|January 7, 2008
|August 14, 2012
|March 2010 (final data collection date for primary outcome measure)
- Change in Waist Circumference [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: Yes ]
A comparison between the ramelteon group and the placebo group in change in waist circumference (measured in cm) measured at Baseline and Week 8.
- Change in Insulin Resistance as Measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: Yes ]
A comparison between the ramelteon group and the placebo group of change in insulin resistance measured by the homeostatic model assessment of insulin resistance (HOMA-IR), assessed at Baseline and Week 8.
- Change in Abdominal Fat (DEXA). [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: Yes ]
A comparison between the ramelteon group and the placebo group of change in abdominal fat measured by a DEXA scan, assessed at Baseline and Week 8.
|Reduction in waist circumference and abdominal fat (DEXA). Insulin resistance as measured by the homeostatic model assessment of insulin resistance (HOMA-IR). [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
|Complete list of historical versions of study NCT00595504 on ClinicalTrials.gov Archive Site
|Fasting triglycerides,increasing fasting HDL, and improving LDL-particle size Food intake and energy expenditure Inflammatory biomarkers Quality of sleep Tardive dyskinesia [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
|Ramelteon as an Adjunct Therapy in Non-Diabetic Patients With Schizophrenia
|Phase IV Study of Ramelteon as an Adjunct Therapy in Non-Diabetic Patients With Schizophrenia
This study involves people who have schizophrenia or schizoaffective disorder who are currently taking antipsychotic medications. Some antipsychotic medications may cause weight gain and may increase the risk of diabetes mellitus and heart disease.The purpose of this study is to find out what happens if another medication (ramelteon) is used along with your antipsychotic medication. We want to find out whether doing this will:
- Change the way your body breaks down fat and sugar.
- Affect your waist size, stomach fat and triglycerides (a type of fat in your blood).
- Improve how your body responds to insulin.
- Affect your quality of sleep.
- Reduce movement disturbances Ramelteon is approved by the U.S. Food and Drug Administration (FDA) to treat people that have difficulty falling asleep. It is not approved for such things as affecting waist size or improving how the body breaks down fat and sugar. Its use in this study is investigational.
|This is an 8-week randomized, double blind, placebo-controlled pilot study with 4- week follow up assessment, of ramelteon 8 mg/day, administered to subjects for 8 consecutive weeks as an adjunctive therapy in 40 non-diabetic schizophrenia subjects to examine ramelteon effects on body composition, glucose and lipid metabolism, sleep quality and symptoms of tardive dyskinesia using the Massachusetts General Hospital General Clinical Research Center. As far as we know, no previous study has been done to explore the potential role of ramelteon in improving metabolic, sleep, and movement disturbances in schizophrenia subjects. The novel approach of adjunctive ramelteon treatment in the schizophrenia population is promising.
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
- Schizoaffective Disorder
- Schizophreniform Disorders
- Drug: Ramelteon
Two week supply of ramelteon 8mg/day first dispensed at baseline. New two week supply of study medication dispensed at each biweekly visit for 8 consecutive weeks.
Other Name: Rozerem
- Drug: Placebo
Two week supply of placebo tablets first dispensed at baseline. New two week supply of placebo dispensed at each biweekly visit for 8 consecutive weeks.
- Ananth J, Venkatesh R, Burgoyne K, Gadasalli R, Binford R, Gunatilake S. Atypical antipsychotic induced weight gain: pathophysiology and management. Ann Clin Psychiatry. 2004 Apr-Jun;16(2):75-85. Review.
- Henderson DC. Schizophrenia and comorbid metabolic disorders. J Clin Psychiatry. 2005;66 Suppl 6:11-20. Review.
- Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs. 2002;16(2):77-89. Review.
- Henderson DC, Copeland PM, Borba CP, Daley TB, Nguyen DD, Cagliero E, Evins AE, Zhang H, Hayden DL, Freudenreich O, Cather C, Schoenfeld DA, Goff DC. Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis. J Clin Psychiatry. 2006 May;67(5):789-97.
- Casey DE, Haupt DW, Newcomer JW, Henderson DC, Sernyak MJ, Davidson M, Lindenmayer JP, Manoukian SV, Banerji MA, Lebovitz HE, Hennekens CH. Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry. 2004;65 Suppl 7:4-18; quiz 19-20. Review.
- Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999 Nov;156(11):1686-96. Review.
- Newcomer JW, Haupt DW, Fucetola R, Melson AK, Schweiger JA, Cooper BP, Selke G. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry. 2002 Apr;59(4):337-45. Review.
