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Gupta P, Muneshwar KN, Juganavar A, Shegekar T. Beyond the Asylum Walls: Tracing the Tapestry of Mental Health Interventions Across Eras and Cultures. Cureus 2023; 15:e48251. [PMID: 38054143 PMCID: PMC10694481 DOI: 10.7759/cureus.48251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 11/04/2023] [Indexed: 12/07/2023] Open
Abstract
This article offers an extensive review of the changing field of mental health therapies, charting a transformational path from traditional methods to modern breakthroughs and speculating on potential future developments. The story develops by investigating historical viewpoints while reflecting on the present and highlighting the lessons learned and their impact on contemporary practices. We have advanced from the stigmatized constraints of asylums to a paradigm that puts human rights, dignity, and individualized, culturally sensitive treatment first. Modern methods are much more varied and evidence-based, from cutting-edge technical advancements to evidence-based psychotherapies. The ethical considerations arising from the delicate balance of pharmacological therapies underline the responsibility of administering drugs that significantly affect mental health. Cultural factors become a pillar, highlighting how crucial cultural sensitivity is to promoting tolerance. By acknowledging how many facets of the human experience are interrelated, holistic methods help close the gap between the mind and body. Integrative medicine and alternative therapies represent a shift away from reductionist approaches and toward a holistic viewpoint. The delivery of mental health treatment is being reimagined by technological advancements, with virtual and digital environments opening up new access and support channels. These developments cut beyond regional boundaries, reinventing conventional therapy dynamics and paving the way for individualized therapies. Cultural concerns highlight the significance of cultural competency in navigating the complex mental health treatment system and adapting interventions to fit the particular requirements of various cultural contexts. With telepsychiatry, virtual reality, and artificial intelligence among the new technologies that promise to further revolutionize mental health therapies, the essay looks to the future. This review concludes by imagining a day when mental health is prioritized, therapies are available, and the diversity of human experience is valued. The path to a society that values, nurtures, and celebrates mental health continues.
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Affiliation(s)
- Prachi Gupta
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Komal N Muneshwar
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Anup Juganavar
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Tejas Shegekar
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Genetic association of the rs17782313 polymorphism with antipsychotic-induced weight gain. Psychopharmacology (Berl) 2023; 240:899-908. [PMID: 36757449 PMCID: PMC10006246 DOI: 10.1007/s00213-023-06331-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023]
Abstract
RATIONALE Weight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design. OBJECTIVE We therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain. METHODS Participants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included. RESULTS Within 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001). CONCLUSION Our results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.
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Muntané G, Vázquez-Bourgon J, Sada E, Martorell L, Papiol S, Bosch E, Navarro A, Crespo-Facorro B, Vilella E. Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis. Eur Psychiatry 2023; 66:e28. [PMID: 36852609 PMCID: PMC10044301 DOI: 10.1192/j.eurpsy.2023.9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to weight gain, its exact role is unknown. METHODS We assembled a population-based FEP cohort of 381 individuals that was split into a Training (n = 224) set and a Validation (n = 157) set to calculate the polygenic risk score (PRS) in a two-step process. In parallel, we obtained reference genome-wide association studies for body mass index (BMI) and schizophrenia (SCZ) to examine the pleiotropic landscape between the two traits. BMI PRSs were added to linear models that included sociodemographic and clinical variables to predict BMI increase (∆BMI) in the Validation set. RESULTS The results confirmed considerable shared genetic susceptibility for the two traits involving 449 near-independent genomic loci. The inclusion of BMI PRSs significantly improved the prediction of ∆BMI at 12 months after the onset of antipsychotic treatment by 49.4% compared to a clinical model. In addition, we demonstrated that the PRS containing pleiotropic information between BMI and SCZ predicted ∆BMI better at 3 (12.2%) and 12 months (53.2%). CONCLUSIONS We prove for the first time that genetic factors play a key role in determining ∆BMI during the FEP. This finding has important clinical implications for the early identification of individuals most vulnerable to weight gain and highlights the importance of examining genetic pleiotropy in the context of medically important comorbidities for predicting future outcomes.
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Affiliation(s)
- Gerard Muntané
- Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Institut de Biologia Evolutiva (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Javier Vázquez-Bourgon
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Psychiatry, University Hospital Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.,Departamento de Medicina y Psiquiatría, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
| | - Ester Sada
- Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Lourdes Martorell
- Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Sergi Papiol
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Psychiatry, Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University, Munich, Germany
| | - Elena Bosch
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Institut de Biologia Evolutiva (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
| | - Arcadi Navarro
- Institut de Biologia Evolutiva (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.,Barcelonaβeta Brain Research Center, Fundació Pasqual Maragall, Barcelona, Spain
| | - Benedicto Crespo-Facorro
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Psychiatry, Instituto de Biomedicina de Sevilla (IBiS), University Hospital Virgen del Rocío, Seville, Spain
| | - Elisabet Vilella
- Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain.,Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
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Wannasuphoprasit Y, Andersen SE, Arranz MJ, Catalan R, Jurgens G, Kloosterboer SM, Rasmussen HB, Bhat A, Irizar H, Koller D, Polimanti R, Wang B, Zartaloudi E, Austin-Zimmerman I, Bramon E. CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis. Front Psychol 2022; 12:768748. [PMID: 35185676 PMCID: PMC8850377 DOI: 10.3389/fpsyg.2021.768748] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Antipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment. METHODS We conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs). RESULTS Twelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = -0.07 (95%CI: -0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: -0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: -0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: -0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: -0.37 to 0.40, p = 0.94) and BMI = -0.08 (95%CI: -0.57 to 0.42, p = 0.77). CONCLUSION Our systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health.
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Affiliation(s)
| | | | - Maria J Arranz
- Fundació Docència I Recerca, Mútua Terrassa, Barcelona, Spain
- Barcelona Clinic Schizophrenia Unit, Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
| | - Rosa Catalan
- Barcelona Clinic Schizophrenia Unit, Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
- CIBERSAM, Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain
| | - Gesche Jurgens
- Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark
| | - Sanne Maartje Kloosterboer
- Department of Hospital Pharmacy and Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Henrik Berg Rasmussen
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Roskilde, Denmark
- Department of Science and Environment, Roskilde University Center, Roskilde, Denmark
| | - Anjali Bhat
- Division of Psychiatry, University College London, London, United Kingdom
| | - Haritz Irizar
- Division of Psychiatry, University College London, London, United Kingdom
| | - Dora Koller
- Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
| | - Renato Polimanti
- Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
| | - Baihan Wang
- Division of Psychiatry, University College London, London, United Kingdom
| | - Eirini Zartaloudi
- Division of Psychiatry, University College London, London, United Kingdom
| | - Isabelle Austin-Zimmerman
- Division of Psychiatry, University College London, London, United Kingdom
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Elvira Bramon
- Division of Psychiatry, University College London, London, United Kingdom
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- Institute of Cognitive Neuroscience, University College London, London, United Kingdom
- Camden and Islington NHS Foundation Trust, London, United Kingdom
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Dobrodeeva VS, Shnayder NA, Novitsky MA, Asadullin AR, Vaiman EE, Petrova MM, Limankin OV, Neznanov NG, Garganeeva NP, Nasyrova RF. Association of a Single-Nucleotide Variant rs11100494 of the NPY5R Gene with Antipsychotic-Induced Metabolic Disorders. Pharmaceutics 2022; 14:pharmaceutics14020222. [PMID: 35213955 PMCID: PMC8876767 DOI: 10.3390/pharmaceutics14020222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 11/29/2022] Open
Abstract
Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, histaminergic and cholinergic. Metabolic disorders are the most severe adverse drug reactions (ADRs) and lead to cardiovascular diseases with a high rate of mortality in patients with SSDs. Neuropeptide Y receptor Y5 (NPY5R) is known in the chain of interaction to target receptors for APs, agouti-related peptide receptors and proopiomelanocortin receptors. We studied the association of the single-nucleotide variants (SNVs) rs11100494 and rs6837793 of the NPY5R gene, and rs16147, rs5573, rs5574 of the NPY gene, with metabolic disorders in Russian patients with SSDs. Methods: We examined 99 patients with SSDs (mean age—24.56 years old). The mean duration of APs monotherapy was 8 weeks. The biochemical blood test included levels of glucose, cholesterol, lipoproteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin. Anthropometry included weight, height, waist circumference and hip circumference. We used real-time PCR to study the carriage of major and minor alleles of the SNV rs11100494 (1164C>A) of the NPY5R gene (chromosome localization—4q32.2). Group 1 comprised 25 patients with SSDs taking APs with a change in body weight of more than 6% since the start of APs therapy. Group 2 comprised 74 patients with SSDs taking APs with a change in body weight of less than 6% since the start of APs therapy. Results: We show the significance of genetic risk factors (carriage of major allele C of SNV rs11100494 of the NPY5R gene) for the development of AP-induced weight gain in Russian patients with SSDs. The allele C predisposes to AP-induced weight gain (OR = 33.48 [95% CI: 12.62; 88.82], p-value < 0.001). Additionally, the results of our study demonstrate that first-generation APs (FGAs) are more likely to cause an increase in serum transaminase levels but are less likely to increase body weight. Second-generation APs (SGAs) are more likely to cause weight gain and changes in serum glucose levels. Conclusion: Our study shows the predictive role of the allele C of SNV rs11100494 of the NPY5R gene in the development of AP-induced weight gain. However, we did not find a significant association between biochemical markers and this SNV in Russian patients with SSDs.
