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Eli Lilly \|[amp ]\| Co. (M.O.S., N.M., P.C., A.B., C.M.B., J.D.), Indianapolis, Indiana 46285; and Indiana University School of Medicine (S.S., H.O.S.), Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dr. Margaret O. Sowell, Lilly Research Laboratories, Eli Lilly \|[amp ]\| Co., Lilly Corporate Center, Drop Code 1758, Indianapolis, Indiana 46285. E-mail: . sowell_margaret_o{at}lilly.com
Abstract
The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on ß-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15–17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp.
Weight increased significantly (P < 0.01) in the olanzapine (2.8 ± 1.7 kg) and risperidone (3.1 ± 2.1 kg) treatment groups. An increase (
25%) in the insulin response to hyperglycemia and a decrease (18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone.
We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic ß-cell function.
THE NEWER ATYPICAL antipsychotics, such as clozapine, olanzapine, risperidone, quetiapine, and ziprasidone, are effective therapy for schizophrenia and are considered by many as first line therapy. These drugs act as antagonists at multiple receptors, including members of the dopaminergic, serotonergic, adrenergic, muscarinic, and histaminergic families (1, 2). Although the precise mechanism of action remains uncertain, the relatively high affinity for serotonergic receptors and the relatively low dopaminergic (D2) activity are believed to contribute to the improved efficacy and increased tolerability of these newer drugs. The serotonergic and histaminergic binding characteristics may contribute to weight gain that can be observed during treatment with these medications.
In addition to weight gain, a number of reports have suggested an association between the atypical antipsychotics and abnormalities in glucose homeostasis, including diabetes mellitus, diabetic ketoacidosis (DKA), and hyperosmolar nonketotic syndrome (reviewed in Refs. 3 and 4 ; 5, 6, 7, 8, 9). A variety of mechanisms have been postulated to account for an association between atypical antipsychotics and abnormalities of glucose metabolism (3, 4). Most invoke a weight-related decrease in insulin sensitivity or a direct drug effect that results in decreased insulin sensitivity or impairs pancreatic ß-cell function (e.g. decreases insulin secretion). Although weight gain is an obvious concern, hyperglycemia with severe metabolic decompensation has been reported in the absence of weight gain and in individuals without obvious risk factors for diabetes (3, 4). A direct drug effect has also been hypothesized based on case reports of patients presenting with DKA that are able to discontinue all antidiabetic therapy after cessation (positive dechallenge) of the suspected antipsychotic and a very small number of cases in which hyperglycemia is reported to return shortly after reintroduction of the antipsychotic (positive rechallenge) (3, 4).
The possibility of a link between schizophrenia or its therapy and diabetes is not new (10). The first reports predate the introduction of pharmacological therapy (11, 12) and increased after the widespread use of phenothiazine derivatives (13, 14, 15, 16, 17, 18, 19). Some of the available data suggested that chlorpromazine might impair insulin secretion in man; however, this finding was not consistently observed.
Given the above considerations and the almost universal requirement for inadequate ß-cell function (absolute or relative) in the development of severe metabolic decompensation (DKA or hyperosmolar state) (20), we directed initial efforts toward clarifying whether subjects treated with olanzapine or risperidone experienced decreased insulin secretion. Using the highly sensitive hyperglycemic clamp, we examined insulin responses during a prolonged hyperglycemic challenge in healthy volunteers before and after 15–17 d of treatment with olanzapine, risperidone, or placebo.
Materials and Methods
Patient population
Subjects were healthy men and women between the ages of 18 and 65 yr, without preexisting conditions that could significantly alter glycemic status. At enrollment, subjects were required to have a history of normal glucose metabolism, a normal physical examination, a fasting glucose below 6.1 mmol/liter, and a body mass index (BMI) of 30 kg/m2 or less. All subjects provided written informed consent after the study procedures and possible treatment adverse effects were fully explained. The protocol was approved by the Indiana University School of Medicine institutional review board.
Subjects with significant comorbid illness, recent hospitalization, a first degree family history of type 1 or type 2 diabetes mellitus, previous exposure to antipsychotic medication, or current use of recreational drugs were excluded. Pregnant or lactating women and sexually active women of childbearing age not actively practicing birth control were also excluded.
Study design
Between 2 and 25 d before initiation of the study, medical history was recorded, and subjects were screened with a physical examination and clinical laboratory tests. Two to 4 d before the baseline clamp, subjects were admitted to an in-patient facility for diet stabilization with an isocaloric diet (25–35 kCal/kg) adjusted for activity level, smoking status, and satiety. The diet had a caloric distribution of 55% carbohydrate, 30% fat, and 15% protein, with a daily salt intake of 6 g. This diet was followed for at least 2 d before the hyperglycemic clamps, and subjects were requested to maintain this diet throughout the active treatment phase.
After the baseline clamp, subjects were randomly assigned to single-blind treatment (investigative staff performing clamps were blinded) with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo. Medications were begun at a half-maximal dose and titrated over 4 d, after which subjects were allowed up to three hospital release passes (72 h each). Subjects were readmitted at least 48 h before the final clamp and had to undergo a urine drug screen for recreational substances upon each readmission. Subjects unable to tolerate the maximum dose of study drug or with a positive urine drug screen upon readmission were discontinued.
Hyperglycemic clamp
Subjects underwent hyperglycemic clamps (21) at baseline before randomization and after 15–17 d of treatment with olanzapine, risperidone, or placebo. Subjects were requested to refrain from alcohol and vigorous exercise for 24 h and from tobacco for 12 h before the clamp. After a 9-h fast, each subject began the clamp procedure at approximately 0700 h.
Subjects were studied in the supine position with catheters inserted in an antecubital vein for infusion of glucose and potassium and into a dorsal hand vein, in a retrograde fashion, for drawing blood samples. The hand was warmed to 60–70 C using a heating pad to obtain arterialized venous blood. Approximately 10 min after catheter insertion, two sets of baseline blood samples were obtained 10 min apart for measurements of glucose, insulin, and C peptide.
After baseline samples were obtained, the hyperglycemic clamp was initiated with a 15-min priming dose of 20% (wt/vol) glucose. This priming dose was based on previous studies in which the mass of glucose required to increase glycemia to the target level (11.1 mmol/liter) was empirically derived using a modification of the Andres method (21). Half of the total glucose mass was infused during the first 5 min, and the remainder during the next 10 min, then the infusion rate was decreased by half to prevent exceeding target glycemia. Plasma glucose values were determined at 5-min intervals using a bedside glucose analyzer, and the glucose infusion rate was adjusted to maintain the target level of glycemia. The procedure was continued for a total of 240 min after initiation of the glucose infusion. Sampling for insulin and C peptide was performed at 2-min intervals from 0–10 min, at 15- to 30-min intervals from 10–120 min, and at 20-min intervals during the final 2 h. Blood glucose levels at steady state varied by less than 5%. To prevent hypokalemia, potassium was infused during the studies at a maximum rate of 0.0038 mEq/kg•min as tolerated.
Fasting measurements of glucose, insulin, and C peptide were calculated as the mean of the 0 and -10 min values collected before the clamp. The insulin responses to hyperglycemia were evaluated as first phase (0–10 min), second phase (10–240 min), and total insulin response (TIR; 0–240 min). In each of these intervals the insulin response was measured by a weighted average of the insulin concentrations measured during that time interval after subtracting the baseline (fasting) concentration. The weight of each measurement was proportional to the time interval between that measurement and the previous one, so that the weighted average represents the average concentration during the whole time interval. The total C peptide response (TCR; 0–240 min) was similarly quantitated. An insulin sensitivity index was calculated by dividing the steady state (180–240 min) average glucose infusion rate (millimoles per liter/kg BW•min) by the average insulin concentration (picomoles per liter).
Analysis of blood samples
Insulin was assayed using the Abbott IMX MEIA system (Abbott Laboratories, Abbott Park, IL), which has an intraassay coefficient of variation of 2.5–4.0% and an interassay coefficient of variation of 4.4–6.0%. C Peptide was analyzed by the BioData 125I C peptide tracer/C peptide-specific primary antibody system (Polymedco, Inc., Cortland Manor, NY).
Statistical methods
An ANOVA model was used to examine the baseline to end point changes in fasting measures (glucose, insulin, and C peptide) as well as the first phase, second phase, and total (0–240 min) insulin and C peptide responses during the hyperglycemic clamps. Treatment effects on study variables were examined using a t test, comparing the change during treatment with olanzapine or risperidone against that with placebo. The above analyses were repeated with change in BMI included as a covariate. Changes in study variables in the absence of weight gain were calculated from the linear regression analyses with therapy and change in BMI as covariates. All tests of hypotheses were two-sided, with a 5% level of significance.
