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The use of the atypical antipsychotics is increasing, and off-label use is widespread. The atypical antipsychotics can cause serious adverse effects and administering them safely requires nurses to be aware of these adverse effects and to know the patient populations that are especially vulnerable.
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The atypical antipsychotics are used to treat patients who have serious psychological disorders such as schizophrenia and bipolar disorder. The atypical antipsychotics, which are sometimes referred to as second-generation antipsychotics, were developed in the late ‘80s and the ‘90s as an alternative to the first-generation antipsychotic drugs such as chlorpromazine, haloperidol and thioridazine. The first –generation antipsychotics had been proven to be effective at controlling the signs and symptoms of serious psychiatric illnesses, particularly schizophrenia, but these drugs, called typical antipsychotics, can and often do cause significant adverse effects like arrhythmias, extrapyramidal symptoms (EPS) and tardive dyskinesia. These adverse effects can be irreversible and/or life-threatening.1 Because of these issues, they are dangerous when taken in overdose; a search was made for safer medications, and the atypical antipsychotics were developed. The term atypical is used because the second-generation antipsychotics are less likely to cause EPS and tardive dyskinesia, adverse effects that were commonly “typical” of the first-generation antipsychotics.2 Second-generation simply indicates that they were developed after the first-generation antipsychotics.
In many ways, the atypical antipsychotics have been an improvement. They are relatively benign when taken in overdose,3,4 and they may be less likely to cause ventricular arrhythmias, sudden cardiac death – a well-documented adverse effect of the antipsychotics – QTc prolongation, and torsades de pointes (possibly) than the first-generation antipsychotics.5,6 They appear to be as effective and no less effective for treating schizophrenia as the first-generation antipsychotics,7,8,9 and they are less likely to cause to cause EPS 2,10,11 and tardive dyskinesia.12
However, atypical antipsychotics are associated with significant adverse effects. The atypical antipsychotics can cause EPS, and although the risk is less than for the typical antipsychotics, it is not insignificant,10 and their use is associated with tardive dyskinesia, as well. Cardiovascular, hematologic (clozapine), and metabolic complications that are potentially serious can occur, as well. In addition, atypical antipsychotics are often prescribed for vulnerable patient populations. The number of children and adolescents who are being prescribed these drugs has been increasing,13 and these patient populations may be more likely than adults to develop adverse effects.14,15
A 2013 article suggested that nurses do not have an in-depth knowledge antipsychotics: 779 direct care professionals were queried, and only 12% of the RNs could identify one serious adverse effect associated with antipsychotics.16 The use of the atypical antipsychotics is increasing, and off-label use is widespread. If these patterns continue nurses will be giving these medications more often, and they will be giving them to patients who are susceptible to the adverse effects. Knowledge of how these drugs work and what they can do will be essential for professional nurses.
There are 13 atypical antipsychotics available in the US. The generic name is followed by the American brand name.
Aripiprazole: Abilify®
Asenapine: Saphris®
Brexpiprazole: Rexulti®
Clozapine: Clozaril®
Iloperidone: Fanapt®
Lurasidone: Latuda®
Olanzapine: Zyprexa®
Olanzapine and fluoxetine: Symbyax®
Paliperidone: Invega®
Pimavanserin Nuplazid®
Quetiapine: Seroquel®
Risperidone: Risperdal®
Ziprasidone: Geodon®
The atypical antipsychotics are antagonists at the dopamine2 (D2) receptors, and they are antagonists at serotonin receptors, particularly the 5-HT2A receptors, and their clinical effectiveness is thought to be mediated through this receptor blockade. The differences between the first-generation antipsychotics and the atypical antipsychotics are:
These differences in D2 receptor antagonism and the serotonin receptor antagonism are thought to account for:
The atypical antipsychotics also bind to α1-adrenergic, histaminic, and muscarinic receptors,17 and antagonism of these receptors accounts for common side effects like drowsiness and orthostatic hypotension. The degree to which these receptors are affected is different for each drug, and the amount of receptor blockade can also be affected by the dose, e.g., the higher the dose of risperidone the greater the degree of D2 receptor blockade.19
Example: Olanzapine is a strong antagonist of the 5-HT2A, 5-HT2C, D1-4, H1, and α1-adrenergic receptors. Olanzapine is a moderate antagonist of 5-HT3 and muscarinic receptors. Given this pharmacological profile, it would be reasonable to expect that olanzapine can cause drowsiness, EPS, and orthostatic hypotension, and would be unlikely to cause anticholinergic effects.
