The pharmacogenetics of antipsychotic-induced adverse events

Purpose of review Antipsychotic drugs are effective in alleviating a variety of symptoms and are medication of first choice in schizophrenia. However, a substantial interindividual variability in side effects often requires a lengthy ‘trial-and-error’ approach until the right medication is found for the right patient. Genetic factors have long been hypothesized to be involved and identification of related gene variants could be used to predict and tailor drug treatment. Recent findings This review highlighting the most recent genetic findings was conducted on the two most common and most well-studied side effects: antipsychotic-induced weight gain and tardive dyskinesia. Summary Regarding weight gain, most promising and most consistent findings were obtained in the serotonergic system (HTR2C) and with hypothalamic leptin–melanocortin genes, in particular with one variant close to the melanocortin-4-receptor (MC4R) gene. With respect to tardive dyskinesia, most interesting findings were generally obtained in genes related to the dopaminergic system (dopamine receptors D2 and D3), and more recently with glutamatergic system genes. Overall, genetic studies have been successful in identifying strong findings, in particular for antipsychotic-induced weight gain and to some extent for tardive dyskinesia. Apart from the need for replication studies in larger and well-characterized samples, the next challenge will be to create predictive algorithms that can be used for clinical practice.

[1]  J. Lieberman,et al.  Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene , 2012, The Pharmacogenomics Journal.

[2]  B. Lerer,et al.  Support for association of HSPG2 with tardive dyskinesia in Caucasian populations , 2011, The Pharmacogenomics Journal.

[3]  T. Kosten,et al.  Brain-Derived Neurotrophic Factor Levels and Its Val66Met Gene Polymorphism Predict Tardive Dyskinesia Treatment Response to Ginkgo Biloba , 2012, Biological Psychiatry.

[4]  J. Lieberman,et al.  The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain , 2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[5]  Annette Lee,et al.  Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. , 2012, Archives of general psychiatry.

[6]  S. Leucht,et al.  Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Pro12Ala , 2012, Molecular Diagnosis & Therapy.

[7]  J. Lieberman,et al.  Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain , 2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  Melissa A. Basford,et al.  Optimizing Drug Outcomes Through Pharmacogenetics: A Case for Preemptive Genotyping , 2012, Clinical pharmacology and therapeutics.

[9]  S. Djurovic,et al.  Genome-wide association study identifies genetic loci associated with body mass index and high density lipoprotein-cholesterol levels during psychopharmacological treatment — a cross-sectional naturalistic study , 2012, Psychiatry Research.

[10]  Young-Min Park,et al.  No Association between PAWR Gene Polymorphisms and Tardive Dyskinesia in Schizophrenia Patients , 2012, Psychiatry investigation.

[11]  C. V. van Duijn,et al.  Candidate Gene-Based Association Study of Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients: A Prospective Study , 2012, PloS one.

[12]  B. Wilffert,et al.  No involvement of the adenosine A2A receptor in tardive dyskinesia in Russian psychiatric inpatients from Siberia , 2012, Human psychopharmacology.

[13]  T. Kosten,et al.  Association between TNF-α promoter −308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia , 2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  J. Lieberman,et al.  Association study between variants of AMP-activated protein kinase catalytic and regulatory subunit genes with antipsychotic-induced weight gain. , 2012, Journal of psychiatric research.

[15]  S. Leucht,et al.  Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine. , 2012, Molecular diagnosis & therapy.

[16]  R. Brook,et al.  Risk Factors Associated With Metabolic Syndrome in Bipolar and Schizophrenia Subjects Treated With Antipsychotics: The Role of Folate Pharmacogenetics , 2012, Journal of clinical psychopharmacology.

[17]  Victoria Kay,et al.  Relaxin polymorphisms associated with metabolic disturbance in patients treated with antipsychotics , 2012, Journal of psychopharmacology.

[18]  J. Kennedy,et al.  Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications , 2012, Molecular Psychiatry.

[19]  Dai Zhang,et al.  Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients , 2012, Behavioral and Brain Functions.

[20]  T. Shinkai,et al.  Genetic association between the dopamine D3 receptor gene polymorphism (Ser9Gly) and tardive dyskinesia in patients with schizophrenia: A reevaluation in East Asian populations , 2012, Neuroscience Letters.

[21]  M. Freidin,et al.  NMDA receptor genotypes associated with the vulnerability to develop dyskinesia , 2012, Translational Psychiatry.

