Study of add-on Ramelteon Therapy on Sleep and Circadian Rhythm Disruption in Patients With Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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.
    

Intervention name(s): Risperidone; Risperidone and Ramelteon; Haloperidol; Haloperidol and Ramelteon
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Risperidone will be prescribed at dose of 2 mg per day; Ramelteon will be prescribed 8mg/day as an add-on therapy to Risperidone 2 mg per day; Haloperidol will be prescribed at a dose of 4 mg per day; Ramelteon will be prescribed 8mg/day as an add-on therapy to Haloperidol 4 mg per day
Intervention MeSH terms: Haloperidol; Risperidone; Haloperidol decanoate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment