Novel antipsychotics and new onset diabetes

BRIEF REPORTS Novel Antipsychotics and New Onset Diabetes Donna A. Wirshing, Brad J. Spellberg, Stephen M. Erhart, Stephen R. Marder, and William C. Wirshing Background: The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non–insulindependent diabetes mellitus. Methods: We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases. Results: Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics. Conclusions: Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychoticassociated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic b-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia. Biol Psychiatry 1998;44: 778–783 © 1998 Society of Biological Psychiatry Key Words: Clozapine, olanzapine, diabetes, side effect, serotonin, atypical antipsychotic

Introduction

A

mong the differences between the new antipsychotics—including clozapine, risperidone, and olanzapine—and conventional antipsychotics are the former’s

From the Department of Psychiatry, West Los Angeles Veterans Affairs Medical Center (DAW, SME, SRM, WCW); Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles School of Medicine (DAW, SME, SRM, WCW); and University of California at Los Angeles School of Medicine, Los Angeles, California (BJS). Address reprint requests to Donna A. Wirshing, MD, West Los Angeles Veterans Affairs Medical Center, 11301 Wilshire Boulevard, Building 210B, Room 15, Los Angeles, CA 90073. Received September 2, 1997; revised January 2, 1998; accepted February 24, 1998.

© 1998 Society of Biological Psychiatry

specific antagonism of serotonin (5-HT) receptors (Hyttel et al 1992; Jann 1991; Moore et al 1992; Schooler 1994) and their more favorable extrapyramidal adverse effect profile (Casey 1996; Lieberman et al 1994; Tollefson et al 1997; Umbricht and Kane 1995); however, despite their paucity of associated extrapyramidal symptoms, the new antipsychotic drugs are not entirely free of adverse effects (Marder et al 1993). Sporadic case reports in the literature have implicated clozapine in the induction of new onset diabetes (Kamran et al 1994; Koren et al 1997; Kostakoglu et al 1996; Koval et al 1994; Peterson and Byrd 1996; Popli et al 1997). Here we report on 3 new cases of clozapine treatmentemergent diabetes and describe the first two published case reports of olanzapine-associated diabetes. We also present a brief review of the literature on this novel topic, and speculate on likely mechanisms of action of novel antipsychotic drug (APD)-associated diabetes.

Case Reports Case 1 Mr. A. is a 47-year-old African-American man with schizophrenia who was treated with clozapine for 8 months. At the time of initiation of clozapine treatment, he had a history of borderline obesity and had demonstrated transient glucose intolerance several years previously during treatment with conventional antipsychotics. His glucose levels for the several years prior to initiation of clozapine therapy had ranged from 78 to 141 mg/dL, and 1 month prior to initiation of therapy his blood glucose was 78. He had no familial risk factors and no history of pancreatitis or other endocrine disorders. He developed diabetes 2 months after beginning treatment with clozapine. At the time of initial glucose elevation, the patient was 20% over ideal body weight, and had experienced a 24 pound (11%) weight gain since the beginning of clozapine treatment. Treatment with oral hypoglycemic agents (OHAs) was initiated but ineffective. The patient’s compliance with both oral hypoglycemics and antipsychotics was poor. His clozapine treatment was discontinued, and he is currently being treated with haloperidol. His weight has remained elevated, and he requires both glyburide (10 mg) and metformin (2500 mg) for continuing diabetes.

Case 2 Mr. B. is a 32-year-old African-American man with schizoaffective disorder who is undergoing treatment with clozapine. He has 0006-3223/98/$19.00 PII S0006-3223(98)00100-0

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no history of obesity, pancreatitis, or other endocrine disorders, and has no family history of diabetes. His blood glucose ranged from 75 to 94 in the several years prior to onset of clozapine therapy. The patient was at his ideal body weight prior to receiving clozapine therapy, but then gained 56 pounds (37% of body weight) in the ensuing months after clozapine was initiated. He was found incidentally to be in a diabetes-induced metabolic acidosis with high levels of ketones 18 months after advent of clozapine treatment. The patient’s psychiatric condition is quite stable on clozapine, and blood glucose is now under good control with glyburide (20 mg).

Case 3 Mr. C. is a 43-year-old African-American man with schizophrenia undergoing treatment with clozapine. He has a family history of adult onset diabetes in both parents, but no history of pancreatitis or other endocrine disorders. His blood glucose ranged from 80 to 90 mg/dL prior to initiation of clozapine therapy. After beginning clozapine, his glucose ranged in the 100s to 200s mg/dL. He was placed on OHAs for progressive episodes of hyperglycemia 6 months after treatment with clozapine was initiated. The patient’s baseline weight at the time clozapine was started was 12% over ideal body weight. It had increased to 20% over ideal body weight before OHAs were added. The patient has remained psychiatrically stable on clozapine, but his diabetes has been difficult to control. For the first time in the 3 years since clozapine was begun, he was hospitalized recently to better control his diabetes. In the inpatient setting, on a strict 1800 kilocalorie diet, the patient’s blood glucose was well controlled, and he was discharged. He is currently taking metformin (1000 mg) alone, which is successfully controlling his glucose levels.

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Case 5 Mr. E. is a 38-year-old African-American man with schizophrenia who is being treated with olanzapine. The patient has a history of obesity but no history of pancreatitis or other endocrine disorders. Both his mother and maternal grandmother suffer from diabetes. The patient’s blood sugar had never exceeded 110 mg/dL prior to initiation of olanzapine therapy, and 1 month prior to initiation of therapy it was 90 mg/dL. The patient’s diabetes developed 3 months after beginning treatment with olanzapine. At that time, the patient was 50% over ideal body weight, although this reflected only a 4% or 11 pound increase in his baseline weight measured prior to treatment. He has been treated with OHAs for three and a half years, and is currently taking glyburide (20 mg) with successful control of his blood sugar. He has been stable on olanzapine for almost 4 years.

Case 6 Mr. F. is a 56-year-old Caucasian man with schizophrenia currently being treated with olanzapine. His family history and previous medical history are unremarkable, except for obesity. Prior to beginning sertindole therapy, his blood glucose had ranged from 87 to 124 mg/dL. He demonstrated transient hyperglycemia during 7 months of treatment with sertindole, which was controlled with dietary restriction alone. Three months after being switched to olanzapine, he developed dietary unresponsive diabetes mellitis. His weight, however, remained unchanged from the time he had been on sertindole therapy. OHAs were initiated with good effect. His weight was unchanged during olanzapine treatment, although he was nearly 25% over ideal body weight at the time treatment was started. The patient has had an excellent clinical response to olanzapine, and for the past 4 years blood glucose is under good control with a low dose (1.25 mg) of glyburide.

Case 4

Discussion

Mr. D. is a 41-year-old African-American man who began clozapine treatment 5 weeks prior to developing diabetes. His family history and personal history were negative for diabetes, although his fasting blood glucose (measured eight times during the year prior to beginning clozapine) ranged between 90 and 123 mg/dL, with an average of 102 mg/dL. His baseline fasting glucose immediately prior to starting clozapine was 90, and he was 38% over his ideal body weight. Five weeks after initiation of clozapine he had a fasting blood glucose measurement of 1028. He had a profound mental status change and was initially placed in the medical intensive care unit. Endocrinologists evaluating him thought that he had suffered a direct toxic effect of the clozapine on the pancreas, as Mr. D. had elevated amylase levels. He was initially treated with insulin; however his Cpeptide measurement was elevated at 4.3 ng/mL, which is consistent with non–insulin-dependent diabetes mellitus (NIDDM), thus he was placed on an OHA and insulin was discontinued. Four weeks after changing over from clozapine to risperidone, his average blood glucose was 140.

These 6 cases of novel APD treatment-emergent diabetes bring the total number of reported cases to 15, all since 1994. Four of our 6 cases involved clozapine, as have all of the previously published cases (Table 1). To our knowledge, our two reports of olanzapine treatmentemergent diabetes are the first to be published. These latter cases would seem to expand the scope of the matter beyond the adverse effect of a single drug, and indicate that the emergence of diabetes may be a common liability among several of the novel APDs. There is no established mechanistic link between novel APDs and glucose homeostasis, but all of these drugs appear to cause more weight gain than conventional medications. Clozapine, risperidone, and olanzapine have all been shown to induce significant weight gain in patients (Cohen et al 1990; Lamberti et al 1992; Leadbetter et al 1992; Mertens 1991; Owens 1994). We have also found that patients taking clozapine, olanzapine, and

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Table 1. Summary of Novel APD-Induced Diabetes Case Reports Author

Date n

Kamran et al Koval et al Kostakoglu et al Peterson and Byrd Koren et al Popli et al Case 1

1994 1994 1996 1996 1997 1997

1 1 1 1 1 4

Drug (dose at time of diabetes onset) Clozapine Clozapine Clozapine Clozapine Clozapine

900 250 400 500 NR

mg mg mg mg

Age/race/sex 41 34 42 46 37

AA M AA F NR M AA M CM

Clozapine 425 mg

32 AA M

Case 2

Clozapine 450 mg

44 AA M

Case 3

Clozapine 200 mg

51 C M

Case 4

Clozapine 900 mg

51 AA M

Clozapine 150 mg

47 AA M

Case 2

Clozapine 400 mg

32 AA M

Case 3

Clozapine 100 mg

43 AA M

Case 4

Clozapine 200 mg

41 AA M

Case 5

Olanzapine 250 mg

38 AA M

Case 6

Olanzapine 25 mg

56 C M

Wirshing et al Case 1

Prior obesity NR NR Obese NR NR

History No No No No No

Hx Hx Hx Hx Hx

Family history

Weight changes during APD therapy

NR FHx IDDM 1 FHx NIDDM FHx type NR No FHx

NR NR NR NR NR

Obese, 11% No Hx FHx IDDM over IBW & NIDDM Obese, 42% No Hx No FHx over IBW NR Hx NIDDM NR NR

Hx NIDDM

NR

8 lbs increase over 5 weeks 3 lbs increase over 5 weeks No weight change from baseline No weight change from baseline

1997 6 Obese, 9% Hx IGT over IBW No obesity No Hx

No FHx

Obese, over Obese, over Obese, over Obese, over

No Hx

FHx NIDDM

No Hx

No FHx

No Hx

No FHx

No Hx

No FHx

13% IBW 38% IBW 42% IBW 27% IBW

No FHx

24 lbs (11%) increase over 8 weeks 56 lbs (37%) increase over 18 months 7 lbs (4%) increase over 20 weeks No weight change from baseline 14 lbs (5%) increase over 12 weeks No weight change from baseline

n, number of patients described in the publication; NR, not reported; AA, African-American; C, Caucasian; M, male; F, female; IBW, ideal body weight; Hx, history; FHx, family history; NIDDM, non–insulin-dependent (type II) diabetes; IDDM, insulin-dependent (type I) diabetes; IGT, impaired glucose tolerance.

risperidone, but not sertindole, gained more weight than those taking haloperidol decanoate (Wirshing et al in submission), and have shown that the degree of weight gain correlated with each drug’s affinity for the H1 receptor. H1 antagonism is well known to cause weight gain (Howarth et al 1984; Wilson and Hillas 1983) and is the suspected mechanism by which conventional medications cause weight gain (Bernstein 1988; Rockwell et al 1983). Sertindole has virtually no H1 antagonism (Leysen et al 1996), and risperidone has little H1 antagonism compared to olanzapine and clozapine, which is consistent with our finding that sertindole and risperidone have caused less increases in weight in our patients than olanzapine and clozapine (Wirshing et al in submission). It is also possible that 5-HT2C antagonism plays a role with the weight gain liability of the new compounds. Tecott et al (1995) developed a strain of mice whose gene for the 5-HT2C receptor was knocked out. These mice became severely obese and had a propensity for seizures. Agents like fenfluramine that have an agonist type effect at the 5-HT2C receptor (Garattini et al 1989) have been found to cause weight loss secondary to reduced food consumption (Luo and Li 1991; Blundell 1977; Walsh et al 1994). In contrast, drugs that antagonize serotonergic

transmission, like the novel antipsychotics, have been found to increase food intake leading to weight gain (Bernstein 1988; Goodall et al 1988; Silverstone and Goodall 1986; Fletcher 1988). Thus, one potential mechanism of diabetes induction is weight gain, caused by an increase in adipose tissue that in turn leads to insulin insensitivity, glucose intolerance, and if sufficiently severe, diabetes. In support of this notion, of the 15 historical published case reports (see Table 1), 12 of the patients possessed prior risk factors for diabetes, including a positive personal history of the disease, positive family history of the disease, or obesity (in the remainder, the presence or absence of risk factors were not clearly described in the reports). This suggests that the novel APDs might induce diabetes by exacerbating existing disease or predisease (i.e., impaired glucose tolerance or obesity), rather than by damaging previously normal homeostatic systems. Novel APDs should therefore be used cautiously in patients who demonstrate one or more risk factors for diabetes. Of course, it is possible that because so many of these patients had preexisting risk factors, their development of diabetes could have been coincidental. In 4 of the case reports, no change in weight was noted

