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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Risperidone
* Drug: Risperidone and Ramelteon
* Drug: Haloperidol
* Drug: Haloperidol and Ramelteon


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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