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Dietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone

David C. Henderson, MD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

Bikash Sharma, MBBS

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

Xiaoduo Fan, MD, MS

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

Christina P. Borba, MPH

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA

Paul M. Copeland, MD

Harvard Medical School, Boston, MA, USA

Oliver Freudenreich, MD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

Corinne Cather, PhD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

A. Eden Evins, MD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

Donald C. Goff, MD

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA

BACKGROUND: High dietary saturated fat (SF) intake is strongly linked to metabolic disturbances. The goal of this study was to understand the relationship between clozapine and risperidone with glucose and lipid metabolism and dietary fat intake in patients with schizophrenia.

METHODS: Thirty-one clozapine-treated patients and 15 risperidone-treated patients were assessed using a 4-day dietary record, an IV glucose tolerance test, and lipid profiles.

RESULTS: Clozapine-treated patients consumed a significantly higher percentage of SF than did risperidone-treated patients (13.7% ± 3.4% vs 10.6% ± 3.0% of total energy; P = .007). Compared with the risperidone group, the clozapine group also had a significantly higher percentage of total fat in their diet (36% ± 6.7% vs 30.9% ± 5.7 % of total energy; P = .007). Similarly, the clozapine group had a significant impairment in insulin sensitivity index (SI), glucose effectiveness (SG), and disposition index (DI) compared with the risperidone group (P < .05). Pearson correlation analysis of both groups showed that dietary SF was significantly correlated with impairment in glucose homeostasis (SG: r = –0.43; P = .004; DI: r = –0.35; P = .02).

CONCLUSION: Abnormal glucose homeostasis in atypical clozapine-treated patients with schizophrenia may be associated with or aggravated by high dietary SF consumption.

KEYWORDS: schizophrenia, clozapine, risperidone, insulin resistance, saturated fat



Treatment with some atypical antipsychotic drugs may cause metabolic side effects such as insulin resistance (IR), dyslipidemia, weight gain, and type 2 diabetes mellitus (T2DM) in patients with schizophrenia.1-7 Interestingly, clozapine and risperidone have a significantly different propensity to cause these metabolic problems, with clozapine being associated with the greater risk.1,3,4,7-10 In a cross-sectional study, Henderson et al4 observed that clozapine-treated patients had a significant reduction in insulin sensitivity index (SI) and a significant reduction in glucose effectiveness (SG) compared with risperidone-treated patients. Although all patients in that study4 were nonobese, a significant fat deposition around the waist was observed in clozapine-treated patients compared with risperidone-treated patients.

In the general population, a diet containing high saturated fat (SF) is also strongly linked to the development of IR, increased blood triglycerides, low-density lipoprotein cholesterol (LDL-C) levels, weight gain, hypertension, and T2DM.11-23 These closely related metabolic problems—individually or cumulatively—put an individual at a greater risk of prematurely developing cardiovascular disease (CVD).24-28 In the schizophrenia population, the prevalence of these metabolic problems is much higher, and consequently, these patients have an increased risk of developing CVDs compared with the general population.29-31 The reason may be due to metabolic abnormalities induced by atypical antipsychotic drugs, superimposed on predisposing factors such as sedentary lifestyles and poor dietary intake, which are highly predominant in the schizophrenia population.32,33 Although schizophrenia patients tend to consume fewer calories, their food choices typically differ from those of the general population, and they are less likely to make healthy dietary choices.32,34-37 Studies suggest that high dietary SF (and low omega 3-polyunsaturated fatty acid [PUFA]) plays a key role in the development of T2DM,38 as well as determining a poor clinical outcome of schizophrenia.39-41 There are no reported studies on whether IR induced by atypical antipsychotic drugs has any relationship to poor dietary profile in this population. However, one study showed that clozapine-treated schizophrenia patients consumed almost twice as much sugar as those patients taking other antipsychotic agents.42 Coccurello et al43 and Fell et al44 observed that olanzapine treatment in mice altered their dietary macronutrient selection, resulting in a preference for a high-fat, high-sugar diet. Identification of a link between poor dietary profile and abnormalities in glucose metabolism induced by atypical antipsychotic drugs in the schizophrenia population would be useful for clinicians; such a link could support use of preventive measures through dietary modification before taking aggressive therapeutic approaches.

