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Low-Dose Clozapine and Diabetic Ketoacidosis

Received March 8, 2002; revision received Sept. 11, 2002; accepted Oct. 4, 2002. From the Department of Psychiatry, Massachusetts General Hospital. Address reprint requests to Dr. Lafayette, Department of Psychiatry, WACC 812, Massachusetts General Hospital, 15 Parkman St., Boston, MA 02114; jlafayette{at}partners.org (e-mail).

Clozapine, an atypical antipsychotic medication, remains the most effective therapy for treatment-resistant schizophrenia. Its efficacy has generally outweighed its potential to induce life-threatening agranulocytosis. In recent years, however, glucose intolerance, diabetes, and diabetic ketoacidosis have emerged as serious medical conditions associated with the use of atypical antipsychotics such as clozapine.

Hagg and associates¹ reported that 12% of 60 clozapine-treated patients developed non-insulin-dependent diabetes mellitus, and Henderson and colleagues reported that 36% of 82 clozapine-treated patients developed diabetes within 5 years.² To date, 12 cases of diabetic ketoacidosis (Table 1) and multiple cases of hyperglycemia have been reported in association with clozapine administration.^2–13 Among the clozapine-treated patients with diabetic ketoacidosis, clozapine doses ranged from 200 mg/day to 500 mg/day (in one, the dose was unreported).^2–12

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TABLE 1. Reported Cases of Diabetic Ketoacidosis Among Clozapine-Treated Patients

We describe the case of a woman who developed diabetic ketoacidosis while taking low-dose clozapine, and we review the literature on new-onset diabetic ketoacidosis during clozapine administration.

Case Report

Ms. A, a single obese 22-year-old woman of Hispanic and Italian origin with schizophrenia and polysubstance dependence, was admitted to an inpatient psychiatric unit with disorganized thinking, paranoia, and auditory hallucinations. She was unpredictably violent and injured several staff members. She remained symptomatic while taking risperidone, 5 mg/day, and her serum prolactin level increased from 9.3 ng/ml to 88 ng/ml (normal range for women: 0–20 ng/ml).

Clozapine was initiated and the dose increased in 25-mg/day increments to 125 mg/day over 3 weeks. Ms. A's concurrent medications included lorazepam, 3 mg/day; risperidone, 5 mg/day; benztropine, 2 mg/day; a multivitamin, and calcium supplements. Urinalyses performed both before and 3 weeks after initiation of clozapine revealed neither abnormal glucose nor ketone levels.

During the 6th week of clozapine treatment, Ms. A had a medroxyprogesterone injection, which she had received previously for birth control, and her clozapine dose was increased to 150 mg/day. She demonstrated a 6-lb weight loss, from 188 to 182 lb. Risperidone was tapered to 2 mg/day and benztropine to 1 mg/day.

During the 9th week of clozapine treatment, Ms. A reported lethargy, menstrual spotting, cramping, breast tenderness, nausea, and vomiting. These symptoms appeared consistent with the effects of medroxyprogesterone. However, at the end of the 10th week, she acutely developed hyperventilation, shortness of breath, and chest discomfort, and she was transferred to an emergency ward. She was diagnosed with diabetic ketoacidosis (with a serum glucose level of 512 mg/dl, a pH level of 7.27, and ketonuria).

Although she had no history of diabetes, her risk factors included obesity, a body mass index of 33 kg/m², and two maternal aunts with non-insulin-dependent diabetes mellitus. One month before Ms. A started clozapine, a random serum glucose measurement was 123 mg/dl. When diabetic ketoacidosis was diagnosed, her glycohemoglobin A₁c level was 12.2% (normal range=3.8%–6.4%).

Ms. A was admitted to an intensive care unit, and clozapine was discontinued. Initially, she required intravenous insulin, which was followed by use of subcutaneous insulin. Risperidone was reinstituted. Upon discharge from the hospital 5 days later, she required 38 units of isophane insulin b.i.d. and 20 units of regular insulin b.i.d.

