Pharmacogenetic-Guided Dosing for Depression

(PGx-GAP Trial)

Overseen By Laina McAusland, MSc

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: University of Calgary

Must be taking: SSRIs

Disqualifiers: Psychosis, Bipolar, Eating disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

11 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a parallel arm randomized (1:1) controlled trial. Adolescents aged 12-17 years (n=452) who are starting or changing a selective serotonin reuptake inhibitor (SSRI) for depression will be randomly allocated to receive 12-weeks of pharmacogenetic-guided antidepressant therapy (experimental intervention) or GLAD-PC guided prescribing (control intervention).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it is for those starting or changing to a new SSRI for depression.

What data supports the effectiveness of pharmacogenetic-guided antidepressant therapy for depression?

Research shows that using genetic tests to guide antidepressant treatment can improve outcomes for people with major depression. These tests help doctors choose the right drug and dose, leading to better improvement, response, and remission rates compared to usual treatment. ^{1 2 3 4 5}

Is pharmacogenetic-guided dosing for depression safe for humans?

Pharmacogenetic testing, which helps tailor antidepressant doses based on genetic differences, is generally considered safe and can improve drug tolerance by adjusting doses to match how individuals metabolize medications. This approach helps avoid adverse drug reactions, which are a significant safety concern in medication use. ^{1 4 5 6 7}

How is pharmacogenetic-guided antidepressant therapy different from other depression treatments?

Pharmacogenetic-guided antidepressant therapy is unique because it uses genetic testing to match patients with the most suitable medication, reducing the trial-and-error process common in depression treatment. This approach aims to improve treatment response rates by considering individual genetic differences that affect how drugs are metabolized and how they work in the body. ^{1 6 8 9 10}

Research Team

Amanda Newton, PhD

Principal Investigator

University of Alberta

Chad Bousman

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for adolescents aged 12-17 who didn't get better or couldn't tolerate the antidepressant fluoxetine. They must be fluent in English, planning to start a new SSRI medication, and have moderate-to-severe depression symptoms without certain genetic tests done before.

Inclusion Criteria

Fluoxetine did not work for me or caused side effects I couldn't tolerate.

QIDS-A17 score greater than or equal to 11 indicating moderate-to-severe symptoms

I plan to begin taking a new SSRI medication.

Exclusion Criteria

I started or plan to start/change psychotherapy or brain stimulation therapy soon.

A score of 2 or 3 on suicide item 13 of the QIDS-A17

High-risk alcohol or substance use (excluding cannabis and tobacco) as indicated by a score of monthly or more on the S2BI

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pharmacogenetic-guided or GLAD-PC guided antidepressant therapy for 12 weeks

12 weeks

Baseline visit, followed by assessments at 4, 8, and 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GLAD-PC guided prescribing
• Pharmacogenetic-guided antidepressant therapy

Trial Overview The study compares two ways of choosing antidepressants: one based on the teen's genetics (experimental) and the other following standard guidelines (control). Each participant will receive their assigned treatment for 12 weeks after being randomly chosen to either group.

Participant Groups

Group I: Pharmacogenetic (PGx)-Guided Experimental Treatment 1 Intervention

Participants and their physician will receive a one-time prescribing report after completing baseline for selective serotonin reuptake inhibitors with dosing information based on CYP2B6, CYP2C19, and CYP2D6 genotype data, and GLAD-PC dosing guidelines for fluoxetine as there are no pharmacogenetic guidelines for this medication.

Group II: Guidelines for Adolescent Depression in Primary Care (GLAD-PC)-Guided Active Control 1 Intervention

Participants and their physician will receive a one-time prescribing report after completing baseline for selective serotonin reuptake inhibitors based on GLAD-PC dosing guidelines.

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

University of Alberta

Collaborator

Trials

957

Recruited

437,000+

Findings from Research

The GeneSight pharmacogenomic test significantly increases the likelihood of response and remission in patients with major depression, showing over double the improvement in depressive symptoms compared to standard treatment after 10 weeks.

Patients identified with severe gene-drug interactions who switched to genetically suitable medications experienced a notable improvement in their symptoms, highlighting the test's potential to optimize antidepressant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Winner, JG., Carhart, JM., Altar, CA., et al.[2022]

Pharmacogenomic tests that analyze CYP2D6 and CYP2C19 genetic variants significantly improve treatment outcomes for major depressive disorders, showing higher odds of improvement (OR: 1.63), response (OR: 1.46), and remission (OR: 1.85) compared to standard treatment.

The analysis included 12 randomized controlled trials, indicating that while pharmacogenomic testing is effective, caution is advised in its application, especially as recent studies showed less favorable remission rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of pharmacogenomic tests including CYP2D6 and CYP2C19 genomic variants for guiding the treatment of depressive disorders: Systematic review and meta-analysis of randomised controlled trials. Arnone, D., Omar, O., Arora, T., et al.[2023]

Pharmacogenetic biomarkers, particularly those related to cytochrome enzymes, are now included in prescribing guidelines, marking a significant advancement towards precision psychiatry that personalizes depression treatment based on genetic information.