As a first approach to studying pharmacologic effects on dietary profile in schizophrenia patients and the possible relation to alterations in glucose metabolism, we chose to compare 2 drugs with different metabolic profiles—clozapine and risperidone. We used a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) and a 4-day food record in stable outpatients with schizophrenia in a cross-sectional design matched by body mass index (BMI) to minimize the confounding effect of differential weight gain between these drugs on glucose metabolism.


The study was approved by the institutional review boards of the Massachusetts General Hospital (MGH) and the Massachusetts Department of Mental Health. A total of 46 schizophrenia outpatients taking either clozapine or risperidone for a minimum of 1 year were recruited from the Freedom Trial Clinic and were studied at the Mallinckrodt General Clinical Research Center (GCRC) at MGH in Boston. Eligibility was determined by an interview and a medical record review for history and recent laboratory values. Patients were excluded on the basis of current substance abuse; pregnancy; diabetes mellitus; thyroid disease; significant medical illness, such as severe cardiovascular, hepatic, or renal disease; or unstable psychiatric illness. Patients treated with the following medications known to affect glucose tolerance were also excluded: oral contraceptives containing norgestrel, steroids, β-blockers, anti-inflammatory drugs (including aspirin and ibuprofen), thiazide diuretics, agents that induce weight loss, and valproate sodium. A urine pregnancy test was performed prior to the study for female patients of childbearing potential. Additionally, since the luteal phase is associated with a reduction in SI,45 menstruating women were interviewed concerning their menstrual history and date of last menses, were instructed to keep a log, and underwent the procedure during the early follicular phase of their menstrual cycle (days 1 to 7).

After providing written informed consent, patients underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV-TR Axis I disorders, research version, patient edition.46 Height was measured using a Harpenden Stadiometer, which was calibrated on a weekly basis. Patients were weighed on a digital electronic scale, and weight was recorded to the nearest 0.1 kg. Patients were given a diet plan calculated to maintain body weight and to provide a minimum of 250 g of carbohydrate for each of the 3 days prior to the FSIVGTT. Patients were also instructed to fast for 12 hours preceding the FSIVGTT and to not take their morning medications the day of the test. Family, residential program staff, and outreach workers assisted patients to maintain a high-carbohydrate intake and to guarantee fasting. Patients were admitted to the MGH-Mallinckrodt GCRC at 6:45 am on the day of the procedure. A complete nutritional assessment was conducted on admission and immediately prior to the initiation of the FSIVGTT. No patient was dropped from the study because of possible diabetes mellitus (fasting plasma glucose [FPG] level ≥126 mg/dL (6.99 mmol/L) at baseline.

Four-day dietary intake

Dietary intake was measured using a 4-day dietary record, and patients recorded their food and beverage consumption for 4 consecutive days (3 weekdays and 1 weekend day).47 To ensure accuracy, records were reviewed by trained dietary interviewers. Interviewers used neutral probing techniques, food models, and measuring tools to ensure completeness. Estimated intake of individual nutrient totals were calculated by the University of Minnesota Nutrition Data System for Research software (version 2.6; Food Database 6A; Nutrient Database 23; Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN).48


For the FSIVGTT, each patient received 2 IV catheters in antecubital veins (one in each arm). Baseline blood samples were drawn for FPG and serum insulin levels, basic chemistry profiles, lipid profile, complete blood count, and serum clozapine or risperidone concentrations 10 minutes prior to the glucose infusion (time, 10 minutes). Glucose 0.3 g/kg in normal saline was administered intravenously for 30 seconds at time 0. Blood samples of approximately 2 mL were withdrawn at –10, –5, 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 25, 27, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100, 110, 120, 140, 160, and 180 minutes for measurement of plasma glucose and serum insulin concentrations.49,50 Twenty minutes after the glucose infusion, 0.05 U/kg Humulin insulin (Eli Lilly and Company, Indianapolis IN) was administered intravenously over 45 seconds.

