title: Evidence for pretreatment LICI deficits among depressed children and adolescents with nonresponse to fluoxetine.
abstract: BACKGROUND
  Research suggests that alterations in gamma-aminobutyric acid receptor functioning have a role in depression. Paired-pulse transcranial magnetic stimulation (TMS) paradigms are noninvasive measures of cortical inhibitory and excitatory circuits.
  
  
  OBJECTIVE
  The present study examined pretreatment short-interval intracortical inhibition (SICI), long-interval cortical inhibition (LICI), and intracortical facilitation (ICF) in children and adolescents with major depressive disorder who were initiating fluoxetine treatment. The primary objective was to examine the relationship of these measures with subsequent treatment response. It was hypothesized that alterations in pretreatment GABA and glutamate mediated neurotransmission, would be associated with fluoxetine nonresponse.
  
  
  METHODS
  Sixteen children and adolescents with major depressive disorder underwent paired-pulse TMS testing before beginning fluoxetine treatment. Response was prospectively characterized by scores of 1 or 2 on the Clinical Global Impression Scale and less than 40 on the Children's Depression Rating Scale-Revised after 6 weeks of fluoxetine treatment (20-40 mg/day).
  
  
  RESULTS
  Eight patients responded to treatment. Least-squares mean LICI values were consistently higher bilaterally for treatment nonresponders. Higher LICI values indicate less inhibition and impaired GABAB functioning. There was no significant effect of treatment response on the measures of SICI and ICF.
  
  
  CONCLUSIONS
  Our findings suggest that deficits in pretreatment GABAB may be related to fluoxetine nonresponse in depressed youth. This is congruent with prior work demonstrating that GABAB interneurons have serotonergic input and antidepressants modulate GABAB receptors. These findings also show that TMS paradigms have utility in studying the neurophysiology and treatment of childhood mood disorders.
  
  
  BACKGROUND
  Cortical Excitability and Inhibition in Children and Adolescents With Major Depressive Disorder, http://www.clinicaltrials.gov/ct2/show/NCT00896090?term=cortical+excitability+and+inhibition&rank=2, NCT00896090; Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse, http://www.clinicaltrials.gov/ct2/show/NCT00612313?term=Sequential+Treatment+and+MDD&rank=1, NCT00612313.
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Electronic address: croarkin.paul@mayo.edu.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Croarkin
authors.affiliation: Department of Clinical Sciences, Division of Biostatistics, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nakonezny
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Husain
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Port
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Tabatha
authors.initials: T
authors.lastname: Melton
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Betsy D
authors.initials: BD
authors.lastname: Kennard
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Emslie
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA.
authors.forename: F Andrew
authors.initials: FA
authors.lastname: Kozel
authors.affiliation: Brain Stimulation Treatment and Research Unit, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
mesh_terms: D000293:Adolescent; D000928:Antidepressive Agents / Q000627:therapeutic use; D002648:Child; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000503:physiopathology / Q000628:therapy*; D019054:Evoked Potentials, Motor / Q000502:physiology*; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009044:Motor Cortex / Q000503:physiopathology*; D009433:Neural Inhibition / Q000502:physiology*; D019233:Retreatment; D050781:Transcranial Magnetic Stimulation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine
keywords: Adolescents; Depression; Fluoxetine; GABA; LICI