The relationship between atypical antipsychotics and hyperglycemia is not completely understood. Epidemiologic studies have shown an increased incidence of diabetes among patients with schizophrenia. We conducted a study to investigate the relationship between atypical antipsychotic therapy and the risk for diabetes. We analyzed data retrospectively from the medical records of 977 patients with schizophrenia who were started on atypical antipsychotics. At 15 weeks, 6 patients developed type 2 diabetes, with an average of 8 weeks to disease onset. All 6 patients gained weight while taking these medications. The results of our study suggest that patients who gain weight while taking atypical antipsychotics are at greater risk for incident diabetes. Such patients will need frequent monitoring of fasting blood glucose levels. If diabetes is diagnosed, patients may need insulin therapy initially, but most could eventually achieve glycemic control with oral hypoglycemic agents.

Diabetes is a major health problem in the United States, and its incidence as well as prevalence are increasing worldwide.¹ Epidemiologic studies indicate an increased prevalence of type 2 diabetes in patients with schizophrenia.² Evidence from the 1989 National Health Interview Survey, which was conducted before the widespread use of atypical antipsychotic medications, showed that women with schizophrenia had a significantly higher body mass index (BMI) than the general population (27.36 kg/m² versus 24.50 kg/m², respectively).³

Schizophrenia is also associated with an increased risk for cardiovascular morbidity and mortality, which is typically attributed to the patients' sedentary lifestyle, unbalanced diet, nicotine use, and obesity. Diabetes may increase this risk further. It is therefore important to avoid further risks and to be aware of the possible diabetogenic effects (ie, inducing insulin resistance) of antipsychotic medications.^4,5

The use of atypical antipsychotics has been increasing, because their beneficial psychiatric effects are associated with a lower incidence of extrapyramidal symptoms than that of conventional antipsychotics. However, follow-up studies have shown that atypical antipsychotics have many metabolic side effects, including obesity, glucose dysregulation, and an increased risk for new-onset diabetes.⁶

The relationship between atypical antipsychotics and hyperglycemia is not completely understood, and studies have produced conflicting results. Some retrospective analyses that compared atypical antipsychotics with placebo or with typical antipsychotics showed no increased risk for hyperglycemia,^7-9 or only a small attributable increased risk.¹⁰ Increasing evidence from case studies, retrospective analyses, and clinical trials, however, suggests that some atypical antipsychotics can increase the risk for metabolic abnormalities, including diabetes, in patients with schizophrenia.^11,12 Although data from double-blind clinical trials are limited, available results are consistent with the positive association demonstrated in case reports.¹³

Among the atypical antipsychotics, clozapine (Clozaril), olanzapine (Zyprexa), and quetiapine (Seroquel) have similar chemical structures, suggesting that they may share similar risks. Nevertheless, differences in their effects have been demonstrated.

The available evidence shows that clozapine and olanzapine appear to have the greatest propensity to induce weight gain, quetiapine and risperidone (Risperdal) have intermediate propensities, and ziprasidone HCl (Geodon) has the lowest propensity.^14,15

We conducted a retrospective study to evaluate the relationship between the use of atypical antipsychotics in patients with schizophrenia and the development of type 2 diabetes. Our study had 3 objectives:

• Determine the incidence and average time to onset of diabetes
• Identify the clinical features of patients who developed diabetes
• Determine the clinical presentation, treatment, and follow-up of these patients.

Methods

In this study, we performed a retrospective analysis of data from the medical records of 977 patients who had been started on atypical antipsychotic therapy between October 2003 and November 2004 at Interfaith Medical Center, New York.

Patients with a documented history of diabetes were excluded from the study. The patients' sex, race, personal history of hyperlipidemia or hypertension, family history of diabetes, blood glucose level, and hyperglycemic symptoms were recorded at the time of diabetes diagnosis. The blood glucose level and hyperglycemic symptoms were assessed again at the end of the follow-up period. BMI was measured at baseline, as well as during antipsychotic therapy. All antihyperglycemic medications prescribed once a patient was diagnosed with diabetes were recorded.

To determine the possible risk factors for new-onset diabetes mellitus after starting therapy with an atypical antipsychotic, we used a group of 60 matched controls who did not develop diabetes while taking these agents. All data were adjusted by age and sex and were then analyzed using logistic regression analysis (Statistical Analysis software version 8). The majority of the patients (n = 656) in our study were African American.

