Antipsychotic Agents Psychiatric Drugs

Patients with psychiatric illness are known to suffer from diabetes more often than the general population (122). A recent Italian study (123) found an overall incidence of diabetes in 95 schizophrenic patients to be 15.8% compared to 3% prevalence in the general Italian population. This increased incidence in diabetes was independent of antipsychotic drug administration (124,125). Apart from genetic predisposition, environmental influences also play a significant role in increased incidence of diabetes as most of the patients with psychiatric illness generally lack insight and do not recognize or complain of the physical symptoms of diabetes. These observations have further increased the concern about the occurrence of diabetes associated with the use of atypical antipsychotic (AAP) drugs. Such a concern is justifiable as diabetes carries a considerable risk of morbidity and mortality.

The first account of disturbance of glucose metabolism in schizophrenic patients dates from 1879 (126) and has been confirmed by many authors (127-129) in the first half of the 20th century. The introduction of neuroleptics also brought a rapid increase in the incidence of type 2 diabetes in these patients. The atypical or second generation antipsychotic drugs, introduced in 1990s, showed less extrapyramidal side effects but seemed to have a stronger diabetogenic effect than classical anti-psychotics (130).

Patients on olanzapine and clozapine carry the highest risk of developing hyperglyce-mia, ketoacidosis and new-onset diabetes than other second-generation antipsychotic agents (131). The risk of developing diabetes with antipsychotic agents is around 4.7%. The risk is lowest with risperidone (132), whereas quetiapine, olanzapine and clozapine are not different in their risk from first-generation antipsychotics.

The mechanisms responsible for the increased diabetes risk with antipsychotic agents are hard to decipher for a number of reasons: (1) most of the patients receive multiple medications simultaneously that makes it difficult to identify a particular drug as a causative agent, and (2) untreated schizophrenic patients have a higher rate of diabetes than general population. However, a number of mechanisms have been postulated to explain this association:

a. Receptor action: It is possible that AAP drugs induce diabetes by blocking dopamine D2 receptors in certain areas of the brain and secondarily increasing neurotensin. Neurotensin causes both antipsychotic as well as diabetogenic actions (133,134).

b. Chemical structure: The fact that all four thieno-benzodiazepine drugs-clozapine, olanzapine, loxitane and amoxapine induce diabetes implies that the three-ring chemical structure may be responsible for it (135).

c. Leptin: The hormone leptin synthesized by adipocytes plays a key role in the regulation of appetite, food intake and body weight by acting in the hypothalamus at leptin receptors. In olanzapine-and clozapine-treated patients, serum leptin levels increase more rapidly than with other AAP drugs. This rapid increase in leptin levels may be a potential mechanism of causing insulin resistance (136-139).

d. Low insulin-like growth factor-I: The insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-I (IGFBP-I) are important for glucose homeostasis. Circulating IGF-I is dependent on growth hormone, insulin levels and nutrition. The median level of IGF-I was significantly lower in patients treated with clozapine compared with the patients on neuroleptics. Therefore, decreased IGF-I may be responsible for diabetes in patients treated with AAP drugs (140).

e. Hyperlipidemia: AAP drugs cause hyperlipidemia of variable degrees. Clozapine causes hypertriglyceridemia as much as 37% from the baseline. It is possible that hypertriglycer-idemia contributes to insulin resistance with these agents (141,142).

f. Genetic predisposition: Since only a small fraction of patients treated with AAP drugs develop diabetes and, in addition, African-American patients treated with AAP agents develop diabetes more often than similarly treated Caucasian patients. This indicates the possible role of genetic predisposition to the adverse effects of these agents (143,144).

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