Laboratory assays

Laboratory assays were performed by the MGH chemistry laboratory and the Mallinckrodt GCRC Core Laboratory. Insulin immunometric assays were performed using an Immulite analyzer (Diagnostic Product Corp; Los Angeles, CA) with an intra-assay coefficient of variation of 4.2% to 7.6%. FPG levels were measured with a hexokinase reagent kit (A-gent glucose test; Abbott, South Pasadena, CA). Glucose assays were run in duplicate, and the intra-assay coefficient of variation ranged from 2% to 3%. Fasting total plasma cholesterol and triglyceride levels were measured enzymatically51 with an intra-assay coefficient of variation of 1.7% to 2.7% and 0.9% to 1.2%, respectively. The high-density lipoprotein cholesterol (HDL-C) fraction was measured after precipitation of low-density and very low-density lipoproteins with dextran sulfate-magnesium52 with an intra-assay coefficient of variation of 0.89% to 1.82%. LDL-C values were estimated indirectly for participants with plasma triglyceride levels <400 mg/dL (4.52 mmol/L).53

Minimal model calculations

The SI, SG, and acute insulin response to glucose (AIRG) were calculated from plasma glucose and serum insulin values using the MINMOD Millennium program developed by Richard Bergman, PhD.50,54 The SI represents the increase in the net fractional glucose clearance rate per unit change in serum insulin concentration after the IV glucose load. The SG represents the net fractional glucose clearance rate due to the increase in glucose, independent of any increase in circulating insulin concentrations above baseline. The AIRG measures the acute (0- to 10-minute) β-cell response to a glucose load calculated by the area under the curve (AUC) higher than basal insulin values. The AIRG was assessed as the incremental AUC (calculated by the trapezoid rule) from 0 to 10 minutes of the FSIVGTT. The disposition index (which equals SI × AIRG)—an index of β-cell function that takes into account the prevailing insulin sensitivity and exploits the hyperbolic relationship between the two49,55—was calculated by the method described by Kahn et al.55 The homeostasis model assessment of insulin resistance (HOMA-IR) is an alternative method to assess insulin resistance and β-cell function on the basis of known relationships with FPG and serum insulin concentrations. The HOMA-IR was calculated using the following formula: fasting serum insulin concentration × FPG concentration/22.5. The HOMA-IR was calculated by taking the mean of 3 fasting values (times, –10, –5, and 0).56,57

Statistical analysis

The data were analyzed using SPSS (version 13.0, SPSS Inc.; Chicago, IL). Descriptive statistics were used to describe demographics and laboratory measures. HOMA-IR was not distributed normally and was, therefore, log transformed before analysis. The Student t-test and chi-square test were used as appropriate to compare demographic and clinical variables between treatment groups. Furthermore, analysis of covariance (ANCOVA) was used to compare glucose metabolism measures and dietary intake measures between treatment groups after controlling for potential confounding variables like age, race, gender, BMI, duration of illness (schizophrenia), and family history of diabetes. Pearson correlation coefficients were used to quantify relations between glucose metabolism measures and dietary SF intake. For all statistical analyses, a P value <.05 (2-tailed) was used to test for statistical significance.


In the clozapine group (N = 31), 28 patients were Caucasian, whereas the risperidone group (N = 15) included 10 Caucasians and 5 African Americans (P = .051). Percentages of male and female and family history of diabetes were similar in both groups. There were no significant differences between groups for age, age at onset of schizophrenia, and weight (TABLE 1). Although not statistically significant, the mean BMI of clozapine-treated patients was greater than that of risperidone-treated patients.