The atypical antipsychotics are available as oral and sublingual tablets, oral liquid preparations, and parenteral preparations: aripiprazole, olanzapine, paliperidone, and risperidone are available in a long-acting IM form. There is no proven difference between the oral and long-acting injectable antipsychotics in terms of efficacy20, and for other benefits like adherence to the medication regimen, adverse effects, and hospitalization there is evidence both pro and con.20-22
Most of the atypical antipsychotics have labeled indications for the treatment of adult patients who have bipolar disorder, major depressive disorder, schizophrenia, or schizo-affective disorder and some, e.g., aripiprazole have FDA approval for treating children and adolescents who have bipolar disorder, either alone or in combination with lithium, for certain signs and symptoms of autism, and for Tourette’s syndrome. The atypical antipsychotics can be used alone, as an adjunct, and for short-term and long-term therapy.
Example: The oral form of olanzapine can be used for maintenance therapy for patients who have bipolar disorder. Short-acting parenteral olanzapine can be used to treat acute agitation in patients who have schizophrenia or bipolar I disorder.
Before starting an atypical antipsychotic, the patient should be assessed for the presence of the following conditions:
Behavioral and psychological problems are common in elderly patients who have dementia.23 Non-pharmacologic treatment is preferred for controlling the behavioral and psychological problems of dementia,23,24 but the typical and the atypical antipsychotics have been and still are used for this purpose. However, this is an off-label use of these drugs, and there are two significant issues involving the atypical antipsychotics in this clinical situation.
First, there is evidence and expert opinion that atypical antipsychotics are not effective for this purpose and/or the level of effectiveness is not significant.23,25-27
Second, the atypical antipsychotics have been associated with increased mortality in elderly patients who have dementia-related psychosis.2,23,28 An analysis by the FDA of 17 placebo-controlled trials in which most of the patients were taking atypical antipsychotics found that the risk of death in the treated patients was 1.6–1.7 times that of the patients who received a placebo (4.5% for the treated patients and 2.6% for patients receiving placebo) and that most of the deaths appeared to be from cardiovascular causes or infection.23 These findings were confirmed by a later data analysis by the FDA,28 and the prescribing information for the atypical antipsychotics contains a US Boxed Warning that states: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. The increased risk of mortality is greater for the first-generation antipsychotics and for the atypical antipsychotics, the risk appears to vary from drug to drug.23 There is also evidence that suggests that antipsychotics, typical and atypical, can increase the risk for myocardial infarction and stroke in patients who have dementia.23 Despite these risks and the US Boxed warning, many elderly patients are prescribed atypical antipsychotics.26
The mechanism of actions - or mechanisms – that underpin these risks are not fully known or understood.23,29 The mortality, stroke, and myocardial infarction associated with these drugs may be caused by the drugs (e.g., QTc prolongation and arrhythmias, complications of excessive sedation), by independent patient risk factors, or a combination of those two.
Movement disorders that can be caused by the atypical antipsychotics include EPS and neuroleptic malignant syndrome.
Antipsychotic-induced EPS are thought to be primarily caused by D2 dopamine receptor antagonism that creates an imbalance between dopaminergic and cholinergic tone in areas of the brain that controls motor movements.30 Extrapyramidal symptoms are a well-known adverse effect of all the antipsychotics, but they are less likely to be caused by the atypical antipsychotics (particularly tardive dyskinesia) because these drugs do not bind to the D2 receptors as strongly nor for as long.30 The risk for EPS differs between drugs: EPS are very uncommon adverse effects of clozapine and quetiapine but are very common in patients taking risperidone.2,17 Extrapyramidal symptoms include akathisia, dystonias, parkinsonism, and tardive dyskinesia.
Akathisia is characterized by intense subjective feelings of restlessness and observable repetitive movements, usually in the lower extremities, like moving from one leg to another, pacing, and leg crossing.31,32 Antipsychotic-induced akathisia usually starts several days after beginning therapy with the drug or when the dose is increased.31,32 It may also occur when the dose is decreased or when the patient discontinues use,33 and late-onset akathisia is possible.31,34
Dystonias are distinctive, abnormal, and involuntary muscle movements caused by simultaneous contractions of agonist and antagonist muscles. An antipsychotic-induced dystonic reaction is usually focal, and they can occur in any part of the body. Dystonias present as rhythmic, repetitive contractions and are characterized by twisting of body parts, abnormal movements, and abnormal postures. They usually begin several hours after taking the first dose, but delayed onset of several days is possible as well,32 and an antipsychotic-induced dystonia can occur if a second antipsychotic is prescribed or when therapy with the drug is stopped. Dystonias are uncomfortable and frightening for the patient, but aside from laryngeal dystonia, which can cause airway obstruction, they are not dangerous. As with akathisia, the reported incidence of this adverse effect varies considerably from drug to drug.
