Aripiprazole

This column offers a question-and-answer forum to help nurses maintain their knowledge of advances in prescribing and psychopharmacology, and implications for safe psychiatric care. Send your questions related to prescribing psychotropic medications to the Editor, Mary Paquette, at: mary@artwindows.com.

Question: Please comment on the metabolic syndrome receiving recent attention in terms of patients on atypical antipsychotic medications.

Deborah Antai-Otong responds: Of great concern are recent reports indicating that atypical antipsychotic medications, particularly clozapine and olanzapine, have serious side effect profiles including significant weight gain, hyperglycemia, and hyperlipidemia when compared to typical antipsychotic medications (Allison et al., 9 1999; Henderson et al., 2000; Lindenmayer et al., 2003; Wirshing et al, 2002). In addition to potential life-threatening medical conditions, metabolic syndrome compromises quality of life and increases nonadherence due to concerns about personal appearance.

This triad-significant weight gain, diabetes, and dyslipidemias-is consistent with hallmark features of metabolic syndrome. Metabolic syndrome refers to a complex medical condition associated with abdominal obesity; abnormalities in glucose, lipid, and cholesterol metabolism; and elevated blood pressure that increases risk of cardiovascular disease (CVD) and type 2 diabetes (Grundy et al., 2004; see Table 1). Abdominal weight gain, type 2 diabetes, and atypical antipsychotic drugs may cause dyslipidemia. Studies have shown that elevated low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels may be independent of weight gain (Wirshing et al., 2002). Even so, there is supporting evidence that dyslipidemia, particularly high TG levels, significantly increase in clients being treated with olanzapine and clozapine (Ghaeli & Dufresne, 9 1999; Lindenmayer et al., 2003; Osser, Najarian, & Dufresne, 1999).

The risk of hyperlipidemia caused by some of these agents is significant because of its high correlation with CVD. Interestingly, the associated risk of CVD is heightened regardless of LDL cholesterol level. Normally, increasing lipids by 10% heightens CVD by 20% to 30%. In comparison, decreasing lipids by 10% decrease heart disease by 20% to 30% (Redelmeier, Tan, & Booth, 1998). Unfortunately, these health risks often go unrecognized and untreated in people with schizophrenia.

What is the pathogenesis of the metabolic syndrome in those taking atypical antipsychotic agents?

The precise explanation for the increased risk of metabolic syndrome linked to atypical antipsychotic drugs remains unknown. Major theories indicate that this disorder may result from abdominal weight gain and dyslipidemias caused by these medications. Other studies suggest these agents affect glucose transport metabolism peripherally in clients, possibly increasing the potential for hyperinsulinemia and peripheral insulin resistance. Increased abdominal adiposity may also decrease skeletal muscle insulin and contribute to hyperglycemia. Obese tissue is also believed to release excess fatty acids and cytokines that induce insulin resistance.

Although there is growing evidence that supports this assumption, this statement is an oversimplification of the relationship of obesity, body fat distribution, and the risk of CVD. Additional hypotheses point to the activity of atypical antipsychotic medication at the serotonin receptors of the beta cells in the pancreas, notably 5HT^sup 1A^ and 5HT^sub 2^ receptors; however, their roles appear complex. Pancreatic function may become depressed in the presence of newer atypical antipsychotic agents and decrease pancreatic beta cell response to increased blood glucose (Ardizzone, Bradley, Freeman, & Dwyer, 2001). This activity is believed to result in dysregulation of beta cell function and subsequently a rise in glucose levels.

Little is known about the process by which atypical antipsychotics cause dyslipidemia. Speculations about the rise in triglycerides and total cholesterol levels suggest that some atypical antipsychotic medications (e.g., olanzapine, clozapine) may increase serum LDL and triglyceride levels and lower high -density lipoprotein (HDL) cholesterol, which may be independent of weight gain (Wirshing et al, 2002). Others argue that drugs such as clozapine may not be an independent cause of these conditions, but instead act as an effect modifier in vulnerable populations by increasing weight or modulating insulin secretion and resistance (Lund, Perry, Brooks, & Arndt, 2001). In contrast, atypical antipsychotic medications such as ziprasidone appears to have demonstrated no weight changes, no alterations in glucose use, and reductions in cholesterol and serum triglycerides (Kato & Goodnick, 2001).

What are major implications for psychiatric nurses who prescribe atypical antipsychotic agents?

The decision to prescribe a specific atypical antipsychotic agent requires understanding its side -effect profile and the risk of obesity and metabolic side effects. Routine monitoring of glucose and lipid levels prior to and during the treatment is important. Psychiatric nurses who prescribe these agents need to understand the treatment approaches for weight gain, type 2 diabetes, hypertension, and hyperlipidemia or dyslipidemias (Meyer, 2001). First-line treatment of the metabolic syndrome includes weight reduction and increased physical activity. Additional treatment considerations should center on reducing blood pressure, lowering triglyceride levels, and increasing HDL cholesterol. It is also important to consider some atypical antipsychotic drugs (e.g., ziprasidone, aripiprazole) that are less likely than others to cause weight gain (Kane, Leucht, Carpenter, & Docherty, 2003; see Table 2).