[22]  A. Devlin,et al.  Cardiometabolic risk and the MTHFR C677T variant in children treated with second-generation antipsychotics , 2012, Translational Psychiatry.

[23]  S. Tsai,et al.  TNF-α −308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment , 2011, Neuroscience Letters.

[24]  B. Lerer,et al.  Association of the ZFPM2 gene with antipsychotic-induced parkinsonism in schizophrenia patients , 2011, Psychopharmacology.

[25]  H. Snieder,et al.  Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients , 2011, Psychopharmacology.

[26]  C. Touma Stress and Affective Disorders: Animal Models Elucidating the Molecular Basis of Neuroendocrine-Behavior Interactions , 2011, Pharmacopsychiatry.

[27]  M. Arranz,et al.  Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia , 2011, Expert review of clinical pharmacology.

[28]  G. Remington,et al.  Genetics of Antipsychotic-induced Side Effects and Agranulocytosis , 2011, Current psychiatry reports.

[29]  J. Hebebrand,et al.  Association Study of Energy Homeostasis Genes and Antipsychotic-Induced Weight Gain in Patients with Schizophrenia , 2010, Pharmacopsychiatry.

[30]  Seung-Gul Kang,et al.  Genetics of tardive dyskinesia. , 2011, International review of neurobiology.

[31]  I. König,et al.  Risk for antipsychotic-induced extrapyramidal symptoms: influence of family history and genetic susceptibility , 2011, Psychopharmacology.

[32]  Lior Greenbaum,et al.  Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia , 2010, Movement disorders : official journal of the Movement Disorder Society.

[33]  T. Egberts,et al.  Combined HTR2C-LEP Genotype as a Determinant of Obesity in Patients Using Antipsychotic Medication , 2010, Journal of clinical psychopharmacology.

[34]  Louise Lantier,et al.  AMPK inhibition in health and disease , 2010, Critical reviews in biochemistry and molecular biology.

[35]  G. E. Callander,et al.  Relaxin family peptide systems and the central nervous system , 2010, Cellular and Molecular Life Sciences.

[36]  Vladimir I. Vladimirov,et al.  Genomewide Association Study of Movement-Related Adverse Antipsychotic Effects , 2010, Biological Psychiatry.

[37]  Norio Ozaki,et al.  Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia , 2010, Neuropsychopharmacology.

[38]  J. Lieberman,et al.  A candidate gene study of tardive dyskinesia in the CATIE schizophrenia trial , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[39]  C. Poole,et al.  The DRD3 rs6280 polymorphism and prevalence of tardive dyskinesia: A meta‐analysis , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[40]  K. Kanyas,et al.  Genome-wide association study of antipsychotic-induced parkinsonism severity among schizophrenia patients , 2009, Psychopharmacology.

[41]  T. Pollmächer,et al.  Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever , 2009, Psychoneuroendocrinology.

[42]  P. Greengard,et al.  Dichotomous Dopaminergic Control of Striatal Synaptic Plasticity , 2008, Science.

[43]  M. Koga,et al.  Pathway-based association analysis of genome-wide screening data suggest that genes associated with the &ggr;-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia , 2008, Pharmacogenetics and genomics.

[44]  J. Lieberman,et al.  Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients. , 2007, The international journal of neuropsychopharmacology.

[45]  G. Remington,et al.  Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients , 2007, Molecular Psychiatry.

[46]  Sang Ki Park,et al.  Par-4 Links Dopamine Signaling and Depression , 2005, Cell.

[47]  J. Auwerx,et al.  Role of peroxisome proliferator-activated receptor γ and retinoid X receptor heterodimer in hepatogastroenterological diseases , 2002, The Lancet.

[48]  Petra Verhoef,et al.  MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. , 2002, JAMA.

[49]  G. Reynolds,et al.  Association of antipsychotic druginduced weight gain with a 5-HT2C receptor gene polymorphism , 2002, The Lancet.

[50]  M. Rietschel,et al.  Familial occurrence of tardive dyskinesia. , 1998, Acta psychiatrica Scandinavica.

[51]  T. Pollmächer,et al.  Plasma levels of cytokines and soluble cytokine receptors during treatment with olanzapine. , 2000, Schizophrenia research.

[52]  T. Pollmächer,et al.  Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. , 1999, Journal of psychiatric research.

[53]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[54]  F. Youssef,et al.  Familial psychosis and vulnerability to tardive dyskinesia. , 1989, International clinical psychopharmacology.

[55]  R. Yassa,et al.  Familial tardive dyskinesia. , 1981, The American journal of psychiatry.