Author
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Editor
Stephen Soreff, MD
President of Education Initiatives
Nottingham, New Hampshire
Faculty
Metropolitan College of Boston University
Boston, Massachusetts
Disclosure: Stephen Soreff, MD, has disclosed no relevant financial relationships.
Antipsychotic drugs are frequently prescribed to treat a wide range of disorders including schizophrenia, Tourette's syndrome, and psychosis. The 2 major classifications for antipsychotic drugs are conventional and atypical. The conventional antipsychotics are older drugs, first developed in the 1950s to treat psychosis, while the atypical medications are newer drugs designed to increase efficacy with a lower side effect profile. Although the newer drugs decrease the incidence of some side effects, particularly extrapyramidal symptoms, they place patients at risk of developing a different set of side effects, such as blood dyscrasias and cardiovascular symptoms.
Antipsychotic medications differ in their effects on neuroreceptors, which accounts for some of the variation in the common side effects found among medications. Commonly experienced side effects for the different neuroreceptors are shown, with atypical antipsychotics generally having a smaller effect profile. Extrapyramidal system side effects include acute dystonia, akinesia, akathisia, and tardive dyskinesia, as well as parkinsonism. Signs of neuroleptic malignant syndrome, another potential side effect of antipsychotic drugs, include hyperthermia, rigidity, and autonomic dysregulation. Although the effects listed are those most commonly encountered by clinicians and traditionally taught in medical schools, ongoing research has revealed that prescribers must be aware of additional potential side effects for both conventional and atypical antipsychotic drugs in specific populations at risk. For example, dysphagia and loss of the gag reflex is of particular concern in men. One should be aware that tardive dyskinesia can also occur with atypical antipsychotic drugs, such as with risperidone.[1]
The use of antipsychotic drugs in younger patients has steadily increased in recent years. Data collected from the US Food and Drug Administration (FDA)[2] regarding outpatient prescription of antipsychotic drugs demonstrate a 22% increase in atypical antipsychotic prescriptions from 2004 to 2008 for patients younger than 17 years of age. The majority of prescriptions were from psychiatrists for the diagnosis of episodic mood disorders. Risperidone was the most common drug prescribed.
The percentage of elderly patients in US nursing homes who are given antipsychotic drugs has also increased in the past 10 years. Data collected from Medicare and Medicaid databases recently published in an article in the American Journal of Geriatric Pharmacotherapeutics are shown.[3] It depicts a statistically significant increase in antipsychotic drug prescriptions from 16.4% in 1996 to 25.9% in 2006. Higher utilization rates were found in nursing homes that were for-profit, had lower Medicare reimbursement rates, and had lower levels of competition. The use of these drugs in the elderly population may be of particular concern for patients with specific risk factors. For example, risperidone can heighten movement disorders in patients with parkinsonism and olanzapine has been associated with uncontrollable muscle movements, especially in elderly women.[4]
In 2004, the FDA issued a warning regarding weight gain, glucose levels, and diabetic control for atypical antipsychotic drugs. Based on the growing body of evidence regarding the relationship between these drugs and the incidence of diabetes mellitus or obesity, the American Diabetes Association (ADA) has published specific recommendations regarding monitoring of cardiometabolic parameters in patients initiating treatment with atypical antipsychotic drugs. They aim to help identify patients with progressive metabolic complications early, before significant morbidity or mortality can develop. Published in 2004, the summary recommendations are shown. More recent studies echo the link between the newer drugs and obesity in children and adolescents.[5]
Despite the guidelines published by the ADA in 2004 for proper screening of individuals starting on an atypical antipsychotic drug, the vast majority of individuals are not properly screened for appropriate metabolic changes. The screening consists of checking pre-treatment lipid and glucose levels. Given the risks of diabetes mellitus and cardiovascular problems in the psychiatric patient population treated with atypical antipsychotic drugs, levels should be repeated regularly during treatment. Data presented from a pre- and postguideline cohort recently published in the American Journal of Psychiatry are shown.[6] Although a statistically significant number of individuals are screened, these levels fall far below acceptable limits. Additionally, the younger the patient, the less likely they were to be screened.
