Clinical trial NCT01431092: Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia
Official title: Prolonged-release Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Schizoaffective Disorder
Bipolar Affective Disorder
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
Collaborators: name: Glostrup University Hospital, Copenhagen
name: Copenhagen Trial Unit, Center for Clinical Intervention Research
First posted: 2011-09-09
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this trial, researchers aim to investigate if prolonged-release melatonin can facilitate the withdrawal of chronic benzodiazepine administration in patients with schizophrenia. Furthermore, researchers will investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life.

Detailed description: Treatment of schizophrenia frequently includes prolonged administration of benzodiazepines despite lack of evidence of its use. It is often difficult to discontinue use of benzodiazepines because of development of dependence.

After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily versus matching placebo, participants are required to slowly taper off their benzodiazepine dose towards no intake. 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, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up.

The results from this trial will assess if 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 compared to the background population. In addition, the data of the trial are also analyzed as an observational cohort design to investigate the association of benzodiazepine dose reduction/discontinuation with psychophysiology, cognition, sleep, quality of life, and other selected variables (not further described below, see trial protocol). Knowledge of these important clinical aspects is lacking in this group of patients.

Eligibility criteria: Inclusion Criteria:

* Patients diagnosed with schizophrenia, schizoaffective disorder, or bipolar affective disorder (ICD-10 criteria for schizophrenia (F20), schizoaffective disorder (F25) or bipolar affective disorder (F31) must be fulfilled at inclusion or previously as documented by chart review; fulfillment of relevant DSM-IV-TR criteria will also be registered).
* Treated with the same antipsychotic drug for at least 3 months before inclusion (change of dose, antipsychotic polypharmacy and prescription/discontinuation of add-on drugs allowed but the basic antipsychotic treatment should be the same).
* Continuously treated with at least one benzodiazepine (chlordiazepoxide, diazepam, clobazam, clonazepam, flunitrazepam, nitrazepam, bromazepam, alprazolam, lorazepam, lormetazepam, oxazepam, triazolam) or benzodiazepine related drug (zolpidem, zopiclone, zaleplon) for at least 3 months before inclusion.
* Age 18+.
* Fertile women: negative pregnancy test at baseline and use of safe contraceptives (intrauterine devices or hormonal contraception) throughout the trial period and 1 day after withdrawal of trial medication. This does not apply to sterile or infertile participants, i.e. surgically sterilized or post menopausal (missing period for at least 12 months before inclusion) women.
* Written informed consent.

Exclusion Criteria:

* Known aggressive or violent behavior.
* Mental retardation, pervasive developmental disorder, or dementia.
* Epilepsy, terminal illness, severe comorbidity or unable to understand Danish.
* Allergic to compounds in the trial medication (melatonin, lactose, starch, gelatin, talc).
* Hepatic impairment (known diagnosis).
* Pregnancy and nursing.
* Missing informed consent.

Primary outcomes:
measure: Benzodiazepine (including benzodiazepine related drugs) dose at 6 months follow-up.
timeFrame: 6 months follow-up.
Secondary outcomes:
measure: Pattern of benzodiazepine dose over time.
timeFrame: 2, 4, and 6 months.
measure: The fraction of participants who has completely discontinued benzodiazepines 6 months after initiating trial medication.
timeFrame: 6 months follow-up.
measure: Pattern of P300 amplitude (psychophysiology) over time.
timeFrame: 2, 4, and 6 months.
measure: Pattern of Brief Assessment of Cognition in Schizophrenia (BACS) composite score over time.
timeFrame: 2, 4, and 6 months.
measure: Sleep efficiency (polysomnography) at 6 months follow-up.
timeFrame: 6 months.
measure: Pittsburgh Sleep Quality Index (PSQI) global score at 6 months follow-up.
timeFrame: 6 months.
measure: Pattern of Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ-2) score over time.
timeFrame: 2, 4, and 6 months.
Other outcomes:
Locations:
city: Glostrup
country: Denmark
facility: 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
Study officials:
affiliation: CNSR/CINS
name: Lone Baandrup, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CNSR/CINS
name: Birte Glenthøj, MD, MSc
role: STUDY_CHAIR
References:
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citation: Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, Zisapel N. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry. 2000 May;61(5):373-7. doi: 10.4088/jcp.v61n0509.
citation: Suresh Kumar PN, Andrade C, Bhakta SG, Singh NM. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2007 Feb;68(2):237-41. doi: 10.4088/jcp.v68n0208.
citation: Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med. 1999 Nov 8;159(20):2456-60. doi: 10.1001/archinte.159.20.2456.
citation: Baandrup L, Fasmer OB, Glenthoj BY, Jennum PJ. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial. BMC Psychiatry. 2016 Oct 13;16(1):348. doi: 10.1186/s12888-016-1062-8.
citation: Baandrup L, Fagerlund B, Jennum P, Lublin H, Hansen JL, Winkel P, Gluud C, Oranje B, Glenthoj BY. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol. BMC Psychiatry. 2011 Oct 5;11:160. doi: 10.1186/1471-244X-11-160.