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Pharmacopsychiatry Jan 2021The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence...
The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (), oxcarbazepine (), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes () is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.
Topics: Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; HLA Antigens; Humans; Pharmacogenomic Testing; Practice Guidelines as Topic; Psychiatry; Urea Cycle Disorders, Inborn
PubMed: 33147643
DOI: 10.1055/a-1288-1061 -
Clinical Pharmacology and Therapeutics Aug 2020Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to... (Meta-Analysis)
Meta-Analysis
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org).
Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Decision-Making; Consensus; Cytochrome P-450 CYP2C9; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Phenotype; Predictive Value of Tests; Risk Assessment; Risk Factors
PubMed: 32189324
DOI: 10.1002/cpt.1830 -
Clinical Pharmacology and Therapeutics Dec 2022Pharmacogenomic (PGx) testing has emerged as a compelling strategy that clinicians can use to inform antidepressant medication selection and dosing, but the clinical... (Meta-Analysis)
Meta-Analysis
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.
Topics: Adult; Humans; Antidepressive Agents; Depression; Depressive Disorder, Major; Pharmacogenomic Testing; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 36111494
DOI: 10.1002/cpt.2748 -
Clinical Pharmacology and Therapeutics Dec 2022The objective of this study was to evaluate the evidence on cost-effectiveness of pharmacogenetic (PGx)-guided treatment for drugs with Clinical Pharmacogenetics...
The objective of this study was to evaluate the evidence on cost-effectiveness of pharmacogenetic (PGx)-guided treatment for drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A systematic review was conducted using multiple biomedical literature databases from inception to June 2021. Full articles comparing PGx-guided with nonguided treatment were included for data extraction. Quality of Health Economic Studies (QHES) was used to assess robustness of each study (0-100). Data are reported using descriptive statistics. Of 108 studies evaluating 39 drugs, 77 (71%) showed PGx testing was cost-effective (CE) (N = 48) or cost-saving (CS) (N = 29); 21 (20%) were not CE; 10 (9%) were uncertain. Clopidogrel had the most articles (N = 23), of which 22 demonstrated CE or CS, followed by warfarin (N = 16), of which 7 demonstrated CE or CS. Of 26 studies evaluating human leukocyte antigen (HLA) testing for abacavir (N = 8), allopurinol (N = 10), or carbamazepine/phenytoin (N = 8), 15 demonstrated CE or CS. Nine of 11 antidepressant articles demonstrated CE or CS. The median QHES score reflected high-quality studies (91; range 48-100). Most studies evaluating cost-effectiveness favored PGx testing. Limited data exist on cost-effectiveness of preemptive and multigene testing across disease states.
Topics: Humans; Pharmacogenomic Testing; Pharmacogenetics; Cost-Benefit Analysis; Warfarin; Carbamazepine
PubMed: 36149409
DOI: 10.1002/cpt.2754 -
Journal of Psychiatric Research Nov 2021Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant... (Review)
Review
Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.
PubMed: 34844049
DOI: 10.1016/j.jpsychires.2021.11.036 -
Journal of Personalized Medicine Nov 2022PGx testing requires a complex set of activities undertaken by practitioners and patients, resulting in varying implementation success. This systematic review aimed... (Review)
Review
PGx testing requires a complex set of activities undertaken by practitioners and patients, resulting in varying implementation success. This systematic review aimed (PROSPERO: CRD42019150940) to identify barriers and enablers to practitioners and patients implementing pharmacogenomic testing. We followed PRISMA guidelines to conduct and report this review. Medline, EMBASE, CINAHL, PsycINFO, and PubMed Central were systematically searched from inception to June 2022. The theoretical domain framework (TDF) guided the organisation and reporting of barriers or enablers relating to pharmacogenomic testing activities. From the twenty-five eligible reports, eleven activities were described relating to four implementation stages: ordering, facilitating, interpreting, and applying pharmacogenomic testing. Four themes were identified across the implementation stages: IT infrastructure, effort, rewards, and unknown territory. Barriers were most consistently mapped to TDF domains: memory, attention and decision-making processes, environmental context and resources, and belief about consequences.
PubMed: 36579514
DOI: 10.3390/jpm12111821 -
Canadian Journal of Psychiatry. Revue... Dec 2021Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to...
BACKGROUND
Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID.
METHODS
We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects).
RESULTS
A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of and polymorphisms, respectively, yielding mostly negative study findings.
CONCLUSIONS
There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.
