Hypothalamic-pituitary-adrenal system, neurotrophic factors and clozapine response: association with FKBP5 and NTRK2 genes.
Clozapine is an atypical antipsychotic drug known as being more effective compared with traditional antipsychotics for patients with poor response or resistance to treatment. It has been demonstrated that clozapine modulates hypothalamic-pituitary-adrenal activity and affects central brain-derived neurotrophic factor levels, which could explain part of its therapeutic efficacy. In this study, we investigated the role of genes related to the hypothalamic-pituitary-adrenal axis (FKBP5 and NR3C1) and neurotrophic factors (BDNF and NTRK2) in clinical response to clozapine in 591 schizophrenia patients. We found significant allelic and genotype associations between FKBP5-rs1360780, NTRK2-rs1778929 and NTRK2-rs10465180 polymorphisms and clozapine response. The haplotypes composed of rs1360780-rs3777747-rs17542466-rs2766533 (FKBP5) and rs1619120-rs1778929-rs10465180 (NTRK2) were also nominally significant. Our results suggest that genetic variability in FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. Further studies are needed to clarify the involvement of these genes in clinical response to atypical antipsychotics.
aAnthropology Section, Department of Animal Biology, Faculty of Biology, University of Barcelona/Biomedicine Institute of the University of Barcelona (IBUB) bClinical Institute of Neuroscience, Hospital Clínic cDepartment of Psychiatry and Clinical Psychobiology, University of Barcelona dBiomedical Research Institute Agustí Pi i Sunyer (IDIBAPS) eTeaching and Research Foundation Mútua Terrassa, University Hospital Mútua Terrassa, Terrassa, Spain/Santa Creu i Sant Pau Hospital, Barcelona fCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain gOptimal Medicine Limited, London, UK.
Marina
M
Mitjans
Rosa
R
Catalán
Mireia
M
Vázquez
Alex
A
González-Rodríguez
Rafael
R
Penadés
Alexandre
A
Pons
Guillem
G
Massana
Janet
J
Munro
Maria J
MJ
Arranz
Bárbara
B
Arias
D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000009:adverse effects / Q000627:therapeutic use*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D010913:Pituitary-Adrenal System / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D020813:Receptor, trkB; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
D014150:Antipsychotic Agents; D003024:Clozapine; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C000591259:tropomyosin-related kinase-B, human