title: Initial phase 2 trial of a nicotinic agonist in schizophrenia.
abstract: OBJECTIVE
  Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia.
  
  
  METHODS
  Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers.
  
  
  RESULTS
  There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A.
  
  
  CONCLUSIONS
  DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.
authors.affiliation: Department of Psychiatry, Denver VA Medical Center and University of Colorado, Denver, CO 80262, USA. Robert.Freedman@UCHSC.edu
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buchanan
authors.forename: Josette G
authors.initials: JG
authors.lastname: Harris
authors.forename: James M
authors.initials: JM
authors.lastname: Gold
authors.forename: Lynn
authors.initials: L
authors.lastname: Johnson
authors.forename: Diana
authors.initials: D
authors.lastname: Allensworth
authors.forename: Alejandrina
authors.initials: A
authors.lastname: Guzman-Bonilla
authors.forename: Bettye
authors.initials: B
authors.lastname: Clement
authors.forename: M Patricia
authors.initials: MP
authors.lastname: Ball
authors.forename: Jay
authors.initials: J
authors.lastname: Kutnick
authors.forename: Vicki
authors.initials: V
authors.lastname: Pender
authors.forename: Laura F
authors.initials: LF
authors.lastname: Martin
authors.forename: Karen E
authors.initials: KE
authors.lastname: Stevens
authors.forename: Brandie D
authors.initials: BD
authors.lastname: Wagner
authors.forename: Gary O
authors.initials: GO
authors.lastname: Zerbe
authors.forename: Ferenc
authors.initials: F
authors.lastname: Soti
authors.forename: William R
authors.initials: WR
authors.lastname: Kem
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010054:Brief Psychiatric Rating Scale; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011950:Receptors, Cholinergic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology; D012720:Severity of Illness Index
chemical_list: D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C088936:3-(2,4-dimethoxybenzylidene)anabaseine