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Recovery From New-Onset Diabetes in a Schizophrenic Man After Withdrawal of Olanzapine

Received July 23, 2001; revised September 26, 2001; accepted October 1, 2001. From Sollentuna Psychiatric Polyclinic, Sollentuna Hospital, Stockholm, Sweden, and Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden. Address correspondence and reprint requests to Dr. Hulting, Department of Endocrinology and Diabetology, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: anna-lena.hulting{at}ks.se

Key Words: Diabetes Mellitus • Antipsychotic Agents • Olanzapine

Among antipsychotic drugs, the atypical agents clozapine and olanzapine appear to have a direct diabetogenic effect,^1–3 whereas most conventional antipsychotics and newer agents, such as risperidone and ziprasidone, seem not to exhibit this type of side effect. Previous case studies have also described patients who developed diabetes mellitus, diabetic ketoacidosis, diabetic coma, or impaired glycemic control of already diagnosed diabetes after beginning clozapine or olanzapine treatment.^3–6 Although the exact mechanisms behind the diabetogenic effect are unknown, clozapine and olanzapine may induce insulin resistance,^4,7,8 which leads to a compensatory increase in insulin secretion (i.e., hyperinsulinemia). In the long run, if this compensation fails, hyperglycemia and diabetes will develop.⁹

We report a case of new-onset diabetes mellitus in an olanzapine-treated schizophrenic man, who recovered from his diabetes after stopping the olanzapine medication. We describe his blood glucose, insulin, lipid, and leptin levels before and during the withdrawal of olanzapine, and when continuing with risperidone and ziprasidone.

Case Report

Mr. X. is a 49-year-old man who started medication with the antipsychotic drug olanzapine. He had a 10-year history of paranoid schizophrenia and was granted an early retirement pension because of his psychotic disorder. Previously, he had been taking different types of conventional antipsychotics, but because of side effects (mainly parkinsonian symptoms), he had changed to clozapine, which he had used during the last 2 years. Clozapine, in turn, was discontinued because of insufficient antipsychotic effect and daytime sedation.

During several years taking antipsychotic medications for his psychotic disorder, Mr. X. had successively gained weight, and was already overweight (102 kg) before he started taking olanzapine. However, after only 5 months of medication with olanzapine (20 mg/day), he had gained an additional 10 kg of weight to 112 kg. Moreover, a fasting blood sample showed a slightly elevated blood glucose level: 7.0 mmol/L (126.1 mg/dL; reference range 3.5–6.4 mmol/L [63.1–115.3 mg/dL]), together with hyperinsulinemia, hyperlipidemia, and hyperleptinemia (Table 1). An initial stage of diabetes was diagnosed. The diabetic state was suspected to be induced by olanzapine because Mr. X. had no family history of diabetes and, during the time he was medicated with conventional antipsychotics, his fasting blood glucose and serum insulin levels were normal: 5.7 mmol/L (102.7 mg/dL) and 63 pmol/L (8.8 µU/mL; reference limit <79 pmol/L [<11.0 µU/mL]), respectively. Also during the clozapine therapy, his fasting blood glucose level was normal, 5.7 mmol/L (102.7 mg/dL), even though he then had moderate hyperinsulinemia, 100 pmol/L (13.9 µU/mL). Mr. X. had no other physical illness or medication that could have influenced his glucose metabolism. Apart from the appetite-stimulating and the possibly diabetogenic effects of olanzapine, Mr. X. was satisfied with the new drug. He experienced an improvement in his general well-being and reported both less discomfort with auditory hallucinations and paranoid delusions and less daytime sedation compared with clozapine. Therefore, he continued with olanzapine (20 mg/day), and because of his overweight and early phase of diabetes, he also received dietary recommendations.

View this table: [in this window] [in a new window]

TABLE 1. Laboratory findings, weight, and body mass index in Mr. X. during therapy with olanzapine, no antipsychotics, risperidone, or ziprasidone. Metric units are put in square brackets [ ], and reference ranges/limits in brackets ( ).

However, Mr. X. was not successful in changing his eating habits and continued to gain weight up to 117 kg. Then, after a total of 24 months of therapy with olanzapine, he exhibited a manifest diabetes mellitus with nocturia, weight loss, and a markedly elevated fasting blood glucose level of 15.3 mmol/L (275.6 mg/dL), together with a decreased insulin level (Table 1).

Therapy with olanzapine was discontinued gradually. After 1 week of therapy with a reduced dose of olanzapine (10 mg/ day), Mr. X. still had nocturia and an elevated fasting blood glucose level of 13.6 mmol/L (245.0 mg/dL), but after 3 more weeks of reduced therapy with olanzapine (5 mg/day), no more weight loss was noticed and the polyuria had disappeared. Moreover, his blood glucose level had nearly normalized, at 7.8 mmol/L (140.5 mg/dL), as well as his hyperlipidemia (Table 1).