Demographic and clinical characteristics of 46 schizophrenia patients treated with clozapine or risperidone

Characteristic Clozapine (N = 31) Risperidone (N = 15) Group comparison P value
Age 41 ± 9 44 ± 10 t (44) = 1.23 .225
Age of illness onset (y) 21 ± 7 25 ± 9 t (44) = 1.02 .316
Gender, N (%)   χ2 (1) = 0.61 .436
Male 24 (77) 10 (67)    
Female 7 (23) 5 (33)
Race, N (%)   χ2 (2) = 5.97 .051
Caucasian 28 (90) 10 (67)    
African American 2 (7) 5 (33)
Hispanic 1 (3) 0 (0)
Family history of diabetes   χ2 (1) = 0.11 .741
Yes 14 (45) 6 (40)    
No 17 (55) 9 (60)
Notes: Values are expressed as mean ± SD unless otherwise indicated.
Glucose metabolism

FSIVGTT with MINMOD analysis showed that SI, SG, and DI differed between groups, with clozapine-treated patients, compared with risperidone-treated patients, exhibiting significantly reduced SI (3.4 ± 3.3 × 10-4 min-1 per μU/mL vs 10.3 ± 6.9 × 10-4 min-1 per μU/mL; P < .001), SG (0.0152 ± 0.0055 min-1 vs 0.0213 ± 0.0053 min-1; P = .002), and DI (981 ± 1347 vs 3568 ± 3134; P = .001). Although not statistically significant, HOMA-IR (log-transformed) was numerically higher in the clozapine group compared with the risperidone group (mean ± SD, 0.2 ± 0.3 vs –0.1 ± 0.3; P = .074) (TABLE 2).


Comparison of glucose metabolism and lipid profile between clozapine and risperidone groups

Measurement Clozapine
Mean ± SD (N = 31)
Mean ± SD (N = 15)
Group comparison P value
Weight (kg) 81 ± 15.5 81.5 ± 31.2 t (44) = 0.08 .935
BMI (kg/m2) 27.3 ± 4.6 25.7 ± 2.8 t (44) = –1.28 .208
Total cholesterol (mg/dL) 167 ± 31 148 ± 46 t (39) = –1.53 .135
HDL-C (mg/dL) 35 ± 13 43 ± 21 t (39) = 1.35 .184
LDL-C (mg/dL) 92 ± 33 89 ± 40 t (36) = –0.30 .765
Triglycerides (mg/dL) 204 ± 139 84 ± 34 t (48) = –0.46 .008
Fasting plasma glucose (mg/dL) 95.8 ± 7.50 88.7 ± 8.4 F (1, 39) = 6.04 .018
Fasting serum insulin (μU/mL) 8.7 ± 6.3 5.2 ± 3.9 F (1, 39) = 1.51 .226
HOMA-IR (log transformed) 0.2 ± 0.3 –0.1 ± 0.3 F (1, 39) = 3.38 .074
SI (x 10–4 min–1 per μU/mL) 3.4 ± 3.3 10.3 ± 6.9 F (1, 39) = 14.96 <.001
SG (min–1) 0.0152 ± 0.0055 0.0213 ± 0.0053 F (1, 36) = 11.32 .002
AIRG (AUC, μU/mL per 10 min) 355 ± 346 421 ± 350 F (1, 35) = 2.24 .143
DI 981 ± 1347 3568 ± 3134 F (1, 38) = 12.51 .001
AIRG: acute insulin response to glucose; AUC: area under the curve; DI: disposition index; HDL-C: high-density lipoprotein cholesterol; HOMA-IR: homeostasis model of assessment of insulin resistance; LDL-C: low-density lipoprotein cholesterol; SG: glucose effectiveness; SI: insulin sensitivity index.

The fasting triglyceride level was significantly higher in the clozapine group compared with the risperidone group (mean ± SD, 204 ± 139 mg/dL vs 84 ± 34 mg/dL; P = .008). Other lipid measurements (total cholesterol, LDL-C, HDL-C) were not statistically significantly different between the 2 groups (TABLE 2).

