Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients

Ammar, Helmi; Chadli, Zohra; Mhalla, Ahmed; Khouadja, S.; Hannachi, Ibtissem; Alshaikheid, Mohammed; Slama, Ahlem; Fredj, Nadia Ben; Fadhel, Najeh Ben; Romdhane, Haifa Ben; Chaabane, Amel; Boughattas, Naceur A.; Gaha, L.; Zarrouk, L.; Aouam, Karim

doi:10.1038/s41397-021-00231-x

Cited by 10 publications

(14 citation statements)

References 46 publications

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“…Ammar H et al, in their study using xxx Tunisian patients with SCZ, they revealed the benefits of genotyping the CYP1A2 gene and the use of therapeutic drug monitoring (TDM) to enhance the effectiveness and safety of Clozapine(31). This study found a significant association between the CYP1A21*_JF polymorphism and Clozapine metabolism, accounting for 24% of the variability in Clozapine concentration-to-dose ratio.…”

Section: Resultsmentioning

confidence: 99%

“…This study found a significant association between the CYP1A21*_JF polymorphism and Clozapine metabolism, accounting for 24% of the variability in Clozapine concentration-to-dose ratio. Moreover, the CYP1A2 −163C>A variant plays a crucial role in the variation of Clozapine exposure (31).…”

Section: Resultsmentioning

confidence: 99%

“…This study found a significant association between the CYP1A21* F polymorphism and Clozapine metabolism, accounting for 24% of the variability in Clozapine concentration-to-dose ratio. Moreover, the CYP1A2 -163C>A variant plays a crucial role in influencing the plasma levels of Clozapine [45]. In Algerian patients with SCZ, those who carry the ‘G’ allele for a gene that codes for the 5-HT2A receptor, one of the targeted receptors for antipsychotic drugs, showed a favourable response to conventional antipsychotics [46].…”

Section: Psychiatric Pharmacogenomics In African Populationsmentioning

confidence: 99%

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Pharmacogenomic Diversity in Psychiatry: Challenges and Opportunities in Africa

Ahmed,

Mulugeta,

Okewole

et al. 2024

Preprint

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Background: Pharmacogenomic studies on psychiatric drugs have slowly identified genetic variations that influence drug metabolism and treatment effectiveness in patients with mental illness. Because most of these studies predominantly centered on people of European descent, there remains a substantial knowledge gap on the clinical implications of current pharmacogenomic evidence in multi-ancestry populations such as Africans. Thus, whether pharmacogenomic (PGx) genetic testing implemented in European populations would be valid for a population of African origin is unknown. The objective of this review was to appraise previous psychiatric pharmacogenomic studies in Africa and highlight challenges and opportunities to initiate PGx testing in the region. Methods: A systematic literature search was conducted on PubMed, Scopus, and Web of Science to identify studies published in the English language from inception up to February 06, 2023. The primary outcomes were treatment response, remission, side effects, and drug metabolism in African psychiatric patients. Results: The review included 42 pharmacogenomic studies that explored the genetic profiles of psychiatric patients in Africa. Despite the limited number of studies, our review found strong evidence of pharmacogenomic diversity within the African populations, highlighting the importance of pharmacogenomic research in this population. A high degree of variability and differences in the frequencies of cytochrome P450 (CYPs) genotypes have been reported within the African population. It is estimated that 28% of North Africans and Ethiopians are ultrarapid metabolizers of several medications, mainly attributed to the increased activity of the CYP2D6 enzyme. This is significantly higher than the prevalence among Caucasians (10%), or Hispanics, Chinese, or Japanese populations (1%). Due to the defective CYP2C19*2 allele (at a frequency of 14%) and CYP2C19*3 allele (2% frequency), 5.2% of Ethiopians were identified as poor metabolizers of S-mephenytoin, a probe substrate used to assess the activity of the cytochrome P450 enzyme. In Tunisian patients with schizophrenia, genotyping the CYP1A2 gene and using therapeutic drug monitoring (TDM) improved the effectiveness and safety of clozapine. Among South African patients with schizophrenia, antipsychotic treatment response was associated with two gene variants (rs13025959 in the MYO7B gene with the C allele and rs10380 in the MTRR gene with the T allele). Conclusion: The review has identified evidence of pharmacogenomic diversity in African populations and recommended expanding pharmacogenomic studies while introducing PGx testing in this population. For the few characterized genes, Africans showed qualitative and quantitative differences in the profile of pharmacogenetic variants when compared to other ethnic groups. Limited research funding, inadequate infrastructure, and a shortage of skilled human resources might be a challenge, but by building upon local successes and through collaborations with international partners, it is possible to establish pharmacogenomic biobanks and leverage global genetic resources to initiate personalized treatment approaches in Africa. Keywords: Pharmacogenomics, Personalized medicine, Psychiatric disorders, Africa, Genetic variants, depression, schizophrenia

