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Prescribing Antipsychotic Medications

A focus on the link between schizophrenia and diabetes.

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The association between schizophrenia and diabetes was first documented in the late 19th century, when medical practitioners noticed that many people with schizophrenia also had diabetes or had family members who had diabetes.1,2 Today, the link between these disorders is widely recognized, but causative relationships are still poorly understood. Patients with severe mental illness (schizophrenia or bipolar illness) are two to three times more likely than the general population to be diagnosed with diabetes (10% to 15% vs. 3.5% to 5%, respectively).1

In their review of the literature, Bushe and Holt3 concluded that schizophrenia was likely an independent risk factor for diabetes. Several authors have attributed a variety of causes to the increased risk of diabetes in patients with schizophrenia, including the modifiable risk factors of poor diet and lack of exercise. Characteristics associated with schizophrenia include under- or unemployment, low income, tobacco smoking and physical inactivity. Each of these factors directly and indirectly contribute to an increased risk for diabetes.4,5 In addition to these risk factors, antipsychotic medications used to manage the symptoms of mental illness have been associated with the onset of diabetes.5-7

Due to rapidly increasing rates of diabetes in the United States, it is important that NPs and PAs who treat patients with schizophrenia are aware of the associations between antipsychotic medications and onset factors for diabetes.

Relationship of Schizophrenia and Diabetes

Schizophrenia is a mental disorder with multiple known causes, including genetic transmission, environmental factors such as prenatal maternal malnutrition or influenza, brain structure abnormalities, and abnormal neurochemistry including excess dopamine and impaired GABA receptor function.8 Classic symptoms of schizophrenia are divided into two categories: positive symptoms such as delusions, hallucinations and disorganized speech and behavior; and negative symptoms described as lack of energy, social withdrawal, lack of motivation and flattened affect.5,8

Diabetes is an inherited or acquired metabolic disorder identified by hyperglycemia that results from a deficiency in both insulin secretion and action.9 It is a serious chronic disorder that places people at risk for cardiovascular disease (CVD) and other illnesses including chronic kidney disease. Type 1 diabetes is the autoimmune loss of insulin-producing beta cells in the pancreas, and type 2 diabetes is impairment in insulin secretion and resistance to insulin functioning.8 Metabolic syndrome is associated with obesity and type 2 diabetes.10

Long before antipsychotic medications became a standard treatment for people with schizophrenia in the 1950s, higher rates of insulin resistance and abnormalities in glucose tolerance were seen in patients with this mental disorder.6 More recently, Ryan and colleagues11 reported that among participants in their study with first-episode schizophrenia who were medication naive, 15% had impaired fasting glucose levels and greater insulin resistance compared to healthy participant controls. Patients with schizophrenia have complicated risk factors that place them at risk for type 2 diabetes, the type of diabetes more common in these patients. These include lifestyle factors of poor diet and lack of exercise, as well as poverty, which often occurs in people with mental illness. People with schizophrenia frequently eat diets high in refined sugars and fats and low in fiber, due in part to inadequate access to costlier fresh fruits and vegetables.

Genetics also play a role in diabetes risk, and strong family associations between diabetes and schizophrenia have been reported in the literature.12,13 Diabetes and other metabolic risk factors (obesity, hyperlipidemia) may help explain the high rates of CVD in patients with schizophrenia. CVD is the most common cause of death in people with schizophrenia, who have a life expectancy 10 to 15 years less than the general population.4

Antipsychotic Therapy and Diabetes

Antipsychotic medications (also known as neuroleptics) have been the main treatment for acute episodes of schizophrenia since the 1950s.1 These medications are also approved to treat mania and mixed state bipolar disorder.2 Two subclasses of antipsychotic medications are available today. Typical or conventional antipsychotic medications still include chlorpromazine (Thorazine), haloperidol (Haldol), thioridazine (Mellaril) and others. Atypical or second-generation antipsychotics include clozapine (Clozaril), olanzapine (Zyprexa), paliperidone (Invega), risperidone (Risperdal) and others. Typical antipsychotics are effective antagonists of the dopamine D2 receptors, primarily affecting dopamine pathways of the brain.

