follow-up of patients with depression in primary care. Patient adherence to antidepressant prescribing using the Medication Adherence Report Scale (MARS-5) at baseline, 4, 8,12 and 26 weeks. We will use PBS data to calculate the Medication Possession Ratio, an objective measure of adherence which is associated with antidepressant response at the completion of the intervention period. (10) Hicks JK, et al.. Clin Pharmacol Ther. 2015;98(2):127-34. (11) Hicks JK, et al. Clin Pharmacol Ther. 2017;102(1):37-44.