Translating Pharmacogenomics and Precision Dosing in Major Depressive Disorder
Education and Research Strategies
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Genetic factors impact pharmacokinetic (drug metabolism) and pharmacodynamic (drug receptor) responses, causing interindividual variabilities in tolerability, therapeutic response and/or adverse effects for a given medication at a standard dose. Pharmacogenomics (PG) is a genetic test assessing multiple variants impacting metabolism/response. PG-guided prescription enables tailored treatment and may be beneficial in depression treatment where current pharmacotherapy is based on trial-and-error iterations. Despite growing evidence, PG uptake remains low in Australia. We therefore sought to identify barriers to PG uptake, develop a model of care for clinical implementation, and investigated the clinical utility and economic implications of PG-guided therapy for depression.
Methods:
This is a multi-stage study with mixed methodologies comprising: Stage 1 where we sought to identify barriers and facilitators for PG adoption as perceived by patients and their clinicians, via a retrospective review of 100 patients who underwent PG testing in a tertiary hospital setting. Based on the findings, we developed a model of care which was implemented in Stage 2 where 78 participants with depression/anxiety were prospectively recruited from the community for PG testing. Within-study end-user experience, potential utilities, and costing implications of PG were explored qualitatively and quantitatively. In Stage 3, we conducted a prospective double-blind randomised controlled trial enrolling 550 people with depression, with 1:1 randomisation to PG-guided versus unguided treatment. Outcome measures include remission in depression, defined as a MADRS score < 10 at week 12; response to antidepressants, defined as > 50% decrease in MADRS score from baseline to week 12; change in DASS-21 score and sub-scores from baseline to week 12; tolerability and adherence to antidepressant therapy. Additional objectives include cost-effectiveness analysis.
Results:
In Stage 1, each patient had 11 high-risk drug-gene interactions (DGIs) (range: 0-49, SD: 13.3) and 55 moderate-risk DGIs (range: 1-149, SD: 28.1). Of 84 patients taking prescription medications, 56 (67%) were taking medications with an actionable DGI (either high-risk or moderate risk). Of those who responded to surveys, 68% of patients understood their PG results; 48% had medications changed following testing. Paired patient-clinician surveys showed patient-perceived utility and experience was positive, contrasting their clinicians’ hesitancy on PG. Insufficient education/training, lack of clinical support, test turnaround time and cost were identified as barriers to adoption.
Conclusion:
PG-guided therapy has the potential to reduce adverse drug reactions and improve patient outcomes in depression pharmacotherapy. Long test turnaround time highlights the importance of pre-emptive testing.
Genetic factors impact pharmacokinetic (drug metabolism) and pharmacodynamic (drug receptor) responses, causing interindividual variabilities in tolerability, therapeutic response and/or adverse effects for a given medication at a standard dose. Pharmacogenomics (PG) is a genetic test assessing multiple variants impacting metabolism/response. PG-guided prescription enables tailored treatment and may be beneficial in depression treatment where current pharmacotherapy is based on trial-and-error iterations. Despite growing evidence, PG uptake remains low in Australia. We therefore sought to identify barriers to PG uptake, develop a model of care for clinical implementation, and investigated the clinical utility and economic implications of PG-guided therapy for depression.
Methods:
This is a multi-stage study with mixed methodologies comprising: Stage 1 where we sought to identify barriers and facilitators for PG adoption as perceived by patients and their clinicians, via a retrospective review of 100 patients who underwent PG testing in a tertiary hospital setting. Based on the findings, we developed a model of care which was implemented in Stage 2 where 78 participants with depression/anxiety were prospectively recruited from the community for PG testing. Within-study end-user experience, potential utilities, and costing implications of PG were explored qualitatively and quantitatively. In Stage 3, we conducted a prospective double-blind randomised controlled trial enrolling 550 people with depression, with 1:1 randomisation to PG-guided versus unguided treatment. Outcome measures include remission in depression, defined as a MADRS score < 10 at week 12; response to antidepressants, defined as > 50% decrease in MADRS score from baseline to week 12; change in DASS-21 score and sub-scores from baseline to week 12; tolerability and adherence to antidepressant therapy. Additional objectives include cost-effectiveness analysis.
Results:
In Stage 1, each patient had 11 high-risk drug-gene interactions (DGIs) (range: 0-49, SD: 13.3) and 55 moderate-risk DGIs (range: 1-149, SD: 28.1). Of 84 patients taking prescription medications, 56 (67%) were taking medications with an actionable DGI (either high-risk or moderate risk). Of those who responded to surveys, 68% of patients understood their PG results; 48% had medications changed following testing. Paired patient-clinician surveys showed patient-perceived utility and experience was positive, contrasting their clinicians’ hesitancy on PG. Insufficient education/training, lack of clinical support, test turnaround time and cost were identified as barriers to adoption.
Conclusion:
PG-guided therapy has the potential to reduce adverse drug reactions and improve patient outcomes in depression pharmacotherapy. Long test turnaround time highlights the importance of pre-emptive testing.