Antipsychotic pharmacogenetics

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual's response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD...

CYP2D6 analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission...

BACKGROUND: Pharmacogenetic analyses can predict interpersonal differences in response to psychopharmacotherapy, which greatly facilitates the selection of the most effective medication at optimal doses. By personalizing therapy in this way, we can minimize adverse drug reactions (ADR) and prevent polypharmacy. Most psychotropic medications are metabolized by the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYPA3A4, which influence drug metabolism and concentration, affecting both efficacy and the occurrence of ADR...

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6 , especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few...

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a pre-clinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella dama- scena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apo- morphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climb- ing behaviours induced by dopaminergic agents...

BACKGROUND: Since being recognized as an important drug-induced clinical entity during the 1960s, tardive dyskinesia (TD) has generated an extensive body of research seeking to understand its clinical characteristics, epidemiology, pathophysiology and management. Modern scientometric approaches allow interactive visualization of large bodies of literature to identify trends and hotspots within knowledge domains. This study thus aimed to provide a comprehensive scientometric review of the TD literature...

Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population...

BACKGROUND: Despite its advantages over other antipsychotics, for treatment-resistant schizophrenia, clinical use of Clozapine (CLZ) is challenging by its narrow therapeutic index and potentially life-threatening dose-related adverse effects. RESEARCH DESIGN AND METHODS: As the potential role in CLZ metabolism is assigned to CYP1A2 enzyme and consequently Cytochrome P450 oxidoreductase (POR) their genetic variations might help to determine CLZ levels in schizophrenia patients...

Antipsychotic (AP)-induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms for the development of AP-induced ADRs is a genetically-determined impairment of AP efflux across the blood-brain barrier (BBB). We present a narrative review of publications in databases (PubMed, Springer, Scopus, Web of Science E-Library) and online resources: The Human Protein Atlas; GeneCards: The Human Gene Database; US National Library of Medicine; SNPedia; OMIM Online Mendelian Inheritance in Man; The PharmGKB...

Cariprazine (CAR) is an antipsychotic drug for the treatment of schizophrenia (SCZ) and bipolar disorder (BD), and it acts as a partial agonist on the dopamine receptors (DR), D2, and D3. Although many single nucleotide polymorphisms (SNPs) in genes coding for these receptors are known to influence response to antipsychotics, to date, no study on CAR pharmacogenetics exists. In this pilot study, we investigated the relationship between SNPs in DRD2 (rs1800497 and rs6277) and DRD3 (rs6280), and response to CAR treatment, evaluated by the psychometric Brief Psychiatric Rating Scale (BPRS), in a cohort of Caucasian patients...

BACKGROUND: Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking. AIM: The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care...

Given the polygenic nature of antipsychotic-induced weight gain (AIWG), we investigated whether polygenic risk scores (PRS) for various psychiatric and metabolic traits were associated with AIWG. We included individuals with schizophrenia (SCZ) of European ancestry from two cohorts (N = 151, age = 40.3 ± 11.8 and N = 138, age = 36.5 ± 10.8). We investigated associations of AIWG defined as binary and continuous variables with PRS calculated from genome-wide association studies of body mass index (BMI), coronary artery disease (CAD), fasting glucose, fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, type 1 and 2 diabetes mellitus, and SCZ, using regression models...

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine...

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients...

Huntington's disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease...

Antipsychotic-induced akathisia (AIA) is a movement disorder characterized by a subjective feeling of inner restlessness or nervousness with an irresistible urge to move, resulting in repetitive movements of the limbs and torso, while taking antipsychotics (APs). In recent years, there have been some associative genetic studies of the predisposition to the development of AIA. Objective : The goal of our study was to review the results of associative genetic and genome-wide studies and to systematize and update the knowledge on the genetic predictors of AIA in patients with schizophrenia (Sch)...

Pharmacokinetics varies widely between children. Many factors play an important role in this variability, such as ontogeny, pharmacogenetics, gender, comorbidities, and drug-drug interactions. Significant work has already been done in adults to understand the impact of genetic polymorphisms on drug-metabolizing enzyme activity and drug response. Data remain poor in children due to ontogeny that impacts genotyping-phenotyping correlation and the difficulty enrolling children in prospective studies. Our study aimed to describe the use of cytochromes P450 (CYP) phenotyping and/or genotyping tests in children in a real-life setting and assess the correlation between the genotype and the phenotype...

OBJECTIVES: Literature on ADHD has taken long strides recently as heaps of new data are pouring in through countless papers. Here, authors try to outline changing paradigms in ADHD practice. DSM-5 changes regarding the typology and diagnostic criteria are highlighted. Overview of co-morbidities, associations, developmental trajectories, and syndromic continuity across lifespan is outlined. Recent insights into aetiology and diagnostic tools are briefly discussed. New medications in the pipeline are also described...

Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i...

BACKGROUND: Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed. AIMS: To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if CYP2C19 and CYP2D6 genetic variation plays a role. METHODS: Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics...