Diabetic Ketoacidosis in a patient treated with olanzapine, valproic acid, and venlafaxine. (Letters to the Editor).

To the Editor: Several reports in the literature have associated treatment with atypical antipsychotic medications with the development of diabetes mellitus or related events, infrequent case reports have described presentations with severe acute complications such as diabetic ketoacidosis. We recently saw a male patient with a history of bipolar disorder who developed the onset of acute diabetic ketoacidosis during treatment with olanzapine, valproic acid and venlafaxine. The patient remains insulin-dependent and frustrated at his newly acquired diabetes mellitus. This case demonstrates the importance of regular monitoring of the blood glucose level and body weight of patients with chronic mental illness, especially patients with a predisposition to diabetes mellitus who are being treated with certain and/or multiple psychotropic medications. Recently, several case reports and clinical trials have suggested the risk for hyperglycemia, diabetes mellitus, and diabetes-related complications emerging during trea tment with atypical antipsychotic medications. (1) Rare case reports have described patients who presented with severe acute complications such as diabetic ketoacidosis. (2)

We present the case of a 35-year-old white man with bipolar disorder, cannabis dependence, and a history of alcohol and cocaine abuse in whom multiple medication trials with antidepressants, methylphenidate, alprazolam, and risperidone had failed. The patient's mood stabilized and his behavior improved during treatment with olanzapine 5 mg at bedtime, valproic acid 1,500 mg qd, and venlafaxine 75 mg qd. Eighteen months later, he developed an acute onset of ketoacidosis and diabetes mellitus. His medications were discontinued at the time of his admission to the intensive care unit, and valproic acid and venlafaxine were soon after restarted. The patient's risk factors for diabetes mellitus included overweight most of his life, with a further weight increase of approximately 60 lb during the previous 18 months, the patient's alcohol abuse history, and his maternal grandfather having diabetes. The patient had no known history of increased blood glucose levels, hypertension, or thyroid dysfunction. At the time of his lone admission to a mental hospital at 24 years of age, his weight had been 205 lb. his height had been recorded as 6 ft, 2.5 in, and his blood glucose level had been measured as 94 mg/dl. No other measurements of the patient's weight or blood glucose level were found in the available psychiatric notes. The patient remained mentally stable but was frustrated at his newly acquired diabetes mellitus type 1 five months after initial presentation to our institution.

Diabetes mellitus is a common illness with an increasing prevalence in the general population that is known to be even more common in schizophrenic patients. Recent studies imply that patients with bipolar disorder may also have a higher rate of diabetes mellitus than reference populations. (3) Whether this greater prevalence can be attributed to the underlying disease or to pharmacotherapy is debated. Known risk factors for diabetes mellitus include a positive family history, nonwhite ethnic background, age older than 45 years, obesity, history of glucose intolerance, sedentary lifestyle, hypertension, and dyslipidemia, possibly as well as thyroid dysfunction and alcohol abuse. Overweight and obesity are increasingly common public health problems among the general population as well as in individuals with mental illness. Lack of exercise and lack of access to health care, poor diet, and alcohol use are widespread in the general population, and more so among people with chronic mental illness, which puts them at an increased risk for acquiring diabetes mellitus. The patient reported a weight increase of 60 lb after he was started on olanzapine, valproic acid, and venlafaxine therapy. Weight gain is a frequent adverse effect of all of these medications. A search of the PubMed on-line database yielded multiple reports in which a number of psychotropic medications, including olanzapine, were associated with glucose dysregulation (eg, hyperglycemia, new diagnosis or exacerbation of previously diagnosed diabetes, ketoacidosis, hyperosmolar coma), (1,2) as well as a few studies in which valproic acid was associated with hyperinsulinemia and insulin resistance. (4) No connection between venlafaxine and glucose dysregulation was found in the literature search. Acute complications such as diabetic ketoacidosis are unusual (estimated rate, less than 1 in 1000 patients treated with olanzapine) and therefore difficult to study. A recent Eli Lilly-sponsored study of insulin-secretory responses in normal individuals found no e vidence of olanzapine or risperidone directly impairing pancreatic [beta]-cell function and insulin secretion, so this study does not support the hypothesis linking these agents to diabetic ketoacidosis. (5)

So, are the medications to be blamed for our patient's new-onset diabetes mellitus? It is possible that this individual with chronic mental illness was more vulnerable because of his genetic predisposition, obesity, and lifestyle. Treatment with psychotropic medications may have stressed his glucose regulatory mechanisms to the point of causing malfunction. Further clinical studies are needed to evaluate the degree to which medications are responsible for the increased incidence and prevalence of diabetes mellitus. Our patient's cannabis use and history of cocaine use also may have resulted in changes in his nutritional status, metabolism, and body weight. A few case reports have connected cannabis abuse with diabetic coma. Additional studies are required regarding the degree to which substance abuse underlies medical conditions. Physicians should inquire about patients' potential risk factors for diabetes mellitus and discuss thoroughly the risks and benefits involved in longterm treatment with psychotropic medications, and monotherapy should be preferred to polypharmacy. It is important to obtain baseline values and regularly recheck patients' blood glucose level and weight. Repeated attempts should be made to educate and encourage patients regarding the benefits of a healthy lifestyle. We have no commercial or proprietary interest in any drug, device, or equipment mentioned and have no financial interest in any item mentioned in this letter.

Sirpa A. Tavakoli, MD

Maria S. Arguisola, MD

Department of Psychiatry

University of Oklahoma College of Medicine-Tulsa Tulsa, OK

References

(1.) Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-566.

(2.) Straker D, Mendelowitz A, Karlin L. Near fatal ketoacidosis with olanzapine treatment. Psychosomatics 2002;43:339-340 (letter).

(3.) Cassidy F, Ahearn E, Carroll BJ. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry 1999;156:1417-1420.

(4.) Pylvanen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isojarvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia 2002;43:514-517.

(5.) Sowell MO, Mukhopadhyay N, Cavazzoni P, Shankar S, Steinberg HO, Breier A, et al. Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo. J Clin Endocrinol Meteb 2002;57:2918-2923.