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from baseline during novel APD therapy. Thus, weight gain cannot be the only mechanism of novel APD-induced diabetes. The drugs may also mediate a biochemical interaction with the glucose homeostatic system. Serotonin is known to play a role in glucose homeostasis, and the novel APDs are thought to exert their antipsychotic effect partially via antagonism of 5-HT receptors (Ames et al 1996). The function of 5-HT in glucose regulation is extremely complex, and the literature on this phenomenon is often contradictory (Baudrie and Chaouloff 1991; Sugimoto et al 1995). It is, though, generally believed that agonism of 5-HT1A receptors lowers blood glucose levels, while antagonism leads to a decrease in insulin and thereby to hyperglycemia (Uvnas-Moberg et al 1996; Wozniak and Linnoila 1991). Decreased serum insulin is probably secondary to 5-HT1A-induced decreased pancreatic b-cell responsiveness to blood sugar levels. In a predisposed subject, this effect might be sufficient to cause diabetes. Although the novel APDs have some activity at 5-HT1A receptor sites, they are much more potent at 5-HT2A/C sites (Leysen et al 1996). These latter receptors also affect alterations in glucose homeostasis. Two specific 5-HT2A/C receptor agonists, (1/2)-2,5-dimethoxy-4-iodoamphetamine (DOI) and a-methyl-5-HT, have been shown to induce hyperglycemia (Chaouloff et al 1990). Ketanserin, a specific antagonist of 5-HT2A/C, blocked intraperitoneal 5-HT-mediated induction of hyperglycemia (Yamada et al 1995), although administration of ritanserin, an antagonist of 5-HT2A/B/C receptors, caused no alteration in blood glucose levels (Wozniak and Linnoila 1991). Thus 5-HT2A/C receptors appear to have opposite effects of 5-HT1A receptors in the glucose homeostatic network. It is therefore difficult to predict the outcome of the simultaneous blockade of 5-HT1A and 5-HT2A/C receptors that occurs with the novel APDs. Any serotonergic link between novel APDs and hyperglycemia remains speculative at the present time. Since 2 of the last 30 subjects that we placed on olanzapine developed diabetes and 4 of the last 40 patients we have placed on clozapine have developed diabetes in our hands, in our population this seems to be a serious risk. In comparison, we have had no episodes of haloperidol- or risperidone-associated diabetes in the last 100 patients we have treated clinically. Further, several reports have found no convincing link between typical antipsychotic therapy and diabetes in schizophrenic patients (Keskiner et al 1973; Mukherjee et al 1989; Schwartz and Munoz 1968). Indeed, one study found a lower incidence of diabetes in schizophrenics who were taking antipsychotic medications than those who were not (Mukherjee et al 1996). Finally, it has been reported that prolactin induces an insulin-resistant state, necessitating elevated insulin levels to

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maintain normal glucose homeostasis (Foss et al 1995; Sorenson and Brelje 1997). Clozapine and olanzapine do not markedly alter prolactin levels, but olanzapine may cause mild prolactin elevation; however, we have no data on serum prolactin levels in our patients, so we cannot address the likelihood of the link between prolactin alterations and atypical antipsychotic treatment-emergent diabetes. Despite the small number of reported cases, there are two demographic trends apparent. First, 14 of the 15 published case reports involve men. The significance of this is unclear, and may reflect some hormonal interaction with glucose metabolism (Andersson et al 1994), or, more likely, selection bias in which fewer women are placed on novel drugs. Second, 5 of our 6 case reports, and 11 of the 14 published cases in which the ethnicities of the patients were disclosed, have involved African-Americans. As noted by Popli et al (1997), there is a higher prevalence of NIDDM in African-Americans compared to Caucasians in the United States (National Diabetes Data Group 1995), and this is likely due to both nutritional factors and impaired access to health care. This could be taken as evidence of the weight-gain mechanism of diabetes induction, as the African-American population is enriched for people with diabetic risk factors. No relationship between dosage of medication and diabetes can be established from our literature review and in our own cases. In all of our cases, we felt that the clinical improvement mediated by the novel APDs exceeded the risks of diabetes. In all cases we were able to gain good control of blood glucose levels with oral antidiabetic agents; however, the patient represented in Case 1 did not cooperate with clozapine treatment and was restarted on conventional agents. His “clozapine-associated” diabetes persisted, as did his increased weight, back on haloperidol therapy. These cases appear to demonstrate that in patients at risk for diabetes, novel agents may hasten the onset of this condition through both direct and indirect effects. It is important to recognize diabetic symptoms early on, intervene quickly with diet, patient education, and if necessary, oral hypoglycemic treatment.

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