Food intake assessment

After controlling for potential confounding variables like age, race, gender, BMI, duration of illness, and family history of diabetes, the analysis of the 4-day food record showed that the clozapine group had a significantly higher percentage of SF in their diet compared with the risperidone group (13.7% ± 3.4% vs 10.6% ± 3.0% of total energy; P = .007). The clozapine group also had significantly high total fat (36.0% ± 6.7% vs 30.9% ± 5.7% of total energy; P = .013), lower carbohydrate intake (48.8% ± 7.5% vs 55.7% ± 9.5% of total energy; P = .009), and higher protein (16.2% ± 3.9% vs 13.8% ± 3.4% of total energy; P = .036) in their diet compared with the risperidone group. There were no statistically significant differences between groups in total energy intake (P = .469), or monounsaturated fat (P = .126) or polyunsaturated fat intake (P = .340) (TABLE 3).


Dietary intake from a 4-day food record analysis: Clozapine-treated vs risperidone-treated schizophrenia patients

Measurement Clozapine
Mean ± SD (N = 31)
Mean ± SD (N = 15)
Group comparison P value
Total energy (kcal) 2092 ± 1009 1923 ± 557 F (1, 40) = .053 .469
Carbohydrate (% total energy) 48.8 ± 7.5 55.7 ± 9.5 F (1, 40) = 7.49 .009
Protein (% total energy) 16.2 ± 3.9 13.8 ± 3.4 F (1, 40) = 4.72 .036
Fat (% total energy) 36.0 ± 6.7 30.9 ± 5.7 F (1, 40) = 6.72 .013
Saturated fat (% total energy) 13.7 ± 3.4 10.6 ± 3.0 F (1, 40) = 8.23 .007
Monounsaturated fat (% total energy) 13.1 ± 2.9 11.8 ± 2.3 F (1, 40) = 2.44 .126
Polyunsaturated fat (% total energy) 6.2 ± 1.4 5.8 ± 2.1 F (1, 40) = 0.93 .340
Association between saturated fat intake and glucose metabolism

Pearson correlation analysis of the entire sample showed significant inverse relationships between the percentage of dietary SF intake and SG (r = –0.43; P = .004) and DI (r = –0.35; P = .020). There was a trend of an inverse relationship between percentage of SF and SI (r = –0.27; P = .068) (FIGURE 1A-C); however, no clear relationship with AIRG (r = –0.20; P = .202) was observed.

Pearson correlation analysis on each group showed that the clozapine group had a significant inverse relationship between percentage of dietary SF intake and SG (r = –0.42; P = .026); however, no relation between dietary SF and any measure of glucose abnormality was found in the risperidone group

FIGURE 1 Pearson correlation analysis on the entire sample of 46 clozapine- or risperidone-treated schizophrenia patients correlating dietary saturated fat with measures of glucose metabolism

SG: glucose effectiveness; SI: insulin sensitivity index.


Our study found that patients with schizophrenia had poorer dietary profiles than those recommended by the Dietary Guidelines for Americans (DGA), issued by the US Departments of Agriculture and Health and Human Services,58 which is consistent with a previous report.34 Both clozapine- and risperidone-treated schizophrenia patients in our study had consumed a significantly higher percentage of SF in their diet than what is recommended (<7% of total calories) by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)59 and the American Heart Association (AHA).60 A striking feature, however, was that patients treated with clozapine consumed significantly more SF in their diet than did patients treated with risperidone. Moreover, compared with the risperidone group, the clozapine group also had significant impairment in glucose homeostasis, as manifested by decreases in SI, SG, and DI. Although nonsignificant, AIRG was also decreased in the clozapine group compared with the risperidone group. These findings are also consistent with our earlier findings.4

The main focus of our study, however, was the relationship between dietary SF intake and the degree of IR in schizophrenia patients treated with clozapine or risperidone—2 drugs having different propensities to cause IR. We found that higher dietary SF intake was proportionally associated with impaired glucose homeostasis in both the clozapine and the risperidone groups. As shown by Pearson correlation analysis, dietary SF was significantly negatively correlated with SG and DI, with a trend toward SI in both groups. When the same analysis was done in each treatment group, the clozapine group, having consumed more SF, had a significant impairment in SG; however, no such relation was found in the risperidone group. Clozapine-treated patients also consumed significantly higher total fat (36.0% ± 6.7% of total energy; near the threshold, as recommended by the NCEP ATP III),59,61 fewer carbohydrates (vs the DGA recommendation of 55% to 60% of total energy) and more protein (vs the DGA recommendation of 15% of total energy) in their diet compared with patients treated with risperidone.

