-
Schizophrenia Research May 2024Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of... (Review)
Review
Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.
Topics: Humans; Schizophrenia; Pharmacogenetics; Genetic Testing; Genetic Counseling; Multifactorial Inheritance; Genetic Predisposition to Disease
PubMed: 37813777
DOI: 10.1016/j.schres.2023.09.042 -
Health Science Reports Jan 2024Pharmacists have been recognized as one of the most qualified healthcare professionals in the clinical implementation of pharmacogenomics, yet its widespread...
BACKGROUND AND AIMS
Pharmacists have been recognized as one of the most qualified healthcare professionals in the clinical implementation of pharmacogenomics, yet its widespread implementation in clinical pharmacy practice has remained limited. The review aims to systematically investigate knowledge, perceptions, and attitudes toward pharmacogenomics among pharmacists and pharmacy students to inform the future delivery of pharmacogenomics education programs.
METHODS
PubMed, MEDLINE, Embase, Scopus, and the International Pharmaceutical Abstracts were searched up to May 17, 2022. Studies were selected if they included data on pharmacists' or pharmacy students' knowledge, perception, or attitude about pharmacogenomics and were published in a peer-reviewed, English-language journal with full-text availability. Any published study not deemed original research was excluded. All included studies were critically appraised using the Center for Evidence-Based Management's critical appraisal tools. The data were descriptively analyzed and presented based on pharmacists' and pharmacy students' knowledge/awareness, perception/attitudes toward pharmacogenomic (PGx), confidence in using or interpreting PGx testing results, and their desire to get further PGx education or their most preferred method of further education.
RESULTS
A combined total of 12,430 pharmacists and pharmacy students from 26 countries are represented in the 52 included studies. Despite overwhelmingly positive attitudes and perceptions toward pharmacogenomics among pharmacists and pharmacy students, an overall lack of adequate knowledge and confidence was found. The review also found a strong desire for further pharmacogenomics education among pharmacists and pharmacy students.
CONCLUSION
Pharmacists and pharmacy students have positive perceptions and attitudes toward pharmacogenomics, which is hindered by a lack of knowledge and confidence. However, inadequate control for confounders, limited representativeness of the studied population or region, and small sample sizes diminish the generalizability of the review results. Knowledge and confidence could be improved through enhanced delivery of pharmacogenomic courses within the pharmacy curriculum and continuing education programs.
PubMed: 38274140
DOI: 10.1002/hsr2.1844 -
Frontiers in Oncology 2023
PubMed: 38260860
DOI: 10.3389/fonc.2023.1343395 -
Cancers Jul 2023Acute myeloid leukemia (AML) is a clonal hematopoietic disease that arises from chromosomal and genetic aberrations in myeloid precursor cells. AML is one of the most... (Review)
Review
Acute myeloid leukemia (AML) is a clonal hematopoietic disease that arises from chromosomal and genetic aberrations in myeloid precursor cells. AML is one of the most common types of acute leukemia in adults; however, it is relatively rare overall, comprising about 1% of all cancers. In the last decade or so, numerous genome-wide association studies (GWAS) have been conducted to screen between hundreds of thousands and millions of variants across many human genomes to discover genetic polymorphisms associated with a particular disease or phenotype. In oncology, GWAS has been performed in almost every commonly occurring cancer. Despite the increasing number of studies published regarding other malignancies, there is a paucity of GWAS studies for AML. In this review article, we will summarize the current status of GWAS in AML.
PubMed: 37509244
DOI: 10.3390/cancers15143583 -
Farmacia Hospitalaria : Organo Oficial... 2023Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the...
Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patients' genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories, and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor, and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adopted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children, and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.
Topics: Pregnancy; Child; Humans; Female; Aged; Precision Medicine; Pharmaceutical Services; Immunosuppressive Agents; Drug Interactions; Pharmacy
PubMed: 37598018
DOI: 10.1016/j.farma.2023.07.004 -
Farmacia Hospitalaria : Organo Oficial... 2023Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the...
Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patient's genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adpoted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.
Topics: Pregnancy; Child; Humans; Female; Aged; Precision Medicine; Pharmaceutical Services; Immunosuppressive Agents; Drug Interactions; Pharmacy
PubMed: 37248115
DOI: 10.1016/j.farma.2023.04.005 -
Pharmacogenetics and Genomics Sep 2023The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport...
OBJECTIVE
The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.
METHODS
We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.
RESULTS
We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P = 0.047).
CONCLUSION
The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Cytochrome P-450 CYP2C9; Fluvastatin; Pharmacogenetics; Simvastatin; Liver-Specific Organic Anion Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 37490620
DOI: 10.1097/FPC.0000000000000504 -
Critical Reviews in Clinical Laboratory... Mar 2024Great strides have been made in the past decade to lower barriers to clinical pharmacogenomics implementation. Nevertheless, PGx consultation prior to prescribing... (Review)
Review
Great strides have been made in the past decade to lower barriers to clinical pharmacogenomics implementation. Nevertheless, PGx consultation prior to prescribing therapeutics is not yet mainstream. This review addresses the current climate surrounding PGx implementation, focusing primarily on strategies for implementation at academic institutions, particularly at The University of Chicago, and provides an up-to-date guide of resources supporting the development of PGx programs. Remaining challenges and recent strategies for overcoming these challenges to implementation are discussed.
Topics: Humans; Precision Medicine; Pharmacogenetics
PubMed: 37776898
DOI: 10.1080/10408363.2023.2255279 -
The American Journal of Psychiatry Jul 2024In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments... (Review)
Review
OBJECTIVE
In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression.
METHODS
The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized.
RESULTS
Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results.
CONCLUSIONS
The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.
Topics: Humans; Pharmacogenetics; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder, Major; Depressive Disorder; Pharmacogenomic Testing
PubMed: 38685859
DOI: 10.1176/appi.ajp.20230657 -
Biomedicine & Pharmacotherapy =... Dec 2023Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and...
Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
Topics: Humans; Azathioprine; Pharmacogenetics; Immunosuppressive Agents; Genotype; Crohn Disease; Methyltransferases; Pyrophosphatases
PubMed: 37857254
DOI: 10.1016/j.biopha.2023.115706