Integrating pharmacogenetic testing with therapeutic drug monitoring and other individual factors, such as symptom profiles and concomitant diseases, could optimize treatment outcomes, although challenges like staff training and infrastructure need to be addressed for widespread implementation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision psychiatry in clinical practice. Zanardi, R., Prestifilippo, D., Fabbri, C., et al.[2021]

In a study of 205 patients, there were significant discrepancies in the phenotypic assignment of CYP2D6 and CYP2C19 genotypes between a commercial pharmacogenetic lab and the Clinical Pharmacogenetics Implementation Consortium (CPIC), with conflicting assignments found in 28.8% and 32.2% of cases, respectively.

These differences in genotype interpretation can lead to varying medication recommendations for antidepressants, highlighting the need for standardization in pharmacogenetic testing to ensure safe and effective prescribing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variability Between Clinical Pharmacogenetics Implementation Consortium (CPIC&#174;) Guidelines and a Commercial Pharmacogenetics Laboratory in Genotype to Phenotype Interpretations For Patients Utilizing Psychotropics. Blazy, C., Ellingrod, V., Ward, K.[2022]

Pharmacogenomic testing in psychiatry has rapidly advanced, allowing clinicians to identify patients' genetic profiles, such as variations in the CYP2D6 gene, which affects how they metabolize certain medications, leading to more personalized treatment plans.

Testing for genes like SLC6A4, which influences responses to selective serotonin reuptake inhibitors, is becoming standard practice, with growing evidence supporting the cost-effectiveness and clinical utility of these tests in optimizing psychotropic medication selection and dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychiatric pharmacogenomic testing in clinical practice. Mrazek, DA.[2022]

Genetic factors significantly influence how antidepressants are processed in the body, affecting their effectiveness and safety, which can be identified through modern genotyping methods.

Adjusting antidepressant dosages based on individual genetic variants, particularly those affecting drug-metabolizing enzymes like cytochrome P450, can improve treatment outcomes and tolerance for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The value of pharmacogenetic tests in antidepressive medication therapy]. Kirchheiner, J., Sasse, J., Roots, I., et al.[2018]

Pharmacogenetic testing can help identify individuals who are slow or fast metabolizers of antidepressants, potentially improving treatment outcomes and reducing the time it takes to find effective therapy for depression, which currently can take up to 6 weeks.

Recent research suggests that genetic variations in the serotonin transporter gene may influence how well patients respond to selective serotonin reuptake inhibitors (SSRIs), offering a promising avenue for personalized treatment strategies in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics: a new diagnostic tool in the management of antidepressive drug therapy. Steimer, W., Müller, B., Leucht, S., et al.[2022]

The pharmacogenetic tool Neuropharmagen® significantly improves treatment outcomes for patients with depression, showing a 1.8-fold increase in the odds of clinical response compared to standard drug selection, based on a meta-analysis of 450 subjects.

In patients with moderate to severe depression, the effectiveness of pharmacogenetic-guided prescriptions is even greater, with an effect size of 0.42, indicating a 2.14-fold increase in the odds of response, suggesting this tool is particularly beneficial for more severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of a Pharmacogenetic Tool at Improving Treatment Efficacy in Major Depressive Disorder: A Meta-Analysis of Three Clinical Studies. Vilches, S., Tuson, M., Vieta, E., et al.[2020]

Pharmacogenetic-guided treatment for major depressive disorder (MDD) resulted in higher quality-adjusted life-years (QALYs) and lower costs compared to standard care, with a cumulative effect of 2.07 QALYs for the pharmacogenetic group versus 1.97 QALYs for standard care over three years.

The pharmacogenetic test (IDGx) not only improved treatment outcomes but also saved $2,918 in direct medical costs and $1,680 in indirect costs, particularly benefiting patients with severe depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of a Pharmacogenetic Test to Guide Treatment for Major Depressive Disorder. Groessl, EJ., Tally, SR., Hillery, N., et al.[2023]

In a clinical trial involving 100 patients with major depressive disorder, pharmacogenomic-based antidepressant treatment (PGATx) showed a significant improvement in depression scores compared to standard treatment, with a mean difference of -4.1 points on the Hamilton Depression Rating Scale.

PGATx also demonstrated better tolerability, with fewer patients dropping out due to adverse events compared to those receiving standard treatment, suggesting it may be a safer option for managing depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pharmacogenomic-based Antidepressant Treatment for Patients with Major Depressive Disorder: Results from an 8-week, Randomized, Single-blinded Clinical Trial. Han, C., Wang, SM., Bahk, WM., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of pharmacogenomic tests including CYP2D6 and CYP2C19 genomic variants for guiding the treatment of depressive disorders: Systematic review and meta-analysis of randomised controlled trials. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Precision psychiatry in clinical practice. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Variability Between Clinical Pharmacogenetics Implementation Consortium (CPIC&#174;) Guidelines and a Commercial Pharmacogenetics Laboratory in Genotype to Phenotype Interpretations For Patients Utilizing Psychotropics. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Psychiatric pharmacogenomic testing in clinical practice. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

[The value of pharmacogenetic tests in antidepressive medication therapy]. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacogenetics: a new diagnostic tool in the management of antidepressive drug therapy. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of a Pharmacogenetic Tool at Improving Treatment Efficacy in Major Depressive Disorder: A Meta-Analysis of Three Clinical Studies. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of a Pharmacogenetic Test to Guide Treatment for Major Depressive Disorder. [2023]

10. Korea (South) pubmed.ncbi.nlm.nih.gov

A Pharmacogenomic-based Antidepressant Treatment for Patients with Major Depressive Disorder: Results from an 8-week, Randomized, Single-blinded Clinical Trial. [2021]