Special Feature
Medical Complications of Atypical Antipsychotics
By Michael F. Barber, Pharm.D.
There have been significant advances in the past decade in the treatment of psychotic disorders, especially schizophrenia. Specifically, atypical antipsychotics, which block the serotonin-2 (5-HT2) receptor more potently than the dopamine-2 (D2) receptor, are effective treatments for psychoses while producing fewer extrapyramidal side effects (e.g. tremor, rigidity). These drugs include risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel). Additionally, atypical antipsychotics have rapidly gained popularity as treatments for other psychiatric conditions, including bipolar disorder, complicated or resistant depression, mood lability of various etiologies, and agitation. As a result, primary care physicians are likely to treat patients who are receiving atypical antipsychotics, despite the low number of patients with schizophrenia seen in a general medical setting.
Most adverse effects of the atypical antipsychotics have been well documented and are predictable, based on the pharmacology of these agents. Examples of such effects include orthostatic hypotenion and nasal congestion resulting from alpha adrenergic antagonism, dry mouth, blurred vision, and constipation from cholinergic blockade, and sedation from histamine blockade. Recently there have been increasing numbers of reports of secondary medically important adverse effects of atypical antipsychotics. These include hyperprolactinemia and impaired glucose tolerance.
While it is well documented that all conventional antipsychotics (e.g. haloperidol) elevate serum prolactin levels, most atypical antipsychotics have minimal effects on prolactin. Clozapine, olanzapine, and quetiapine have all been shown to cause transient, modest increases in prolactin, generally within the normal range, which are probably clinically insignificant.1 Risperidone, however, is much less "atypical" in this regard, causing clinically significant increases in serum prolactin levels, roughly similar in magnitude to the conventional antipsychotics.2 This characteristic of risperidone is consistent with its propensity to cause extrapyramidal side effects in dose dependent fashion. Put simply, risperidone effectively loses its "atypical" profile at doses above 6 mg/day. Galactorhea may also occur with even low doses of risperidone, although the incidence is not known. The increase in prolactin induced by risperidone and the conventional antipsychotics may result in several clinically important medical complications such as menstrual disturbances, infertility, sexual dysfunction, gynecomastia, and galactorrhea. Most of these adverse effects are personal in nature and may be embarrassing for patients to discuss with their physicians. In fact, a study of schizophrenic patients by Windgassen et al.3 reported that most patients failed to report such side effects whereas close clinical observations and direct questioning revealed an incidence of galactorrhea in nearly half of the female cohort.
While there are no long-term data available on the sequelae of antipsychotic-induced hyperprolactinemia, there may be an increased risk for certain medical complications. Since elevated prolactin levels result in impaired secretion of leutinizing hormone and follicle stimulating hormone, antipsychotic-induced hyperprolactinemia may result in estrogen deficiency in female patients. Presumably, this could further lead to increased risks for cardiovascular disease as well as decreased bone mineral density and osteoporosis. Further, there is some evidence for a link between chronic hyperprolactinemia and breast cancer.4
If a patient develops prolactin-related adverse effects secondary to risperidone or other antipsychotics, the risks of continuing therapy must be weighed against the benefits of maintenance antipsychotic treatment. Since the atypical antipsychotics (other than risperidone) are less likely to cause prolactin-related adverse effects, perhaps the patient could be switched. Switching agents is often best accomplished with the use of a cross-taper and, in general, a psychiatrist should be involved when it is necessary to switch antipsychotic medications.
In addition to their effects on prolactin, antipsychotics may also alter glucose metabolism.5 Again, while this effect has been known to occur with the older 'conventional' antipsychotics, the atypicals agents clozapine and olanzapine have been associated with impaired glucose tolerance in published reports.6-8 Further, there are two documented cases of diabetic ketoacidosis associated with clozapine use in patients who were also receiving lithium.9,10 Many of these instances occurred in patients with a pre-existing diagnosis of diabetes mellitus; however, impaired glucose tolerance often occurred in patients without such diagnosis. In most cases, patients were found to have risk factors for the development of type 2 diabetes. Thus, it is possible that the use of antipsychotics may be the precipitating factor in exacerbating diabetes in predisposed patients.
The cause of impaired glucose metabolism induced by antipsychotics is unknown. Since atypical antipsychotics are known to cause weight gain 11, it is possible that this could lead to insulin resistance in predisposed patients. Yazici et al.12 have reported that clozapine increases mean levels of blood glucose, insulin, and C-peptide, suggesting that antipsychotic use may lead to insulin resistance. In addition to the weight gain caused by the antihistaminic and antiserotonergic properties, Wirshing et al suggest that antipsychotics may decrease pancreatic beta-cell responsiveness via serotonin-1A antagonism; however, this has not been investigated. It is well documented that chronically poor glucose control leads to significant medical morbidity. Additionally, it is important to note that abnormal glucose metabolism may increase the risk for the development of tardive dyskinesia.13,14
The management of impaired glucose control secondary to antipsychotics is not clearly established. It would seem appropriate to treat patients with education, dietary restrictions, and oral hypoglycemics. Alternatively, psychiatric consultation may be warranted to determine whether the offending antipsychotic should be discontinued or switched.
In summary, there are many medically important side effects of atypical antipsychotics that have largely gone unnoticed until recently. The primary care physician should be aware of the potential of these agents to cause such complications as hyperprolactinemia and impaired glucose. This should lead to better monitoring and more appropriate treatment of these conditions. Psychiatric consultation may be quite helpful where indicated, since the best treatment may be the discontinuation of the antipsychotic agent.
References
1. Dickson RA, et al. Neuroleptic-induced hyperprolactinemia. Schizophr Res 1999 Mar 1; 35(S1): S75-S86.
2. American Psychiatric Association, 1997. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 154 (Suppl. 4):1-63.
3. Windgassen K, et al. Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology 1996; 33:142-146.
4. Cohn JB, et al. Effects of bromocriptine mesylate on induced hyperprolactinemia in stabilized psychiatric outpatients undergoing neuroleptic treatment. Neuropsychobiology 1985; 13:173-179.
5. Hagg S, et al. Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 1998 Jun;59(6):294-99.
6. Popli AP, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58:108-111.
7. Ober SK, et al. Hyperglycemia and olanzapine. Am J Psychiatry. 1999 Jun;156(6):970.
8. Wirshing DA, et al. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998 Oct 15;44(8):778-783.
9. Koval MS, et al. Diabetic ketoacidosis associated with clozapine treatment (letter). Am J Psychiatry 1994; 151:1520-1521.
10. Peterson GA, et al. Diabetic ketoacidosis from clozapine and lithium cotreatment (letter). Am J Psychiatry 1996; 153:737-738.
11. Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand 1999 Jul;100(1):3-16.
12. Yazici KM, et al. The effect of clozapine on glucose metabolism. Exp Clin Endocrinol Diabetes 1998;106(6):475-477.
13. Mukherjee S, Mahadik S. Diabetes mellitus and tardive dyskinesia, in neuroleptic-induced movement disorders, Yassa R (ed). New York, Cambridge University Press, 1997.
14. Schultz SK, et al. Impaired glucose tolerance and abnormal movements in patients with schizophrenia. Am J Psychiatry 1999;156(4):640-642.
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