The study cohort consisted of 977 patients with schizophrenia who did not have a history of diabetes and who were started on atypical antipsychotic therapy. The patients were followed for an average of 15 weeks. Fasting blood glucose and body weight were measured at baseline and then every 2 weeks during the study.

Results

After 15 weeks of therapy with atypical antipsychotics, 6 of the 977 patients (4 men and 2 women) were diagnosed with diabetes, based on a fasting blood glucose level greater than 125 mg/dL. The overall incidence rate of new-onset diabetes was 0.61%. The average time to onset of diabetes was 8 weeks (range, 2-15 weeks).

In the first National Health and Nutrition Examination Survey (1971-1987),¹⁶ the age-adjusted, 16-year incidence of type 2 diabetes in blacks was 10.9% for men and 15.0% for women; in whites, it was 6.9% for men and 7.0% for women. Adjusting these data for a follow-up of 15 weeks would yield an incidence rate of 0.19% in black men, 0.27% in black women, and 0.12% in white men and women. Hence, the 15-week incidence rate of 0.61% of diabetes after starting atypical antipsychotics in our patient population is more than double the rate found in the general population.

The incidence of new-onset diabetes in our study was highest with olanzapine, whether as monotherapy or in combination with another atypical antipsychotic agent (Table 1).

Patient characteristics

Average age for the entire cohort was 40.8 years (range, 24-56 years); two thirds of the patients were black (n = 656); 50% of the patients either had a personal history of hyperlipidemia or a family history of diabetes.

At baseline, 5 patients were overweight (BMI ≥25 kg/m²), with an average BMI of 29.97 kg/m² (range, 21.38-45.18 kg/m²). All 6 patients diagnosed with diabetes gained weight during atypical antipsychotic therapy, with an average BMI increase of 6.25% (range, 1.35%-11.77%); 5 patients had a BMI increase of 5% or more (Table 2).

The control group consisted of 60 consecutive patients (33 men, 27 women) who were admitted to the psychiatric unit at Interfaith Medical Center in November 2004; they too were started on atypical antipsychotic therapy for schizophrenia, but they did not develop diabetes. The average age of the control group was 45.4 years (range, 22-79 years), and the average duration of follow-up was 4.6 months (range, 0.5-14.0 mo).

After adjusting for age, sex, race, and history of hyperlipidemia or hypertension, logistic regression analysis showed that a 5% or more increase in BMI after starting atypical antipsychotic therapy was significantly (P = .02) associated with the risk of new-onset diabetes (odds ratio, 0.067; 95% confidence interval, 0.006-0.703). None of the other factors was significantly associated with diabetes risk (Table 3).

Of the 6 patients who developed diabetes after starting atypical antipsychotic therapy, 3 were symptomatic at the time of diagnosis. Common presenting symptoms were polyuria, polydipsia, generalized weakness, and lethargy. Average blood glucose level (random) at the time of diagnosis of this group was 414 mg/dL (range, 231-741 mg/dL).

Treatment and follow-up

The atypical antipsychotics were discontinued in 4 of the 6 patients who developed diabetes. Initially, diabetes was treated with an oral hypoglycemic agent in 2 patients and with insulin in 4 patients. At the end of the first month of treatment, the diabetes was well-controlled with oral hypoglycemic therapy in 5 patients (83.3%), and 1 patient still required insulin. The average follow-up was 4.5 months (range, 1.5-7.0 mo). At the time of last follow-up, the diabetes of 4 of the 6 patients was well-controlled with oral hypoglycemic therapy (Table 4). The other 2 patients had stopped taking all medications on their own. Upon questioning, both admitted to having hyperglycemic symptoms, but both refused further testing.

