A report in the January issue of the Archives of General Psychiatry reinforces earlier observations that some antipsychotic drugs may increase the risk for, or even cause, diabetes in patients with schizophrenia. Since these drugs are often prescribed to patients with Alzheimer disease, and given the evidence of a link between diabetes and AD, this issue may become an important one in the AD clinical world, as well.

Psychiatrists have reported a trend toward greater incidence of type 2 ("insulin-resistant") diabetes mellitus in schizophrenia patients who take some of the newer, so-called "atypical," antipsychotic drugs. However, it is unclear whether this would be a direct effect of the drugs on glucose metabolism, or a secondary effect of the drugs promoting diabetes risk factors such as obesity or lipid abnormalities. David C. Henderson and colleagues at Massachusetts General Hospital and Harvard University assessed glucose function in a group of 36 non-obese patients with schizophrenia. They found that the atypical drugs olanzapine and clozapine increase insulin resistance and impair glucose effectiveness, relative to the drug risperidone, also in the atypical category. Since these patients were not obese, and had no differences in their lipid levels among the three drug groups, the researchers suggest that the drugs affect glucose metabolism directly.

Insulin resistance is the failure of cells to respond to insulin's signals to take up glucose from the blood, and it represents a major risk factor for type 2 diabetes. But interestingly, it may also be a risk factor for AD (see ARF related news story). The possibility that elderly patients taking antipsychotic drugs for behavioral symptoms, especially due to dementia, may be at increased risk of diabetes has been noted by some researchers (Lee et al., 2004). The doses given to these patients are typically less than those taken by younger people with schizophrenia, but altered pharmacokinetics may put older people at relatively greater risk.

Regarding possible mechanisms, the authors note, "The lower glucose effectiveness values observed in patients treated with clozapine and olanzapine could result from several mechanisms, including reduced functioning of glucose transporters or an impairment in the suppression of hepatic glucose production." However, they also point out the possibility that schizophrenia itself might be associated with insulin resistance and diabetes, independent of any effect of the drugs.—Hakon Heimer


  1. Antipsychotic medications include haloperidol, thiothixine, trifluoperazine, perphenazine, thioridazine, and then the newer antipsychotics, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. The latter are called “atypical” or “second-generation” antipsychotics because of their various pharmacological actions in addition to the mainly postsynaptic D2 receptor blockade which characterizes the older “conventional,” “typical,” or “first-generation” antipsychotics.

    Since their introduction in the early 1990s, the atypicals have become the pharmacological standard of care for treating younger, mixed-aged adults with schizophrenia. In part, this was because of the view that atypicals are more effective than are conventional antipsychotics on the “negative” signs and symptoms of schizophrenia, that is, the apathy, loss of motivation, and social withdrawal. Secondly, atypicals cause fewer motor system adverse events, including extrapyramidal system or parkinsonian signs and symptoms, less akinesia, very little or no tardive dyskinesia (involuntary movements), and much less hypothalamic dysregulation leading to neuroleptic malignant syndrome than the conventionals.

    Henderson and colleagues further explore the relatively recent realization that some atypical antipsychotics may cause “Metabolic Syndrome.” This loose term encompasses a clustering of cardiovascular risk factors including hyperglycemia, hypertriglyceridemia, hyperlipidemia but low HDL-cholesterol, truncal obesity, and hypertension. This is of such concern that the FDA has added warnings to the prescribing information for atypicals. One potential antecedent mechanism for metabolic syndrome is insulin resistance. For this reason, Henderson’s group investigated insulin insensitivity with three atypicals and found that olanzapine and clozapine (two very similar molecules) indeed cause it, while risperidone doesn’t.

