title: Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial.
abstract: BACKGROUND
  Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.
  
  
  METHODS
  Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.
  
  
  RESULTS
  A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.
  
  
  CONCLUSIONS
  Our data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.
  
  
  BACKGROUND
  ClinicalTrials NCT01431092 , clinicaltrials.gov. Registered 31 August 2011.
authors.affiliation: Center for Neuropsychiatric Schizophrenia Research (CNSR) & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Copenhagen University Hospital, Mental Health Center Glostrup, Mental Health Services-Capital Region of Denmark, DK-Glostrup, Denmark. lone.baandrup@regionh.dk.
authors.forename: Lone
authors.identifier: http://orcid.org/0000-0003-1662-2720
authors.initials: L
authors.lastname: Baandrup
authors.affiliation: Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, Section for Psychiatry, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Ole Bernt
authors.initials: OB
authors.lastname: Fasmer
authors.affiliation: Center for Neuropsychiatric Schizophrenia Research (CNSR) & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Copenhagen University Hospital, Mental Health Center Glostrup, Mental Health Services-Capital Region of Denmark, DK-Glostrup, Denmark.
authors.forename: Birte Yding
authors.initials: BY
authors.lastname: Glenthøj
authors.affiliation: Rigshospitalet, Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Center for Healthy Ageing, Faculty of Health Sciences, University of Copenhagen, DK 2600, Glostrup, Denmark.
authors.forename: Poul Jørgen
authors.initials: PJ
authors.lastname: Jennum
mesh_terms: D056044:Actigraphy; D000328:Adult; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000627:therapeutic use; D002940:Circadian Rhythm / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000627:therapeutic use; D008875:Middle Aged; D012146:Rest; D013375:Substance Withdrawal Syndrome
chemical_list: D001569:Benzodiazepines; D008550:Melatonin
keywords: Benzodiazepines; Bipolar disorder; Circadian rhythm; Circadian rhythms; Discontinuation; Randomized clinical trial; Schizophrenia; Withdrawal