No effect of adjunctive, repeated dose intranasal insulin treatment on body metabolism in patients with schizophrenia☆
Introduction
Patients with schizophrenia have a 20% shorter life expectancy than the general population, and a greater vulnerability to some serious medical illnesses (Marder et al., 2004). The prevalence of obesity among individuals with schizophrenia and affective disorders is 1.5–2.0 times higher than in the general population (Karpati et al., 2004). While atypical antipsychotic agents have many notable benefits compared to conventional antipsychotic agents in treating schizophrenia and other psychiatric illnesses, their use has been associated with reports of weight gain and obesity, which are associated with increased risk of other metabolic complications including dyslipidemia, diabetes, and cardiovascular diseases (Henderson, 2005).
The maintenance of weight is the result of a balance between energy intake and expenditure (Rosenbaum et al., 1997). Resting energy expenditure (REE) is variable among individuals and is the largest component of energy expenditure, comprising 60–80% of non-activity total energy expenditure (Goran, 2000). In recent years, insulin also emerged as an important determinant of energy expenditure (Schwartz et al., 1995, Perseghin et al., 2002). A recent study from our group demonstrated that higher fasting serum insulin levels are associated with increased REE in non-diabetic schizophrenia patients (Fan et al., 2006). The mechanisms linking insulin and REE are still unclear. However, this linkage could be at least partially due to the interaction between insulin and the increased activity of the sympathetic nervous system, which is consequently associated with increased REE (Berne et al., 1992, Vollenweider et al., 1993).
One important action of insulin in the brain is on food intake and weight control (Schwartz and Porte, 2005). Centrally available insulin reduces food intake and body weight in a dose-dependent manner when chronically infused into the ventricular system in rats (Brief and Davis, 1984). These effects are also obtained in rats after a single acute injection of insulin (Air et al., 2002). On the other hand, administering insulin antibodies into ventromedial areas of hypothalamus increases food intake and body weight (Gerozissis, 2003), and the deletion of central insulin receptors is accompanied by hyperphagia, obesity and hyperlipidemia in rats (Bruning et al., 2000, Obici et al., 2002).
Previous studies examined the effect of centrally available insulin through intranasal delivery on food intake and body composition in healthy subjects. A study of 8-week intranasal insulin treatment (40 IU 4 times per day) in 12 healthy men and 8 healthy women was reported (Hallschmid et al., 2004). Insulin treated men lost 1.28 kg body weight and 1.38 kg body fat, and their waist circumference decreased by 1.63 cm (p's < 0.05); in contrast, insulin treated women did not lose body fat but gained 1.04 kg body weight (p < 0.05). In a separate study, single dose of 160 IU insulin or placebo were administered intranasally to a total of 32 healthy subjects (14 men, 18 women), and then food intake from an ad libitum breakfast buffet was measured. Insulin treatment decreased food intake in men but not in women (Benedict et al., 2008). These findings suggest a gender difference of insulin signaling in the brain, which is consistent with the results from animal studies (Clegg et al., 2003).
Intranasal administration of insulin, which is non-invasive and does not induce hypoglycemic reaction (Hilsted et al., 1995), provides a practical tool to examine the potential role of insulin in improving metabolic disturbances in patients with schizophrenia.
We conducted an 8-week, randomized, placebo-controlled, double-blinded study to examine how adjunctive insulin therapy might affect psychopathology, cognition and body metabolism in patients with schizophrenia. The findings on psychopathology and cognition, as well as the tolerability of study drug, have been reported elsewhere (Fan et al., in press). The study failed to demonstrate any significant benefit of intranasal insulin treatment in improving clinical symptoms of schizophrenia or cognitive function even though intranasal insulin was well tolerated by the study subjects. We now present the findings on body composition and lipid particle sizes using whole body dual-energy X-ray absorptiometry (DXA) and nuclear magnetic resonance (NMR) spectroscopy respectively.
Section snippets
Subjects
Adult outpatients with schizophrenia or schizoaffective disorder were recruited from an urban community mental health clinic. Psychiatric diagnosis was determined using the Structure Clinical Interview for DSM-IV (SCID). Other inclusion criteria included: 1) age 18 to 65 years; 2) stable dose of the current antipsychotic drug for at least 1 month; 3) English speaking. Exclusion criteria were: 1) inability to provide informed consent; 2) current substance abuse; 3) significant medical conditions
Results
Forty-five subjects were randomized (21 in the insulin group, 24 in the placebo group); 39 subjects completed the week-8 metabolic assessment, therefore were included in the final data analysis. The insulin group (N = 18) tended to have a higher education level (p = 0.060), and also tended to be older (p = 0.086) than the placebo group (N = 21). There were no significant differences between the two groups in age of illness onset, BMI, HOMA-IR, gender, race, marital status, diagnosis (schizophrenia or
Discussion
This was the first study to examine the potential impact of adjunctive intranasal insulin treatment on body metabolism in patients with schizophrenia using relatively sophisticated techniques including DXA to assess body composition, and NMR spectroscopy to measure lipid particle size. The 8-week study failed to show beneficial effect of intranasal insulin treatment on any of the major metabolic outcome measures.
Previous studies in healthy human subjects have suggested a gender difference in
Role of funding source
Dr. Fan has received research support or honoraria from Eli Lilly, AstraZeneca, Bristol-Myer-Squibb, Janssen, and Pfizer. Dr. Freudenreich has received research support or honoraria from AstraZeneca, Bristol-Myer-Squibb, Janssen, Eli Lilly, Cephalon and Pfizer. Dr. Goff has received research support or honoraria from Bristol-Myers Squibb, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Sovay, Hoffman-La Roche, Cypress, Dainippon Sumitomo, Abbott Laboratories,
Contributors
Dr. J Li, Dr. X Li and Dr. Fan were responsible for the analysis and interpretation of the data for this paper. All authors contributed to the writing of the paper.
Conflict of interest
None of the authors has any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence, or be perceived to influence, their work as submitted in the uploaded material.
Acknowledgments
None.
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This study was supported by grant 5K23MH082098 from the National Institutes of Health (Dr. Fan), the NARSAD Young Investigator Award (Dr. Fan), grant M01-RR-01066 and grant UL1 RR025758-01 from the National Institutes of Health, National Center for Research Resources General Clinical Research Centers Program (MGH Clinical Research Center), and an investigator initiated trial grant from the Eli Lilly and Company (Dr. Fan).
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