    The researchers focus on younger adults with schizophrenia, for whom these drugs constitute standard pharmacological care over long periods of time. Henderson and colleagues also speculate that antipsychotic medications may contribute to the increased morbidity and decreased longevity associated with the illness; this is one reason why it is unknown whether people with schizophrenia are at increased risk for dementia. Of course, it is not clear whether schizophrenia itself or other factors (such as genetics, environment, trauma, diet, or physical inactivity) put a person at risk for metabolic syndrome, which is then uncovered or exacerbated by atypical antipsychotics, or whether the drug is the antecedent event. The second most common use of atypical antipsychotics is for treating the delusions, aggression, and hallucinations that occur in a substantial proportion of people with dementia. Of the three atypicals studied by Henderson and colleagues, risperidone and olanzapine have been most widely used for this indication and also have been studied in more placebo-controlled trials than the others. (Clozapine is not used because of significant rates of leukopenia that are higher in the elderly than in younger people, and the requirement for monitoring with at least monthly WBC counts). Other atypicals used to treat patients with dementia include quetiapine and aripiprazole. Quetiapine is especially favored for treating delusions and hallucinations occurring in patients with Parkinson disease, mainly because of its lack of parkinsonian adverse events, and seems particularly effective for this indication at low doses.

    The doses of antipsychotics used in people with dementia are lower than those used in people with schizophrenia: about 1-2 mg/d versus 5 mg/d or more for risperidone; 5 mg/d versus 10-15 mg/d for olanzapine; at least 100 to 200 mg/d versus greater than 500 mg/d for quetiapine; 5 to 10 mg/d versus about 15 mg/d of aripiprazole. These doses have been determined mainly through placebo-controlled clinical trials in nursing home patients, generally short-term, lasting 6 to 12 weeks.

    Metabolic syndrome subsequent to antipsychotics is virtually unstudied in the elderly. At best, post hoc analyses of these clinical trials have analyzed random blood glucose, blood pressure, or weight. They usually found no “statistically significant” differences or slight increases between patients treated with antipsychotics and placebo. The CATIE Alzheimer's disease effectiveness trial provides the opportunity to follow outpatients treated with atypical antipsychotics, some of whom will have been treated over 36 weeks. The trial may provide some information on metabolic syndrome, but was not primarily designed for this.

    Because the components of metabolic syndrome are risk factors for cardiovascular disease as well as for Alzheimer disease, vascular dementia, and cognitive impairment, it is possible that the use of atypicals in some people with dementia might express or exacerbate cardiovascular disease, perhaps through a mechanism of insulin resistance as described by Henderson and colleagues.

    Of recent concern is the association of atypicals, risperidone and olanzapine in particular, with cerebrovascular adverse events (e.g., mainly stroke and transient ischemic attacks) in subjects from these same dementia nursing home trials (see ARF related drug news story). Post-hoc analyses of the trials revealed the potential for increased risks for cerebrovascular adverse events at about three times the risks of placebo, and absolute risk differences of about 1 to 2 percent in excess of the 1 percent placebo rate over the generally 6- to 12-week trial periods. This concern led to the addition of warnings to the prescribing information for risperidone and olanzapine. (There is some basis to suggest that the cerebrovascular effects tended to occur in patients with existing vascular risk factors including hypertension). It is speculative to consider a relationship between use of atypicals, insulin resistance, hypertension, increased lipids, and the cerebrovascular events.

    All this makes the use of antipsychotics in dementia more controversial than it has been. However, the adequate treatment of psychosis occurring in dementia, especially in the presence of aggression or marked agitation, is particularly difficult. When psychosocial and environmental interventions fail to relieve the suffering, most expert clinicians believe that atypical antipsychotics are the most effective approach. General guidelines include the expectation for response within about 2 to 4 weeks, maintenance of medication for about 2 to 3 months, and trial discontinuations. Alternative psychopharmacological interventions, such as anticonvulsants, antidepressants, benzodiazepines, and cholinesterase inhibitors, just haven’t been as broadly effective, and they leave patients and caregivers to contend with a different set of adverse events.


    . An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003 Jul 14;163(13):1524-8. PubMed.

    . Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol. 2000 Oct;20(10):2255-60. PubMed.

    . Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004 Oct 12;63(7):1187-92. PubMed.

    . National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. Am J Geriatr Psychiatry. 2001 Fall;9(4):346-60. PubMed.

    . The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004 Nov 10;292(18):2237-42. PubMed.

    View all comments by Lon S. Schneider

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News Citations

  1. Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition

Paper Citations

Further Reading

Primary Papers

  1. . Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry. 2005 Jan;62(1):19-28. PubMed.