title: Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial.
abstract: BACKGROUND
  There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.
  
  
  METHODS
  Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.
  
  
  RESULTS
  In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms.
  
  
  CONCLUSIONS
  These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.
authors.affiliation: Department of Psychiatry, Helsinki University Central Hospital, University of Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Tiihonen
authors.forename: Tero
authors.initials: T
authors.lastname: Hallikainen
authors.forename: Olli-Pekka
authors.initials: OP
authors.lastname: Ryynänen
authors.forename: Eila
authors.initials: E
authors.lastname: Repo-Tiihonen
authors.forename: Irma
authors.initials: I
authors.lastname: Kotilainen
authors.forename: Markku
authors.initials: M
authors.lastname: Eronen
authors.forename: Päivi
authors.initials: P
authors.lastname: Toivonen
authors.forename: Kristian
authors.initials: K
authors.lastname: Wahlbeck
authors.forename: Anu
authors.initials: A
authors.lastname: Putkonen
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004351:Drug Resistance; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D014227:Triazines; D000077213:Lamotrigine