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      Pharmacogenetics and Gender Association with Psychotic Episodes on Nortriptyline Lower Doses: Patient Cases

      research-article
      Author(s): 1, 2 , * , 1
      Publication date (Electronic):
      Journal: ISRN Pharmaceutics
      Publisher: International Scholarly Research Network

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          Abstract

          The variation in individual responses to psychotropic drug treatment remains a critical problem in the management of psychotic disorders. Although most patients will experience remission, some patients may develop drug-induced adverse effects that may range from troublesome to life threatening. Antidepressants are freely prescribed by general practitioners, and there should be constant awareness in the medical community about possible serious side effects. We describe two cases of adverse drug reactions on low dosage treatment that led to extreme psychotic episodes as examples of the potential for dangerous side effects. The patients developed adverse reactions on the normal recommended dosage of nortriptyline, a tricyclics antidepressant (TCA). Both were females, with no history of antidepressant treatment, unsocial behaviour, nor any family history of psychosis, but both experienced severe psychiatric symptoms. Pharmacogenetic tests can easily be performed and interpreted according to the likelihood of adverse reactions and should be included in toxicity interpretation.

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          CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants.

          L Dianne Bradford (2002)
          Over 40 cytochrome P450 (CYP) 2D6 allelic variants have been discovered thus far. The alleles may be classified on the basis of the level of activity for which they encode CYP2D6 enzymes, into functional, non-functional and reduced function groups. CYP2D6 allele frequency is known to vary amongst racial/ethnic groups. Generally, for European Caucasians and their descendants, the functional group of alleles are predominant, with a frequency of 71%. Non-functional alleles represent 26% of the variability, mainly CYP2D6*4. In Asians and their close descendants, functional alleles represent only ~ 50% of the frequency of CYP2D6 alleles. Asians and Pacific Islanders have a high frequency (median = 41%) of a reduced function allele, CYP2D6*10, contributing to the population shift to the right of metabolic rates indicating slower metabolism. Information concerning Amerindians from North (Canada), Central and South America indicate comparatively low frequencies of CYP2D6*10, perhaps a "founders" effect. The frequency of functional alleles in Africans and African Americans is also about 50%. Both Africans and African Americans have reduced function alleles representing 35% of allele variation, mainly CYP2D6*17. African Americans, however, have more than twice the median frequency of nonfunctional alleles compared with Africans (14.5% vs 6.3%). Non-functional and reduced function alleles represent about 50% of allele frequency in Black populations but a much greater variety than carried in Asians. Since alleles which encode for no or reduced functioning clearly affect metabolic activity of drugs mediated by CYP2D6, studies are needed in populations in which these alleles play a major role in order to assure optimal dosing recommendations are based on empirical pharmacogenetics.
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            Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.

            D Marez, M. Legrand, N. Sabbagh … (1997)
            The polymorphic cytochrome P450 CYP2D6 is involved in the metabolism of various drugs of wide therapeutic use and is a presumed susceptibility factor for certain environmentally-induced diseases. Our aim was to define the mutations and alleles of the CYP2D6 gene and to evaluate their frequencies in the European population. Using polymerase chain reaction-single strand conformation polymorphism analysis, 672 unrelated subjects were screened for mutations in the 9 exons of the gene and their exon-intron boundaries. A total of 48 point mutations were identified, of which 29 were novel. Mutations 1749 G-->C, 2938 C-->T and 4268 G-->C represented 52.6%, 34.3% and 52.9% of the mutations in the total population, respectively. Of the eight detrimental mutations detected, the 1934 G-->A, the 1795 Tdel and the 2637 Adel accounted for 65.8%, 6.2% and 4.8% respectively, within the poor metabolizer subgroup. Fifty-three different alleles were characterized from the mutation pattern and by allele-specific sequencing. They are derived from three major alleles, namely the wild-type CYP2D6*1A, the functional CYP2D6*2 and the null CYP2D6*4A. Five allelic variants (CYP2D6*1A, *2, *2B, *4A and *5) account for about 87% of all alleles, while the remaining alleles occur with a frequency of 0.1%-2.7%. These data provide a solid basis for future epidemiological, clinical as well as interethnic studies of the CYP2D6 polymorphism and highlight that the described single strand conformation polymorphism method can be successfully used in designing such studies.
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              PM frequencies of major CYPs in Asians and Caucasians.

              Takaharu Mizutani (2015)
              Many administered drugs are first activated by phase I drug-metabolizing enzymes, such as cytochrome P450 (CYP), and then conjugated with ligands such as UDPGA, PAPS, and glutathione by phase II drug-metabolizing enzymes, and finally excreted by transporters. There are some defective activity mutants due to CYP polymorphisms. In these cases, drugs are not metabolized [poor metabolizer (PM)], the high drug levels in blood are maintained, and toxic effects appear in the patients. To clarify the ratio of PMs, in the general population, it is necessary to estimate the drug level to not only prevent toxic reactions, but also to provide more efficient drug therapies, according to their polymorphic information about CYPs. In Caucasians and Asians, PM and allele frequency levels of CYPs (CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are summarized from previous findings. In Caucasians, high PM ratios (7%) of CYP2D6 deriving from the high frequency of CYP2D6*4 and CYP2D6*5, and 2% CYP2C19 from CYP2C19*2, were found. Meanwhile, in Asians, high PM ratios (19%) of CYP2C19 from high frequencies of CYP2C19*2 and CYP2C19*3, and 2% to 4% CYP2A6 from CYP2A6*4, were found. In both populations, the PM frequencies of the CYP3A4 of major drug-metabolizing CYP and CYP2C9 were low.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ISRN Pharm
                Journal ID (publisher-id): PHARMACEUTICS
                Title: ISRN Pharmaceutics
                Publisher: International Scholarly Research Network
                ISSN (Print): 2090-6145
                ISSN (Electronic): 2090-6153
                Publication date (Print): 2011
                Publication date (Electronic): 20 July 2011
                Volume: 2011
                Electronic Location Identifier: 805983
                Affiliations
                1Diversity Health Institute, Western Sydney Local Health District, North Parramatta, NSW 2151, Australia
                2DHI Lab, ICPMR Building, Westmead Hospital, Level 2 Westmead, NSW 2145, Australia
                Author notes

                Academic Editors: E. Hassan, G. Lentini, and C. Saturnino

                Article
                DOI: 10.5402/2011/805983
                PMC ID: 3263719
                PubMed ID: 22389859
                SO-VID: 9b2a26fd-32a1-4c45-8439-be5f5f869ab5
                Copyright © Copyright © 2011 I. Piatkov and T. Jones.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 6 April 2011
                Date accepted : 20 May 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

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