Discussion

Monitoring blood glucose level

In our study, the incidence of type 2 diabetes after starting atypical antipsychotic therapy was higher than the incidence of new-onset diabetes in the general population.¹⁶ The risk for diabetes was greatest with olanzapine, either as monotherapy or in combination with other atypical antipsychotics. The average time to onset of diabetes was 8 weeks (range, 2-15 wk). This rapid progression to diabetes highlights the importance of monitoring fasting blood glucose levels before prescribing atypical antipsychotics and at frequent intervals after starting the therapy, which is supported by recent studies.^17,18

Two large, 1-year studies published in 2006 compared the risk for new-onset diabetes among patients treated with atypical antipsychotics.^17,18 In one of these studies, of 15,676 patients, the hazard ratios for incident diabetes were 1.64 with olanzapine, 1.60 with risperidone, and 1.67 with quetiapine (compared with haloperidol). The risk for diabetes was greater in patients younger than 50 years.¹⁸ The second study of 412 patients demonstrated a significant association between diabetes risk and the use of olanzapine (odds ratio, 8.4) but not of risperidone or quetiapine (versus haloperidol).¹⁷

The traditional risk factors for diabetes, such as hyperlipidemia and a family history of diabetes, were present in only 50% of the patients diagnosed with diabetes. Analysis showed a significant association between a BMI increase of 5% or more after starting atypical antipsychotic therapy and the risk for new-onset diabetes. Other factors were not statistically significant, possibly because of the small size of the study population.

Only 3 of the 6 patients had hyperglycemic symptoms at the time they were diagnosed with diabetes. This highlights the importance of monitoring blood glucose levels in all patients before prescribing atypical antipsychotics. All patients who continued oral hypoglycemic therapy were well-controlled at 4.5-month follow-up, including those who had initially required insulin.

We found no remission of diabetes at the end of the 15-week follow-up, whether atypical antipsychotic therapy was stopped or continued. Longer-term follow-up is needed to determine whether diabetes will remit in these patients.

Our finding that olanzapine was associated with the greatest risk for diabetes agrees with the findings of earlier studies that compared the atypical antipsychotics and their risk of diabetes.^14,15,17,18

Possible mechanisms

The increased risk for diabetes with certain antipsychotics may be associated with the risk of treatment-induced weight gain. By causing obesity, these agents can indirectly promote the development of insulin resistance and type 2 diabetes. In addition, atypical antipsychotics may directly induce hyperinsulinemia, which may be followed by weight gain, insulin resistance, and drug-induced diabetes that may require insulin treatment.¹⁹

Other mechanisms, including effects on central neurotransmitters and direct effects on glucose and lipid metabolism, may also contribute to disordered glucose metabolism.^11,20 Atypical antipsychotics can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. These agents impair the insulin-responsive glucose transport system, as well as lipolysis in adipocytes. This process directly induces insulin resistance and alters lipogenesis and lipolysis, promoting progressive lipid accumulation and adipocyte enlargement. These effects on adipocytes could explain, in part, the connection between atypical antipsychotics and weight gain and diabetes.²⁰ These agents exert their obesitogenic effect via the production of ghrelin, and their diabetogenic effect by enhancing resistin and tumor necrosis factor-a production.

Clinical challenges

Uncertainty about the mechanisms underlying the link between various antipsychotics and type 2 diabetes mellitus raises questions about routine clinical management. In particular, what monitoring should be undertaken in patients treated with antipsychotics, and how should diabetes that emerges during treatment be managed? The best practical method for screening for diabetes is also unclear.

In the absence of symptoms of diabetes, the American Diabetes Association recommends either the fasting plasma glucose or oral glucose tolerance test for diagnosing diabetes.¹ Fasting plasma glucose is the best screening test, but it may be difficult to perform in psychiatric populations. Random blood or capillary glucose measurements, although generally subject to variations in relation to eating, have reasonable sensitivity if results are interpreted according to the age of the patient and the time since the last meal.²¹

Despite the risk for serious medical complications, physicians must treat patients with mental disorders. Atypical antipsychotics can improve the quality of life for many patients with schizophrenia. Whether the benefits of these medications outweigh their risks is a matter of debate.⁴ Physicians must consider the individual patient and consult with the patient to weigh the potential risks and benefits and ensure that risks are carefully monitored during treatment. Frequent screening for type 2 diabetes should be performed, given its prevalence, its associated morbidity and mortality, and the availability of potentially effective treatments.

Conclusion

The data available so far, including the results of our study, indicate that atypical antipsychotics (especially olanzapine) are associated with an increased risk for developing diabetes. Patients may develop diabetes as early as 2 weeks after starting atypical antipsychotic therapy, or as late as 15 weeks. Our study suggests that patients whose BMI increases by 5% or more are at greatest risk. Physicians should monitor blood glucose levels and BMI (or weight) before prescribing atypical antipsychotic therapy and at frequent intervals during therapy. In our study, diabetes was well-controlled with oral hypoglycemic therapy, regardless of the initial method of treatment. Two recent studies reinforce the findings in our study, but additional large, prospective trials are needed to determine the long-term incidence of the disease in patients with schizophrenia who are treated with atypical antipsychotics.

