New-Onset Diabetes and Ketoacidosis in a Patient Treated with Olanzapine

Several case reports published since the introduction of atypical antipsychotics suggest an association between these medications and both new-onset diabetes mellitus and diabetic ketoacidosis. The latter is a potentially life threatening medical emergency. We report the case of a 41-year-old African American woman with schizophrenia who developed type 2 diabetes and ketoacidosis 7 months after commencing olanzapine therapy. This case adds to the evidence in the literature that patients who develop ketoacidosis while taking antipsychotic medications tend to be female and relatively young, a disproportionate number of whom are African American. The frequency of these reports suggests that clinicians should monitor serum glucose levels periodically in all patients treated with atypical antipsychotics, particularly in those at increased risk for diabetes.

Henry L. McCurtis, MD, Assistant Professor of Clinical Psychiatry; Charles U. Nnadi, MD, MS; Assistant Clinical Professor of Psychiatry; Olukayode O. Awosika, MD, Chief Resident, College of Physicians and Surgeons, Columbia University, Harlem Hospital Center, Department of Psychiatry, New York, NY

Case Presentation

A 41-year-old single African American woman with no history of diabetes mellitus was diagnosed with schizophrenia (paranoid type) in 1997. She started attending the psychiatric mental health clinic as an outpatient in 2001. Her medical history included peptic ulcer disease, obesity, dyslipidemia, hypertension, and a family history of diabetes (ie, mother and older sister). She smoked 3 cigarettes daily for the past 5 years.

The patient was initially maintained on 4 mg/day of risperidone (Risperdal) at bedtime. The drug was discontinued after a few months because her serum prolactin level increased to 80.85 ?g/L and then to 109.57 ?g/L, despite reducing the dose to 3 mg/day.

She was cross-tapered to haloperidol (Haldol), 5 mg twice daily. Her symptoms were controlled with haloperidol and, 2 months after discontinuing the risperidone, her prolactin level fell to 19.36 ?g/L. After 10 months, however, she refused to continue haloperidol therapy. Her random serum glucose level was 74 mg/dL in December 2001.

In January 2002, she had a glucose tolerance test because she was obese. Her fasting glucose level was 117 mg/dL, and the 1-, 2-, and 3-hour postprandial levels were 177 mg/dL, 158 mg/dL, and 99 mg/dL, respectively.

She began taking olanzapine (Zyprexa) in December 2002, and her symptoms were controlled with an average dose of 21.6 mg/day. In early April 2003, her serum glucose level increased to 146 mg/dL (Figure), and she was counseled about diabetes risk modification.

In July 2003, she complained of throat pain, weakness, and lassitude, along with polyuria and polydipsia of 3 days' duration. Results of laboratory tests revealed leukocytosis (white blood cell count, 19.9 x 10⁹/L, with 86.7% neutrophils and 6.2% lymphocytes); hematocrit, 46.7%; hyperglycemia (glucose, 865 mg/dL); acidosis with anion gap of 25 mmol/L and ketonemia (sodium, 130 mmol/L; potassium, 5.2 mmol/L; chloride, 93 mmol/L; CO2, 12 mmol/L; blood urea nitrogen, 12 mg/dL; creatinine, 1.5 mg/dL; pH, 7.2; and acetone positive). Urinalysis showed clear urine, with glucose, 3+; ketones, 3+; red blood cells, 2+; trace protein; and presence of trichomonas. She received 2 doses of insulin and was transferred to the emergency department, where her blood glucose level was recorded as 492 mg/dL.

The patient was admitted to the intensive care unit with a diagnosis of new-onset diabetes with ketoacidosis. She was treated with intravenous fluids, insulin, and metronidazole (Flagyl), and the olanzapine was discontinued. Her serum glycosylated hemoglobin (Hb A1c) level, which was 6.2% in May 2003, had increased to 26.3%. The patient was stabilized with metformin HCl (Glucophage), 500 mg twice daily; glyburide (Dia-Beta, Micronase), 5 mg/day; and lansoprazole (Prevacid), 30 mg/day. She was discharged home after 6 days. Her psychotic symptoms are currently controlled with molindone HCl (Moban), 25 mg twice daily. In January 2004, her random serum glucose level was 113 mg/dL and her Hb A1c level, 6.7%. She continues to receive oral hypoglycemic therapy.

Discussion

Several risk factors for the development of diabetes have been identified (Table). Our patient had a few of these risk factors (ie, African American race, obesity, a family history of diabetes). Nevertheless, glucose dysregulation was not evident before she started taking the antipsychotic drug. It is important to note that during previous sequential exposure to risperidone and haloperidol, her glucose levels remained within normal range. Her development of ketoacidosis, which is usually seen in type 1 diabetes, despite absence of significant physical illness (eg, infection) might suggest an unusual pathogenesis for her diabetes. Although ketoacidosis is more common with type 1 diabetes, it can also occur with type 2, usually in association with the stress of another illness, such as infection.

The importance of race

The effect of race cannot be overlooked, as the literature suggests that African American and Hispanic patients tend to have increased maximum glucose levels during treatment with olanzapine, whereas non-Hispanic white patients are more likely to show a decrease.¹ It is thus possible that the acute onset of ketoacidosis and type 2 diabetes in this case was related to the use of olanzapine. This report also raises the question of whether African Americans who are taking atypical antipsychotics are at increased risk for ketoacidosis because of the enormous pharmacogenetic implication.

