Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients.

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review.

Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this review, we describe the path that led to the emergence of PGx in psychiatry, the current evidence base and implementation status of PGx in the psychiatric clinic, and finally, the future growth potential of precision psychiatry via the convergence of the PGx-guided strategy with emerging technologies and approaches (i.e. pharmacoepigenomics, pharmacomicrobiomics, pharmacotranscriptomics, pharmacoproteomics, pharmacometabolomics) to personalize treatment of psychiatric disorders.

Pharmacomicrobiomics of Antidepressants in Depression: A Systematic Review.

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 Testing and Depressive Symptom Remission: A Systematic Review and Meta-Analysis of Prospective, Controlled Clinical Trials.

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.

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis.

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, pcorrected = 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.

Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders.

OBJECTIVES: Partial response to pharmacotherapy is common in major depressive disorder (MDD) and many patients require alternative pharmacotherapy or augmentation, including adjunctive L-methylfolate. Given that L-methylfolate augmentation is rarely included in major clinical practice guidelines, we sought to systematically review evidence for L-methylfolate augmentation in adults with MDD and to examine its efficacy meta-analytically. METHODS: We systematically searched PubMed for articles up to December 31, 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Included studies were published in peer-reviewed, English-language journals and examined L-methylfolate adjunctive therapy in depressive disorders or its effect on antidepressant response. A fixed- and random-effects meta-analysis and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted. RESULTS: Qualitative assessment of nine articles (N=6,707 patients) suggests that adjunctive L-methylfolate improved antidepressant response. In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N=483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p=0.004). A meta-analysis of four studies (N=507) using a continuous measure of depressive symptoms showed a similar effect of adjunctive L-methylfolate (standardized mean difference=- 0.38, 95% CI=- 0.59 to-0.17, p=0.0003). CONCLUSION: Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.

Economic Burden of Depression and Associated Resource Use in Manitoba, Canada.

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.

Canadian Medication Cost Savings Associated with Combinatorial Pharmacogenomic Guidance for Psychiatric Medications.

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 (p<0.0001). For patients ages <65 and ≥65, prescription medication costs were $979 and $1178 CAD PMPY lower, respectively, for patients who followed the report recommendations (p=0.0004 and p=0.13). Prescription drug fills from the US pharmacy claims were concordant with the Canadian Formulary; 62% of fills matched at both the drug name and dose strength, 81% matched at drug name, and >99% matched at the therapeutic chapter. CONCLUSIONS: 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.

Economic Utility: Combinatorial Pharmacogenomics and Medication Cost Savings for Mental Health Care in a Primary Care Setting.

PURPOSE: This study was an analysis based on a previously completed prospective study investigating medication costs of patients with mental illness guided by using the GeneSight proprietary combinatorial pharmacogenomic (PGx) test. The primary objective of this study was to determine potential cost savings of combinatorial PGx testing over the course of 1 year in patients with mental illness treated by primary care providers (PCPs) and psychiatrists who had switched or added a new psychiatric medication after patients failed to respond to monotherapy. The current evaluation details cost savings of treatment decisions congruent and incongruent with the combinatorial PGx test recommendations specific to PCPs and psychiatrists. METHODS: This study was a subanalysis of a 1-year, prospective trial comparing medication costs of 2168 patients undergoing GeneSight testing. Pharmacy claims were provided by a pharmacy benefits manager, comparing medication costs 6 months before combinatorial PGx testing and followed up for 1 year after the testing. This analysis compared congruence and cost savings per patient based on the type of health care provider administering care. FINDINGS: Using data from a large pharmacy benefits manager, we found that PCPs treat the majority of mental health patients receiving psychotropic medication prescriptions, including treatment-resistant patients. PCPs congruent with combinatorial PGx testing provided the most medication cost savings for payers and patients at $3988 per member per year (P < 0.001). IMPLICATIONS: Health care providers treating patients with mental illness can significantly reduce medication costs by following the combinatorial PGx report recommendations. PCPs, who treat the majority of patients with mental illness, reported a significant reduction in medication costs for both central nervous system and non-central nervous system drugs.

Pilot study of cryoplasty with use of PolarCath peripheral balloon catheter system for dialysis access.

PURPOSE: To evaluate the safety and feasibility of cryoplasty as the initial balloon treatment for dialysis access venous stenoses. MATERIALS AND METHODS: Twenty patients with grafts (n = 18) or arteriovenous fistulas (n = 2) were enrolled in an institutional review board-approved prospective study. Patients with high venous dialysis pressures (n = 7), poor flow (n = 3), abnormal thrill (n = 3), nonmaturation (n = 2), poor clearance (n = 2), edema (n = 1), prolonged bleeding (n = 1), or recurrent clotting (n = 1) in the presence of stenoses >/=50% were eligible. Mean stenosis measurement was 62.8% (range, 51%-82%). Mean lesion length was 2.57 cm (range, 0.4-5.7 cm). Device success required complete cryoplasty balloon expansion. Procedure success required anatomic success combined with a clinical or hemodynamic indicator of success. Primary circuit patency ended with any restenosis. Primary lesion patency ended with index lesion restenosis. RESULTS: The device success rate was 53% (nine of 17). The anatomic success rate after cryoplasty was 35% (seven of 20). Eighty percent of lesions (16 of 20) were treated with conventional percutaneous transluminal angioplasty (PTA) balloons after cryoplasty. The procedure success rate after supplemental PTA was 80% (16 of 20). The primary circuit patency rates were 82% (14 of 17) at 3 months and 19% (three of 16) at 6 months. The primary lesion patency rates were 88% (15 of 17) at 3 months and 25% (four of 16) at 6 months. All patients reported pain during cryoplasty, and the 16 who underwent supplemental PTA described cryoplasty as more painful than PTA. Cryoplasty-related complications included one case of transient spasm. CONCLUSIONS: Use of the PolarCath peripheral balloon catheter system as the initial balloon for dialysis access venous stenoses is safe but painful. Anatomic success rates after cryoplasty are low. Results of cryoplasty supplemented by PTA appear comparable to those of PTA alone.