Study of add-on Ramelteon Therapy on Sleep and Circadian Rhythm Disruption in Patients With Schizophrenia

May 2, 2019 updated by: RITUPARNA MAITI, All India Institute of Medical Sciences, Bhubaneswar
The proposed study has been planned to evaluate the effect of add-on ramelteon on sleep pattern/quality and circadian rhythm disruption in patients with schizophrenia.

Study Overview

Detailed Description

Schizophrenia is a mental dysfunction of thought, perception and behaviour which can be attributed to complex and dynamically interacting perturbations in multiple neurochemical systems. Along with these cardinal features of schizophrenia, sleep disorders and disturbed circadian rhythm are commonly encountered among patients. Markedly decreased sleep efficiency, delayed sleep onset and frequent awakenings are most common observations. Endogenous melatonin is a dependable biomarker of circadian rhythmicity and, it has already been found that the nocturnal rise of endogenous melatonin is blunted leading to circadian dysrhythmia in schizophrenia.

The antipsychotics prescribed for the condition though cause improvement in the cardinal symptoms of the disease but have no significant effect on melatonin levels. The blunted peak of night time melatonin secretion are not restored or even decreased even after several months therapy with antipsychotics. In this clinical scenario, add-on therapy with sedative/ hypnotics along with antipsychotics is mandate for a prescription. Previous studies revealed that add-on therapy with benzodiazepines can worsen the already existing derangement in circadian rhythm by decreasing secretion of nocturnal melatonin. A long term add on therapy with benzodiazepines in patients on antipsychotics has been found to have an increased risk of death.

Addition of melatonin to the pharmacotherapy of schizophrenia elevates mood and daytime functioning in addition to improved sleep in schizophrenia patients. Melatonin, apart from being a hypnotic and circadian rhythm restoring compound, also possess neuroprotective, anti-neuroinflammatory and antioxidant properties. The rate limiting step of melatonin biosynthetic pathway is the alkylation of serotonin to N- acetyl serotonin, catalyzed by enzyme AANAT (aryl-alkylamine- N-acetyl-transferase). Study of AANAT enzyme and its modulation to achieve normal rhythmical secretion of melatonin can also be a potential target for resynchronising the circadian rhythm.

Ramelteon is a melatonin receptor agonist approved for treatment of insomnia by the USFDA. It exerts its action by acting on MT1 and MT2 receptors at suprachiasmatic nucleus. The long term safety of ramelteon has been evaluated by several workers and found no significant adverse effects like abuse liability, rebound insomnia and cognitive impairment. In contrast to melatonin, it shows higher-binding affinity for MT1 and MT2 receptors, more lipophilic and has a longer half-life(t1/2 of melatonin is 20-50 min whereas that of ramelteon is 1-2.6 hrs and that of its active melabolite M-II is 2-5 hrs). In addition, ramelteon has been already evaluated as a potential adjunctive treatment for learning and memory deficits in schizophrenia.

The sleep and circadian rhythm disorders in schizophrenia have so far been given very less importance by researchers and there are limited studies targeting or modulating the melatonin pathway. Therefore, proposed study has been planned to evaluate the effect of add-on ramelteon on sleep pattern/quality and circadian rhythm disruption in patients with schizophrenia.

Study Type

Interventional

Enrollment (Actual)

120

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Odisha
      • Bhubaneswar, Odisha, India, 751019
        • All India Institute Of Medical Sciences (AIIMS)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • All adult patients of either sex with age range 18-65 years with the clinical diagnosis of schizophrenia. (DSM-V)
  • Treatment naïve patients or patients who had not taken any treatment for at least 4 weeks before inclusion.
  • Legal guardian of patients consenting to participate in the study by signing the informed consent form.

Exclusion Criteria:

  • Schizoaffective disorder or schizophrenia with somatoform disorders.
  • Highly agitated patients who need immediate treatment.
  • Patients who are already under treatment for the presenting conditions.
  • Patients with comorbid substance abuse or history of organicity
  • Patients with known history of dementia, obstructive sleep apnoea syndrome, diabetes mellitus.
  • Pregnant and nursing women.
  • History of allergy or hypersensitivity to ramelteon.
  • Legal guardian of patients not willing to participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Risperidone group
Schizophrenia patients with predominant negative symptoms on Risperidone monotherapy
Risperidone will be prescribed at dose of 2 mg per day
Experimental: Risperidone with Ramelteon group
Schizophrenia patients with predominant negative symptoms on Risperidone with add-on Ramelteon therapy
Ramelteon will be prescribed 8mg/day as an add-on therapy to Risperidone 2 mg per day
Active Comparator: Haloperidol group
Schizophrenia patients with predominant positive symptoms on Haloperidol monotherapy
Haloperidol will be prescribed at a dose of 4 mg per day
Experimental: Haloperidol with Ramelteon group
Schizophrenia patients with predominant positive symptoms on Haloperidol with add-on Ramelteon therapy
Ramelteon will be prescribed 8mg/day as an add-on therapy to Haloperidol 4 mg per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in serum melatonin over 4 weeks from baseline
Time Frame: Baseline and 4 weeks
ELISA
Baseline and 4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in quality of sleep over 4 weeks from baseline
Time Frame: Baseline and 4 weeks
Pittsburgh Sleep Quality Index (PSQI) scoring
Baseline and 4 weeks
Change in urinary melatonin(6MTs) over 4 weeks from baseline
Time Frame: Baseline and 4 weeks
HPLC
Baseline and 4 weeks
Change in serum AANAT enzyme over 4 weeks from baseline
Time Frame: Baseline and 4 weeks
ELISA
Baseline and 4 weeks
Change in severity of symptoms of schizophrenia over 4 weeks from baseline
Time Frame: Baseline and 4 weeks
PANSS Scoring
Baseline and 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: DEBASISH HOTA, DM, AIIMS, Bhubaneswar

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2017

Primary Completion (Actual)

June 15, 2018

Study Completion (Actual)

August 31, 2018

Study Registration Dates

First Submitted

March 6, 2017

First Submitted That Met QC Criteria

March 6, 2017

First Posted (Actual)

March 9, 2017

Study Record Updates

Last Update Posted (Actual)

May 3, 2019

Last Update Submitted That Met QC Criteria

May 2, 2019

Last Verified

May 1, 2019

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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