Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial

BMC Psychiatry

Erin L Reutenauer¹  Vinod H Srihari¹  Sinan Guloksuz¹  Cenk Tek¹ 

[1] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

关键词: Antipsychotics;    Weight Loss;    Metabolic Syndrome;    Obesity;    Severe Mental Illness;    Schizophrenia;    Naltrexone;   

Others  :  1124017
DOI  :  10.1186/1471-244X-13-176

 received in 2013-06-19, accepted in 2013-06-24,  发布年份 2013

【 摘 要 】

Background

Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI ≥ 28) with SMI, who gained weight while being treated with antipsychotics.

Methods and design

One hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-α) will be evaluated. The data will be analyzed by applying linear mixed effect models.

Discussion

This is the first large scale study investigating the safety and efficacy of naltrexone in antipsychotic induced weight gain; and hopefully, this may lead to a novel pharmacological option for management of this major health problem.

Trial registration

This trial is registered in http://www.clinicaltrials.gov webcite as NCT01866098

【 授权许可】

   
2013 Tek et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Phutane VH, Tek C, Chwastiak L, Ratliff JC, Ozyuksel B, Woods SW, Srihari VH: Cardiovascular risk in a first-episode psychosis sample: a 'critical period' for prevention? Schizophr Res 2011, 127(1–3):257-261.
• [2]Chwastiak LA, Tek C: The unchanging mortality gap for people with schizophrenia. Lancet 2009, 374(9690):590-592.
• [3]Ratliff JC, Palmese LB, Reutenauer EL, Srihari VH, Tek C: Obese schizophrenia spectrum patients have significantly higher 10-year general cardiovascular risk and vascular ages than obese individuals without severe mental illness. Psychosomatics 2013, 54(1):67-73.
• [4]Newcomer JW, Hennekens CH: Severe mental illness and risk of cardiovascular disease. JAMA 2007, 298(15):1794-1796.
• [5]Jones DR, Macias C, Barreira PJ, Fisher WH, Hargreaves WA, Harding CM: Prevalence, severity, and co-occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004, 55(11):1250-1257.
• [6]Keck PE, McElroy SL: Bipolar disorder, obesity, and pharmacotherapy-associated weight gain. J Clin Psychiatry 2003, 64(12):1426-1435.
• [7]Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J: 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009, 374(9690):620-627.
• [8]Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP, Weiden PJ, Cheskin LJ: The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiat 1999, 60(4):215-220.
• [9]Saari KM, Lindeman SM, Viilo KM, Isohanni MK, Jarvelin MR, Lauren LH, Savolainen MJ, Koponen HJ: A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 Birth Cohort study. J Clin Psychiatry 2005, 66(5):559-563.
• [10]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, 156(11):1686-1696.
• [11]Lieberman JA: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J Clin Psychiatry 2007, 68(2):e04.
• [12]Zipursky RB, Gu H, Green AI, Perkins DO, Tohen MF, McEvoy JP, Strakowski SM, Sharma T, Kahn RS, Gur RE, et al.: Course and predictors of weight gain in people with first-episode psychosis treated with olanzapine or haloperidol. The British journal of psychiatry : the journal of mental science 2005, 187:537-543.
• [13]Casey DE, Zorn SH: The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001, 62(Suppl 7):4-10.
• [14]Arranz B, Rosel P, Ramirez N, Duenas R, Fernandez P, Sanchez JM, Navarro MA, San L: Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patients. J Clin Psychiatry 2004, 65(10):1335-1342.
• [15]Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL: H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2003, 28(3):519-526.
• [16]Marston OJ, Heisler LK: Targeting the serotonin 2C receptor for the treatment of obesity and type 2 diabetes. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 2009, 34(1):252-253.
• [17]Stice E, Yokum S, Zald D, Dagher A: Dopamine-based reward circuitry responsivity, genetics, and overeating. Curr Top Behav Neurosci 2011, 6:81-93.
• [18]Berridge KC: Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev 1996, 20(1):1-25.
• [19]Yeomans MR, Gray RW: Opioid peptides and the control of human ingestive behaviour. Neurosci Biobehav Rev 2002, 26(6):713-728.
• [20]Bodnar RJ: Endogenous opioids and feeding behavior: a 30-year historical perspective. Peptides 2004, 25(4):697-725.
• [21]Levine AS, Billington CJ: Opioids as agents of reward-related feeding: a consideration of the evidence. Physiol Behav 2004, 82(1):57-61.
• [22]Cota D, Tschop MH, Horvath TL, Levine AS: Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 2006, 51(1):85-107.
• [23]Scavo D, Barletta C, Vagiri D, Burla F, Fontana M, Lazzari R: Hyperendorphinemia in obesity is not related to the affective state. Physiol Behav 1990, 48(5):681-683.
• [24]Melchior JC, Rigaud D, Chayvialle JA, Colas-Linhart N, Laforest MD, Petiet A, Comoy E, Apfelbaum M: Palatability of a meal influences release of beta-endorphin, and of potential regulators of food intake in healthy human subjects. Appetite 1994, 22(3):233-244.
• [25]Volkow ND, Wang GJ, Baler RD: Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci 2011, 15(1):37-46.
• [26]Wang GJ, Volkow ND, Fowler JS: The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin Ther Targets 2002, 6(5):601-609.
• [27]Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS: Brain dopamine and obesity. Lancet 2001, 357(9253):354-357.
• [28]Ratliff JC, Palmese LB, Reutenauer EL, Liskov E, Grilo CM, Tek C: The effect of dietary and physical activity pattern on metabolic profile in individuals with schizophrenia: a cross-sectional study. Compr Psychiatry 2012, 53(7):1028-1033.
