RESUMO
Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long-term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin-1, encoded by the dystrobrevin-binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three-marker haplotypes to be associated with TD occurrence and TD severity (p < 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin-1 may be an option in the prevention and treatment of TD.
Assuntos
Disbindina/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , MasculinoRESUMO
BACKGROUND: Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior. METHODS: Here, we review the literature on suicide epigenetics over the past 10 years. RESULTS: There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes. LIMITATIONS: Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide. CONCLUSIONS: It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.
Assuntos
Sistema Hipotálamo-Hipofisário , Suicídio , Epigênese Genética/genética , Epigenômica , Humanos , Sistema Hipófise-Suprarrenal , Fatores de Risco , Ideação SuicidaRESUMO
PURPOSE OF REVIEW: This review highlights recent advances in the investigation of genetic factors for antipsychotic response and side effects. RECENT FINDINGS: Antipsychotics prescribed to treat psychotic symptoms are variable in efficacy and propensity for causing side effects. The major side effects include tardive dyskinesia, antipsychotic-induced weight gain (AIWG), and clozapine-induced agranulocytosis (CIA). Several promising associations of polymorphisms in genes including HSPG2, CNR1, and DPP6 with tardive dyskinesia have been reported. In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia. Similarly, several consistent findings primarily from genes modulating energy homeostasis have also been reported (e.g. MC4R, HTR2C). CIA has been consistently associated with polymorphisms in the HLA genes (HLA-DQB1 and HLA-B). The association findings between glutamate system genes and antipsychotic response require additional replications. SUMMARY: The findings to date are promising and provide us a better understanding of the development of side effects and response to antipsychotics. However, more comprehensive investigations in large, well characterized samples will bring us closer to clinically actionable findings.
Assuntos
Antipsicóticos , Farmacogenética , Esquizofrenia , Antipsicóticos/efeitos adversos , Antipsicóticos/classificação , Antipsicóticos/farmacocinética , Resistência a Medicamentos/genética , Humanos , Farmacogenética/métodos , Farmacogenética/tendências , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/genética , Discinesia Tardia/prevenção & controle , Resultado do TratamentoRESUMO
Tardive dyskinesia (TD) is a potentially irreversible and often debilitating movement disorder secondary to chronic use of dopamine receptor blocking medications. Genetic factors have been implicated in the etiology of TD. We therefore have reviewed the most promising genes associated with TD, including DRD2, DRD3, VMAT2, HSPG2, HTR2A, HTR2C, and SOD2. In addition, we present evidence supporting a role for these genes from preclinical models of TD. The current understanding of the etiogenesis of TD is discussed in the light of the recent approvals of valbenazine and deutetrabenazine, VMAT2 inhibitors, for treating TD.
Assuntos
Discinesia Tardia/genética , Animais , Antipsicóticos/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , HumanosRESUMO
Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD.