South African Psychiatry - February 2019

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FEATURE Pharmacodynamic genes affect what the medication does to the body and alter the efficacy or side-effect profiles. A well-known example is the correlation between carbamazepine-induced Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and the HLA-B*1502 allele in some Asian populations. The correlation in some ethnicities is very high (odds ratio for developing carbamazepine-induced SJS/TEN if positive for HLA-B*1502 is 2504 in the Han Chinese). SJS or TEN conditions are life-threatening, which has led to the FDA recommendation that patients of Asian ancestry be assessed for this allele prior to the initiation of carbamazepine therapy. PHARMACOGENOMICS: SOME COMMON METHODOLOGIES There is an abundance of pharmacogenetic testing options. These vary in their validity, costs, positive and negative predictive values, turn-around-times and the clinical usefulness of the information. Selecting a particular methodology depends on what information is being sought. It is always advisable to discuss the options with the pathologist overseeing the assays, because the methodology is matched to the information required by the clinician. TRADITIONAL SANGER SEQUENCING Sanger sequencing is the ‘gold standard’ for detecting genetic variants. The method evaluates variations in PCR-amplified fragments with optimal sensitivity and specificity. While it has an excellent accuracy and reasonable read length it is unsuitable to study multiple targets. The technique involves DNA synthesis in the presence of chain-terminating inhibitors followed by capillary electrophoresis, hence the throughput can be time-consuming and labour intensive. The cost is generally very low and is ideal for examining a few genetic variants, especially when they are in close proximity to each other. REAL TIME PCR Real time PCR-based SNP genotyping assays allow the detection of single genetic polymorphisms that are associated with a particular drug metabolism phenotype. The assay is usually a single real time PCR reaction that discriminates alleles based on sequence-specific oligonucleotide probes that carry a fluorescent reporter dye for identification. The reaction either occurs or fails depending upon the allele being amplified. The assay is rapid (a few hours) but does not involve sequencing of a particular region. The assay is relatively cheap and there are several commercial pre-designed SNP genotyping assays from Roche, ThermoFisher, Applied Biosystems, and many others. NEXT GENERATION SEQUENCING (NGS) NGS refers to the large-scale DNA sequencing technology that follows a ‘sequencing-by-synthesis principle’ to generate data from the entire exome or genome. The advantage of NGS over sanger sequencing or single PCR assays, is the capacity for high throughput. NGS can generate millions to billions of nucleotide sequence data in a single experiment. It may, therefore, identify multiple variants in a single individual and is commonly used in the discovery of novel genetic variants that influence drug response. Due to the massive amounts of data generated, the skills required for analyses, the infrastructure and technology requirements, and the costs associated with these analyses can be prohibitive). THE SHEER SCALE OF THE DATA PRODUCED BY NGS IS FAR MORE THAN ROUTINE PATHOLOGISTS AND CLINICAL SCIENTISTS ARE EQUIPPED TO DEAL WITH. These sorts of assays, therefore, are usually more appropriate for research institutions. MATRIX-ASSISTED LASER DESORPTION/ IONIZATION TIME-OF-FLIGHT (MALDI- TOF) MASS SPECTROMETRY (MS) The MALDI-TOF MS technology is one of the methodologies that fills the gap between analyzing only a couple of variants by PCR or Sanger sequencing, and the huge amounts of data generated by NGS. This is clinically helpful, because clinicians often wish to have information concerning multiple variants (between five and several hundred), but not on the scale that NGS provides. Genetic variants are identified based on the differences in their molecular charge-mass ratios. PCR amplicons are generated that differ in their nucleotide sequences, which are identified by the time-of-flight of the molecules between two poles, rather than the sequencing of the fragments. The assay is as accurate and has the same positive and negative predictive values as the Sanger sequencing gold standard. The cost of the analysis is also comparable and there is currently at least one (Agena BioScience) commercially available product (Box 1). PHARMACOGENOMIC DATA In its most simplistic form, pharmacogenomic data are presented as the phenotype with the associated phenotype (for example, Table I). The patient’s genotype may be the allelic variant or a copy number variant and the corresponding phenotype listed as either poor, extensive or intermediate metabolizer of drugs. This, however, is only a very general approach and what is more typical is that the data are interpreted by the clinical scientist or pathologist with respect to a specific set of medications. 28 * SOUTH AFRICAN PSYCHIATRY ISSUE 18 2019