The initiation of antipsychotic medications in children and adolescents is associated with rapid and significant weight gain, as well as varied metabolic changes. Data from the Second-Generation Antipsychotropic Treatment Indications, Effectiveness, and Tolerability in Youth (SAIETY) study recently published in the Journal of the American Medical Association is shown. In the study, after 10.8 weeks of treatment, subjects treated with second-generation antipsychotic drugs gained significantly more weight than patients who refused treatment. A number of other metabolic changes were also noted, particularly with the use of olanzapine. This evidence suggests that the benefits of second-generation antipsychotic drugs must be more closely balanced with the increased cardiometabolic risks in children and adolescents.[7]
Additional data confirming the metabolic effect of atypical antipsychotic use in youth was presented at the American Academy of Child and Adolescent Psychiatry meeting. Retrospective data from psychiatric emergency department admissions in Vancouver, Canada, demonstrate a significantly increased prevalence of metabolic syndrome and associated features in youth treated with atypical antipsychotic drugs (27%) vs those who have never taken such medications (2.9%). Although there are no current formal recommendations for regular monitoring of metabolic parameters in youth taking atypical antipsychotics like there are for adults, physicians may want to be more vigilant given these recent findings.[8]
Children and adolescents respond differently to antipsychotic drugs than adults. In general, they are more likely to experience extrapyramidal side effects than adults. Interestingly, children and adolescents are at risk of developing withdrawal dyskinesia, but it is frequently reversible, unlike in adults. Data demonstrating prolactin-related, cardiac, liver, and sedating effects are available, but large studies establishing prevalence and incidence are limited. Guidelines for proper monitoring of children and adolescents on antipsychotic agents are available. One guideline published in the Journal of American Academy of Child and Adolescent Psychiatry is shown.[9]
The initiation of antipsychotic medication in the elderly with diabetes mellitus has been shown to increase the risk for serious hyperglycemic episodes. Data from a recent study published in the Archives of Internal Medicine are shown. In this study, patients 66 years or older with preexisting diabetes mellitus who were started on an antipsychotic drug were observed for an average of 2 years. There was a statistically significant increase in the number of hospitalizations for hyperglycemia compared with matched controls. Most events occurred within 2 weeks of drug initiation. The effect of antipsychotic drugs on blood glucose levels is theorized to be related to either dopaminergic influence of blood glucose or insulin secretion. Physicians should be particularly vigilant about monitoring glycemic control in elderly patients with diabetes mellitus who are starting any antipsychotic medication.[10]
Atypical antipsychotic drugs are associated with weight gain in older women, an effect that increases with length of drug exposure. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) recently published in the American Journal of Psychiatry are shown. Although most patients were overweight at randomization, patients continued to gain weight the longer they were taking medication. Although both men and women were enrolled, only women gained weight, a finding not completely understood. There were no statistically significant changes in blood pressure, triglycerides, or glucose levels. These data parallel the metabolic changes found with antipsychotic use in youth. Given these new results, physicians must be more vigilant about monitoring the effectiveness of atypical antipsychotics and consider switching to a different agent if the benefits are not substantial and the patient is gaining weight.[11]
The FDA has issued warnings about the risk for sudden death in elderly patients with dementia treated with both conventional and atypical antipsychotic drugs. In 2005, the FDA released a warning about atypical antipsychotic drugs based on data from studies that collectively demonstrated an approximately 1.6- to 1.7-fold increase in mortality among elderly patients who were prescribed an atypical antipsychotic drug, most commonly from cardiac or infectious etiologies. In 2008, the FDA then released a warning that conventional antipsychotic drugs share the increased risk for death in elderly patients with dementia-related psychosis. Data from 1 study cited by the FDA, published in the Annals of Internal Medicine, are shown. Based on the collective data, the FDA recommends that elderly patients should not be prescribed antipsychotic drugs for dementia-related psychosis.[12]
More recent studies have attempted to determine the etiology of the increased mortality in elderly patients recently prescribed antipsychotic drugs. Cohort data among all British Columbia residents aged 65 and older initiated on an antipsychotic from 1996 to 2004 recently published in the Journal of the American Geriatrics Society are shown. An increased risk for cardiovascular mortality, presumed to be secondary to QT prolongation and arrhythmias, represents the majority of the increased mortality in individuals initiated on antipsychotic medication, either conventional or atypical.[13]
There are some data that psychotropic medications may increase the risk for falls in the elderly. Guidelines published in 2001 by the American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention recommend that patients who have fallen may benefit from discontinuation of psychotropic medications.[14] A recent meta-analysis published in the Archives of Internal Medicine in 2009 about the effect of neuroleptic and antipsychotic drugs on falls is shown. Although an association was found between falls and neuroleptic/antipsychotic drugs in the unadjusted analysis, it was not statistically significant when adjustments were made for confounders, with an adjusted odds ratio of 1.39 (95% confidence interval, 0.94-2.00).[15] Prescribers are advised to be cautious about initiating antipsychotic medications in elderly patients at risk for falls without additional safeguards. Hypotension is also a concern with some of the new antipsychotic preparations, such as olanzapine. It is worth repeating -- when prescribing medications for elderly patients -- go low (dosage) and slow (increments).
Author
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Editor
Stephen Soreff, MD
President of Education Initiatives
Nottingham, New Hampshire
Faculty
Metropolitan College of Boston University
Boston, Massachusetts
Disclosure: Stephen Soreff, MD, has disclosed no relevant financial relationships.
