Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

Abstract

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient’s genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.

Associations of HLA genetic variants with carbamazepine‐induced cutaneous adverse drug reactions: An updated meta‐analysis

“… 1 , 39 Further, the clinical efficacy and safety of CBZ may also be affected by the genetic polymorphisms of CYP3A4/5 , CYP2C8 , ABCB1 , etc., which were not considered in this analysis. 40 , 41 …”

“…Although the present analysis focused on and addressed nine HLA variants with CBZ‐induced cADRs, other potential HLA risk alleles (e.g., HLA‐B*57:01 , HLA‐Cw*08:01 , and HLA‐DRB1*12:02 ) were not included in this analysis which may increase the risk of developing cADRs for patients taking CBZ 1,39 . Further, the clinical efficacy and safety of CBZ may also be affected by the genetic polymorphisms of CYP3A4/5 , CYP2C8 , ABCB1 , etc., which were not considered in this analysis 40,41 …”

Mycotherapy: Potential of Fungal Bioactives for the Treatment of Mental Health Disorders and Morbidities of Chronic Pain

“…Mood disorders * Lithium Multiple mechanisms including modulation of (GABA)-ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellular signalling pathways [22,23] First-line treatment for prevention of manic and depressive episodes of bipolar disorder (BD) [24] Cardiac problems, cognitive problems, acne, psoriasis, thyroid problems, nausea, vomiting, weight gain, hyponatremia, sedation, decreased libido, and teratogenic [25] valproic acid First-line treatment for acute mania and maintenance of BD [26] Cardiac problems, cognitive problems, hair loss, hypothyroidism, aplastic anaemia, Leukopenia, increased transaminases, hepatitis, SLE-like syndrome, hyponatremia, tremor, decreased libido, infertility and teratogenic [25] Carbamazepine Effective as a monotherapy to treat manic symptoms of bipolar or as adjunct to lithium or valproic acid [27] Cardiac problems, cognitive problems, acne, hair loss, hypothyroidism, PCOS. diarrhoea, nausea, vomiting, pancreatitis, increased transaminases, metabolic syndrome, weight gain, sedation, tremor, decreased sexual function, infertility and teratogenic [25] Psychotic disorders First-generation antipsychotics (FGA) e.g., Chlorpromazine, haloperidol D2 antagonists: work by inhibiting dopaminergic neurotransmission [28] Effective in the treatment and maintenance of schizophrenia, acute mania with psychotic symptoms, major depressive order with psychotic features, and delusional disorder [28] Adverse (5-HT 2A/2C antagonism) receptors [31] Effective as an adjunctive therapy in treatment of AN, increasing appetite and decreasing anxiety and ruminating thoughts involving body image and food [32] Dizziness, orthostatic hypotension, hypercholesterolemia, hypertriglyceridemia, hyperglycaemia, weight gain, extra-pyramidal symptoms, dry mouth, hyperprolactinemia, and insomnia [32] Antidepressants(SSRIs, SNRIs, TCAs, MAOIs) Defined above…”

Pharmacogenetics in Primary Headache Disorders

“…The mechanism of action of CBZ is not well understood, but it has been suggested that it binds mainly to sodium channels and also interacts with calcium and potassium channels. CBZ is a positive allosteric modulator of GABA-A receptor ( Iannaccone et al, 2021 ). CBZ is almost entirely metabolized in the liver by epoxidation and hydroxylation ( Fricke-Galindo et al, 2018b ).…”