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Affiliation(s)
- Vera S. Dobrodeeva
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
- Correspondence: (V.S.D.); (N.A.S.); (R.F.N.); Tel.: +7-(812)-620-02-20-78-13 (V.S.D., N.A.S. & R.F.N.)
| | - Natalia A. Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia;
- Correspondence: (V.S.D.); (N.A.S.); (R.F.N.); Tel.: +7-(812)-620-02-20-78-13 (V.S.D., N.A.S. & R.F.N.)
| | - Maxim A. Novitsky
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
| | - Azat R. Asadullin
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
- Department of Psychiatry and Addiction, Bashkir State Medical University, 450008 Ufa, Russia
| | - Elena E. Vaiman
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
| | - Marina M. Petrova
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia;
| | - Oleg V. Limankin
- P.P. Kashchenko Saint Petersburg Psychiatric Hospital No. 1, Gatchinsky District, 190005 Leningrad, Russia;
- Department of Psychotherapy and Sexology, I.I. Mechnikov North-Western State University, 191015 Saint Petersburg, Russia
- Saint Petersburg Postgraduate Institute of Medical Experts, 194044 Saint Petersburg, Russia
| | - Nikolay G. Neznanov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
- Department of Psychiatry and Addiction, I.M. Pavlov First Saint Petersburg State Medical University, 197022 Saint Petersburg, Russia
| | - Natalia P. Garganeeva
- Department of General Medical Practice and Polyclinic Therapy, Siberian State Medical University, 634050 Tomsk, Russia;
| | - Regina F. Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (M.A.N.); (A.R.A.); (E.E.V.); (N.G.N.)
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443099 Samara, Russia
- Correspondence: (V.S.D.); (N.A.S.); (R.F.N.); Tel.: +7-(812)-620-02-20-78-13 (V.S.D., N.A.S. & R.F.N.)
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Asadi M, Amoli M, Ansari Y, Far I, Pashaie N, Noroozi N. Association study of Melanocortin-4 Receptor (rs17782313) and PKHD1 (rs2784243) variations and early incidence of obesity at the age of maturity. ADVANCES IN HUMAN BIOLOGY 2022. [DOI: 10.4103/aihb.aihb_160_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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7
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Docherty JR, Alsufyani HA. Pharmacology of Drugs Used as Stimulants. J Clin Pharmacol 2021; 61 Suppl 2:S53-S69. [PMID: 34396557 DOI: 10.1002/jcph.1918] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/22/2021] [Indexed: 12/21/2022]
Abstract
Psychostimulant, cardiovascular, and temperature actions of stimulants involve adrenergic (norepinephrine), dopaminergic (dopamine), and serotonergic (serotonin) pathways. Stimulants such as amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 to inhibit reuptake of neurotransmitter or cause release by reverse transport. Stimulants may have additional effects involving pre- and postsynaptic/junctional receptors for norepinephrine, dopamine, and serotonin and other receptors. As a result, stimulants may have a wide range of possible actions. Agents with cocaine or MDMA-like actions can induce serious and potentially fatal adverse events via thermodysregulatory, cardiovascular, or other mechanisms. MDMA-like stimulants may cause hyperthermia that can be life threathening. Recreational users of stimulants should be aware of the dangers of hyperthermia in a rave/club environment.
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Affiliation(s)
| | - Hadeel A Alsufyani
- Department of Physiology, King Abdulaziz University, Jeddah, Saudi Arabia
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Su Y, Yan H, Guo L, Lu T, Zhang D, Yue W. Association of MTHFR C677T Polymorphism With Antipsychotic-Induced Change of Weight and Metabolism Index. Front Psychiatry 2021; 12:673715. [PMID: 34093281 PMCID: PMC8177429 DOI: 10.3389/fpsyt.2021.673715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 03/31/2021] [Indexed: 11/13/2022] Open
Abstract
Although antipsychotic medication contributed to the improvement of psychotic symptoms and reduced relapse, it induced weight gain and metabolic syndrome during antipsychotic medication treatment, which was seriously concerning. To investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism with antipsychotic-induced weight gain and metabolism parameter change, we employed 1,868 patients with schizophrenia in this study and randomly allocated them to seven antipsychotic medication treatment groups. All patients received antipsychotics monotherapy and were followed up for 6 weeks. Height, body weight, and metabolic parameters of the patients were measured at baseline and at 2, 4, and 6 weeks after antipsychotic treatment. We genotyped blood DNA from patients for MTHFR C677T polymorphisms and performed quantitative analyses using analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) among three genotype groups. We found a predominant association between MTHFR C677T and body weight mass index (BMI) change after 6-week risperidone treatment. After 6-week treatment of risperidone, the BMI change rate (%) of MTHFR C677 carriers was significantly higher than that of MTHFR TT genotype carriers [CC (2.81 ± 6.77)%, CT (3.79 ± 5.22)%, TT (1.42 ± 3.53)%, F = 4.749, P = 0.009]. Some of the abnormal metabolic parameters were found to be associated with the MTHFR 677T, including higher levels of low-density lipoprotein and waist circumference. Validation was performed in an independent cohort, consisting of 252 patients with schizophrenia treated with three atypical antipsychotic drugs. Overall, the MTHFR C677 was associated with high risk of antipsychotic-induced weight gain and metabolism abnormalities.
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Affiliation(s)
- Yi Su
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China
| | - Hao Yan
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China
| | - Liangkun Guo
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China
| | - Tianlan Lu
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China
| | | | - Dai Zhang
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.,Peking-Tsinghua Joint Center for Life Sciences, Peking University, Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.,Department of Translational Medicine Core, Chinese Institute for Brain Research, Beijing, China
| | - Weihua Yue
- Institute of Mental Health, Peking University Sixth Hospital, Beijing, China.,Key Laboratory of Mental Health, Ministry of Health and National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.,Department of Translational Medicine Core, Chinese Institute for Brain Research, Beijing, China
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9
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Genetic Profiles Playing Opposite Roles of Pathogenesis in Schizophrenia and Glioma. JOURNAL OF ONCOLOGY 2020; 2020:3656841. [PMID: 32565801 PMCID: PMC7275202 DOI: 10.1155/2020/3656841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/27/2020] [Indexed: 11/17/2022]
Abstract
Background Patients diagnosed with schizophrenia were found having lower risks to develop cancers, including glioma. Based on this epidemiology, we hypothesized that there were gene profiles playing opposite roles in pathogenesis of schizophrenia and glioma. Methods Based on GEO datasets and TCGA, key genes of schizophrenia genes on the opposite development of glioma were screened by different expressed genes (DEGs) screening, weighted gene coexpression network analysis (WGCNA), disease-specific survival (DSS), and glioma grading and verified by gene set enrichment analysis (GSEA). Results First, 612 DEGs were screened from schizophrenia and control brain samples. Second, 134 key genes more specific to schizophrenia were left by WGCNA, with 93 key genes having annotations in TCGA. Third, DSS of glioma helped to find 42 key gene expressions of schizophrenia oppositely associated with survival of glioma. Finally, 24 key genes showed opposite expression trends in schizophrenia and different glioma grading, i.e., the upregulated key genes in schizophrenia expressed increasingly in higher grade glioma, and vice versa. CAMK2D and MPC2 were taken as the examples and evaluated by GSEA, which indeed showed opposite trends in the same pathways of schizophrenia and glioma. Conclusion This workflow of selecting novel targeted genes which may have opposite roles in pathogenesis of two diseases was firstly and innovatively generated by our team. Some filtered key genes were indeed found by their potential effects in several mechanism studies, indicating our process could be effective to generate novel targeted genes. These 24 key genes may provide potential directions for future biochemical and pharmacotherapeutic research studies.
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ter Hark SE, Jamain S, Schijven D, Lin BD, Bakker MK, Boland-Auge A, Deleuze JF, Troudet R, Malhotra AK, Gülöksüz S, Vinkers CH, Ebdrup BH, Kahn RS, Leboyer M, Luykx JJ. A new genetic locus for antipsychotic-induced weight gain: A genome-wide study of first-episode psychosis patients using amisulpride (from the OPTiMiSE cohort). J Psychopharmacol 2020; 34:524-531. [PMID: 32126890 PMCID: PMC7222287 DOI: 10.1177/0269881120907972] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds. AIMS We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain. METHODS All subjects included for this genome-wide association study (n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment. RESULTS Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; β=1.05; p=3.66 × 10-08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (p=1.0 × 10-03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain. CONCLUSION Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.
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Affiliation(s)
- Sophie E ter Hark
- Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands
| | - Stéphane Jamain
- Psychiatrie Translationnelle, Inserm U955, Créteil, France,Faculté de Médecine, Université Paris Est, Créteil, France,Fondation FondaMental, Créteil, France
| | - Dick Schijven
- Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands
| | - Bochao D Lin
- Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands
| | - Mark K Bakker
- Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands
| | - Anne Boland-Auge
- Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, Evry, France
| | - Jean-François Deleuze
- Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, Evry, France
| | - Réjane Troudet
- Psychiatrie Translationnelle, Inserm U955, Créteil, France,Faculté de Médecine, Université Paris Est, Créteil, France,Fondation FondaMental, Créteil, France
| | - Anil K Malhotra
- The Zucker School of Medicine at Hofstra/Northwell, Hempstead, United States of America
| | - Sinan Gülöksüz
- Department of Psychiatry and Neuropsychology, School for Mental Health Neuroscience Maastricht University Medical Center, Maastricht, The Netherlands,Department of Psychiatry, Yale School of Medicine, New Haven, United States of America
| | - Christiaan H Vinkers
- Department of Psychiatry, Amsterdam UMC (location VUmc), Amsterdam, The Netherlands,Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Amsterdam, The Netherlands
| | - Bjørn H Ebdrup
- Centre for Neuropsychiatric Schizophrenia Research, Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - René S Kahn
- Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands,Department of Psychiatry, Icahn School of Medicine, Mount Sinai, United States of America
| | - Marion Leboyer
- Psychiatrie Translationnelle, Inserm U955, Créteil, France,Faculté de Médecine, Université Paris Est, Créteil, France,Fondation FondaMental, Créteil, France,AP-HP, DHU Pe-PSY, Pôle de Psychiatrie et d’addictologie des Hôpitaux universitaires Henri Mondor, Créteil, France
| | - Jurjen J Luykx
- Department of Translational Neuroscience, Utrecht University, Utrecht, The Netherlands,Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands,GGNet Mental Health, Apeldoorn, The Netherlands,Jurjen J Luykx, Departments of Translational Neuroscience and Psychiatry, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands.
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11
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Guan F, Zhang T, Han W, Zhu L, Ni T, Lin H, Liu D, Chen G, Xiao J, Li T. Relationship of SNAP25 variants with schizophrenia and antipsychotic-induced weight change in large-scale schizophrenia patients. Schizophr Res 2020; 215:250-255. [PMID: 31653583 DOI: 10.1016/j.schres.2019.09.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 05/19/2019] [Accepted: 09/23/2019] [Indexed: 01/16/2023]
Abstract
The SNAP25 gene is involved in the development of antipsychotic-induced weight gain (AIWG) or metabolic syndrome during antipsychotics use in Americans and Europeans, but its role in Asians remains unknown. To identify common variants in SNAP25 associated with schizophrenia and evaluate their effects on AIWG and antipsychotic responses in Han Chinese individuals with schizophrenia, we conducted a two-stage case-control study of 3,243 patients and 6,154 healthy controls. 2128 inpatients in the replication stage have received conventional treatment with an antipsychotic monotherapy (Haloperidol, Olanzapine or Risperidone) for 10 weeks at least. Weight change, antipsychotic responses and metabolic indices change were assessed during treatments. Three SNPs were significantly associated with schizophrenia in samples (rs6039769, P = 6.64 × 10-7; rs3787283, P = 0.004283; rs3746544, P = 2.51 × 10-6). Of these, rs6039769 is a novel schizophrenia-associated SNP and is uncorrelated with the other two variants, which have previously been associated with schizophrenia in European-ancestry samples. Rs6039769 was significantly associated with AIWG (P < 0.001), but not with antipsychotic responses or metabolic indices. Another two SNPs were not associated with AIWG or antipsychotic responses or metabolic indices. Overall, there were significant differences in antipsychotic responses and metabolic indices among the three treatment groups. Our findings suggest that SNAP25 gene may contribute to the susceptibility of AIWG and even metabolic disturbances. A prior identification of high-risk of patients with rs6039769 would contribute to a better precision of the pharmacological treatment.
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Affiliation(s)
- Fanglin Guan
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tianxiao Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Wei Han
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Li Zhu
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tong Ni
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Huali Lin
- Xi'an Mental Health Center, 15 Yanyin Road, Xi'an, Shaanxi, 710086, China
| | - Dan Liu
- Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Gang Chen
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Jing Xiao
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Tao Li
- Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China; Department of Forensic Pathology, School of Medicine & Forensics, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi, 710061, China.
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Zhuravleva EO, Vel’ts NY, Snegireva II, Kutekhova GV, Alyautdin RN. Pharmacogenetic Tests for Antipsychotic-Induced Weight Gain. Pharm Chem J 2019. [DOI: 10.1007/s11094-019-02059-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Tiwari AK, Zhang D, Pouget JG, Zai CC, Chowdhury NI, Brandl EJ, Qin L, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ. Impact of histamine receptors H1 and H3 polymorphisms on antipsychotic-induced weight gain. World J Biol Psychiatry 2019; 19:S97-S105. [PMID: 27855565 DOI: 10.1080/15622975.2016.1262061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG. METHODS We analysed 40 tagSNPs in HRH1 (n = 34) and HRH3 (n = 6) in schizophrenia/schizoaffective disorder patients (n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates. RESULTS In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (P = 0.043; β = 1.658; n = 77). We observed nominal association for two HRH1 SNPs rs346074 (P = 0.002; β = -5.024) and rs13064530 (P = 0.004; β = -5.158) in patients of African ancestry treated with either clozapine or olanzapine (n = 37). However, the above associations are not significant after correcting for multiple testing. In HRH3, we did not observe association in either ancestry. CONCLUSIONS The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.
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Affiliation(s)
- Arun K Tiwari
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,b Department of Psychiatry , University of Toronto , Toronto , ON , Canada
| | - Danning Zhang
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Jennie G Pouget
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,b Department of Psychiatry , University of Toronto , Toronto , ON , Canada
| | - Clement C Zai
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,b Department of Psychiatry , University of Toronto , Toronto , ON , Canada
| | - Nabilah I Chowdhury
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Eva J Brandl
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,c Department of Psychiatry and Psychotherapy , Campus Mitte, Charité Universitätsmedizin Berlin , Berlin , Germany
| | - Li Qin
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Natalie Freeman
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Jeffrey A Lieberman
- d Department of Psychiatry, College of Physicians and Surgeons , Columbia University and the New York State Psychiatric Institute , New York City , NY , USA
| | - Herbert Y Meltzer
- e Northwestern University Feinberg School of Medicine , Chicago , IL , USA
| | - James L Kennedy
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,b Department of Psychiatry , University of Toronto , Toronto , ON , Canada
| | - Daniel J Müller
- a Neurogenetics Section, Neuroscience Department , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada.,b Department of Psychiatry , University of Toronto , Toronto , ON , Canada
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Crespo-Facorro B, Prieto C, Sainz J. Altered gene expression in antipsychotic-induced weight gain. NPJ SCHIZOPHRENIA 2019; 5:7. [PMID: 30971689 PMCID: PMC6458173 DOI: 10.1038/s41537-019-0075-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 03/08/2019] [Indexed: 12/17/2022]
Abstract
Antipsychotic drugs are one of the largest types of prescribed drugs. However, antipsychotic-induced weight gain (AIWG) is a major problem for the patients. AIWG increases cardiovascular and cerebrovascular morbidity and mortality, and reduces quality of life and drug compliance. To characterize changes in gene expression related to AIWG, we sequenced total messenger RNA from the blood samples of two groups of schizophrenia patients before and after 3 months of treatment with antipsychotics. The "weight gain" group was defined by an increase of body mass index (BMI) >1.5 points (18 patients; median BMI increase = 2.69) and the "no weight gain" group was defined by a change of BMI between <1.0 and >-1.0 points (18 patients; median BMI increase = 0.26). We found 115 genes with significant differential expression in the weight gain group before and after medication and 156 in the no weight gain group before and after medication. The weight gain group was significantly enriched with genes related to "obesity" and "BMI" (Fisher; p = 0.0002 and 0.01, respectively) according to the Gene Reference into Function (GeneRIF) database. In the no weight gain group, the enrichment was much smaller (Fisher; p = 0.02 and 0.79). This study is a first step toward detecting genetic factors that cause AIWG and to generating prediction tests in future studies with larger data sets.
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Affiliation(s)
- Benedicto Crespo-Facorro
- Department of Psychiatry, School of Medicine, University Hospital Marqués de Valdecilla, IDIVAL, HU Virgen del Rocio-IBIS-Universidad de Sevilla, University of Cantabria, Santander, Spain. .,CIBERSAM - Centro Investigación Biomédica en Red Salud Mental, Santander, Spain.
| | - Carlos Prieto
- Bioinformatics Service, Nucleus, University of Salamanca (USAL), Salamanca, Spain
| | - Jesus Sainz
- Spanish National Research Council (CSIC), Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), Santander, Spain.
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Das S, Dey JK, Prabhu N, David S, Kumar A, Braganza D, Shanthi M. Retraction: Association Between 5‐HTR2C –759C/T (rs3813929) and –697G/C (rs518147) Gene Polymorphisms and Risperidone‐Induced Insulin Resistance Syndrome in an Indian Population. J Clin Pharmacol 2017; 58:399. [DOI: 10.1002/jcph.1012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain. Schizophr Res 2017; 187:67-73. [PMID: 28693754 PMCID: PMC5660917 DOI: 10.1016/j.schres.2017.06.046] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 01/09/2023]
Abstract
Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (<0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG.
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Pringsheim T, Kelly M, Urness D, Teehan M, Ismail Z, Gardner D. Physical Health and Drug Safety in Individuals with Schizophrenia. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2017; 62:673-683. [PMID: 28718324 PMCID: PMC5593246 DOI: 10.1177/0706743717719898] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND While antipsychotic medications are the mainstay of therapy for individuals with schizophrenia and psychotic disorders, their use is associated with adverse effects on physical health that require the attention and care of prescribers. METHODS We used the ADAPTE process to adapt existing guideline recommendations from the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the dosing of antipsychotics and antipsychotic polypharmacy, screening for adverse effects of antipsychotics, and management of metabolic and extrapyramidal side effects to the Canadian context. RESULTS Prescribers are encouraged to use the lowest effective dose and to avoid the routine use of multiple antipsychotics. Scheduled monitoring of body mass index, waist circumference, blood pressure, glucose, lipids, prolactin, electrocardiograms, and extrapyramidal symptoms is recommended. Lifestyle interventions are recommended to mitigate antipsychotic-induced weight gain. Prescribers should follow Canadian guidelines on the treatment of obesity, dyslipidemia, and diabetes. Recommendations on antipsychotic drug choice are made for users particularly concerned about extrapyramidal symptoms. CONCLUSION Careful monitoring and attention by prescribers may mitigate adverse effects associated with antipsychotic medications.