- Henderson DC, Cagliero E, Copeland PM, Borba CP, Evins E, Hayden D, Weber MT, Anderson EJ, Allison DB, Daley TB, Schoenfeld D, Goff DC. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry. 2005 Jan;62(1):19-28.
- Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes. 1998 Oct;47(10):1643-9.
- Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, Andres R, Saudek C, Edelstein SL, Arakaki R, Murphy MB, Shamoon H; Diabetes Prevention Program Research Group. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. 2005 Aug;54(8):2404-14.
- Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennett PH, Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993 Dec 30;329(27):1988-92.
- Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006 Jul;116(7):1813-22. Review.
- Weyer C, Tataranni PA, Bogardus C, Pratley RE. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care. 2001 Jan;24(1):89-94.
- Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes. 2004 Aug;53(8):2087-94.
- Hayashi T, Boyko EJ, Leonetti DL, McNeely MJ, Newell-Morris L, Kahn SE, Fujimoto WY. Visceral adiposity and the risk of impaired glucose tolerance: a prospective study among Japanese Americans. Diabetes Care. 2003 Mar;26(3):650-5.
- Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes. 1997 Oct;46(10):1579-85.
- Kelley DE, Thaete FL, Troost F, Huwe T, Goodpaster BH. Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance. Am J Physiol Endocrinol Metab. 2000 May;278(5):E941-8.
- Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest. 1989 Apr;83(4):1168-73.
- Müller N, Riedel M, Gruber R, Ackenheil M, Schwarz MJ. The immune system and schizophrenia. An integrative view. Ann N Y Acad Sci. 2000;917:456-67. Review.
- Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, Kenis G, Bosmans E, de Jongh R, Altamura CA. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res. 2002 Apr 1;54(3):281-91.
- Sirota P, Meiman M, Herschko R, Bessler H. Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients. Psychiatry Res. 2005 Apr 15;134(2):151-9.
- Rapaport MH, Lohr JB. Serum-soluble interleukin-2 receptors in neuroleptic-naive schizophrenic subjects and in medicated schizophrenic subjects with and without tardive dyskinesia. Acta Psychiatr Scand. 1994 Nov;90(5):311-5.
- Naudin J, Capo C, Giusano B, Mège JL, Azorin JM. A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res. 1997 Aug 29;26(2-3):227-33.
- Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E, Pioli R, Altamura C, Scharpé S, Maes M. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998 Jun 22;32(1):9-15.
- McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, Yao J, Peters JL. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry. 1995 Sep;152(9):1291-7.
- Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004 Jul;65(7):940-7.
- Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, Ulmschneider M, Engel RR, Möller HJ, Schwarz MJ. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002 Jun;159(6):1029-34.
- Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005 Jun 15;57(12):1594-6.
- Sjöholm A, Nyström T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006 Jan-Feb;22(1):4-10. Review.
- Chandalia M, Cabo-Chan AV Jr, Devaraj S, Jialal I, Grundy SM, Abate N. Elevated plasma high-sensitivity C-reactive protein concentrations in Asian Indians living in the United States. J Clin Endocrinol Metab. 2003 Aug;88(8):3773-6.
- Monti JM, Monti D. Sleep disturbance in schizophrenia. Int Rev Psychiatry. 2005 Aug;17(4):247-53. Review.
- Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004 Mar;161(3):414-25. Review.
- Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, Elizur A, Weizman R. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry. 2001 Nov;58(11):1049-52.
- Abílio VC, Vera JA Jr, Ferreira LS, Duarte CR, Carvalho RC, Grassl C, Martins CR, Torres-Leite D, Bignotto M, Tufik S, Ribeiro Rde A, Frussa-Filho R. Effects of melatonin on orofacial movements in rats. Psychopharmacology (Berl). 2002 Jun;161(4):340-7. Epub 2002 Apr 26.
- Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005 Jul;27(2):131-6. Review.
- Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen DD. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology. 2000 Feb;141(2):487-97.
- Raskind MA, Burke BL, Crites NJ, Tapp AM, Rasmussen DD. Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats. Neuropsychopharmacology. 2007 Feb;32(2):284-8. Epub 2006 May 10.
- 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.
- 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.
- 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.
- Evans DR, Parikh VV, Khan MM, Coussons C, Buckley PF, Mahadik SP. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids. 2003 Dec;69(6):393-9.
- Fan X, Pristach C, Liu EY, Freudenreich O, Henderson DC, Goff DC. Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res. 2007 Jan 15;149(1-3):267-71. Epub 2006 Nov 16.