Prior to prescribing an atypical antipsychotic medication, it is incumbent on the prescribing psychiatric nurse to perform a thorough psychiatric and medical history of the patient's current medical problems and history (e.g., diabetes, CVD), including family history, measures of weight, height, and adiposity, and to monitor these over time. In addition, the prescriber must determine the basis for the choice and switching of medications. Ordering and reviewing the results of diagnostic studies and physical examination are crucial to making an informed decision about which antipsychotic medication to prescribe.

Suggestions for initial diagnostic studies include:

* Baseline fasting glucose or hemoglobin A^sub 1c^ (HgA^sub 1c^)

* Metabolic profile

* Lipid profile

* Electrocardiogram (ECG)

* A complete physical including blood pressure

* Accurate weight

* Body mass index

* Waist circumference

Additional medical conditions that need to be ruled out include endocrine, cardiovascular, pulmonary, gastrointestinal, and infectious disorders. Identifying and treating these conditions is critical to the patient's overall health, functional status, quality of life, and safety.

Equally important is establishing a collaborative relationship with an internist or primary care provider who specializes in diabetes. Psychiatric nurses must be more alert to the need to assess the holistic medical and psychiatric needs of clients during the initial evaluation and throughout the course of treatment to identify persons at risk of metabolic syndrome ( see Table 2).

Summary

Despite the plethora of evidence that demonstrates the efficacy of novel antipsychotic medications, there are mounting concerns about their side effects. Major concerns are data that link some agents with metabolic effects, such as obesity, type 2 diabetes, and CVD. For these reasons, patients receiving novel antipsychotic medications must be closely monitored for metabolic side effects and treated to reduce risk factors associated with CVD.

References

Albert, K.G., & Zimmet, P.Z. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: diagnosis and classification of diabetes: Provisional report to a WHO consultation. Diabetic Medicine, 15,539-553.

Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Cappelleri, J.C., Infante, M.C., & Weiden, PJ. (1999). Antipsychotic-induced weight gain: A comprehensive research synthesis. American Journal of Psychiatry, 156, 1686-1696.

Ardizzone, T.D., Bradley, R.J., Freeman, A.M., III, & Dwyer, D.S. (2001). Inhibition of glucose transport in PC12 cells by atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Research, 923, 82 -90.

Ghaeli, P., & Dufresne, R. (1999). Elevated serum triglycerides with clozapine resolved with risperidone in four patients. Pharmacotherapy, 19,1099-1101.

Grundy, S.M., Brewer, H.B., Cleeman, J.l, Smith, S.C., & Lenfant, C. (2004). Definition of metabolic syndrome [report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition], Circulation, 109,433-438.

Henderson, D.C., Cagliero, F., Gray, C., Nasrallah, R.A., Hayden, D.L., Schoenfeld, D.A., & Goff, D.C. (2000). Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five -year naturalistic study. American Journal of Psychiatry, 157, 975-981.

Kane, J.M., Leucht, S., Carpenter, D., & Docherty, J.P. (2003). Expert consensus guideline series: Optimizing pharmacologie treatment of psychotic disorders. Journal of Clinical Psychiatry, 64(Suppl. 12), 1-100.

Kato, M.M., & Goodnick, P.J. (2001). Antipsychotic medication: Effects on regulation of glucose and lipids. Expert Opinion Pharmacotherapy, 2,1571-1582.

Lindenmayer, J.P., Czobor, P., Volavka, J., Citrome, L., Sheitman, B., McEvoy, J.P., et al. (2003). Changes in glucose and cholesterol in patients with schizophrenia treated with typical or atypical anti-psychotics. American Journal of Psychiatry, 160, 290-296.

Lund, B.C., Perry, P.J., Brooks, J.M., & Arndt, S. (2001). Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension. Archives of General Psychiatry, 58, 1172-1176.

Meyer, J. (2001). Novel antipsychotics and severe hyperlipidemia. Journal of Clinical Pharmacology, 21, 369-374.

Osser, D.N., Najarian, D.M., & Dufresne, R.L. (1999). Olanzapine increases weight and serum triglyceride levels. Journal of Clinical Psychiatry, 60, 767 -770.

Redelmeier, D.A., Tan, S.H., Booth, G.L. (1998). The treatment of unrelated disorders in patients with chronic medical diseases. New England Journal of Medicine, 338, 1516-1520.

Wirshing, D.A., Boyd, J.A., Meng, L.R., Ballon, J.S., Marder, S.R., & Wirshing, W.C. (2002). The effects of novel antipsychotics on glucose and lipid levels. Journal of Clinical Psychiatry, 63, 856-865.

World Health Organization. (1999). Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO consultation. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, Switzerland: Author. Retrieved February 5, 2004, from whqlibdoc. who.int/hq/1999/WHO_NCD_NCS_99.2.pdf

Deborah Antai-Otong, MS, RN, CNS, NP, CS, FAAN

Deborah Antai-Otong, MS, RN, CNS, NP, CS, FAAN

Mental Health Provider and Program Specialist

Employee Support Program

VA North Texas Health Care System, Dallas, TX

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