title: Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.
abstract: BACKGROUND
  Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life.
  
  
  METHODS
  Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s) and at least one benzodiazepine derivative for the last three months before inclusion.
  
  
  METHODS
  currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up.
  
  
  CONCLUSIONS
  The results from this trial will examine whether melatonin has a role in withdrawing long-term benzodiazepine administration in schizophrenia patients. This group of patients is difficult to treat and therefore often subject to polypharmacy which may play a role in the reduced life expectancy of patients compared to the background population. The results will also provide new information on the association of chronic benzodiazepine treatment with sleep, psychophysiology, cognition, social function, and quality of life. Knowledge of these important clinical aspects is lacking in this group of patients.
  
  
  BACKGROUND
  ClinicalTrials NCT01431092.
authors.affiliation: Center for Neuropsychiatric Schizophrenia Research (CNSR) & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), University of Copenhagen, Mental Health Centre Glostrup, Mental Health Services - Capital Region of Denmark, Glostrup, Denmark. lone.baandrup@regionh.dk
authors.forename: Lone
authors.initials: L
authors.lastname: Baandrup
authors.forename: Birgitte
authors.initials: B
authors.lastname: Fagerlund
authors.forename: Poul
authors.initials: P
authors.lastname: Jennum
authors.forename: Henrik
authors.initials: H
authors.lastname: Lublin
authors.forename: Jane L
authors.initials: JL
authors.lastname: Hansen
authors.forename: Per
authors.initials: P
authors.lastname: Winkel
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
authors.forename: Bob
authors.initials: B
authors.lastname: Oranje
authors.forename: Birte Y
authors.initials: BY
authors.lastname: Glenthoj
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011618:Psychotic Disorders / Q000188:drug therapy; D012559:Schizophrenia / Q000188:drug therapy*; D019966:Substance-Related Disorders / Q000517:prevention & control*
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D010919:Placebos; D001569:Benzodiazepines; D008550:Melatonin