title: COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine.
abstract: OBJECTIVE
  Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems.
  
  
  METHODS
  107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively.
  
  
  RESULTS
  We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects.
  
  
  CONCLUSIONS
  The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.
authors.affiliation: Department of Clinical Neurosciences, I.R.C.C.S. San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Bosia
authors.forename: Cristina
authors.initials: C
authors.lastname: Lorenzi
authors.forename: Adele
authors.initials: A
authors.lastname: Pirovano
authors.forename: Carmelo
authors.initials: C
authors.lastname: Guglielmino
authors.forename: Federica
authors.initials: F
authors.lastname: Cocchi
authors.forename: Marco
authors.initials: M
authors.lastname: Spangaro
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Enrico
authors.initials: E
authors.lastname: Smeraldi
authors.forename: Roberto
authors.initials: R
authors.lastname: Cavallaro
mesh_terms: D000328:Adult; D054316:Biomarkers, Pharmacological; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D054316:Biomarkers, Pharmacological; D044282:Receptor, Serotonin, 5-HT1A; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D003024:Clozapine; D004298:Dopamine
keywords: PANSS; Positive and Negative Symptoms Scale; clozapine; genetic polymorphisms; negative symptoms; psychopharmacogenetics; psychosis; schizophrenia