Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia (SMART)

This study has been completed.
Sponsor:
Collaborators:
Glostrup University Hospital, Copenhagen
Copenhagen Trial Unit, Center for Clinical Intervention Research
Information provided by (Responsible Party):
Lone Baandrup, University of Copenhagen
ClinicalTrials.gov Identifier:
NCT01431092
First received: August 31, 2011
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Schizophrenia
Schizoaffective Disorder
Bipolar Affective Disorder
Drug: Placebo
Drug: Melatonin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Prolonged-release Melatonin Versus Placebo for Benzodiazepine Discontinuation in Patients With Schizophrenia: a Randomized Clinical Trial

Resource links provided by NLM:


Further study details as provided by University of Copenhagen:

Primary Outcome Measures:
  • Benzodiazepine (including benzodiazepine related drugs) dose at 6 months follow-up. [ Time Frame: 6 months follow-up. ] [ Designated as safety issue: No ]
    The general linear model is used with the outcome measure (dose after 6 months) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.


Secondary Outcome Measures:
  • Pattern of benzodiazepine dose over time. [ Time Frame: 2, 4, and 6 months. ] [ Designated as safety issue: No ]
    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

  • The fraction of participants who has completely discontinued benzodiazepines 6 months after initiating trial medication. [ Time Frame: 6 months follow-up. ] [ Designated as safety issue: No ]
    The analysis will be done using a logistic regression model where logit(p) is the dependent variable, p is the probability of completing the withdrawal, and a binary intervention indicator is the independent variable.

  • Pattern of P300 amplitude (psychophysiology) over time. [ Time Frame: 2, 4, and 6 months. ] [ Designated as safety issue: No ]
    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

  • Pattern of Brief Assessment of Cognition in Schizophrenia (BACS) composite score over time. [ Time Frame: 2, 4, and 6 months. ] [ Designated as safety issue: No ]
    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric, or a first order autoregressive.

  • Sleep efficiency (polysomnography) at 6 months follow-up. [ Time Frame: 6 months. ] [ Designated as safety issue: No ]
    The general linear model is used with the outcome measure (sleep efficiency) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

  • Pittsburgh Sleep Quality Index (PSQI) global score at 6 months follow-up. [ Time Frame: 6 months. ] [ Designated as safety issue: No ]
    The general linear model is used with the outcome measure (PSQI) as the dependent variable and the indicator of intervention and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

  • Pattern of Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ-2) score over time. [ Time Frame: 2, 4, and 6 months. ] [ Designated as safety issue: No ]
    The mixed model with repeated measures will be used to analyze the time course. The model is outcome measure = int + baseline + a*t + b*t*t + c*baseline*t + d*baseline*t*t + e*I + f*I*t + g*I*t*t where t is time, I the intervention indicator, int the intercept, and a through g the coefficients. Using Akaike's criterium the best co-variance matrix is first chosen among an unstructured, a compound symmetric or a first order autoregressive.


Enrollment: 86
Study Start Date: October 2011
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Melatonin Drug: Melatonin
Prolonged-release melatonin (Circadin®) 2 mg, once daily, 1-2 hours before bedtime.
Other Names:
  • Prolonged-release melatonin
  • Circadin®
Placebo Comparator: Placebo Drug: Placebo
Both Circadin and placebo are encapsulated in lactose containing gelatin capsules to optimize the blinding.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01431092

Locations
Denmark
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, 2600
Sponsors and Collaborators
Lone Baandrup
Glostrup University Hospital, Copenhagen
Copenhagen Trial Unit, Center for Clinical Intervention Research
Investigators
Principal Investigator: Lone Baandrup, MD, PhD CNSR/CINS
Study Chair: Birte Glenthøj, MD, MSc CNSR/CINS
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Lone Baandrup, MD, Ph.D., University of Copenhagen
ClinicalTrials.gov Identifier: NCT01431092     History of Changes
Other Study ID Numbers: 2010-024065-46, 2010-024065-46
Study First Received: August 31, 2011
Last Updated: June 5, 2014
Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics
Denmark: Danish Medicines Agency

Additional relevant MeSH terms:
Bipolar Disorder
Genetic Diseases, X-Linked
Psychotic Disorders
Schizophrenia
Mood Disorders
Affective Disorders, Psychotic
Mental Disorders
Genetic Diseases, Inborn
Schizophrenia and Disorders with Psychotic Features
Melatonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014