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Affiliation(s)
- Tamara Pringsheim
- 1 Department of Clinical Neurosciences, Psychiatry, Pediatrics and Community Health Sciences, University of Calgary, Calgary, Alberta
| | - Martina Kelly
- 2 Department of Family Medicine, University of Calgary, Alberta
| | - Doug Urness
- 3 Clinical Department Head, Addiction and Mental Health, Central Zone, Alberta Health Services, Edmonton, Alberta
| | - Michael Teehan
- 4 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia
| | - Zahinoor Ismail
- 5 Department of Psychiatry and Clinical Neurosciences, University of Calgary, Calgary, Alberta
| | - David Gardner
- 6 Department of Psychiatry and College of Pharmacy, Dalhousie University, Halifax, Nova Scotia
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Freyberg Z, Aslanoglou D, Shah R, Ballon JS. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia. Front Neurosci 2017; 11:432. [PMID: 28804444 PMCID: PMC5532378 DOI: 10.3389/fnins.2017.00432] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 07/13/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs) which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.
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Affiliation(s)
- Zachary Freyberg
- Department of Psychiatry, University of PittsburghPittsburgh, PA, United States
- Department of Cell Biology, University of PittsburghPittsburgh, PA, United States
| | - Despoina Aslanoglou
- Department of Psychiatry, University of PittsburghPittsburgh, PA, United States
| | - Ripal Shah
- Department of Psychiatry and Behavioral Sciences, Stanford UniversityStanford, CA, United States
| | - Jacob S. Ballon
- Department of Psychiatry and Behavioral Sciences, Stanford UniversityStanford, CA, United States
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Fjukstad KK, Engum A, Lydersen S, Dieset I, Steen NE, Andreassen OA, Spigset O. Metabolic risk factors in schizophrenia and bipolar disorder: The effect of comedication with selective serotonin reuptake inhibitors and antipsychotics. Eur Psychiatry 2017; 48:71-78. [PMID: 29331603 DOI: 10.1016/j.eurpsy.2017.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 03/30/2017] [Accepted: 04/01/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The aim of this observational study was to investigate the relationship between metabolic factors and use of selective serotonin reuptake inhibitors (SSRIs) combined with olanzapine, quetiapine or risperidone. METHODS Data from the Norwegian Thematically Organized Psychosis study, a cross-sectional study on 1301 patients with schizophrenia (n=868) or bipolar disorder (n=433), were analyzed. As exposure variables in the linear regression model were included the dose or serum concentration of SSRIs (n=280) and of olanzapine (n=398), quetiapine (n=234) or risperidone (n=128). The main outcome variables were levels of total cholesterol, low and high density lipoprotein (LDL and HDL) cholesterol, triglycerides and glucose. RESULTS One defined daily dose (DDD) per day of an SSRI in addition to olanzapine was associated with an increase in total cholesterol of 0.16 (CI 0.01 to 0.32) mmol/L (P=0.042) and an increase in LDL-cholesterol of 0.17 (CI 0.02 to 0.31) mmol/L (P=0.022). An SSRI serum concentration in the middle of the reference interval in addition to quetiapine was associated with an increase in total cholesterol of 0.39 (CI 0.10 to 0.68) mmol/L (P=0.011) and an increase in LDL-cholesterol of 0.29 (0.02 to 0.56) mmol/L (P=0.037). There were no such effects when combined with risperidone. CONCLUSIONS The findings indicate only minor deteriorations of metabolic variables associated with treatment with an SSRI in addition to olanzapine and quetiapine, and none when combined with risperidone. These results suggest that SSRIs can be used in combination with antipsychotics, and that the possible increase in cardiovascular risk is negligible.
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Affiliation(s)
- K K Fjukstad
- Department of Psychiatry, Nord-Trøndelag Hospital Trust, Levanger Hospital, Norway; Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
| | - A Engum
- Department of Psychiatry, St. Olav University Hospital, Trondheim, Norway
| | - S Lydersen
- Regional Centre for Child and Youth Mental Health and Child Welfare - Central Norway, Trondheim, Norway
| | - I Dieset
- NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - N Eiel Steen
- NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Drammen District Psychiatric Center, Clinic of Mental Health and Addiction, Vestre Viken Hospital Trust, Drammen, Norway
| | - O A Andreassen
- NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - O Spigset
- Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway
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Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease. ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS 2016; 2:121-130. [PMID: 29067299 PMCID: PMC5644277 DOI: 10.1016/j.trci.2016.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The use of antipsychotic medications in Alzheimer's disease has been associated with an increased risk of mortality in clinical trials. However, an older postmortem literature suggests that those with schizophrenia treated in an era of exclusively conventional antipsychotic medications had a surprisingly low incidence of tau pathology. No previously published studies have investigated the impact of conventional antipsychotic exposure on tau outcomes in a tau mouse model of AD. METHODS In two experiments, transgenic rTg (tauP301L) 4510 tau mice were treated with either haloperidol or vehicle and phosphotau epitopes were quantified using high-sensitivity tau ELISA. RESULTS After treatments of 2 and 6 week's duration, mice treated with haloperidol evidenced a significant reduction in tau phosphorylation associated with an inactivation of the tau kinase AMPK. DISCUSSION The data suggest that D2 receptor blockade reduces tau phosphorylation in vivo. Future studies are necessary to investigate the impact of this reduction on tau neuropathology.
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MacNeil RR, Müller DJ. Genetics of Common Antipsychotic-Induced Adverse Effects. MOLECULAR NEUROPSYCHIATRY 2016; 2:61-78. [PMID: 27606321 DOI: 10.1159/000445802] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 03/24/2016] [Indexed: 12/12/2022]
Abstract
The effectiveness of antipsychotic drugs is limited due to accompanying adverse effects which can pose considerable health risks and lead to patient noncompliance. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual susceptibility to antipsychotic-induced adverse effects (AAEs), thereby improving clinical outcomes. We reviewed the literature on the PGx of common AAEs from 2010 to 2015, placing emphasis on findings that have been independently replicated and which have additionally been listed to be of interest by PGx expert panels. Gene-drug associations meeting these criteria primarily pertain to metabolic dysregulation, extrapyramidal symptoms (EPS), and tardive dyskinesia (TD). Regarding metabolic dysregulation, results have reaffirmed HTR2C as a strong candidate with potential clinical utility, while MC4R and OGFR1 gene loci have emerged as new and promising biomarkers for the prediction of weight gain. As for EPS and TD, additional evidence has accumulated in support of an association with CYP2D6 metabolizer status. Furthermore, HSPG2 and DPP6 have been identified as candidate genes with the potential to predict differential susceptibility to TD. Overall, considerable progress has been made within the field of psychiatric PGx, with inroads toward the development of clinical tools that can mitigate AAEs. Going forward, studies placing a greater emphasis on multilocus effects will need to be conducted.
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Affiliation(s)
- Raymond R MacNeil
- Mood Research Laboratory, Department of Psychology, Queen's University, Kingston, Ont., Canada
| | - Daniel J Müller
- Departments of Psychiatry, University of Toronto, Toronto, Ont., Canada; Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Ont., Canada; Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada
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22
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Tiwari AK, Brandl EJ, Zai CC, Goncalves VF, Chowdhury NI, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ. Association of orexin receptor polymorphisms with antipsychotic-induced weight gain. World J Biol Psychiatry 2016; 17:221-9. [PMID: 26447462 DOI: 10.3109/15622975.2015.1076173] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. METHODS Schizophrenia or schizoaffective disorder subjects (n = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. RESULTS Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P = 0.043) and rs12662510 (P = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. CONCLUSION This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.
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Affiliation(s)
- Arun K Tiwari
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Eva J Brandl
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada .,b Department of Psychiatry and Psychotherapy, Campus Mitte , Charité Universitätsmedizin Berlin , Berlin , Germany
| | - Clement C Zai
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada .,c Department of Psychiatry , University of Toronto , Toronto , ON , Canada
| | - Vanessa F Goncalves
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Nabilah I Chowdhury
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Natalie Freeman
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Jeffrey A Lieberman
- d Department of Psychiatry, College of Physicians and Surgeons , Columbia University and the New York State Psychiatric Institute , New York City , NY , USA , and
| | - Herbert Y Meltzer
- e Department of Psychiatry and Behavioural Sciences , Northwestern University , Chicago , IL , USA
| | - James L Kennedy
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada
| | - Daniel J Müller
- a Pharmacogenetics Research Clinic, Neurogenetics Section , Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , Toronto , ON , Canada .,c Department of Psychiatry , University of Toronto , Toronto , ON , Canada
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Zai CC, Tiwari AK, Chowdhury NI, Brandl EJ, Shaikh SA, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ. Association Study of Serotonin 3 Receptor Subunit Gene Variants in Antipsychotic-Induced Weight Gain. Neuropsychobiology 2016; 74:169-175. [PMID: 28531893 PMCID: PMC5653224 DOI: 10.1159/000457903] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 01/18/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND Schizophrenia (SCZ) is a chronic severe neuropsychiatric disorder, where pharmacological treatment has been hindered by adverse effects, including antipsychotic-induced weight gain (AIWG) and related complications. Genetic studies have been exploring the appetite regulation and energy homeostasis pathways in AIWG with some promising leads. The serotonin system has been shown to participate in these pathways. METHODS In the current study, we examined single nucleotide polymorphisms across the serotonin receptor genes HTR3A and HTR3B. Prospective weight change was assessed for a total of 149 SCZ patients of European ancestry. RESULTS We did not find the tested HTR3A or HTR3B gene markers to be associated with AIWG in our sample. CONCLUSION Our preliminary findings suggest that these receptors may not play a major role in predicting AIWG.
