PharmGKB summary

Mi, Huaiyu; Thomas, Paul D.; Ring, Huijun Z.; Jiang, Rong; Sangkuhl, Katrin; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e32833ee605

Cited by 13 publications

(2 citation statements)

References 97 publications

(111 reference statements)

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“…An additional consideration is that the allele frequencies of variants in DRD2 differ across populations, with the -141C Del variant known to be more common in persons of African Ancestry (up to approximately 60%), such as our patient [ 25 , 26 ]. While extensive differences in antipsychotic responsiveness are not usually observed across race groups, one previous study showed that the proportion of patients being prescribed antipsychotic dosages above the recommended range (300–1000 chlorpromazine equivalents) was 10% higher in African Americans compared to Caucasians ( p -value = 0.003).…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report

et al. 2017

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BackgroundGiven the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.Case presentationA 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient’s symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.ConclusionsWe report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report

et al. 2017

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“…The high-affinity antagonism of CPZ to dopaminergic D2 receptors determines not only the therapeutic effect, but also the development of EPS [7,8]. It also has anticholinergic and antihistaminergic effects: dry mouth; blurred vision; retention of urine; anxiety; tremor; weight gain; lowering blood pressure; dizziness [9]; hyperprolactinemia [10]. It causes a hypotensive effect, disrupt the intracardiac impulse conduction, lengthening the QT interval as adrenergic antagonist [11].…”

Section: Figure 1 2-chloro-10-[3-(dimethylamino) Propyl] Phenothiazine -Chlorpromazine Hydrochloride Formulamentioning

confidence: 99%

Pharmacogenetics of chlorpromazine and its role in the development of antipsychotic-induced parkinsonism

Vaiman

Novitsky

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2021

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Antipsychotics (AP) is a group of psychotropic drugs for the treatment of mental disorders, in particular schizophrenia. In the mid-1950s, the first AP was synthesized (known as chlorpromazine (CPZ)). This drug has revolutionized the treatment of psychotic disorders. This drug, in addition to the antipsychotic effect, caused severe adverse drug reactions in patients, in particular from the neurological system, such as AP-induced extrapyramidal syndrome (EPS) — chlorpromazine-in-duced parkinsonism (CPZ-IP). CPZ-IP characterized by the occurrence of motor disorders. CPZ-IP is as a result of damage to the basal ganglia and subcortical-thalamic connections. Drug-induced EPS is subdivided into primary and secondary. Among the primary EPS, drug-IP is the most common (the leading form of secondary parkinsonism). Pharmacogenetic markers of CPZ safety are being actively studied. Some pharmacogenetic markers of therapy safety have been established: single nucleotide variants/polymorphisms of candidate genes for dopaminergic receptors D2 and D3 (DRD2 (rs1799732 (-141C Ins/Del)), DRD3 (rs6280 (Ser9Gly)), laforine phosphatase (EPM2A (rs1415744 (C/T)).

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Databases in the area of pharmacogenetics

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In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field.

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PharmGKB summary

Cited by 13 publications

References 97 publications

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report

Pharmacogenetics of chlorpromazine and its role in the development of antipsychotic-induced parkinsonism

Databases in the area of pharmacogenetics

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