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

Schizophrenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03075657
• Other study ID #: T/IM-NF/Pharma/01/17
• Status: Completed
• Phase: Phase 4
• Start date: May 1, 2017
• Est. completion date: August 31, 2018

Study information

• Verified date: May 2019
• Source: All India Institute of Medical Sciences, Bhubaneswar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: August 31, 2018
• Est. primary completion date: June 15, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Risperidone
Risperidone will be prescribed at dose of 2 mg per day
• Risperidone and Ramelteon
Ramelteon will be prescribed 8mg/day as an add-on therapy to Risperidone 2 mg per day
• Haloperidol
Haloperidol will be prescribed at a dose of 4 mg per day
• Haloperidol and Ramelteon
Ramelteon will be prescribed 8mg/day as an add-on therapy to Haloperidol 4 mg per day

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences (AIIMS)	Bhubaneswar	Odisha

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, Bhubaneswar

Country where clinical trial is conducted

India, 

References & Publications (18)

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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 p — View Citation

Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. — View Citation

Cohrs S, Pohlmann K, Guan Z, Jordan W, Meier A, Huether G, Rüther E, Rodenbeck A. Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects. Psychopharmacology (Berl). 2004 Jul;174(3):414-20. Epub 2004 Jan 20. — View Citation

Cohrs S. Sleep disturbances in patients with schizophrenia : impact and effect of antipsychotics. CNS Drugs. 2008;22(11):939-62. Review. — View Citation

Hajak G, Rodenbeck A, Bandelow B, Friedrichs S, Huether G, Rüther E. Nocturnal plasma melatonin levels after flunitrazepam administration in healthy subjects. Eur Neuropsychopharmacol. 1996 May;6(2):149-53. — View Citation

Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006 Oct;63(10):1149-57. — View Citation

Kabuto M, Namura I, Saitoh Y. Nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humans. Endocrinol Jpn. 1986 Jun;33(3):405-14. — View Citation

Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. — View Citation

Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms. 1997 Dec;12(6):657-65. Review. — View Citation

Mann K, Rossbach W, Müller MJ, Müller-Siecheneder F, Pott T, Linde I, Dittmann RW, Hiemke C. Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine. Psychoneuroendocrinology. 2006 Feb;31(2):256-64. Epub 2005 Sep 26. — View Citation

Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. doi: 10.1111/j.1755-5949.2008.00066.x. Review. — View Citation

Monteleone P, Natale M, La Rocca A, Maj M. Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change after subchronic treatment with antipsychotics. Neuropsychobiology. 1997;36(4):159-63. — View Citation

Robinson S, Rosca P, Durst R, Shai U, Ghinea C, Schmidt U, Nir I. Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients. Acta Psychiatr Scand. 1991 Sep;84(3):221-4. — View Citation

Spadoni G, Bedini A, Lucarini S, Mor M, Rivara S. Pharmacokinetic and pharmacodynamic evaluation of ramelteon : an insomnia therapy. Expert Opin Drug Metab Toxicol. 2015 Jul;11(7):1145-56. doi: 10.1517/17425255.2015.1045487. Epub 2015 May 8. Review. — View 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. — View Citation

Wehr TA, Aeschbach D, Duncan WC Jr. Evidence for a biological dawn and dusk in the human circadian timing system. J Physiol. 2001 Sep 15;535(Pt 3):937-51. — View Citation

Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry. 2012 Apr;200(4):308-16. doi: 10.1192/bjp.bp.111.096321. Epub 2011 Dec 22. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

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