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Affiliation(s)
- Clement C. Zai
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1S8, Canada,Laboratory Medicine and Pathobiology, University of Toronto, ON, M5T 1S8, Canada
| | - Arun K. Tiwari
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1S8, Canada
| | - Nabilah I. Chowdhury
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada
| | - Eva J. Brandl
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1S8, Canada,Department of Psychiatry and Psychotherapy, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Sajid A. Shaikh
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada
| | - Natalie Freeman
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada
| | - Jeffrey A. Lieberman
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York Presbyterian Hospital & Columbia University Medical Center, New York, NY, USA
| | - Herbert Y. Meltzer
- Dept Psychiatry & Beh Sci, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - James L. Kennedy
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1S8, Canada,Corresponding Authors: Dr. Daniel J. Müller; Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada, Tel: (416) 535-8501 ext. 36851; Fax: (416) 979-4666; . Dr. James L. Kennedy; Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, R31 250 college Street, Toronto, ON, M5T 1R8, Canada, Tel: (416) 979-4987; Fax: (416) 979-4666;
| | - Daniel J. Müller
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada,Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1S8, Canada,Corresponding Authors: Dr. Daniel J. Müller; Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada, Tel: (416) 535-8501 ext. 36851; Fax: (416) 979-4666; . Dr. James L. Kennedy; Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, R31 250 college Street, Toronto, ON, M5T 1R8, Canada, Tel: (416) 979-4987; Fax: (416) 979-4666;
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Matei VP, Mihailescu A, Paraschiv G, Al-Bataineh R, Purnichi T. WEIGHT GAIN AND ANTIPSYCHOTICS. DATA FROM EUFEST STUDY. ACTA ENDOCRINOLOGICA-BUCHAREST 2016; 12:177-184. [PMID: 31149084 DOI: 10.4183/aeb.2016.177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Context Schizophrenia is a chronic disease most frequently necessitating lifelong antipsychotic treatment. Selecting which antipsychotic is to be prescribed in an individual schizophrenia patient represents an important clinical decision that need to take into account efficacy and side effects. Objective Evaluating weight gain related with one year antipsychotic treatment in antipsychotic naive first-episode schizophrenia patients. Design This study is an analysis of weight gain associated with typical or atypical antipsychotics used in European First Episode Schizophrenia Trial (EUFEST) study. Subjects and Methods 113 first episode naïve antipsychotic schizophrenia patients included in EUFEST - Romanian cohort, who were randomized to one of the 5 treatment arms. Weight was obtained at baseline, 3, 6, 9 and 12 months for the 5 antipsychotics (typical-Haloperidol; atypical-Olanzapine, Amisulpride, Ziprasidone, Quetiapine). Results There are no statistically significant differences between groups treated with typical or atypical antipsychotics or between any individual antipsychotics concerning weight gain during the study. Weight gain was the highest in the first 3 months (57.49%) for all the studied neuroleptics. At the end of the study, the less increase was observed with ziprasidone (3.87 kg) and the highest with olanzapine (9.83 kg). Conclusion Increase in weight has taken place for each individual neuroleptic, but also as a group (all neuroleptics) in the first three months (57.49%). Therefore, we should address the issue of weight gain with great care, especially in first period of antipsychotic administration, in order to fast deploy intervention tailored to maintain pre-treatment weight.
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Affiliation(s)
- V P Matei
- "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - A Mihailescu
- "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - G Paraschiv
- University of Medicine and Pharmacy, Craiova, Psychiatry Department, Craiova, Romania
| | - R Al-Bataineh
- "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, Bucharest, Romania
| | - T Purnichi
- "Prof. Dr. Alexandru Obregia" Clinical Psychiatric Hospital, Bucharest, Romania
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Kobayashi Y, Kulikova SP, Shibato J, Rakwal R, Satoh H, Pinault D, Masuo Y. DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain. World J Biol Chem 2015; 6:389-408. [PMID: 26629322 PMCID: PMC4657125 DOI: 10.4331/wjbc.v6.i4.389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/20/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions.
METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis.
RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region.
CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report.
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Wang F, Mi W, Ma W, Ma C, Yang Y, Zhang H, Du B, Li K, Liu C, Wang L, Lu T, Zhang H, Lv L, Zhang D, Yue W. A pharmacogenomic study revealed an association between SLC6A4 and risperidone-induced weight gain in Chinese Han population. Pharmacogenomics 2015; 16:1943-9. [PMID: 26556226 DOI: 10.2217/pgs.15.133] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: We carried out a pharmacogenomic study in order to identify susceptible genes for antipsychotics induced weight gain within the Chinese Han population. Materials & methods: We enrolled 216 patients with schizophrenia in our study. All of them underwent risperidone monotherapy, and fulfilled 4-week follow-up. Weight gain was measured before treatment and 4 weeks later. Seven hundred and sixty-eight SNPs from 85 genes were calculated for association with weight gain percentage. Results: Fifty-seven SNPs located at 16 genes with a p-value less than 0.05.4 SNPs located on serotonin transporter gene (solute carrier family 6, member 4, SLC6A4) remained significant after multitest correction (rs3813034, p = 0.000357, q = 0.08, rs1042173, rs4325622, rs9303628, p = 0.000451, q = 0.08). Conclusion: SLC6A4 might be susceptible gene for risperidone-induced weight gain within the Chinese Han population.
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Affiliation(s)
- Fang Wang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
- Beijing Children’s Hospital, Capital Medical University, Beijing 100191, China
| | - Weifeng Mi
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Wenbin Ma
- Jinzhou Kangning Hospital, Jinzhou, Liaoning 121013, China
| | - Cuicui Ma
- Jinzhou Kangning Hospital, Jinzhou, Liaoning 121013, China
| | - Yongfeng Yang
- Department of Psychiatry of the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China
- Henan Mental Hospital, Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Hongxing Zhang
- Department of Psychiatry of the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China
- Henan Mental Hospital, Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Bo Du
- Hebei Mental Health Center, Baoding, Hebei 071000, China
| | - Keqing Li
- Hebei Mental Health Center, Baoding, Hebei 071000, China
| | - Chenxing Liu
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Lifang Wang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Tianlan Lu
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Hongyan Zhang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Luxian Lv
- Department of Psychiatry of the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453002, China
- Henan Mental Hospital, Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Dai Zhang
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
| | - Weihua Yue
- Peking University Sixth Hospital (Institute of Mental Health), Beijing 100191, China
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Health (Peking University), Beijing 100191, China
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Castellani CA, Melka MG, Diehl EJ, Laufer BI, O'Reilly RL, Singh SM. DNA methylation in psychosis: insights into etiology and treatment. Epigenomics 2015; 7:67-74. [PMID: 25687467 DOI: 10.2217/epi.14.66] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Evidence for involvement of DNA methylation in psychosis forms the focus of this perspective. Of interest are results from two independent sets of experiments including rats treated with antipsychotic drugs and monozygotic twins discordant for schizophrenia. The results show that DNA methylation is increased in rats treated with antipsychotic drugs, reflecting the global effect of the drugs. Some of these changes are also seen in affected schizophrenic twins that were treated with antipsychotics. The genes and pathways identified in the unrelated experiments are relevant to neurodevelopment and psychiatric disorders. The common cause is hypothesized to be aberrations resulting from medication use. However, this needs to be established by future studies that address the origin of methylation changes in psychosis.
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Dong L, Yan H, Huang X, Hu X, Yang Y, Ma C, Du B, Lu T, Jin C, Wang L, Yu H, Dong Z, Li W, Ruan Y, Zhang H, Zhang H, Mi W, Ma W, Li K, Lv L, Zhang D, Yue W. A2BP1 gene polymorphisms association with olanzapine-induced weight gain. Pharmacol Res 2015; 99:155-61. [DOI: 10.1016/j.phrs.2015.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 06/09/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
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Association study of GABAA α2 receptor subunit gene variants in antipsychotic-associated weight gain. J Clin Psychopharmacol 2015; 35:7-12. [PMID: 25514066 DOI: 10.1097/jcp.0000000000000261] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Schizophrenia treatment has been hampered by undesirable adverse effects, including weight gain and associated complications. Recent candidate gene studies have been exploring the appetite regulation pathways in antipsychotic-associated weight gain (AAWG) with some promising leads. Genome-wide association studies of obesity have pointed to a number of potential candidate genes, such as MC4R, that were later found to be shared with AAWG. GABAA α2 receptor subunit (GABRA2) was another potential candidate gene for obesity from genome-wide association studies; however, it has not been explored in AAWG. We examined 9 single nucleotide polymorphisms across the GABRA2 gene. Prospective weight change was assessed for a total of 160 schizophrenia patients of European ancestry. The rs279858 marker was associated with percent weight change, with the patients homozygous for the TT genotype experiencing higher percentage weight gain on average than the C allele carriers (P = 0.009). When we performed the analysis considering each clinical site using a meta-analytic method, the results remained statistically significant (P = 1.4e-4). These findings became even more significant when we considered only patients taking clozapine or olanzapine, the 2 medications with higher risk for weight gain (P < 1e-10). GABRA2 genetic variants may play a role in predicting AAWG. However, replication in larger and independent samples is required.