• [29]Kirkpatrick B, Messias EM, Tek C: Substance abuse and the heterogeneity of schizophrenia a population-based study. Schizophr Res 2003, 62(3):293-294.
• [30]Baptista T, Lacruz A, Angeles F, Silvera R, de Mendoza S, Mendoza MT, Hernandez L: Endocrine and metabolic abnormalities involved in obesity associated with typical antipsychotic drug administration. Pharmacopsychiatry 2001, 34(6):223-231.
• [31]O'Malley SS, Froehlich JC: Advances in the use of naltrexone: an integration of preclinical and clinical findings. Recent developments in alcoholism : an official publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism 2003, 16:217-245.
• [32]Atkinson RL, Berke LK, Drake CR, Bibbs ML, Williams FL, Kaiser DL: Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther 1985, 38(4):419-422.
• [33]Zimmermann U, Rechlin T, Plaskacewicz GJ, Barocka A, Wildt L, Kaschka WP: Effect of naltrexone on weight gain and food craving induced by tricyclic antidepressants and lithium: an open study. Biol Psychiatry 1997, 41(6):747-749.
• [34]Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O'Neil PM, Perri MG, Pi-Sunyer FX, Rock CL, Erickson JS, et al.: Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity 2011, 19(1):110-120.
• [35]Greenway FL, Dunayevich E, Tollefson G, Erickson J, Guttadauria M, Fujioka K, Cowley MA, Group NBS: Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. J Clin Endocrinol Metabol 2009, 94(12):4898-4906.
• [36]George TP, Vessicchio JC, Termine A, Bregartner TA, Feingold A, Rounsaville BJ, Kosten TR: A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Biol Psychiatry 2002, 52(1):53-61.
• [37]Del Boca FK, Kranzler HR, Brown J, Korner PF: Assessment of medication compliance in alcoholics through UV light detection of a riboflavin tracer. Alcohol Clin Exp Res 1996, 20(8):1412-1417.
• [38]Dubbert PM, King A, Rapp SR, Brief D, Martin JE, Lake M: Riboflavin as a tracer of medication compliance. J Behav Med 1985, 8(3):287-299.
• [39]Overall JE, Gorham DR: The Brief Psychiatric Scale. Psychol Rep 1962, 10(3):799-812.
• [40]Kay SR, Fiszbein A, Opler LA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987, 13(2):261-276.
• [41]Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory for measuring depression. Arch Gen Psychiatry 1961, 4:561-571.
• [42]Stunkard AJ, Messick S: The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res 1985, 29(1):71-83.
• [43]Foster GD, Wadden TA, Swain RM, Stunkard AJ, Platte P, Vogt RA: The Eating Inventory in obese women: clinical correlates and relationship to weight loss. International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 1998, 22(8):778-785.
• [44]Toll BA, Katulak NA, Williams-Piehota P, O'Malley S: Validation of a scale for the assessment of food cravings among smokers. Appetite 2008, 50(1):25-32.
• [45]Semanik P, Lee J, Manheim L, Dipietro L, Dunlop D, Chang RW: Relationship between accelerometer-based measures of physical activity and the Yale Physical Activity Survey in adults with arthritis. Arthritis Care Res 2011, 63(12):1766-1772.
• [46]Lindamer LA, McKibbin C, Norman GJ, Jordan L, Harrison K, Abeyesinhe S, Patrick K: Assessment of physical activity in middle-aged and older adults with schizophrenia. Schizophr Res 2008, 104(1–3):294-301.
• [47]Skouroliakou M, Giannopoulou I, Kostara C, Vasilopoulou M: Comparison of predictive equations for resting metabolic rate in obese psychiatric patients taking olanzapine. Nutrition 2009, 25(2):188-193.
• [48]Ritsner M, Kurs R, Gibel A, Ratner Y, Endicott J: Validity of an abbreviated quality of life enjoyment and satisfaction questionnaire (Q-LES-Q-18) for schizophrenia, schizoaffective, and mood disorder patients. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 2005, 14(7):1693-1703.
• [49]Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical care 1992, 30(6):473-483.
• [50]Reine G, Simeoni MC, Auquier P, Loundou A, Aghababian V, Lancon C: Assessing health-related quality of life in patients suffering from schizophrenia: a comparison of instruments. Eur Psychiatry 2005, 20(7):510-519.
• [51]Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K: The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta psychiatrica Scandinavica Supplementum 1987, 334:1-100.
• [52]Posner K, Oquendo MA, Gould M, Stanley B, Davies M: Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 2007, 164(7):1035-1043.
• [53]Addington D, Addington J, Maticka-Tyndale E: Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl 1993, 22:39-44.
• [54]Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO: The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991, 86(9):1119-1127.
• [55]Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L: The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 2004, 68(2–3):283-297.
• [56]Keefe RS, Poe M, Walker TM, Harvey PD: The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome. J Clin Exp Neuropsychol 2006, 28(2):260-269.
• [57]Faul F, Erdfelder E, Lang AG, Buchner A: G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007, 39(2):175-191.
• [58]Newcomer JW: Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005, 19(Suppl 1):1-93.
• [59]Wahlbeck K, Tuunainen A, Ahokas A, Leucht S: Dropout rates in randomised antipsychotic drug trials. Psychopharmacology 2001, 155(3):230-233.
• [60]Perkins DO: Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 2002, 63(12):1121-1128.
• [61]Rudd P, Byyny RL, Zachary V, LoVerde ME, Titus C, Mitchell WD, Marshall G: The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther 1989, 46(2):169-176.
• [62]Srihari VH, Tek C, Chwastiak LA, Woods SW, Steiner JL: Best practices: surveillance and management of diabetes in a CMHC population. Psychiatr Serv 2007, 58(9):1151-1153.