Use of antipsychotics

Though the natural course of new-onset diabetes associated with antipsychotic use is still not fully understood, postulated underlying mechanisms include (1) decreased tissue sensitivity to insulin independent of atypical medications, (2) increased serum insulin resistance related to atypical medications, (3) effects of atypical medications on serotonin receptors (5HT2A and 5HT2C) in the pancreatic beta cells, and (4) overuse of insulin caused by weight gain.^1,2

A literature search of the National Library of Medicine online database yielded numerous case reports associating various psychotropic medications, including olanzapine, with glucose dysregulation. Fourteen of these reports described 16 patients who developed ketoacidosis while taking olanzapine, 44% of whom were African Americans.^3-14 In addition, there were 25 reported cases of fatal ketoacidosis associated with olanzapine.⁶ The mean time between atypical antipsychotic exposure and the development of diabetes or ketoacidosis was 3 months, with a range of 10 days to 18 months.¹ Patients who developed ketoacidosis tended to be younger women (mean age, 37 years; range, 16-56 years) who gained less weight compared with those who did not develop ketoacidosis (36.4 lb vs 47.6 lb, respectively). The former also presented with significantly higher blood glucose than those who developed diabetes but not ketoacidosis. (Our patient was 41-years-old at the time of diagnosis.)

Reports differ on the relative risk for new-onset diabetes associated with antipsychotic medication use. A recent large study of 56,849 patients treated with antipsychotic monotherapy showed that risk for diabetes was low, ranging from 2% or less with clozapine (Clozaril) and olanzapine to 0.05% with risperidone.¹⁵ Another study compared the frequency of newly reported type 2 diabetes in untreated psychosis patients and those treated with risperidone, olanzapine, clozapine, or high-potency and low-potency conventional antipsychotics.¹⁶

Olanzapine, clozapine, and some of the conventional antipsychotics appeared to increase the risk of developing or exacerbating preexisting type 2 diabetes; the odds of developing diabetes for risperidone- treated patients was not significantly different from that of untreated patients.¹⁶ However, another study on the efficacy of olanzapine in 55 treatment-refractory patients with schizophrenia showed a posttreatment incidence rate of hyperglycemia and diabetes that was comparable to that of the general population (5.5%-7.2% vs 6%-8%, respectively).¹

A more recent retrospective case-control study of 3115 adults (=18 years old) who were treated for at least 1 year with olanzapine, risperidone, or a phenothiazine nonetheless confirmed the increased relative risk of developing diabetes mellitus among patients taking olanzapine compared with those taking typical phenothiazines, and there was no evidence that the development of diabetes was associated with weight gain. Although patients taking risperidone also gained weight, they were not found to have similar risk.¹⁷

New labeling for antipsychotics

In September 2003, the Food and Drug Administration ruled that product labeling for all atypical antipsychotics must be updated to include a warning about the potential for hyperglycemia and diabetes, thus suggesting it is a class effect. To the best of our knowledge, there have been no cases of diabetes or ketoacidosis reported with the use of the newer antipsychotics aripiprazole (Abilify) or ziprasidone (Geodon). Of the older- generation antipsychotics, chlorpromazine HCl (Thorazine) and thioridazine HCl (Mellaril) have been most commonly associated with diabetes.

An association between diabetes and schizophrenia was described before antipsychotic medications became available, but prevalence of this association has increased significantly after the introduction of these agents. However, it is unclear whether treatment with olanzapine places individuals at risk for ketoacidosis. Controlled studies are needed to authenticate an association between ketoacidosis and olanzapine.

Recent Recommendations

In light of the increasing number of reports concerning an association between some of the antipsychotic medications and patient weight gain, diabetes onset, and impaired lipid profile, concern has risen about the use of these agents and the potential risk for cardiovascular disease associated with these conditions. This is particularly so because the relative risk of cardiovascular disease is also significantly greater in people with mental illnesses than in the general population.

Therefore, in November 2003, the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity convened a panel of experts to investigate the nature of the association between these health risks and use of antipsychotic agents as well as the added risk of cardiovascular disease.¹⁸ The panel outlined a set of recommendations for the prevention and treatment of associated risks in patients using antipsychotic medications¹⁸:

1. Assess the patient's metabolic risks when prescribing the antipsychotic agents.

2. Educate the patient, family, and caregiver about potential risks.

3. Screen for baseline measurements: body mass index (BMI), waist circumference, blood pressure (BP), fasting blood glucose, fasting lipid profile. Screen before or as soon as clinically possible after prescribing the medication.

4. Take a personal/family history: obesity, diabetes, dyslipidemia, hypertension, cardiovascular disease.

5. Monitor: BMI at 4 and 8 weeks after initiating drug therapy, then every 3 months; waist circumference, annually; fasting plasma glucose and BP at 12 weeks then annually; fasting lipid profile at 12 weeks, then every 5 years.

6. Refer to a specialist when appropriate.

Conclusion

Atypical antipsychotics are now frequently prescribed for psychotic and mood disorders because of their favorable side-effect profiles compared with conventional antipsychotics. However, concern is increasing about associated metabolic complications, such as hyperlipidemia, diabetes mellitus, or obesity. To reduce the risk of morbidity and mortality in an already compromised patient population, clinicians must monitor the weight and serum glucose and lipid levels of patients treated with antipsychotics. This will ensure early recognition and prompt individualized treatment of any complications that may arise. n

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