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Shams TA, Müller DJ. Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep 2014; 16:473. [PMID: 25138234 DOI: 10.1007/s11920-014-0473-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Antipsychotic-induced weight gain (AIWG) is a prevalent side effect of antipsychotic treatment, particularly with second generation antipsychotics, such as clozapine and olanzapine. At this point, there is virtually nothing that can be done to predict who will be affected by AIWG. However, hope for the future of prediction lies with genetic risk factors. Many genes have been studied for their association with AIWG with a variety of promising findings. This review will focus on genetic findings in the last year and will discuss the first epigenetic and biomarker findings as well. Although there are significant findings in many other genes, the most consistently replicated findings are in the melanocortin 4 receptor (MC4R), the serotonin 2C receptor (HTR2C), the leptin, the neuropeptide Y (NPY) and the cannabinoid receptor 1 (CNR1) genes. The study of genetic risk variants poses great promise in creating predictive tools for side effects such as AIWG.
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Affiliation(s)
- Tahireh A Shams
- Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada
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Ma X, Maimaitirexiati T, Zhang R, Gui X, Zhang W, Xu G, Hu G. HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. Int J Psychiatry Clin Pract 2014; 18:229-42. [PMID: 25152019 DOI: 10.3109/13651501.2014.957705] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients. METHODS Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). RESULTS Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients. CONCLUSIONS Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.
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Affiliation(s)
- Xiaojie Ma
- Department of Geriatrics, The Fourth People's Hospital of Urumqi City , Urumqi, Xinjiang Province , P. R. China
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Kao ACC, Müller DJ. Genetics of antipsychotic-induced weight gain: update and current perspectives. Pharmacogenomics 2014; 14:2067-83. [PMID: 24279860 DOI: 10.2217/pgs.13.207] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Antipsychotic medications are used to effectively treat various symptoms for different psychiatric conditions. Unfortunately, antipsychotic-induced weight gain (AIWG) is a common side effect that frequently results in obesity and secondary medical conditions. Twin and sibling studies have indicated that genetic factors are likely to be highly involved in AIWG. Over recent years, there has been considerable progress in this area, with several consistently replicated findings, as well as the identification of new genes and implicated pathways. Here, we will review the most recent genetic studies related to AIWG using the Medline database (PubMed) and Google Scholar. Among the steadiest findings associated with AIWG are serotonin 2C receptors (HTR2C) and leptin promoter gene variants, with more recent studies implicating MTHFR and, in particular, MC4R genes. Additional support was reported for the HRH1, BDNF, NPY, CNR1, GHRL, FTO and AMPK genes. Notably, some of the reported variants appear to have relatively large effect sizes. These findings have provided insights into the mechanisms involved in AIWG and will help to develop predictive genetic tests in the near future.
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Affiliation(s)
- Amy C C Kao
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, University of Toronto, Toronto, ON, Canada
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Gagliano SA, Tiwari AK, Freeman N, Lieberman JA, Meltzer HY, Kennedy JL, Knight J, Müller DJ. Protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene variants in antipsychotic-induced weight gain. Hum Psychopharmacol 2014; 29:330-5. [PMID: 24737441 DOI: 10.1002/hup.2407] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 03/13/2014] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients. METHODS DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine (N = 99). Linear regression based on an additive model was performed with the inclusion of relevant covariates. RESULTS Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing. CONCLUSIONS Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted.
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Affiliation(s)
- Sarah A Gagliano
- Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Kao ACC, Rojnic Kuzman M, Tiwari AK, Zivkovic MV, Chowdhury NI, Medved V, Kekin I, Zai CC, Lieberman JA, Meltzer HY, Bozina T, Bozina N, Kennedy JL, Sertic J, Müller DJ. Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances. J Psychiatr Res 2014; 54:36-42. [PMID: 24725652 DOI: 10.1016/j.jpsychires.2014.03.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 02/11/2014] [Accepted: 03/13/2014] [Indexed: 10/25/2022]
Abstract
Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.
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Affiliation(s)
- A C C Kao
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON, Canada
| | - M Rojnic Kuzman
- Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - A K Tiwari
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | | | - N I Chowdhury
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - V Medved
- Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - I Kekin
- Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - C C Zai
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - J A Lieberman
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA
| | - H Y Meltzer
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - T Bozina
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - N Bozina
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - J L Kennedy
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - J Sertic
- Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia
| | - D J Müller
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2014; 39:1347-54. [PMID: 24196945 PMCID: PMC3988538 DOI: 10.1038/npp.2013.312] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 10/08/2013] [Accepted: 10/22/2013] [Indexed: 01/07/2023]
Abstract
Mitochondria are the main source of energy for neurons and have a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mitochondrial genes, particularly those involved in oxidative phosphorylation or involved in oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis, would be associated with antipsychotic-induced weight gain (AIWG). In total, we selected 28 genes and analyzed 60 SNPs (50 are functional), in 283 schizophrenia subjects, treated with atypical medications for up to 14 weeks. Association between AIWG (as measured by the % of weight gain from baseline) and SNP genotypes were tested using linear regression with treatment duration, baseline body weight, and medication type as covariates. We observed a significant association between rs6435326 in the NDUFS1 gene and AIWG in the subset of European patients (N=150, Pcorrected=0.02). The haplotype carrying the risk alleles of rs6435326 and two other SNPs (rs1053517 and rs1801318) in NDUFS1 was also nominally associated with percentage of weight gain (T-C-G vs A-T-A, P=0.005). In addition, stepwise linear regression was performed to select important variables predictive of the outcome, and a gene-gene interaction analysis was carried out. We observed a significant interaction between the TT risk genotype of rs6435326 in NDUFS1 and AG genotype of rs3762883 in COX18 (Pcorrected=0.001). A permutation-based test of all 60 SNPs jointly showed significant association with weight gain (P=0.02). Finally, our replication study of rs6435326, rs1053517 and rs1801318 in NDUFS1 using samples from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that rs1801318 was significantly associated with AIWG (N=200, Pcorrected=0.04), and the three SNPs were collectively associated with AIWG (P=0.04). In conclusion, our findings suggest an association between NDUFS1 and AIWG in schizophrenia subjects. To the best of our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG.
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Brandl EJ, Tiwari AK, Chowdhury NI, Zai CC, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ. Genetic variation in the GCG and in the GLP1R genes and antipsychotic-induced weight gain. Pharmacogenomics 2014; 15:423-31. [DOI: 10.2217/pgs.13.247] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Aim: GLP-1 plays a key role in glucose metabolism and influences antipsychotic-induced weight gain (AIWG). Our study is the first to investigate the encoding gene, GCG, and the GLP-1 receptor gene, GLP1R, and association with AIWG. Materials & methods: In 216 schizophrenic patients treated with antipsychotics for up to 14 weeks, we investigated four GCG and 33 GLP1R polymorphisms. Statistical analyses were conducted using SPSS, Haploview 4.2, UNPHASED 3.1.4 and the R-package mbmdr. Results: We observed association of rs13429709 near GCG with AIWG (pcorr = 0.044) in patients of European ancestry receiving olanzapine or clozapine (n = 87). We also found significant gene–gene interaction between rs13429709 and rs2268639 in GLP1R. Only nonsignificant trends were observed for GLP1R polymorphisms with AIWG. Conclusion: We found significant association of rs13429709 with AIWG. Although there was no significant finding for GLP1R, the observed trends and interaction suggest this to be an interesting gene for further examination. Original submitted 17 October 2013; Revision submitted 11 December 2013
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Affiliation(s)
- Eva J Brandl
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Arun K Tiwari
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
| | - Nabilah I Chowdhury
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Clement C Zai
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Jeffrey A Lieberman
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University & the New York State Psychiatric Institute, New York City, NY, USA
| | - Herbert Y Meltzer
- Department of Psychiatry & Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - James L Kennedy
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Daniel J Müller
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health, Toronto, ON, Canada
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Brandl EJ, Kennedy JL, Müller DJ. Pharmacogenetics of antipsychotics. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2014; 59:76-88. [PMID: 24881126 PMCID: PMC4079237 DOI: 10.1177/070674371405900203] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. METHODS We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. RESULTS Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. CONCLUSION First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings.