Antipsychotic-induced parkinsonism causes signs and symptoms that are essentially identical to those of Parkinson disease, including (but not limited to) bradykinesia, cogwheel rigidity, gait disturbances and neuro-psychiatric problems.32,35,36 Parkinsonism usually begins within a day to weeks after therapy begins or when the dose is increased. However, an onset of several months is possible,35 and parkinsonism may begin:
The incidence of antipsychotic-induced parkinsonism has been reported to be 20%-40%.35,37
Tardive dyskinesia is an EPS that is characterized by rhythmic, repetitive movements, most noticeably in and around the face, lips, and tongue: repetitive tongue protruding and lip-smacking are very common to this disorder. The term tardive is used because the onset of this EPS can be months or years after starting therapy with an antipsychotic.2,36
Tardive dyskinesia is notoriously resistant to treatment, and its clinical course is very variable. If therapy with the drug continues the symptoms may stay the same, improve, or worsen, but complete remission seldom occurs,32,36 and even if therapy with the drug is stopped, complete remission may take months or years.38 The true incidence of tardive dyskinesia caused by antipsychotics is not known, but it has been reported to be between 20%-32%.36,39 The atypical antipsychotics are much less likely than the first-generation drugs to cause this adverse effect.40
Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect of the atypical antipsychotics41-43 that is characterized by hyperthermia (>38° C), a “lead-pipe” muscular rigidity, mental status changes, and autonomic dysfunction reflected by hypertension and tachycardia.42,43 The risk for developing NMS appears to be the same for the atypical and typical and fortunately, NMS is rare: the reported incidence is 0.1%-0.3%,42 and the fatality rate is between 5%-20%.43 Neuroleptic malignant syndrome typically occurs 2-10 days after administration of a drug (a later onset can occur), and it is thought to be caused by an abrupt blockade of the D2 receptors.
Extrapyramidal symptoms are less likely to occur with the atypical antipsychotics that with the typical psychotics, there are differences between them in terms of occurrence, and rate of and for some of the second-generation drugs, the incidence of EPS is relatively low.2,44 However, less likely and low are relative terms, and the atypical antipsychotics do present what could reasonably be called a significant risk for EPS.45
The atypical antipsychotics can cause hyperglycemia and hyperglycemic complications, hyperlipidemia, hyperprolactinemia, and weight gain.2
Hyperglycemia: In 2003, the FDA issued a warning that the second-generation antipsychotics have an adverse effect on glucose metabolism, and research has confirmed that the atypical antipsychotics can cause hyperglycemia, diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic nonketotic coma, and they increase the risk of developing type 2 diabetes.46,47 Abnormal glucose metabolism in patients who take atypical antipsychotics may be caused by a direct drug effect,46 but also in part by weight gain, and by the patient’s psychiatric illness; people who have schizophrenia are more likely than the general population to develop type 2 diabetes.48 The incidence of hyperglycemia and the risk of developing type 2 diabetes from atypical antipsychotics is not known, and some of these drugs are more likely than others to affect glucose metabolism.2,49 Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma are rare adverse effects of antipsychotics.50 The atypical antipsychotics may cause hyperglycemia soon after therapy with the drug is started and even after a single dose.51
Hyperlipidemia: The atypical antipsychotics can cause hyperlipidemias like elevations of fasting serum cholesterol and serum triglycerides.2 There are big differences between the atypical antipsychotics in the prevalence of dyslipidemias, e.g., dyslipidemias are common in patients taking olanzapine, but they are uncommon in patients taking aripiprazole,52,53 and the drugs that cause significant weight gain are associated with a higher risk of dyslipidemias.53 The long-term significance of this adverse effect is not clear; the cause is not fully understood, but it is likely to be a combination of direct drug effect and patient variables.2
Hyperprolactinemia: Hyperprolactinemia is a well-known adverse effect of the typical antipsychotics2 and as with the other metabolic effects, the prevalence of this adverse effect varies from drug to drug.2 Hyperprolactinemia has been associated with sexual dysfunction and with the development of certain cancers like breast cancer that may be prolactin-dependent, but according to clinical research and prescribing information, the use of atypical antipsychotics does not increase the risk of tumorigenesis.54
Weight gain: Weight gain and an increased BMI caused by an atypical antipsychotic can be significant, particularly for certain drugs such as olanzapine. Yang et al. found that after 12 weeks of olanzapine therapy, the subjects’ weight increased from 49.75 ±6.34 to 55.37±7.20 and their BM increased from 19.51±2/64 to 21.71±2.86.55
Other adverse effects include anticholinergic signs/symptoms, dysphagia and aspiration, CNS depression, hepatic and renal dysfunction, falls and fractures, hematologic disorders including (but not limited to) agranulocytosis and neutropenia, orthostatic hypotension, prolonged QT syndrome, and sexual dysfunction.2,56-58 The incidence of these adverse effects varies from drug to drug (e.g., neutropenia is a common adverse effect of clozapine), hepatic and renal dysfunction are very uncommon, and some of these adverse effects only occur in specific patient populations or if risk factors like specific electrolyte abnormalities are present.
