Integrating pharmacogenetics into clinical practice: Opportunities and challenges for the pharmaceutical care of patients with major depression

An individual’s genetic makeup can affect the pharmacokinetic and pharmacodynamic behavior of a drug, which may have a clinically relevant impact on the drug’s efficacy and tolerability. Pharmacogenetics aims to identify patients who are susceptible to therapy failure, adverse drug reactions or severe toxicities, as a result of their genetic predisposition. Such genetic information may be used to individualize pharmacotherapy to increase effectiveness and minimize adverse drug reactions. Multiple international consortia are translating pharmacogenetic (PGx) findings from research into recommendations for clinical practice, to support the use of genetic information in optimizing pharmacotherapy in terms of drug selection and dosing. Such recommendations exist for several antidepressants commonly used in Switzerland, including the selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, paroxetine and sertraline). Pharmacotherapy with antidepressants is an important pillar in the treatment of patients with major depressive disorder (MDD). However, it is known that about half of these patients do not respond sufficiently to a first-line treatment. As mentioned before, genetic predisposition is one factor affecting antidepressant efficacy and tolerability. Still, clinicians in Switzerland do not routinely consider PGx information in the pharmacotherapeutic management of patients with MDD. This thesis investigates the integration of PGx into clinical practice and evaluates opportunities and challenges for the pharmaceutical care of MDD patients in this context. The thesis presented here consists of four parts (A–D):
Project A: In a prospective, observational case study we collected and analyzed individual patient cases from primary and secondary care, where PGx information was used by pharmacists to elucidate histories of therapy failure and adverse drug reactions, as well as to elaborate recommendations for further therapy optimization. This thesis gives an insight into five exemplary patient cases related to antidepressant treatment in secondary care. The application of individual PGx information to real-world, depressive-disorder patient cases did not always prove to be straightforward. Despite the availability of PGx dosing guidelines for certain drug-gene pairs, evidence for precise PGx-based drug selection and dosing is still fragmentary. Moreover, the integration of PGx information required consideration and evaluation of additional individual factors, including non-genetic factors such as the patients’ comedication and comorbidities.
Project B: Pharmacists already consider several interindividual factors when analyzing a patient’s medicines to propose interventions for therapy optimization and are an important point of contact for patients and healthcare professionals concerning drug-related problems. Accordingly, owing to the identified complexity of applying PGx information in individual patient cases (Project A) and the lack of education being described as a major barrier to the adoption of PGx in clinical practice, we developed and conducted a continuing education program. The aim of this training program was to prepare Swiss pharmacists for the application of PGx information in clinical practice. After attending the program, participants showed measurable improvement in both knowledge and skills to apply PGx information in providing pharmaceutical care to patients. However, the actual implementation of a PGx service presented several challenges for the participating pharmacists. One major challenge appeared to be the lack of interprofessional networks and physician support for such a PGx service.
Project C: In order for the PGx information processed by pharmacists to be taken into account in the treatment of patients, close collaboration with other healthcare professionals, especially the treating physician, is of importance. Based on our working experience with over 140 patient cases in the aforementioned observational case study, we defined a six-step-approach for the implementation of a pharmacist-led PGx testing and counseling service (PGx service) for primary and secondary care settings. In this approach, pharmacists play a key role in enabling an individual and comprehensive evaluation of the patients’ PGx profile by integrating this information into a medication review. In this way, non-genetic factors that may enhance or compensate for the genetic predisposition are also taken into account.
Project D: To evaluate the impact of the proposed pharmacist-led PGx service (Project C) on patient outcomes, we developed a clinical trial addressing antidepressant therapy in MDD patients. The PrePGx study is a multi-center, open-label, randomized controlled, parallel three-arm trial. We compare pharmacist-guided preemptive PGx testing for the selection and dosing of an antidepressant (intervention arm) to the current standard approach (control arm), where the psychiatrist prescribes the antidepressant without information on the patient’s PGx profile and without a consultation with a pharmacist. We anticipate that this trial will have a direct impact on the application and handling of PGx information in routine psychiatric and pharmacy practice.