Within 3 weeks of discontinuing clozapine, Ms. A no longer required insulin. While she was on a diabetic diet, her fasting serum glucose levels were between 80 mg/dl and 110 mg/dl. Her risperidone dose was increased to 5 mg/day, and her psychosis improved significantly.

Discussion

Diabetic ketoacidosis is an acute metabolic complication of diabetes that is usually associated with insulin-dependent disease. Symptoms of diabetic ketoacidosis usually include anorexia, nausea, vomiting, hyperventilation, increased urine production, and abdominal pain, followed by a change in mental status. A diagnosis of diabetic ketoacidosis consists of hyperglycemia (a serum glucose level >250 mg/dl), a low serum bicarbonate level (<15 meq/ liter), and a pH less than 7.3, with ketonemia and ketonuria.¹⁴ The risk factors for developing diabetic ketoacidosis during clozapine treatment are unclear. Known risk factors for non-insulin-dependent diabetes mellitus in the general population include a family history of diabetes mellitus, prolonged obesity, age greater than 45 years, hypertension, hyperlipidemia, and a history of gestational diabetes.¹⁵

Our patient developed diabetic ketoacidosis while taking 150 mg/day of clozapine; moreover, her diabetes resolved 3 weeks after discontinuation of clozapine. To the best of our knowledge, this dose is the lowest recorded in a clozapine-treated patient who developed new-onset diabetic ketoacidosis.

To date, 12 cases of clozapine-associated diabetic ketoacidosis have been reported. Of these 12 patients, six had a family history of diabetes,^5–7,9,10 two of those with a family history of diabetes were obese,⁹ two had obesity as their only risk factor,^4,11 and one had gained 56 lb while taking clozapine;¹² the risk factors for two cases were not reported.^2,3 Of interest, Henderson and colleagues² found that weight gain did not correlate with the development of diabetes in 30 of 82 clozapine-treated patients who developed diabetes over a 5-year period.

Race may also be a risk factor for clozapine-associated diabetic ketoacidosis. Non-insulin-dependent diabetes mellitus is more common in African Americans, Hispanic Americans, Native Americans, Asian Americans, and Pacific Islanders.¹⁵ Of the patients with clozapine-associated diabetic ketoacidosis, five were African American,^6,8–10,12 two were African Caribbean,^3,11 two were Caucasian,^4,7 and in two cases, race was not reported.^2,5 Our patient was of Hispanic and Italian origin.

Age and gender may be risk factors for diabetic ketoacidosis. Ten of the previously reported patients were between the ages of 30 and 50 years.^3–12 One patient was 19,² and our patient was 22 years old. While this may suggest that older patients are at greater risk, it may be that clozapine is started at a later age (because of its serious side effects and previous attempts with other antipsychotic medications). Diabetic ketoacidosis associated with clozapine may be more common in men. Nine of the 12 reported patients were men.^2–5,8–12

Consideration must also be given to the impact of other medications on the onset of diabetic ketoacidosis. Our patient was taking several medications when she was diagnosed with diabetic ketoacidosis. Lorazepam and benztropine are not generally associated with hyperglycemia or diabetic ketoacidosis. Our patient had received a medroxyprogesterone injection; however, a review of the literature failed to reveal an association with medroxyprogesterone or a significant increase in oral glucose tolerance tests,¹⁶ making it an unlikely contributor to diabetic ketoacidosis. Risperidone, however, is a potential confounding factor. Possible contributions from risperidone include an elevated random glucose level before clozapine therapy and a substantially elevated hemoglobin A₁c level, an indicator of glucose control over 3 months when measured while the patient has diabetic ketoacidosis.

In one study of glucose regulation during antipsychotic treatment, patients treated with risperidone had higher fasting and postload glucose levels than healthy comparison subjects; however, these differences in glucose levels were not significant compared to patients treated with typical antipsychotics.¹⁷ There has been a case of risperidone-associated diabetic ketoacidosis in the literature.¹⁸ Risperidone has also been reported in the literature to be used without complications in schizophrenia patients with comorbid diabetes mellitus.^12,19,20 However, Wirshing and colleagues²¹ recently reported two cases of new-onset diabetes in risperidone-treated patients. Both subjects were African American, overweight, or obese before risperidone initiation and gained significant weight while receiving treatment with risperidone.

Another possible confounder with risperidone treatment was our patient's elevated prolactin level. Prolactinemia has been associated with glucose intolerance.²² It is possible that risperidone, in combination with low-dose clozapine, increased our patient's risk of developing diabetic ketoacidosis. However, since the patient was treated with risperidone alone after her diabetic ketoacidosis episode and her glucose values normalized, the impact of risperidone may be negligible.

Our patient's diabetes resolved completely 3 weeks after discontinuation of clozapine. In the other seven cases in which clozapine was discontinued after an episode of diabetic ketoacidosis, only three had complete resolution of diabetes; two patients required treatment for diabetes when clozapine⁴ or risperidone⁸ was restarted. Of interest, in these four patients in whom diabetes had resolved, lower doses of clozapine (150 to 325 mg/day) were received.^4,6,8 One case demonstrated resolution of diabetes when clozapine was lowered to 200 mg/day (after diabetic ketoacidosis was noted at 300 mg/day).²

Reports of hyperglycemia associated with clozapine have occurred with doses as low as 100 mg/day. In that case report, clozapine was continued, and the patient required an oral hypoglycemic medication.¹² In a patient with hyperglycemia (while taking 150 mg/day of clozapine), an oral hypoglycemic agent was required even after discontinuation of clozapine.¹²

Several mechanisms for clozapine-associated diabetes mellitus have been proposed. Clozapine-treated patients appear to experience insulin resistance.^17,23,24 Insulin resistance can be due to abnormalities at any step in the entire insulin action sequence, for example, receptor defects or postreceptor defects in insulin action. It is also possible that atypical antipsychotic agents cause a decrease in insulin-sensitive glucose transporters or an inability to stimulate recruitment of glucose transporters from microsomes to the plasma membrane. Long-term exposure to high concentrations of glucose and insulin reduces the subsequent ability of insulin to maximally stimulate glucose transport by inhibiting transporter translocation.²⁵ Dwyer and colleagues²⁶ reported that in vitro pimozide, fluphenazine, chlorpromazine, and clozapine inhibited glucose transport in rat pheochromocytoma cells, while haloperidol and sulpiride did not. Dwyer and associates²⁷ also reported that fluphenazine, chlorpromazine, and clozapine inhibited glucose transporter 3, while the haloperidol effect was significantly less. Alternatively, it may be that antagonism at serotonin 5-HT_1A receptors by atypical antipsychotic agents may decrease pancreatic B-cell responsiveness to blood sugar levels, resulting in impairment of glucose metabolism.¹²

Reports of diabetic ketoacidosis associated with low-dose clozapine and reports of severe hyperglycemia and diabetic ketoacidosis associated with olanzapine²⁸ highlight the importance of monitoring patients closely for diabetes while they are treated with atypical antipsychotics. Henderson and associates² have recommended screening for diabetes every 6 months in patients receiving clozapine. Given that three of the 12 patients in the literature had diabetic ketoacidosis begin within 1 month and another six within 3 months of the initiation of clozapine, clinicians might consider checking glucose levels every 4 weeks, particularly after initiation of the drug. We have started routinely checking blood glucose levels with a finger stick on a monthly basis in clozapine-treated patients on our psychiatric inpatient unit.

Further research is warranted to learn more about the risk factors for clozapine-associated diabetic ketoacidosis, to determine whether the dose of clozapine contributes to the risk for diabetic ketoacidosis, and to establish whether diabetes will resolve upon lowering of the dose or discontinuation of the medication.

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