Results
A total of 73 subjects were screened, and complete data were available for 48 subjects. Among subjects completing the protocol, there were no significant differences in baseline characteristics between the treatment groups, except that there were no females and there were 30% fewer total subjects in the risperidone arm (Table 1
). Fewer subjects randomized to risperidone completed the protocol due to study discontinuations (3 patients withdrew consent, 1 patient became pregnant, 1 patient had a positive drug screen, and 1 patient’s samples could not be analyzed) with blinded replacement. There was no apparent association between study discontinuations in the risperidone group and adverse events reported. There was 1 subject discontinuation in both the olanzapine and placebo-treated groups (both patients withdrew consent). We did note among subjects completing the protocol that somnolence was reported frequently among those receiving active therapies (35% olanzapine, P = 0.008 vs. placebo; 31% risperidone, P = 0.023 vs. placebo).
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). Weight increased significantly (3 kg; P < 0.01 within group) from baseline to end point in both the olanzapine and risperidone treatment groups (Table 2). Although subjects were requested to maintain an isocaloric diet of fixed composition throughout the study, they were allowed up to 9 d as out-patients. Diet composition and caloric intake were not closely monitored during the out-patient phases, and weight gain is probably a consequence of increased food intake in the two active therapy groups. We also observed significant increases (38%) in fasting insulin and C peptide (10–20%) in both the olanzapine and risperidone treatment groups. Increases in fasting insulin of comparable magnitude have been described in other short-term studies of hypercaloric feeding (22) and with high carbohydrate diets (23).
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Hyperglycemic clamps were performed at baseline and after 15–17 d of treatment. Plasma glucose levels were clamped at 11.1 mmol/liter for 240 min in both studies. The glucose infusion rate required to maintain this level of hyperglycemia over the course of the clamp were unchanged at the final study for all treatment groups (Table 3 and data not shown).
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). Mean C peptide levels were unchanged in all three treatment groups.
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) insulin responses were slightly lower at the end point than at baseline. Significant increases in the mean change in first phase (69.0 ± 95.4 mmol/liter; 38.7%), second phase (117.0 ± 201 mmol/liter; 22.3%), and TIR (Fig. 1) insulin responses were noted for the olanzapine group (P < 0.01 within group). Changes of comparable magnitude were observed in the risperidone group for first phase (35.4 ± 54.0 mmol/liter; 30.2%), second phase (90.0 ± 171.6 mmol/liter; 22.5%), and TIR (Fig. 1) insulin responses. Quantitation of the mean change in TCR confirmed that no significant changes occurred in any of the groups from baseline to end point. Although the hyperglycemic clamp is primarily used to assess insulin secretion, an index of insulin sensitivity can be obtained from steady state data. The ratio of the mean glucose infusion rate (M, which at steady state is a measure of glucose utilization) to the average insulin level, I, provides an index of insulin sensitivity that has been shown to correlate with direct measures obtained from a euglycemic clamp (24, 25). Data collected during the final hour of the clamps were used to calculate the insulin sensitivity index. Similar results were obtained using the third hour data (results not shown).
The mean glucose infusion rate and insulin at steady state did not significantly change in the placebo group (Table 3). There was also no significant change in the steady state mean glucose infusion rate, but there was an increase (15%) in mean insulin in the two active therapy groups. These data clearly demonstrate that even after 4 h of continuous stimulation, subjects treated for 15–17 d with olanzapine or risperidone were able to maintain an appropriate insulin response.
The increase in steady state insulin without concurrent change in M resulted in slightly lower indexes of insulin sensitivity in the active therapy groups. The magnitude of the decrease in insulin sensitivity observed with both drugs (18%) was identical; however, the within-group baseline to end point changed achieved statistical significance only for the olanzapine group (P = 0.038, n = 17 within the olanzapine group; P = 0.157, n = 13 within the risperidone group). The change in M/I ratio in the olanzapine and risperidone groups was not significantly different from that in the placebo group.
Impact of weight gain
Significant weight gain was observed in the olanzapine and risperidone treatment groups, and as expected, we found that changes in the clamp TIR (r = 0.5576; P = 0.02) were correlated with the change in BMI. A similar relationship between changes in BMI and fasting insulin was observed (r = 0.645; P = 0.08). To determine whether patients treated with olanzapine or risperidone experienced a weight-independent effect on fasting insulin levels, insulin secretion during the hyperglycemic clamps, or insulin sensitivity indexes, multivariate regression analyses were performed to predict mean changes in these variables in the absence of weight gain (no change in BMI). These analyses revealed that in the absence of weight gain, treatment with neither olanzapine nor risperidone was associated with a significant change in fasting insulin or clamp results (Table 4).
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Discussion
Using the gold standard for assessing insulin secretory capacity, we found no evidence that patients treated with the atypical antipsychotic drugs, olanzapine and risperidone, experienced a direct impairment of insulin secretion. An increase in the TIR during the clamp was seen with both drugs and was most likely related to weight gain observed during therapy. Importantly, even when the impact of weight gain was accounted for, we found no evidence that patients treated with olanzapine or risperidone experienced decreased insulin or C peptide responses during the hyperglycemic challenge.