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Psychiatric Pharmacogenomics In African Populationsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenomic Diversity in Psychiatry: Challenges and Opportunities in Africa

Ahmed,

Mulugeta,

Okewole

et al. 2024

Preprint

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“…CYP1A2 and CYP2C19 activity scores were elevated and reduced in patients with clozapine resistance, respectively [ 100 ]. In addition, the CYP1A2*1F AA and AC genotypes [ 98 ], as well as the CYP2C19 *1/*17 genotype and *2 allele carriers [ 27 ] were at increased risk of developing clozapine resistance. The CYP1A2-163A allele was associated with clozapine resistance in smokers only [ 99 ].…”

Section: Resultsmentioning

confidence: 99%

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Ying

Chew

McIntyre

et al. 2023

Genes

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Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.

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“…Visually, most of the drugs induced acute changes in the brain activities as shown in their T ‐score BAMs. For example, clozapine, an antipsychotic drug, [ 31 ] robustly increased the neural activities in the forebrain, cerebellum and hindbrain; sertraline and fluoxetine, selective serotonin reuptake inhibitors, [ 32 ] both used as antidepressant drugs, resulted in increased calcium fluctuations in the forebrain and partials of the hindbrain but slightly silenced the activities elsewhere in the brain (Figure 4e ). To further extract the intrinsic coherence among all the T ‐score BAMs, we first applied principal component analysis (PCA) to reduce the dimensionality and noise (Figure S12 , Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Fish Capsules: A System for High‐Throughput Screening of Combinatorial Drugs

et al. 2022

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Large‐scale screening of molecules heavily relies on phenotyping of small living organisms during preclinical development. However, deep profiling candidate therapeutics on whole animals typically requires laborious manipulations and anesthetic treatment using traditional techniques or automated tools. Here, a novel fish capsule system that combines automated zebrafish encapsulating technology and droplet microarray strategy for in vivo functional screening of mono/polytherapies is described. This platform enables automated, rapid zebrafish orientation and immobilization in agarose to generate large‐scale fish capsules by using a microfluidic device. Based on the effect of discontinuous dewetting, the prompt trapping of fish capsules in the aqueous arrays is successfully demonstrate. This system provides the capability to integrate pharmaceutical treatments with real‐time multispectral microscopic imaging in a simple, pipetting‐free and highly parallel manner. Coupling with machine learning algorithms, a small library of compounds is screened and analyzed, and clues about how to exploit compound combinations as therapeutic candidates are obtained. It is believed that this proposed strategy can be readily applied to multiple fields and is especially useful in the exploration of combinatorial drugs with limited amounts of samples and resources to accelerate the identification of novel therapeutics for precision medicines.

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Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients

Cited by 10 publications

References 46 publications

Pharmacogenomic Diversity in Psychiatry: Challenges and Opportunities in Africa

Pharmacogenomic Diversity in Psychiatry: Challenges and Opportunities in Africa

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Fish Capsules: A System for High‐Throughput Screening of Combinatorial Drugs

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