The facilitative glucose transporter (GLUT-2) and glucose-phosphorylating enzyme (glucokinase) are considered the key factors for glucose sensing by the pancreatic β cell (AIRG). A high-fat diet is known to reduce both GLUT-2 and glucokinase function.62 Furthermore, a high-fat diet and specific free fatty acids induce oxidative stress and apoptosis of β-cell mass and compromise their function. SI highlights the overall sensitivity of insulin receptors.62 At the molecular level, defects of insulin signaling, such as reduced insulin receptor tyrosine kinase activity and reduced postreceptor phosphorylation, lead to IR. Similarly, SG is closely dependent on the cellular glucose transport system (GLUT-4) and therefore indicates the availability and functional capacity of GLUT-4 receptors. A significant decrease in SG in our study could be due to either reduced functioning of GLUT-4 or impairment of hepatic glucose production.4 Under normal conditions, a reduction in SI is compensated with an acute increase in insulin secretion (AIRG), and vice versa, to preserve normoglycemia. DI should therefore be constant in normal patients and reduced in impaired glucose tolerance. Also, if SI declines, the same feedback mechanism helps to compensate the disturbance by increasing SG and vice versa. A significantly impaired SG and DI, with a trend toward impaired SI and no association with AIRG in relation to dietary SF in both of our study groups, suggests that this sophisticated negative feedback mechanism of glucose homeostasis may be disrupted by SF. The mechanism linking dietary SF to IR at the molecular level is not precisely understood; however, some evidence suggests that it may be mediated through the specific fatty acid component of cell membranes, which influence insulin action through several potential mechanisms, including altering insulin receptor binding affinity and influencing ion permeability and cell signaling.63,64

The association of higher dietary SF intake with impairment in SG within the clozapine group elucidates a possible mechanism of clozapine-induced IR. Clozapine incubated with rat pheochromocytoma cells has also been shown to impair glucose transporters.65 However, the natural progression of IR to development of overt T2DM is a gradual process, and several other metabolic abnormalities that develop during this progression, such as high plasma triglycerides, low HDL-C, abdominal obesity, and essential hypertension, may hasten this process.

A naturalistic study of 82 schizophrenia patients taking clozapine found that new-onset T2DM developed in 36.6% of patients within a follow-up period of only 5 years.66 Serum triglyceride levels were significantly increased, but total cholesterol was increased nonsignificantly. Weight was significantly increased over time and correlated with serum triglycerides and total serum cholesterol levels; however, weight gain was not a significant risk factor for developing T2DM.66 A 10-year naturalistic study of 96 clozapine-treated schizophrenia patients from the same cohort, however, found that obesity, serum triglycerides, and total serum cholesterol were all significantly correlated with the development of T2DM and the risk of cardiovascular mortality.67 Metabolic problems observed in these 2 naturalistic studies66,67 have been strongly linked to dietary SF.

Clozapine-treated patients in our study had a significantly higher plasma triglyceride level and lower HDL-C (not significant) than patients treated with risperidone. These 2 abnormal lipid levels in our clozapine-treated patients are the most characteristic lipid abnormalities associated with IR.68 Hence, chronic dietary SF intake may play a negative role in the development of metabolic problems in clozapine-treated patients with schizophrenia.