- Fan X, Anderson EJ, Copeland PM, Borba CP, Nguyen DD, Freudenreich O, Goff DC, Henderson DC. Higher fasting serum insulin is associated with increased resting energy expenditure in nondiabetic schizophrenia patients. Biol Psychiatry. 2006 Dec 15;60(12):1372-7. Epub 2006 Aug 22.
- Ventura J, Liberman RP, Green MF, Shaner A, Mintz J. Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res. 1998 Jun 15;79(2):163-73.
- Ritz R CJ: Indirect Calorimetry. Monitoring in Respiratory Care. St Louis, MO, Mosby-Yearbook, Inc, 1993
- Schakel SF, Sievert YA, Buzzard IM. Sources of data for developing and maintaining a nutrient database. J Am Diet Assoc. 1988 Oct;88(10):1268-71.
- Kelly TL, Berger N, Richardson TL. DXA body composition: theory and practice. Appl Radiat Isot. 1998 May-Jun;49(5-6):511-3.
- Visser M, Fuerst T, Lang T, Salamone L, Harris TB. Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study--Dual-Energy X-ray Absorptiometry and Body Composition Working Group. J Appl Physiol (1985). 1999 Oct;87(4):1513-20.
- McNamara JR, Schaefer EJ. Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions. Clin Chim Acta. 1987 Jun 30;166(1):1-8.
- Warnick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982 Jun;28(6):1379-88.
- Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972 Jun;18(6):499-502.
- Kay SR, Opler LA, Lindenmayer JP. The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl. 1989 Nov;(7):59-67.
- Rey JM, Hunt GE, Johnson GF. Assessment of tardive dyskinesia in psychiatric outpatients using a standardized rating scale. Aust N Z J Psychiatry. 1981 Mar;15(1):33-7.
- Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, Rodríguez MJ, Rele R, Orta J, Kharbeng A, Araya S, Gervin M, Alonso J, Mavreas V, Lavrentzou E, Liontos N, Gregor K, Jones PB; SOHO Study Group. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl. 2003;(416):16-23.
- HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62.
- Heinrichs DW, Hanlon TE, Carpenter WT Jr. The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 1984;10(3):388-98.
- Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life Res. 2000;9(7):847-54.
- Endicott J, Spitzer RL, Fleiss JL, Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry. 1976 Jun;33(6):766-71.
- Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220-33.
- Hoddes E, Zarcone V, Smythe H, Phillips R, Dement WC. Quantification of sleepiness: a new approach. Psychophysiology. 1973 Jul;10(4):431-6.
- Hays RD, Martin SA, Sesti AM, Spritzer KL. Psychometric properties of the Medical Outcomes Study Sleep measure. Sleep Med. 2005 Jan;6(1):41-4. Epub 2004 Nov 11.
- Levine S. The management of resistant depression. Acta Psychiatr Belg. 1986 Mar-Apr;86(2):141-51.
|March 2010 (final data collection date for primary outcome measure)
- diagnosis of schizophrenia, schizoaffective disorder, any subtype or schizophreniform disorder
- male or female, age 18-65 years
- treatment with clozapine, olanzapine, quetiapine or risperidone
- well established compliance with medications
- Body Mass Index (BMI) of > 27 Kg/m² with any component of metabolic syndrome or insulin resistance or a BMI of > 30 Kg/m²:
- inability to provide informed consent
- substance and alcohol abuse
- significant medical illness, including congestive heart failure, severe hepatic impairment, severe Chronic Obstructive Pulmonary Disease (COPD), severe sleep apnea, severe cardiovascular disease or renal disease
- current history of diabetes mellitus or thyroid disease
- women who are pregnant, breastfeeding, or who are unwilling or unable to use an effective form of birth control during the entire study
- psychiatrically unstable, patients with major depression
- patients treated with medications known to affect glucose tolerance such as birth control pills containing norgestrel, steroids, beta blockers, anti-inflammatory drugs (including daily aspirin and ibuprofen), thiazide diuretics; and agents that induce weight loss will be excluded from the study
- treatment with fluvoxamine in the or ketoconazole past two weeks
- treatment with fluconazole (a strong CYP2C9 inhibitor).
- subjects treated with ziprasidone and aripiprazole conventional agents
- treatment with sedative-hypnotics such as barbiturates, zolpidem, eszopiclone, zaleplon. The use of stable daily doses of benzodiazepines is allowed.
- known hypersensitivity to ramelteon or any of its components
|18 Years to 65 Years
|Contact information is only displayed when the study is recruiting subjects
|David C. Henderson, Massachusetts General Hospital
|Massachusetts General Hospital
||David C. Henderson, M.D.
||Massachusetts General Hospital
|Massachusetts General Hospital