Example: All the atypical antipsychotics can cause QTc prolongation, and QTc prolongation is a risk factor for torsades de pointes. The incidence of torsades de pointes associated with the atypical antipsychotics is not known, but it is rare,59 and a prolonged QTc is only one of many factors that can precipitate torsades de pointes in a patient taking an atypical antipsychotic.
The atypical antipsychotics are not categorized as antidepressants, but some have a labeled use for treating patients who have major depressive disorder. The prescribing information for these drugs has a US Boxed Warning that advises clinicians that in the first few weeks of treatment, children, adolescents, and adults 18-24 are at risk for suicidal behavior and ideation. The role of medications in decreasing or increasing the risk for suicide is complex, but clozapine has a labeled use for reducing the risk of suicide in patients who have schizophrenia or schizoaffective disorder, and there is evidence that some of the other atypical antipsychotics decrease the risk of suicide.60,61
Drowsiness and orthostatic hypotension are common adverse effects of the atypical antipsychotics, and these medications are associated with a risk for falls. Patients who are receiving an atypical antipsychotic should have a routine assessment of ambulatory status/ability, neurological status, and orthostatic vital signs.
Extrapyramidal symptoms cannot be completely prevented, but assessment for their presence and early detection may help lessen the consequences. Three important points to remember:
Weight, serum glucose, serum cholesterol, serum lipids, and serum prolactin should be periodically checked.
The physician should be notified if the patient has hypocalcemia, hypokalemia, or hypomagnesemia if the QTc > 500 msec or > 60 msec above the patient’s baseline. If a new medication is prescribed, check to see if it may affect the pharmacokinetics of the atypical antipsychotic.
Example: Fluoxetine is a strong inhibitor of CYP2D6 and iloperidone is a substrate of this enzyme. Concurrent use of these medications could increase the serum level of iloperidone.62
Abruptly stopping the use of an atypical antipsychotic may cause a discontinuation syndrome that can have significant clinical effects.63,64 Therapy with an atypical antipsychotic should be discontinued slowly, and the dose should be gradually tapered.2
The patient who is receiving an atypical antipsychotic should be informed about the signs and symptoms of metabolic disturbances, EPS, CNS depression, and orthostatic hypotension. The patient may be able to detect subtle, early symptoms of these adverse effects before they are noticed by the nurse. Second, these adverse effects are often the reason for non-compliance with and discontinuation, so early detection is important.
A 15-year-old male, S.L., has been diagnosed with type I bipolar disorder, and he was prescribed lithium carbonate, 600 mg in divided doses. The patient’s symptoms of depression and mania were lessened, but not to an optimal degree, and the dose of lithium was gradually increased to 1200 mg a day, This seemed to help, but the increased dose also caused nausea and anorexia. In response, the psychiatrist decided to reduce the lithium dose and to prescribe olanzapine, starting at 2.5 mg a day and increasing to 10 mg a day. After a month of taking lithium and olanzapine the patient reported that his feelings of depression and mania were much less frequent and less severe but he has gained 15 pounds, and his serum glucose is 142 mg/dL, and his serum triglycerides are 175 mg/dL. The psychiatrist is concerned about the laboratory values and the possibility that the patient will stop taking the olanzapine because of the weight; abruptly stopping the drug may worsen his bipolar disorder and possibly cause discontinuation syndrome. The psychiatrist decided to taper the dose of olanzapine slowly and to prescribe aripiprazole; this drug is reported to be much less likely than olanzapine to cause weight gain and other metabolic derangements. After two months the patient’s serum glucose and serum triglycerides are within normal limits, as are all other blood studies, and he is back to his original weight. He is doing well socially and in school and objectively and subjectively his depression and mania are much less frequent and severe.
M.B. is a 79-year-old female who was recently diagnosed with Alzheimer’s disease and Alzheimer’s related dementia. She has been a resident at a local nursing home for two months, and until recently she has seemed to be content with her daily routine, but for the past week, she has had intermittent episodes of agitation and several severe emotional outbursts. During one of these episodes, she struck a staff member. Despite several weeks of non-pharmacological interventions, the patient’s behavioral and emotional status worsened, and she started on risperidone. Prior to starting the drug, a physical examination was performed, a 12-lead ECG was done, serum glucose, calcium, magnesium, and potassium were measured, and a lipid panel was done. Ambulatory status was assessed, body weight was measured, and orthostatic vital signs were checked. Her medication profile was carefully reviewed. After reviewing the data, the psychiatrist decided that it would be safe to begin therapy with risperidone. After several weeks of receiving the drug, the staff noted a significant improvement, but they continued to monitor the patient for adverse effects, and routine ECG and laboratory and assessments were continued.