The dietary preference of an individual is largely determined by physical and psychological health status.69 Studies show that a strong sense of coherence is associated with health-promoting food choices.70,71 The negative symptoms of schizophrenia—and side effects of drugs like clozapine, which is a potent histamine H1 antagonist—may increase appetite, decrease physical activity (due to sedation and fatigue), and influence food choices, such as a preference for easily obtainable, inexpensive foods that are high in SF. The palatable dietary selection containing SF in the clozapine group could also be due to its antagonism at serotonin receptor 5-HT(2c), which is associated with food preference and diet control in human.72 Ryan et al36 observed that even drug-free patients experiencing the first episode of schizophrenia had IR when compared with healthy patients. However, the same study observed that drug-naïve schizophrenia patients had consumed more SF than did healthy patients and had elevated cortisol levels.

It is logical to assume that high dietary consumption of SF, along with atypical antipsychotic drug treatment, may work synergistically to develop metabolic problems and CVD in patients with schizophrenia. In light of this association, if atypical antipsychotics cause schizophrenia patients to prefer to consume more SF, this knowledge may help to prevent the development of metabolic problems associated with these drugs by a simple approach to dietary modification, eg, by substituting SF with a healthier fat such as polyunsaturated fatty acids (PUFA). Replacing SF with PUFA in a patient’s diet may improve insulin sensitivity, decrease LDL-C and triglyceride concentrations, decrease blood pressure, and reduce the risk for CVD.60,64,73-83 Dietary PUFA has also been found to improve cognition in Alzheimer’s disease and schizophrenia.57,84-87

There are a number of limitations to our study. First, since drug treatment was not randomized and assessment was cross-sectional, the finding of an association between clozapine and risperidone treatments and dietary consumption of SF with regard to impairment of glucose metabolism cannot be established as a causal relationship. The small sample size also limits examination of mediating models to assess the relationships between the antipsychotic drugs, SF intake, and IR. Also, clozapine-treated patients are more likely to be treatment resistant and have a greater severity of illness and lifetime exposure to antipsychotic drugs, which may represent a selection bias. However, the age of onset of schizophrenia was similar in both groups. Second, although patients recorded their dietary intake for 4 days, it is possible that they had a different dietary pattern on other days. Third, other anticipated abnormalities in glucose and lipid metabolism associated with SF were limited due to the small sample size and the cross-sectional nature of our study.


Our findings provide a foundation for future research on overall dietary patterns and food choices by patients with schizophrenia. Improved understanding of the numerous modifiable dietary constituents that cause metabolic problems may guide development of preventive nutritional intervention strategies at the individual and population levels. Studies that include larger samples and varying durations of prospective atypical antipsychotic agent exposure, with limitations in dietary SF, are urgently needed to evaluate whether the development of IR can be prevented or controlled among patients with schizophrenia.

ACKNOWLEDGMENTS: Funding: Stanley Foundation, National Institutes of Health National Center for Research Resources Grant 5MO1RR01066-24 (General Clinical Research Center), and a NARSAD New Investigator Award (D.C.H.).

This data has not been published or presented elsewhere.

DISCLOSURES: Dr. Henderson receives research support and/or honoraria from Bristol-Myers Squibb, Covance, Janssen, L.P., Pfizer Inc, PriMedia, Reed Medical Education, Solvay Pharmaceuticals, and Takeda. Dr. Goff receives research support and/or honoraria from Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo Pharma, Forest Laboratories, Genactics, Janssen, L.P., MedReviews, LLC, Organon, Pfizer Inc, PriMedia, Proteus, Reed Medical Education, Solvay/Wyeth, Vanda Pharmaceuticals, XenoPort, and Xytis. Dr. Copeland receives research support and/or honoraria from Eli Lilly and Company, Merck, Takeda, and sanofi-aventis. Dr. Fan receives research support and honoraria from Eli Lilly and Company. Dr. Freudenreich receives research support and/or honoraria from Cephalon, PriMedia, and Reed Medical Education. Dr. Evins receives research support from the Consortium of Developmental Disabilities Councils (CDDC), GlaxoSmithKline, the National Institute on Drug Abuse (NIDA), and Pfizer Inc. Dr. Cather, Dr. Sharma, and Ms. Borba report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.


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CORRESPONDENCE: David C. Henderson, MD, Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114 USA E-MAIL: dchenderson@partners.org