PACE Case: Pharmacogenomic Testing Utility in Mental Health

A 70-year-old female PACE participant has a past medical history of major depressive disorder (MDD), bipolar disorder, post-traumatic stress disorder, generalized anxiety disorder (GAD), gastroesophageal reflux (GERD), cerebrovascular accident from atrial septal aneurysm, chronic pain, and mild chronic kidney disease (CrCl 65 mL/min). She was a victim of domestic violence and has a history of prescription drug abuse. The participant has been admitted to the hospital multiple times for psychiatric reasons since the 1960s. Her most recent hospitalization was due to suicidal ideation and recurring MDD with GAD. She admits to medication non-adherence and is interested in improving her compliance.

Concerned for the participant’s mental health, the PACE prescriber requests the CareKinesis pharmacist review her medication regimen with the goal of stabilizing her psychiatric symptoms and reducing her medication risk score, which is currently 31 out of 50 (high). To provide improved individualization of the participant’s medication regimen for optimization and mitigation of potential adverse effects (ADEs), the prescriber also orders a pharmacogenomic (PGx) test.

The participant’s current medication regimen includes:

  • Apixaban 5 mg, PO BID for anticoagulation
  • Atenolol 25 mg, PO Daily for hypertensive renal disease
  • Carbamazepine 400 mg, PO Daily for MDD and bipolar disorder
  • Esomeprazole 20 mg, PO Daily for GERD
  • Furosemide 20 mg, PO Daily for edema
  • Gabapentin 300 mg, PO TID for neuropathic pain
  • Risperidone 1 mg, PO QHS for MDD and bipolar disorder
  • Trazodone 50 mg, PO QHS for MDD and bipolar disorder

Genetic polymorphisms and PGx results of key CYP enzymes:

  • CYP2C9 – Intermediate metabolizer
  • CYP2D6 – Intermediate metabolizer
  • CYP3A4 – Rapid metabolizer

Labs of interest:

  • Carbamazepine level: 2.8 (4-12 mg/L)

The CareKinesis pharmacist reviewed the participant’s medication regimen for multi-drug interactions along with drug-gene interactions, which are drug interactions caused by polymorphisms in an individual’s genetic makeup.

Multi-drug interactions identified by the pharmacist included:

  • Competitive inhibition interaction with co-administration between:
    • Risperidone vs. trazodone: Since risperidone has greater affinity for CYP3A4, have a potential increase in trazodone concentration (up to 2-fold).
    • Esomeprazole vs. apixaban: Since esomeprazole has greater affinity for CYP3A4, have a potential increase in apixaban concentration (up to 2-fold).
    • However, induction of the CYP3A4 enzyme via carbamazepine, a well-known enzyme inducer, results in increased enzyme activity of CYP3A4 and lower concentrations of trazodone, risperidone, apixaban, and carbamazepine itself (it is an auto-inducer and speeds up its own breakdown).

Drug-gene interactions identified by the pharmacist included:

  • As a CYP3A4 rapid metabolizer the participant’s enzyme activity is increased, potentially reducing the concentrations of all drug substrates: trazodone, risperidone, esomeprazole, carbamazepine, and apixaban.
  • As a CYP2D6 intermediate metabolizer, the participant’s enzyme activity is decreased, which may result in increased concentration of risperidone.
  • Although the participant is a CYP2C9 intermediate metabolizer, no medications in her regimen currently breakdown through this pathway.

Based on the pharmacist’s findings, and knowing the participant’s genetic makeup, the following recommendations were provided to the PACE prescriber for consideration:

  1. Apixaban: over time, apixaban concentration may decrease, thus there may be a risk of pharmacotherapy failure (i.e., clotting). Monitor for effectiveness and toxicity (i.e., bleeding) and consider alternative agents, such as dabigatran (non-CYP450, may need to renally dose).
  2. Carbamazepine: over time, carbamazepine concentration may decrease, thus there may be a risk of pharmacotherapy failure (i.e., mood irregularity). The decreased concentration is evident with the subtherapeutic carbamazepine level. Monitor for effectiveness (i.e., improved mood) and toxicity (i.e., nausea, dizziness, sedation); as clinically appropriate, consider alternative mood-stabilizing agents, such as valproic acid (non-CYP450).
  3. Esomeprazole: over time, esomeprazole concentration may decrease, thus there may be a risk of pharmacotherapy failure (i.e., GERD symptoms). Monitor for effectiveness (i.e., improved GERD symptoms) and consider alternative PPI if acid-suppression therapy is still indicated, such as pantoprazole 20 mg daily, which is metabolized only by CYP2C19 enzyme for which this participant is a normal metabolizer. Alternatively, if clinically appropriate, to mitigate potential ADE risk with long-term PPI therapy, consider an H2-receptor antagonist, such as ranitidine 150 mg QHS (non-CYP450).
  4. Risperidone: over time, risperidone concentration may be affected with either an increase or decrease, causing a risk of toxicity (i.e., sedation, dizziness) or pharmacotherapy failure (i.e., mood irregularity). Monitor for toxicity and effectiveness (i.e., improved mood) and consider alternative medications that may be better tolerated, such as selective serotonin reuptake inhibitors (SSRIs) (i.e., sertraline, escitalopram, or citalopram). The participant is a normal metabolizer for enzyme CYP2C19, the main metabolizing enzyme for the SSRIs noted. If alternative is to be trialed, recommend a gradual dose reduction taper to discontinue risperidone.
  5. Trazodone: over time, trazodone concentration may decrease, thus there may be a risk of pharmacotherapy failure (i.e., mood irregularity). Monitor for effectiveness and toxicity (i.e., sedation, headache).

Conclusion:
The PGx test allowed the pharmacist to offer the PACE prescriber a different perspective on this participant’s medication regimen. Analyzing patient genetic makeup may enable prescribers and pharmacists to select safer, more appropriate medications for patients in complex cases.

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