Acknowledgments

Special thanks to Eric A Jaffe, MD, Jochanan M. Weisenfreund, MD, Maria F. Renedo, MD, and Zwege Deribe, MD, Interfaith Medical Center, Brooklyn, NY.

SELF-ASSESSMENT TEST

1. Compared with conventional antipsychotics, atypical antipsychotics have been associated with a decreased risk for all the following conditions, except:
   
   
   1. Tardive dystonia
   2. Dyskinesia
   3. Glucose dysregulation
   4. Agitation


2. Which of these agents appears to be associated with the highest incidence of new-onset diabetes?
   
   
   1. Clozapine
   2. Quetiapine
   3. Risperidone
   4. Olanzapine


3. Which factor has been found to be independently associated with incident diabetes during atypical antipsychotic therapy?
   
   
   1. Family history of diabetes
   2. Personal history of hyperlipidemia
   3. BMI ≥25 kg/m²
   4. BMI increase ≥5%


4. Based on the present study, which statement about the treatment of atypical antipsychotic–induced diabetes is true?
   
   
   1. Patients rarely require insulin
   2. Oral hypoglycemic therapy must typically be combined with insulin to achieve glycemic control
   3. Patients can be switched from insulin to oral hypoglycemic therapy
   4. Diabetes will remit once the atypical antipsychotic is withdrawn


5. Which statement about the use of atypical antipsychotics in patients with schizophrenia is not true?
   
   
   1. Benefits may not always outweigh risks
   2. Patients should be informed about potential metabolic risks
   3. Fasting plasma glucose is the best screening test in psychiatric patients
   4. Blood glucose levels and BMI should be measured before and during treatment

(Answers at end of references list)

References

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5. Cohen D. Atypical antipsychotics and new onset diabetes mellitus. An overview of the literature. Pharmacopsychiatry. 2004;37:1-11.
6. Jin H, Meyer JM, Jeste DV. Atypical antipsychotics and glucose dysregulation: a systematic review. Schizophr Res. 2001;71:195-212.
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9. Østbye T, Curtis LH, Masselink LE, et al. Atypical antipsychotic drugs and diabetes mellitus in a large outpatient population: a retrospective cohort study. Pharmacoepidemiol Drug Saf. 2005;14:407-415.
10. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry. 2004;161:1709-1711.
11. Haupt DW. Differential metabolic effects of antipsychotic treatments. Eur Neuropsychopharmacol. 2006;16(suppl 3):S¹⁴9-S¹⁵5.
12. Guo JJ, Keck PE Jr, Corey-Lisle PK, et al. Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, population-based, case-control study. J Clin Psychiatry. 2006;67:1055-1061.
13. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother. 2003;37: 1849-1857.
14. Ashim S, Warrington S, Anderson IM. Management of diabetes mellitus occurring during treatment with olanzapine: report of six cases and clinical implications. J Psychopharmacol. 2004;18:128-132.
15. Moisan J, Grégoire JP, Gaudet M, et al. Exploring the risk of diabetes mellitus and dyslipidemia among ambulatory users of atypical antipsychotics: a population-based comparison of risperidone and olanzapine. Pharmacoepidemiol Drug Saf. 2005;14:427-436.
16. Lipton RB, Liao Y, Cao G, et al. Determinants of incident non– insulin-dependent diabetes mellitus among blacks and whites in a national sample. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol. 1993;138:826-839.
17. Lambert MT, Copeland LA, Sampson N, et al. New-onset type-2 diabetes associated with atypical antipsychotic medications. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:919-923.
18. Lambert BL, Cunningham FE, Miller DR, et al. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol. 2006;164:672-681.
19. Melkersson KI, Dahl ML, Hulting AL. Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose-insulin homeostasis and lipid metabolism. Psychopharmacology (Berl). 2004;175:1-6.
20. Newcomer JW. Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry. 2004;65(suppl 18): 36-46.
21. US Preventive Services Task Force. Screening for type 2 diabetes in adults: recommendations and rationale. Ann Intern Med. 2003;138: 212-214.

Answers: 1. C; 2. D; 3. D; 4. C; 5. C.