Because Mr. X.'s mental status remained stable, the olanzapine medication was stopped. Three weeks later, the fasting blood glucose level was 7.0 mmol/L (126.1 mg/dL), and after 6 weeks without olanzapine, his blood glucose level had completely normalized, at 5.3 mmol/L (95.5 mg/dL), although he was still overweight (101 kg) (Table 1). However, Mr. X. then had a psychotic relapse with increased auditory hallucinations. In view of his previous experience of limited antipsychotic effect as well as side effects of clozapine and conventional antipsychotics, risperidone (up to 4 mg/day) was ordered.

Treatment with risperidone improved Mr. X.'s mental status. However, during therapy with risperidone, he again exhibited an increased blood glucose level, 6.9–7.1 mmol/L (124.3–127.9 mg/dL), together with hyperinsulinemia and a slight weight gain up to 102 kg (Table 1). At the same time, he showed an elevated prolactin level, 19–21 µg/L (normal reference limit for men, <10 µg/L). Because impaired glucose tolerance in diabetic subjects may improve after lowering prolactin levels,¹⁰ and because Mr. X. also continued to gain weight (up to 104 kg) with risperidone, we once again changed his antipsychotic agent, now to ziprasidone (160 mg/day). However, therapy with ziprasidone was not successful. Mr. X. had a psychotic relapse with increased auditory hallucinations and depressed mood. Furthermore, he still exhibited an elevated blood glucose level, 6.9–7.4 mmol/L (124.3–133.3 mg/dL) (Table 1), despite a normalized prolactin level of 9 µg/L. Therefore, ziprasidone was discontinued and risperidone was reinstated, which led to an improvement of his mental status. Moreover, Mr. X. received strict dietary recommendations, and 1 month later a normalized blood glucose level (5.1 mmol/L) was noted.

Discussion

The description of this case shows that medication with olanzapine in an already overweight patient can lead to further weight gain as well as insulin resistance and diabetes mellitus; on the other hand, ceasing medication can result in improvement of diabetes with normalization of blood glucose, insulin, lipid, and leptin levels. Our case study is one of six^6,11–13 that have described recovery from new-onset diabetes mellitus or diabetic ketoacidosis in olanzapine-treated patients after stopping therapy with olanzapine. One of those six patients recovered from his diabetes only by discontinuing olanzapine and instituting dietary control, as in Mr. X., whereas the other five patients received peroral antidiabetic agents and/or insulin therapy during a shorter period before improvement.^6,11–13

The finding of hyperinsulinemia together with overweight in Mr. X., already present during the clozapine therapy, may point to the existence of a clozapine-induced insulin-resistant state, also before beginning with olanzapine. However, after 5 months of medication with olanzapine, a slight hyperglycemia was found despite further hyperinsulinemia, which suggests an incipient failure to compensate for the insulin resistance and a development of diabetes. Later on, the hyperinsulinemia disappeared and manifest diabetes mellitus was obvious, with marked hyperglycemia, polyuria, and weight loss.

Moreover, the development of diabetes in Mr. X. was accompanied by hyperlipidemia, which is supported by the fact that hyperlipidemia and especially hypertriglyceridemia may be connected with insulin resistance and diabetes.⁹ In fact, the hyperlipidemia in Mr. X. was nearly normalized by discontinuing olanzapine and changing to risperidone or ziprasidone. In comparison, three earlier studies have shown that olanzapine use was associated with an increase in blood lipid levels,^4,14,15 whereas one study reported no increment in blood lipids during ziprasidone therapy.¹⁶ Concerning risperidone and blood lipid disturbances, no reports have been published to our knowledge.

Likewise, hyperleptinemia was noted at the same time that Mr. X.'s diabetes developed. The hormone leptin is synthesized by adipocytes at levels proportional to body adiposity.¹⁷ A firm correlation has been established between serum leptin levels and body mass index, with high leptin levels found in healthy overweight people.^17,18 In addition, hyperleptinemia may be connected with insulin resistance and the development of diabetes mellitus.¹⁹ In Mr. X., hyperleptinemia was found during olanzapine treatment as diabetes gradually developed, with a regression toward normal leptin levels after discontinuation of this antipsychotic and improvement of the glucose tolerance.

It should also be noted that before diabetes mellitus became manifest, Mr. X. had signs of the metabolic syndrome,²⁰ with insulin resistance, hyperlipidemia, and overweight. Because the metabolic syndrome increases the risk not only of diabetes, but also of cardiovascular disease,²⁰ we suggest that weight as well as fasting levels of blood glucose and blood lipids should be monitored before and during treatment with antipsychotics, especially with agents such as olanzapine and clozapine.^2–4,21,22 If clinical and laboratory signs of diabetes or of the metabolic syndrome are found, as in Mr. X., a change from olanzapine to other newer agents (e.g., ziprasidone or risperidone) or to conventional antipsychotics is to be recommended. Only if treatment with alternative antipsychotics fails to improve the patient's mental status should olanzapine be maintained, along with concomitant therapy for the hyperglycemia and hyperlipidemia with antidiabetics, insulin therapy, and/or lipid-lowering agents.

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