Lisa Brown

This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction.

Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical efficacy of this strategy has been questioned. We systematically reviewed and meta‐analyzed clinical trials for an association between the use of PGx‐guided antidepressant therapy and depressive symptom remission in patients with major depressive disorder (MDD). We included prospective, controlled clinical trials published in English up to July 12, 2022. Data extraction and synthesis adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Each trial was assessed for risk of bias and a random‐effects model was used to estimate pooled risk ratios. Thirteen trials comprising 4,767 patients were analyzed, including 10 randomized controlled trials, and three open label trials. Across all included trials, those that received PGx‐guided antidepressant therapy (n = 2,395) were 1.41 (95% confidence interval (CI) = 1.15–1.74, P = 0.001) more likely to achieve remission compared with those that received unguided antidepressant therapy (n = 2,372). Pooled risk ratios for randomized controlled trials and open label trials were 1.46 (95% CI: 1.13–1.88) and 1.26 (95% CI = 0.84–1.88), respectively. These results suggest that PGx‐guided antidepressant therapy is associated with a modest but significant increase in depressive symptom remission in adults with MDD. Efforts to address the heterogeneity in PGx test composition (i.e., genes and alleles tested) and accompanying prescribing recommendations across trials will likely reduce the uncertainty about the efficacy of PGx‐guided antidepressant therapy in the literature.

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20–15.80, p_corrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

An emerging body of literature demonstrates differences in the gut microbiome (GMB) of patients with major depressive disorder (MDD) compared to healthy controls (HC), as well as the potential benefits of prebiotic, probiotic, and synbiotic treatment. We conducted a systematic review of 24 observational studies (n = 2817), and 19 interventional trials (n = 1119). We assessed alpha diversity, beta diversity, and taxa abundance changes in patients with MDD relative to HC, as well as the effect of prebiotics, probiotics, and synbiotics on depressive symptoms in individuals with clinical or subclinical depression. We observed no significant differences in alpha diversity but a significant difference in beta diversity between patients with MDD and HC. There were fluctuations in the abundance of specific taxa in patients with MDD relative to HC. Probiotic and synbiotic, but not prebiotic, treatment showed a modest benefit in reducing depressive symptoms in patients with MDD over four to nine weeks. The GMB profiles of patients with MDD differ significantly from HC, but further studies are needed to elucidate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and over longer follow-up before these therapies are implemented into clinical practice.

Pharmacogenomic (PGx) testing is being increasingly recognized by clinicians as an essential tool to guide medication decisions for treatment of psychiatric illnesses. Extensive implementation of PGx testing, however, varies by setting and location. In this retrospective study, we reviewed charts from 592 patients diagnosed with a psychiatric disorder at the Loyola University Medical Center, for whom PGx testing was performed. Information collected included demographics at the time of testing, psychiatric diagnosis, medical and psychiatric history and medications prior and after PGx testing. Of the 592 charts analyzed, the most common primary diagnoses were depression (52%) and anxiety (12%). Prior to PGx testing, 72% of patients were prescribed three or more medications, whereas, after testing, only 44% were prescribed three or more medications included in the test panel (p < 0.0001). The most common clinical consideration on the PGx reports was recommendation to reduce dosages (33%). After PGx testing, the proportion of patients taking incongruent medications decreased from 26% to 19% and that of patients taking congruent medications increased from 74% to 81% (p = 0.006). The results from this retrospective data analysis demonstrated a reduction in polypharmacy and an increase in recommendation-congruent medication prescribing resulting from implementation of PGx testing.

Objective: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). Design: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. Setting: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. Participants: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. Intervention: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). Outcomes: Mean percent symptom improvement, response rate, and remission rate at week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. Results: At week 8, symptom improvement was not significantly different for guided-care than for TAU (A = 8.1%, t=1.64, df= 187; p = 0.102); however, guided-care showed significantly improved response (A = 13.6%, t = 2.16, df= 187; p = 0.032) and remission (A = 12.7%, t = 2.49, df= 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (x = 19.3, df=2;p Am J Geriatr Psychiatry 2020; 28:933–945)

Aim: To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions...

Objectives: To characterize the health-care utilization and economic burden associated with depression in Manitoba, Canada. Methods: Patient-level data were retrieved from the Manitoba Centre for Health Policy administrative, clinical, and laboratory databases for the study period of January 1, 1996, through December 31, 2016. Patients were assigned to the depression cohort based on diagnoses recorded in hospitalizations and outpatient physician claims, as well as antidepressant prescription drug claims. A comparison cohort of nondepressed subjects, matched with replacement for age, gender, place of residence (urban vs. rural), and index date, was created. Demographics, comorbidities, intentional self-harm, mortality, health-care utilization, prescription drug utilization, and costs of health-care utilization and social services were compared between depressed patients and matched nondepressed patients, and incidence rate ratios and hazard ratios were reported. Results: There were 190,065 patients in the depression cohort and 378,177 patients in the nondepression cohort. Comorbidities were 43% more prevalent among depressed patients. Intentional self-harm, all-cause mortality, and suicide mortality were higher among patients with depression than the nondepression cohort. Health-care utilization—including hospitalizations, physician visits, physician-provided psychotherapy, and prescription drugs—was higher in the depression than the nondepression cohort. Mean health-care utilization costs were 3.5 times higher among depressed patients than nondepressed patients ($10,064 and $2,832, respectively). Similarly, mean social services costs were 3 times higher ($1,522 and $510, respectively). Overall, depression adds a total average cost of $8,244 ( SD = $40,542) per person per year. Conclusions: Depression contributes significantly to health burden and per patient costs in Manitoba, Canada. Extrapolation of the results to the entire Canadian health-care system projects an excess of $12 billion annually in health system spending.

Objective: To estimate Canadian pharmacy cost savings associated with psychiatric medication prescribing that is guided by combinatorial pharmacogenomic testing in patients switching or augmenting their psychiatric medication. Methods: Pharmacy claims data from a United States (US) pharmacy benefit manager were analyzed for 1662 patients who recently augmented or switched to a different antidepressant or antipsychotic medication and underwent combinatorial pharmacogenomic testing. Costs of prescription medications were translated to the Canadian healthcare system by matching drug names and doses using the Ontario Drug Benefit Formulary. One-year costs (2017 CAD) were compared between patients whose clinician prescribed antidepressants or antipsychotics that were consistent (congruent) or inconsistent (incongruent) with the combinatorial pharmacogenomic test recommendations. Results: Patients whose psychiatric medication treatment was congruent with the combinatorial pharmacogenomic test report saved $1061 CAD per member per year (PMPY) on prescription medication costs relative to patients whose medications were incongruent with their test report (pConclusions: Antidepressant and antipsychotic prescribing that was congruent with combinatorial pharmacogenomic test guidance was associated with significant cost savings on Canadian prescription medications according to the Ontario Drug Benefit Formulary.