Topics: Adolescent; Adult; Antipsychotic Agents; Autism Spectrum Disorder; Child; Humans; Intellectual Disability; Pharmacogenomic Testing; Psychotropic Drugs; Serotonin Plasma Membrane Transport Proteins
PubMed: 33222504
DOI: 10.1177/0706743720971950 -
The Pharmacogenomics Journal May 2022The major challenges that delay the implementation of pharmacogenomics based clinical practice in the developing countries, primarily the low- and middle-income... (Review)
Review
The major challenges that delay the implementation of pharmacogenomics based clinical practice in the developing countries, primarily the low- and middle-income countries need to be recognized. This review was conducted to systematically review evidence of the cost-effectiveness for the conduct of pharmacogenomics testing in the developing countries. Studies that evaluated the cost-effectiveness of pharmacogenomics testing in the developing countries as defined by the United Nations were included in this study. Twenty-seven articles met the criteria. Pharmacogenomics effectiveness were evaluated for drugs used in the treatment of cancers, cardiovascular diseases and severe cutaneous adverse reactions in gout and epilepsy. Most studies had reported pharmacogenomics testing to be cost-effective (cancers, cardiovascular diseases, and tuberculosis) and economic models were evaluated from multiple perspectives, different cost categories and time horizons. Additionally, most studies used a single gene, rather than a gene panel for the pharmacogenomics testing. Genotyping cost and frequency of risk alleles in the populations influence the cost-effectiveness outcome. Further studies are warranted to examine the clinical and economic validity of pharmacogenomics testing in the developing countries.
Topics: Cardiovascular Diseases; Cost-Benefit Analysis; Developing Countries; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35319010
DOI: 10.1038/s41397-022-00272-w -
Pharmacogenomics Jan 2022Pharmacogenomic testing can indicate which drugs may have limited therapeutic action or lead to adverse effects, hence guiding rational and safe prescribing. However,... (Meta-Analysis)
Meta-Analysis
Pharmacogenomic testing can indicate which drugs may have limited therapeutic action or lead to adverse effects, hence guiding rational and safe prescribing. However, in the UK and other countries, there are still significant barriers to implementation of testing in primary care. This systematic review presents the barriers and enablers to the implementation of pharmacogenomics in primary care setting. MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched through to July 2020 for studies that reported primary qualitative data of primary care professionals and patient views. Following screening, data extraction and quality assessment, data synthesis was undertaken using meta-aggregation based on the theoretical domain's framework (TDF). Confidence in the synthesized findings relating to credibility and dependability was established using CONQual. Eligible papers were categorized into six TDF domains - knowledge; social and professional roles; behavioral regulation; beliefs and consequences; environmental context and resources; and social influences. From 1669 citations, eighteen eligible studies were identified across seven countries, with a sample size of 504 participants including both primary care professionals and patients. From the data, 15 synthesized statements, all with moderate CONQual rating emerged. These categories range from knowledge, awareness among Primary Care Physicians and patients, professional relationships, negative impact of PGx, belief that PGx can reduce adverse drug reactions, clinical evidence, cost-effectiveness, informatics, reporting issues and social issues. Through use of TDF, fifteen synthesized statements provide policymakers with valuable recommendations for the implementation of pharmacogenomics in primary care. In preparation, policymakers need to consider the introduction of effective educational strategies for both PCPs and patients to raise knowledge, awareness, and engagement. The actual introduction of PGx will require reorganization with decision support tools to aid use of PGx in primary care, with a clear delegation of roles and responsibilities between general professionals and pharmacists supplemented by a local pool of experts. Furthermore, policy makers need to address the cost effectiveness of pharmacogenomics and having appropriate infrastructure supporting testing and interpretation including informatic solutions for utilizing pharmacogenomic results.
Topics: Health Services Accessibility; Humans; Pharmacogenomic Testing; Primary Health Care
PubMed: 34911350
DOI: 10.2217/pgs-2021-0131 -
Journal of Personalized Medicine Jun 2022Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical...
Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager (Revman, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark) and R language and environment for statistical computing (version 4.1.0 for Windows, R Core Team, Vienna, Austria) software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05, p = 0.31). AA homozygotes had smaller improvements in parameters pertaining to lung functions (−0.14, 95%CI: −0.23 to −0.05, p = 0.002) in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) (−0.11, 95%CI: −0.14 to −0.08, p < 0.00001), but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response.
PubMed: 35887565
DOI: 10.3390/jpm12071068