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Affiliation(s)
- Eva J Brandl
- Postdoctoral Research Fellow, Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario
| | - James L Kennedy
- Head, Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario; Director, Neuroscience Research Department, Neuroscience Department, CAMH, Toronto, Ontario; l'Anson Professor of Psychiatry and Medical Science, University of Toronto, Toronto, Ontario
| | - Daniel J Müller
- Head, Pharmacogenetics Research Clinic, Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario; Associate Professor, University of Toronto, Toronto, Ontario
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Melka MG, Laufer BI, McDonald P, Castellani CA, Rajakumar N, O'Reilly R, Singh SM. The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum. Clin Epigenetics 2014; 6:1. [PMID: 24382160 PMCID: PMC3895844 DOI: 10.1186/1868-7083-6-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 12/04/2013] [Indexed: 12/23/2022] Open
Abstract
Background The mechanism of action of olanzapine in treating schizophrenia is not clear. This research reports the effects of a therapeutic equivalent treatment of olanzapine on DNA methylation in a rat model in vivo. Genome-wide DNA methylation was assessed using a MeDIP-chip analysis. All methylated DNA immunoprecipitation (MeDIP), sample labelling, hybridization and processing were performed by Arraystar Inc (Rockville, MD, USA). The identified gene promoters showing significant alterations to DNA methylation were then subjected to Ingenuity Pathway Analysis (Ingenuity System Inc, CA, USA). Results The results show that olanzapine causes an increase in methylation in 1,140, 1,294 and 1,313 genes and a decrease in methylation in 633, 565 and 532 genes in the hippocampus, cerebellum and liver, respectively. Most genes affected are tissue specific. Only 41 affected genes (approximately 3%) showed an increase and no gene showed a decrease in methylation in all three tissues. Further, the two brain regions shared 123 affected genes (approximately 10%). The affected genes are enriched in pathways affecting dopamine signalling, molecular transport, nervous system development and functions in the hippocampus; ephrin receptor signalling and synaptic long-term potentiation in the cerebellum; and tissue morphology, cellular assembly and organization in the liver. Also, the affected genes included those previously implicated in psychosis. Conclusions The known functions of affected genes suggest that the observed epigenetic changes may underlie the amelioration of symptoms as well as accounting for certain adverse effects including the metabolic syndrome. The results give insights into the mechanism of action of olanzapine, therapeutic effects and the side effects of antipsychotics.
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Affiliation(s)
| | | | | | | | | | | | - Shiva M Singh
- Molecular Genetics Unit, Department of Biology, The University of Western Ontario, London, ON N6A 5B7, Canada.
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Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison. SCHIZOPHRENIA RESEARCH AND TREATMENT 2014; 2014:758212. [PMID: 24772351 PMCID: PMC3977437 DOI: 10.1155/2014/758212] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/31/2014] [Accepted: 02/04/2014] [Indexed: 12/21/2022]
Abstract
We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil (n = 516) or aripiprazole (n = 162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (-2.8 ± 0.4 versus 0.4 ± 0.6; P < 0.001). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (-15.58 ± 1.58 versus -12.03 ± 0.99; P = 0.045). The incidences of SAEs (8.2% versus 3.1%; P = 0.032) and discontinuation due to AEs (16.2% versus 8.7%; P = 0.020) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.gov NCT01328093.
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Thompson MD, Cole DEC, Capra V, Siminovitch KA, Rovati GE, Burnham WM, Rana BK. Pharmacogenetics of the G protein-coupled receptors. Methods Mol Biol 2014; 1175:189-242. [PMID: 25150871 DOI: 10.1007/978-1-4939-0956-8_9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pharmacogenetics investigates the influence of genetic variants on physiological phenotypes related to drug response and disease, while pharmacogenomics takes a genome-wide approach to advancing this knowledge. Both play an important role in identifying responders and nonresponders to medication, avoiding adverse drug reactions, and optimizing drug dose for the individual. G protein-coupled receptors (GPCRs) are the primary target of therapeutic drugs and have been the focus of these studies. With the advance of genomic technologies, there has been a substantial increase in the inventory of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms and insertion or deletions that have potential to alter GPCR expression of function. In vivo and in vitro studies have determined functional roles for many GPCR variants, but genetic association studies that define the physiological impact of the majority of these common variants are still limited. Despite the breadth of pharmacogenetic data available, GPCR variants have not been included in drug labeling and are only occasionally considered in optimizing clinical use of GPCR-targeted agents. In this chapter, pharmacogenetic and genomic studies on GPCR variants are reviewed with respect to a subset of GPCR systems, including the adrenergic, calcium sensing, cysteinyl leukotriene, cannabinoid CB1 and CB2 receptors, and the de-orphanized receptors such as GPR55. The nature of the disruption to receptor function is discussed with respect to regulation of gene expression, expression on the cell surface (affected by receptor trafficking, dimerization, desensitization/downregulation), or perturbation of receptor function (altered ligand binding, G protein coupling, constitutive activity). The large body of experimental data generated on structure and function relationships and receptor-ligand interactions are being harnessed for the in silico functional prediction of naturally occurring GPCR variants. We provide information on online resources dedicated to GPCRs and present applications of publically available computational tools for pharmacogenetic studies of GPCRs. As the breadth of GPCR pharmacogenomic data becomes clearer, the opportunity for routine assessment of GPCR variants to predict disease risk, drug response, and potential adverse drug effects will become possible.
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Affiliation(s)
- Miles D Thompson
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8,
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del Castillo N, Zimmerman M B, Tyler B, Ellingrod VL, Calarge C. 759C/T Variants of the Serotonin (5-HT2C) Receptor Gene and Weight Gain in Children and Adolescents in Long-Term Risperidone Treatment. CLINICAL PHARMACOLOGY & BIOPHARMACEUTICS 2013; 2:110. [PMID: 24772381 PMCID: PMC3997261 DOI: 10.4172/2167-065x.1000110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Great inter-individual variability exists in the susceptibility to gain weight during antipsychotic treatment. Thus, we examined whether the -759C/T variants in the promoter region of the 5HT2C receptor gene were differentially associated with weight gain in children and adolescents in long-term risperidone treatment. METHODS Medically healthy 7 to 17 year-olds, treated with risperidone for ≥ six months, were enrolled. Anthropometric measurements, laboratory tests, and treatment history were obtained upon enrollment and from medical records. The effect of the genotype on the trajectory of age-sex-adjusted weight and body mass index (BMI) z scores before and after the onset of risperidone treatment was investigated. RESULTS In 124 subjects (90% males, mean age: 11.8 years) treated with risperidone for a mean of 2.8 years, weight and BMI z scores significantly increased after starting risperidone. This change was similar across the two genotype groups as were changes in several cardiometabolic variables. CONCLUSION In contrast to other reports, the T allele failed to confer protection against excessive weight gain or cardiometabolic abnormalities in this group of children and adolescents chronically treated with risperidone.
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Affiliation(s)
| | - Bridget Zimmerman M
- Department of Biostatistics, The University of Iowa College of Public Health, USA
| | - Billie Tyler
- Department of Psychiatry, University of Iowa, USA
| | - Vicki L Ellingrod
- Department of Clinical Social and Administrative Sciences, College of Pharmacy, Department of Psychiatry, School of Medicine, University of Michigan, USA
| | - Chadi Calarge
- Department of Psychiatry, The University of Iowa Carver College of Medicine, Psychiatry Research, USA
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Hu X, Zhang J, Jin C, Mi W, Wang F, Ma W, Ma C, Yang Y, Li W, Zhang H, Du B, Li K, Liu C, Wang L, Lu T, Zhang H, Lv L, Zhang D, Yue W. Association study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43:197-202. [PMID: 23306218 DOI: 10.1016/j.pnpbp.2012.12.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/19/2012] [Accepted: 12/11/2012] [Indexed: 12/30/2022]
Abstract
Recent researches have implicated that mutations in the neurexin-3 (NRXN3) gene on chromosome 14q24.3-q31.1 might play a role in addiction, autism, and obesity. In order to explore the association of NRXN3 polymorphisms with schizophrenia, we examined seven single nucleotide polymorphisms (SNPs) in NRXN3 spanning 1.33 Mb of this gene, in a Chinese Han sample of 1214 schizophrenic patients and 1517 healthy control subjects. Our results showed that three SNPs were associated with schizophrenia (rs7157669: A>C, p=0.006; rs724373: C>T, p=0.014; rs7154021: C>T, p=0.018). After being corrected for multiple tests, the association of rs7157669 remained significant but those for two others were modest. According to the linkage disequilibrium pattern, the 7 SNPs may construct 3 haplotype blocks. Several haplotypes were significantly associated with schizophrenia, constructed by rs11624704-rs7157669-rs724373 (AAC, p=0.003; ACT, p=0.007, both remained significant after permutation tests), rs7154021-rs7142344 (TT, p=0.024; CT, p=0.012), respectively. Among the patients, 326 ones at first onset have received 6-week monotherapy of risperidone. Further analyses showed that two SNPs were associated with percentage of bodyweight gain following a 6-week therapy of risperidone (rs11624704: p=0.03; rs7154021: p=0.008) and rs7154021 remained significant after permutation test. Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia and have a role in bodyweight gain related to therapy of risperidone in Chinese Han population.
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Affiliation(s)
- Xiaofeng Hu
- Institute of Mental Health, Peking University, Beijing 100191, China
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Rinella ES, Still C, Shao Y, Wood GC, Chu X, Salerno B, Gerhard GS, Ostrer H. Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery. J Clin Endocrinol Metab 2013; 98:E1131-6. [PMID: 23633212 PMCID: PMC3667258 DOI: 10.1210/jc.2012-3421] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss. OBJECTIVE Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery. DESIGN We conducted a genome-wide association study using a 2-stage phenotypic extreme study design. SETTING Patients were recruited from a comprehensive weight loss program at an integrated health system. PATIENTS Eighty-six obese (body mass index >35 kg/m(2)) patients who had the least percent excess body weight loss (%EBWL) and 89 patients who had the most %EBWL at 2 years after surgery were genotyped using Affymetrix version 6.0 single-nucleotide polymorphism (SNP) arrays. A second group from the same cohort consisting of 164 patients in the lower quartile of %EBWL and 169 from the upper quartile were selected for evaluation of candidate regions using custom SNP arrays. INTERVENTION We performed RYGB surgery. MAIN OUTCOME MEASURES We assessed %EBWL at 2 years after RYGB and SNPs. RESULTS We identified 111 SNPs in the first-stage analysis whose frequencies were significantly different between 2 phenotypic extremes of weight loss (allelic χ(2) test P < .0001). Linear regression of %EBWL at 2 years after surgery revealed 17 SNPs that approach P < .05 in the validation stage and cluster in or near several genes with potential biological relevance including PKHD1, HTR1A, NMBR, and IGF1R. CONCLUSIONS This is the first genome-wide association study of weight loss response to RYGB. Variation in weight loss outcomes after RYGB may be influenced by several common genetic variants.