Atypical antipsychotic medications are known to be more effective than the typical antipsychotics in addressing the negative symptoms of schizophrenia. Atypical antipsychotics affect several dopamine pathways and block 5HT2A receptors, adding serotonin antagonism to the inhibition of dopamine. This is thought to explain the decreased extrapyramidal adverse effects associated with the typical antipsychotic medications. Extrapyramidal adverse effects include movement disorders, Parkinsonian tremors, tardive dyskinesia and akathisia (a syndrome consisting of a sense of restlessness and urge to move).8 Although atypical antipsychotic medications cause less extrapyramidal side effects, they are associated with an increased risk for metabolic abnormalities resulting in weight gain, hyperglycemia and diabetes.7

Pendlebury and Holt5 reported that a relationship between antipsychotic treatment of schizophrenia and emergent diabetes was recognized in the 1960s, but the phenomenon was ignored primarily because no alternatives to treatment for schizophrenia existed. Concern about treatment-related diabetes returned after atypical antipsychotic medications were introduced.5,14 Both typical and atypical antipsychotic medications are associated with weight gain, hyperglycemia and dyslipidemias. Among the typical antipsychotics, chlorpromazine and thioridazine cause greater weight gain than fluphenazine (Prolixin) and haloperidol. Of the atypical agents, ziprasidone (Geodon) and aripiprazole (Abilify) have the lowest reports of weight gain after a year of treatment and may not affect lipid levels.2 However, Llorente and Urrutia2 reported a connection between the start of any antipsychotic medication (typical or atypical) and new onset of type 2 diabetes within 6 months, often associated with weight gain and obesity.

Currently, there is no clear evidence of a causal mechanism between any type of antipsychotic medication and diabetes.7,15 Smith and colleagues7 conducted a review and meta-analysis of 11 studies that examined the relationship between antipsychotic medications and diabetes. They concluded that observational bias probably existed in most of the studies. The findings indicated greater associations between increased diabetes risk and atypical antipsychotic medications than with the typical antipsychotic medications. Sernyak and colleagues15 conducted a large retrospective review of more than 60,000 records of military veterans diagnosed with schizophrenia and found that patients treated with typical and atypical antipsychotic medications had a high incidence of diabetes. In fact, younger and middle-aged patients (younger than 40 and those 50 to 59) who received atypical antipsychotic medications had a significantly higher rate of diabetes than those treated with the typical antipsychotic medications. There were no significant associations in the older age groups.

Sernyak and colleagues15 determined that the likelihood of diabetes was greater in patients taking the atypical medications clozapine, olanzapine and quetiapine and recommended that clinicians review and prescribe antipsychotic medications in terms of the necessity for treatment and the risk for diabetes. The authors stressed the need to identify prediabetes and diabetes by screening patients who are treated with antipsychotic medications.

Implications for NPs and PAs

NPs and PAs experienced in the care of patients with schizophrenia will be involved in prescribing antipsychotic medications. Prescreening for baseline weight, glucose, Hgb A1c, lipids and triglycerides and continued monitoring of these values throughout the course of antipsychotic treatment is essential.16 The first priority is to treat the acute psychosis (disorganized thoughts, hallucinations, delusions) using the medication best suited to meet that need. But the medication best suited to treat the psychotic symptoms may have a higher risk of adverse effects on glucose control, lipids and weight gain.

Prescribing an atypical antipsychotic medication is usually preferred over a typical antipsychotic due to the higher risk for extrapyramidal adverse effects in the latter group. The atypical antipsychotic medications of choice for a newly diagnosed patient with schizophrenia who has existing diabetes (or prediabetes with hyperglycemia and dyslipidemia) would be ziprasidone or aripiprazole; these two medications are associated with relatively fewer adverse effects on lipids and weight gain than other atypical antipsychotic medications.17 However, ziprasidone and aripiprazole are newer atypical antipsychotics and more costly than earlier medications in this group.

Risperidone (Risperdal) is a less expensive alternative. Sernyak and colleagues15 compared typical agents with atypical antipsychotics and found that clozapine, olanzapine and quetiapine showed significant association with diabetes. In this study, risperidone did not. Stahl17 reported that the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE trials) identified risperidone as presenting intermediate risk for weight gain in adults with cardiometabolic risk and a diabetes warning from the FDA. It does cause problematic weight gain in children. As with all antipsychotic medications, prescribing warnings include the possible effects of neuroleptic malignant syndrome (NMS) and suicidal thoughts. NMS is a life-threatening condition and a complication of antipsychotic medication therapy.

