title: Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia.
abstract: BACKGROUND
  Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI in patients treated with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or are related to clozapine treatment.
  
  
  METHODS
  TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine.
  
  
  RESULTS
  CSP was significantly longer after 6 weeks of treatment with clozapine (p=0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p>0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p>0.05).
  
  
  CONCLUSIONS
  This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABAB mediated inhibitory neurotransmission. Potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia.
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Kaster
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Danilo
authors.initials: D
authors.lastname: de Jesus
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Radhu
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Faranak
authors.initials: F
authors.lastname: Farzan
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Blumberger
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tarek K
authors.initials: TK
authors.lastname: Rajji
authors.affiliation: Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Melbourne, Victoria, Australia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fitzgerald
authors.affiliation: Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D003024:Clozapine / Q000627:therapeutic use*; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000187:drug effects; D005260:Female; D018756:GABA Antagonists / Q000627:therapeutic use*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology*; D050781:Transcranial Magnetic Stimulation; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid; D003024:Clozapine
keywords: Clozapine; Cortical inhibition; GABA; Schizophrenia; Transcranial magnetic stimulation