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Affiliation(s)
- Erica S Rinella
- Department of Surgery, New York University Langone Medical Center, New York, New York 10016, USA
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Milano W, De Rosa M, Milano L, Capasso A. Antipsychotic drugs opposite to metabolic risk: neurotransmitters, neurohormonal and pharmacogenetic mechanisms underlying with weight gain and metabolic syndrome. Open Neurol J 2013; 7:23-31. [PMID: 23894259 PMCID: PMC3722531 DOI: 10.2174/1874205x01307010023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/15/2013] [Accepted: 03/20/2013] [Indexed: 12/16/2022] Open
Abstract
Important sources of metabolic diseases such as obesity and metabolic syndrome are significantly more prevalent in patients treated with antipsychotic drugs than the general population and they not only reduce the quality of life but also significantly reduce the life expectancy, being important risk factors for cardiovascular disease. The pathogenic mechanisms underlying these events are not entirely clear they are complex and multi-determined or not tied to a single defining event. In this review we examine the literature on the interactions of antipsychotic drugs with neurotransmitters in the brain, with pharmacogenetics hormones and peripheral mechanisms that may induce, albeit in different ways between different molecules, not only weight gain but also 'onset of major diseases such as diabetes, dyslipidemia and hypertension that are the basis of the metabolic syndrome. Today, the possible metabolic changes induced by various antipsychotic drugs and their major physical health consequences, are among the major concerns of clinicians and it is therefore necessary to monitor the main metabolic parameters to prevent or minimize any of these patients as well as the metabolism events associated with the use of antipsychotic drugs.
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Affiliation(s)
- Walter Milano
- Mental Health Unit- District 24 – ASL Napoli 1 Center, Italy
| | - Michele De Rosa
- Mental Health Unit- District 24 – ASL Napoli 1 Center, Italy
| | - Luca Milano
- Mental Health Unit- District 24 – ASL Napoli 1 Center, Italy
| | - Anna Capasso
- Department of Pharmacy, University of Salerno, Italy
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Ozomaro U, Wahlestedt C, Nemeroff CB. Personalized medicine in psychiatry: problems and promises. BMC Med 2013; 11:132. [PMID: 23680237 PMCID: PMC3668172 DOI: 10.1186/1741-7015-11-132] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 04/19/2013] [Indexed: 01/29/2023] Open
Abstract
The central theme of personalized medicine is the premise that an individual's unique physiologic characteristics play a significant role in both disease vulnerability and in response to specific therapies. The major goals of personalized medicine are therefore to predict an individual's susceptibility to developing an illness, achieve accurate diagnosis, and optimize the most efficient and favorable response to treatment. The goal of achieving personalized medicine in psychiatry is a laudable one, because its attainment should be associated with a marked reduction in morbidity and mortality. In this review, we summarize an illustrative selection of studies that are laying the foundation towards personalizing medicine in major depressive disorder, bipolar disorder, and schizophrenia. In addition, we present emerging applications that are likely to advance personalized medicine in psychiatry, with an emphasis on novel biomarkers and neuroimaging.
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Affiliation(s)
- Uzoezi Ozomaro
- University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Claes Wahlestedt
- University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA
- Center for Therapeutic Innovation, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Psychiatry and Behavioral Sciences, University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Charles B Nemeroff
- University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA
- Center for Therapeutic Innovation, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Psychiatry and Behavioral Sciences, University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA
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Isom AM, Gudelsky GA, Benoit SC, Richtand NM. Antipsychotic medications, glutamate, and cell death: A hidden, but common medication side effect? Med Hypotheses 2013; 80:252-8. [DOI: 10.1016/j.mehy.2012.11.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 11/27/2012] [Indexed: 12/25/2022]
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Guenette MD, Hahn M, Cohn TA, Teo C, Remington GJ. Atypical antipsychotics and diabetic ketoacidosis: a review. Psychopharmacology (Berl) 2013; 226:1-12. [PMID: 23344556 DOI: 10.1007/s00213-013-2982-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 12/19/2012] [Indexed: 11/24/2022]
Abstract
RATIONALE Atypical antipsychotics have been linked to weight gain and type 2 diabetes, but are also associated with diabetic ketoacidosis (DKA), which can occur more acutely and in the absence of weight gain. OBJECTIVES Our aim was to review current case reports of DKA in the context of atypical antipsychotic treatment to better understand (a) the scope of the problem, (b) its relationship to different atypical agents, (c) risk factors, (d) long-term outcome, and (e) putative mechanisms of action. METHOD Searches in PubMed/Medline, as well as the University of Toronto's Scholar Portal, were performed for all relevant articles/abstracts in English. RESULTS Sixty reports, yielding 69 cases, affirm that DKA is a rare but serious risk with almost all atypical antipsychotics; however, liability seems to vary between agents, at least partially mirroring risk of weight gain. Mean age of onset was 36.9 years (range 12-80), with 68 % of cases occurring in males, and 41 % in individuals of African American or African Caribbean descent. Over one third of cases present with either no weight gain or weight loss, and 61 % of these require ongoing treatment for glycemic control. Death occurred in 7.25 % of cases. CONCLUSION While the underlying mechanisms are not well understood, antipsychotic-related DKA can occur soon after treatment onset and in the absence of weight gain. Although rare, clinicians must remain vigilant given its acute onset and potential lethality.
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Affiliation(s)
- Melanie D Guenette
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Room 2374, Toronto, Ontario, Canada M5S 1A8
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Chronic olanzapine administration in rats: Effect of route of administration on weight, food intake and body composition. Pharmacol Biochem Behav 2013; 103:717-22. [DOI: 10.1016/j.pbb.2012.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 11/10/2012] [Accepted: 12/01/2012] [Indexed: 11/23/2022]
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Abstract
Weight gain is a frequent adverse effect of many second-generation antipsychotic (SGA) drugs. Although a number of candidate gene studies have focused on SGA-related weight gain, a clinical benefit for pharmacotherapy has not been achieved as yet. Genome-wide association studies offer great potential of identifying novel candidate genes and help to complete the search for relevant polygenetic risk factors. A polymorphism near the human melanocortin 4 receptor gene (MC4R) was associated with overweight and body mass index in recent studies. Owing to the central role of the MC4R receptor in energy homeostasis, we investigated the influence of the rs17782313 polymorphism on SGA-related weight gain. Three hundred forty-five white inpatients receiving different atypical antipsychotics (clozapine, olanzapine, risperidone, paliperidone, quetiapine, or amisulpride) were included in a naturalistic design. After 4 weeks of treatment, patients homozygous for the rs17782313 C-allele had a significantly higher risk of weight gain and body mass index increase, with a dose effect of the C-allele. In a subpopulation without additional weight gain-inducing comedication, the 106 TT-allele carriers gained on average 1.09% of their baseline weight within the 4 weeks of treatment, whereas the 57 CT-allele carriers and the 9 CC-allele carriers gained 3.28% and 5.47% (P = 0.003). Our findings indicate that the rs17782313 polymorphism could increase the amount of SGA-related weight gain and may influence MC4R expression, which could result in an imbalance of energy homeostasis. Nevertheless, further studies are needed to elucidate the role and mechanism of this polymorphism.
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Cai J, Yi Z, Lu W, Fang Y, Zhang C. Crosstalk between 5-HT2cR and PTEN signaling pathway in atypical antipsychotic-induced metabolic syndrome and cognitive dysfunction. Med Hypotheses 2013; 80:486-9. [PMID: 23375407 DOI: 10.1016/j.mehy.2013.01.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/05/2013] [Accepted: 01/09/2013] [Indexed: 12/27/2022]
Abstract
Accumulating evidence indicates that chronic treatment with atypical antipsychotics (AAPs) leads to metabolic syndrome (MetS) and cognitive dysfunction. It has been found that patients receiving antipsychotic treatment with MetS have significantly worse cognitive function when compared to those without the MetS, suggesting an intrinsic relationship between MetS and cognitive dysfunction. Thus, investigating the reasons for the side effects induced by AAPs is an important step in the effort to understand the patholophysiology of this condition. The 5-HT2c receptor (5-HT2cR) antagonist properties of AAPs are likely to contribute to AAP-induced MetS. There is crosstalk between phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and 5-HT2cR. PTEN negatively regulates the activity of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which plays an important role in obesity-induced insulin resistance in peripheral tissue. In the central nervous system, PI3K/AKT signaling modulates synaptic plasticity, a mechanism underlying learning and memory processes. This suggests that PI3K/AKT signaling contributes to both metabolic and cognitive activities. Since PTEN negatively regulates PI3K/AKT signaling and has crosstalk with 5-HT2cR, we hypothesized that the 5-HT2cR antagonism of AAPs may disrupt its crosstalk with PTEN and then trigger the PI3K/AKT signaling, and AAP-induced MetS and cognitive impairments may occur via this analogous signaling pathway.
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Affiliation(s)
- Jun Cai
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China
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