The primary clinical symptoms of NMS are hyperthermia, muscle rigidity, mental status changes and autonomic dysfunction including tachypnea, arrhythmias, diaphoresis and flushing of the skin.18,19 When prescribing risperidone, NPs and PAs need to know that drug-to-drug interactions that increase blood levels of risperidone involve fluoxetine, paroxetine and clozapine. On the other hand, phenytoin, carbamazepine and phenobarbital tend to decrease the effectiveness of risperidone. With this latter group of medications, patients taking risperidone, as well as patients known to be extensive or poor metabolizers of risperidone, require dosage adjustment and careful monitoring for effective responses to the medications.20

Stahl17 reported that rather than prescribe atypical antipsychotic medications for patients with prediabetes or diabetes, some clinicians are returning to prescribing low doses of typical antipsychotic medications. However, careful monitoring for extrapyramidal symptoms and continued monitoring for weight, serum glucose and lipids remains advised. A new atypical antipsychotic, lurasidone HCI (Latuda) is reported to show lower levels of glucose, hyperlipidemia and weight gain than other atypical medications.21,22 NPs and PAs who prescribe lurasidone HCI should continue to monitor patients carefully for routine serum glucose, lipids, triglycerides and weight.

Regardless of which group of antipsychotic medications is prescribed, the NP or PA needs to teach patients with schizophrenia and their families about beneficial lifestyle changes such as diet control, increased exercise and smoking cessation programs as part of a complete plan of care.

Balancing Risks and Benefits

Because antipsychotic medications are associated with some level of risk for adverse effects (e.g., weight gain, hyperglycemia, hyperlipidemia, insulin resistance and diabetes), NP and PA prescribers must balance risks and benefits when managing psychosis. Changing antipsychotic therapy from one atypical medication to another or to a typical medication may be advisable. Before starting a patient on any antipsychotic medication therapy, the NP or PA should initiate prescreening for weight, hyperglycemia and hyperlipidemia and continue monitoring these risk factors for diabetes throughout the duration of therapy.

References

1. Holt RI, et al. Diabetes and schizophrenia 2005: are we any closer to understanding the link? J Psychopharmacol. 2005;19(6 Suppl):56-65.

2. Llorente MD, Urrutia V. Diabetes, psychiatric disorders, and the metabolic effects of antipsychotic medications. Clin Diabetes. 2006;24(1):18-24.

3. Bushe C, Holt R. Prevalence of diabetes and impaired glucose tolerance in patients with schizophrenia. Br J Psychiatry Suppl. 2004;47:S67-71.

4. Brown S, et al. The unhealthy lifestyle of people with schizophrenia. Psychol Med. 1999;29(3):697-701.

5. Pendlebury J, Holt R. Managing diabetes in people with severe mental illness. J Diabetes Nurs. 2010;14(9):328-339.

6. Buse JB, et al. A retrospective cohort study of diabetes mellitus and antipsychotic treatment in the United States. J Clin Epidemiol. 2003;56(2):164-170.

7. Smith M, et al. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2008;192(6):406-411.

8. Koda-Kimble MA, et al. Diabetes, Schizophrenia. In: Applied Therapeutics: The Clinical Use of Medications. 9th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009: 269-277.

9. King H. WHO and the International Diabetes Federation: regional partners. Bull World Health Organ. 1999;77(12):954.

10. Sadock BJ, Sadock VA. In: Kaplan & Sadock's Pocket Handbook of Clinical Psychiatry. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2010: 269-277.

11. Ryan MC, et al. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry. 2003;160(2):284-289.

12. Cheta D, et al. A study on the types of diabetes mellitus in first degree relatives of diabetic patients. Diabete Metab. 1990;16(1):11-15.

13. Geddes J, et al. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ. 2000;321(7273):1371-1376.

14. Mukherjee S, et al. Family history of type 2 diabetes in schizophrenic patients. Lancet. 1989;1(8636):495.

15. Sernyak MJ, et al. Association of diabetes mellitus with the use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry. 2002;159(4):561-566.

16. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus Development Conference on Antipsychotic Medications and Obesity and Diabetes. Diabetes Care. 2004;27(2):596-601.

17. Stahl SM. Antipsychotic Agents. In: Stahl's Essential Psychopharmacology. San Diego, Calif.: Cambridge University Press; 2008: 342, 386, 416, 421.

18. Factor S, et al eds. Neuroleptic malignant syndrome. In: Medications Induced Movement Disorders. 2nd ed. Malden, MA: Blackwell Publishing; 2005: 174-212.

19. Strawn JR, et al. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876.

20. Deglin JH, et al. Davis's Medications Guide for Nurses. 12th ed. Philadelphia: F.A. Davis; 2010: 1117.

21. Meltzer HY, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and Olanzapine-controlled study. Am J Psychiatry. 2011;168(9):957-967.

22. Latuda (lurasidone HCL). Full prescribing information. Sunovion Pharmaceuticals. http://www.latudahcp.com/index.html  

 

Ann M. Collins is a family and psychiatric-mental health nurse practitioner who practices in the Detroit area. She has completed a disclosure statement and reports no relationships related to this article.




     

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