FEATURE Table II provides an example of a recommended psychiatric drug prescription panel based on pharmacogenetic data. Phenotype Genotype Poor metabolizer CYP2D6*3–*8, *11,*16, *18– *21, *38, *40, *42, *44, *56, *62 Extensive metabolizer Intermediate metabolizer CYP2D6*2, *17 x 2, *27, *35, *39, *48 CYP2D6*10, *14, *17, *18, *36, *41, *47, *49 – *51, *54, *55, *57 Table I Genotype-based phenotype classifications The traditional PGx nomenclature system describes each haplotype with a unique label comprising the name of the gene followed by the major (*) allele assignment based on the genetic variant identified. These haplotypes are then linked to a specific phenotype and can be categorized in several groups such as ‘Poor Metabolizer’ (PM), ‘Extensive Metabolizer’ (EM) or ‘Intermediate Metabolizer’ (IM) according to the enzyme’s functionality. The table illustrates the variant alleles and their classification for CYP2D6 variants. Used as directed Citalopram (Celexa) Desvenlafaxine (Pristiq) Escitalopram (Lexapro) Fluvoxamine (Luvox) Selegiline (Emsam) Sertraline (Zoloft) Use with caution Duloxetine (Cymbalta) Mirtazapine (Remeron) Trazodone (Desyrel) Use with great increased caution and with more frequent monitoring Amitriptyline (Elavil) Bupropion (Wellbutrin) Clomipramine (Anafranil) Desipramine (Norpramin) Fluoxetine (Prozac) Imipramine (Tofranil) Nortriptyline (Pamelor) Paroxetine (Paxil) Venlafaxine (Effexor) Table II Example of the recommended psychiatric drug usage An individual was identified with the genotype CYP2D6*4/*4 (poor metabolizer) and CYP2C19 1/*1 (extensive metabolizer). The recommendations associated with this combined genotype are listed. ARE THE PHARMACOGENOMIC DATA APPLICABLE IN SA, AND ARE THEY APPROPRIATE FOR PSYCHIATRISTS WORKING IN SA? We return to the question posed at the beginning of this article. There is no doubt that an individual’s genetic makeup is key to creating personalized drugs with greater efficacy and safety. The pharmacogenomic data published by reputable scientists and institutions are, of course, subject to the same peer review standards as any other scientific analyses. THEY ARE APPLICABLE. THE MORE IMPORTANT QUESTION, HOWEVER, IS HOW APPROPRIATE THEY ARE TO THE SOUTH AFRICAN CONTEXT. THIS IS THE CRUX OF THE MATTER. AS THINGS STAND, THERE IS UNFORTUNATELY NO SATISFACTORY ANSWER EXCEPT FOR THE ONE: “IT DEPENDS”. For example, the environment, diet, age, lifestyle, and state of health may all influence a person’s response to medicines. These factors are, in many instances, not comparable to the regions where the data were generated. In addition, even at the genetic level, the way a person responds to a drug (this includes both positive and negative reactions) is a complex trait that is influenced by many different genes and not just the typical analyses provided by the pharmacogenomic data. The complexity of the genotype-phenotype map was discussed in a previous issue (“Evolution and the molecular basis of psychiatric illness” Issue 5, November 2015). A good example of this is the association between carbamazepineinduced SJS/TEN and the HLA-B*1502 genotype alluded to above. In the Han Chinese the correlation is extremely strong (OR=2504), but the same genotype is not correlated with SJS or TEN in other Asian populations. In black South Africans, there is a dearth of information, although research institutions like the SBIMB (Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand), the Genomics Research Institute (University of Pretoria), and others have research programmes underway to address this gap in knowledge. AS WITH SO MANY ASPECTS OF HEALTH IN SA, DECISION-MAKING TRENDS DIFFER BETWEEN THE PRIVATE AND PUBLIC SECTORS. THESE DIFFERENCES MIRROR THE EXTREME INEQUALITY AMONG DIFFERENT POPULATION GROUPS IN SA. IN THE IDEAL SCENARIO, KNOWING THE INDIVIDUAL’S GENOTYPE IS SOMETIMES HELPFUL, BECAUSE IT MAY PROVIDE AN ADDITIONAL LAYER OF INFORMATION TO PATIENT MANAGEMENT. This is especially true if the individual is not responding as expected to a particular drug regimen. In other instances, there is simply not enough information and knowing an individual’s genotype may have no bearing whatsoever on current patient management. SOUTH AFRICAN PSYCHIATRY ISSUE 18 2019 * 29
Page 1 and 2: ISSN 2409-5699 ABOUT the discipline
Page 3 and 4: Features THE GLOBAL BURDEN 7 OF DIS
Page 5 and 6: FROM THE EDITOR Dear Reader, Welcom
Page 7 and 8: FEATURE THE GLOBAL BURDEN OF DISEAS
Page 9 and 10: FEATURE YEARS LIVED WITH DISABILITY
Page 11 and 12: FEATURE FACTORS AFFECTING BURDEN OF
Page 13 and 14: FEATURE Kristiansen CB, Munk-Jorgen
Page 15 and 16: Young Psychiatrist Leadership and P
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Page 25 and 26: FEATURE THE 2018 OXFORD DICTIONARY
Page 27: FEATURE PHARMACOGENOMIC T E S T I N
Page 31 and 32: Biological Psychiatry Congress 2019
Page 34 and 35: FEATURE THE CHALLENGES OF PERINATAL
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SASOP HEADLINE FEBRUARY 2019 EDITOR
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SASOP HEADLINE errors, as well as a
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South African Psychiatry - February 2019

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