We observed significant increases in TIR, but no changes in TCR, in the active therapy groups. The relationship among insulin secretion, insulin clearance, and peripheral C peptide levels is quite complex (26); however, the results of this study are suggestive of a weight-related decrease in insulin clearance. Modulation of the insulin clearance in response to body fat or weight changes has been described by others (27, 28). Regardless, the absence of a decrease in insulin or C peptide levels during the hyperglycemic clamps strongly argues against a direct negative effect of these antipsychotic drugs on pancreatic ß-cell function.
Case reports of diabetes temporally associated with antipsychotic treatment in the absence of weight gain (3, 4) have been offered as evidence of a direct drug effect on glucose homeostasis. However, neither obesity nor weight gain is a prerequisite for the development of diabetes (29), and weight loss may actually precede the diagnosis of this disease (30, 31). Therefore, caution should be exercised in invoking a direct drug effect in cases of new-onset diabetes in antipsychotic drug-treated patients who do not experience weight gain.
Cases of positive dechallenge after episodes of DKA in patients with psychosis treated with atypical antipsychotics have also been interpreted as supporting a direct drug effect (3, 4). Although classically considered a hallmark of autoimmune type 1 diabetes, DKA does occur in patients with type 2 diabetes and can be the presenting abnormality (32, 33, 34, 35). The natural history for this subgroup of patients with type 2 diabetes is interesting and relevant to the evaluation of diabetes during treatment with olanzapine and risperidone. For some patients with type 2 diabetes who present with DKA it is not uncommon, after resolution of the acute event to observe a period in which normoglycemia is maintained in the absence of antidiabetic therapy or is adequately managed with oral agents alone. It is also noteworthy that in many instances physicians have been unable to identify a triggering event, that might have contributed to the metabolic decompensation. Given this pattern of disease, it is likely that some cases of positive dechallenge may simply reflect the natural history of a subgroup of patients with type 2 diabetes. Reports of positive rechallenge with antipsychotics have been infrequent, making conclusions in these cases difficult (36, 37, 38, 39).
Two limitations of the current study warrant specific comment. First, healthy nonpsychiatric subjects were studied in this protocol. As the prevalence of diabetes in schizophrenics appears to exceed that in the general patient population (10), it could be argued that nonpsychiatric subjects do not possess the same susceptibility to pancreatic dysfunction during treatment with antipsychotics as patients with schizophrenia. The results of the current study cannot rule out this possibility, and ultimately, large scale epidemiological studies will be required to clarify whether patients receiving atypical antipsychotics exhibit higher rates of diabetes or a greater tendency for a DKA-prone subtype of type 2 diabetes than patients receiving other therapies or the nonpsychiatric population. Another potential limitation is the relatively short duration of drug exposure (a maximum of 17 d) employed in this protocol. At the time this study was initiated, at least 6 of 35 published case reports of diabetes during treatment with atypical agents recorded glycemic abnormalities within 30 d of exposure (3, 4). Furthermore, in a small prospective study of clozapine-treated patients, changes in glucose tolerance were reported in some subjects within 1 wk of the initial therapy (40). Therefore, we believed that 15–17 d would provide adequate exposure, particularly with use of the prolonged hyperglycemic challenge.
In summary, healthy volunteers treated with olanzapine or risperidone for 15–17 d exhibited very similar changes in insulin levels (fasting and clamp) that appear to be largely related to weight gain. We found no evidence that patients treated with either drug experienced decreased insulin secretion or significant weight-independent effects on insulin sensitivity as assessed by the hyperglycemic clamp. Overall, these data do not support a direct effect of olanzapine or risperidone to decrease insulin secretion or insulin sensitivity.
Acknowledgments
We thank Dr. Anne Pickard (Eli Lilly \|[amp ]\| Co.), Dr. Anantha Shekhar (Indiana University and Methodist Hospital Department of Psychiatry), and the staff of the Methodist Hospital (Indianapolis, IN) for assisting with the in-patient phases of this protocol. We also thank Dr. Christopher Carlson for helping with the preparation of this manuscript.
Footnotes
This work was supported by Eli Lilly \|[amp ]\| Co..
Abbreviations: BMI, Body mass index; DKA, diabetic ketoacidosis; TCR, total C peptide response; TIR, total insulin response.
Received November 28, 2001.
Accepted March 4, 2002.
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) and end point (
) hyperglycemic clamps are shown and are expressed as means (SD). SD are shown in parentheses.