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Atypical Antipsychotics (FL INITIAL Autonomous Practice - Pharmacology)

2 Contact Hours including 2 Advanced Pharmacology Hours
Only FL APRNs will receive credit for this course.
This course is only applicable for Florida nurse practitioners who need to meet the autonomous practice initial licensure requirement.
This peer reviewed course is applicable for the following professions:
Advanced Practice Registered Nurse (APRN)
This course will be updated or discontinued on or before Monday, February 20, 2023

Nationally Accredited

CEUFast, Inc. is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. ANCC Provider number #P0274.


Outcomes

The use of 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 know the especially vulnerable patient populations.

Objectives

After finishing this module, the reader will be able to:

  1. Describe the mechanism of action of the atypical antipsychotics.
  2. Discuss labeled uses for the atypical antipsychotics.
  3. Identify significant adverse effects caused by the atypical antipsychotics.
  4. Discuss patient monitoring during the use of an atypical antipsychotic.
  5. Discuss nursing care issues associated with the administration of the atypical antipsychotics.
CEUFast Inc. and the course planners for this educational activity do not have any relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
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Author:    Dana Bartlett (RN, BSN, MA, MA, CSPI)

Introduction

The atypical antipsychotics are used to treat 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 control the signs and symptoms of serious psychiatric illnesses, particularly schizophrenia. Still, these drugs, called typical antipsychotics, can and often cause significant adverse effects like arrhythmias, extrapyramidal symptoms (EPS), and tardive dyskinesia. These adverse effects can be irreversible or life-threatening (Nuciform et al., 2017). Because these issues are dangerous when taken in overdose, a search was done 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 (Jibson, 2018). 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, 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 (Beach et al., 2018; Kapitanyan & Su, 2018). They appear to be as effective and no less effective for treating schizophrenia than the first-generation antipsychotics. They are less likely to cause EPS and tardive dyskinesia (Radhakrishnan et al., 2019).

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. Their use is also associated with tardive dyskinesia (Radhakrishnan et al., 2019). 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, and these patient populations may be more likely than adults to develop adverse effects (Lee et al., 2018).

The use of 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. Knowing how these drugs work and what they can do will be essential for professional nurses.

Pharmacology of the Atypical Antipsychotics

There are 13 atypical antipsychotics available in the US. The American brand name follows the generic 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. 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:

  • The degree and duration of the D2 blockade are far less, and;
  • The serotonin receptor blockade (Katzung, 2019).

These differences in D2 receptor antagonism and the serotonin receptor antagonism are thought to account for:

  • The decreased risk of EPS, and;
  • The antipsychotic effects of these drugs.

The atypical antipsychotics bind to α1-adrenergic, histaminic, and muscarinic receptors (Katzung, 2019). 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. 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 (Lauriello & Campbell, 2017).

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, risperidone, a long-acting IM form. There is no proven difference between oral and long-acting injectable antipsychotics in terms of efficacy. There is evidence both pro and con evidence for other benefits like adherence to the medication regimen, adverse effects, and hospitalization (Lauriello & Campbell, 2017).

Indications for Use

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 Tourette's syndrome. The atypical antipsychotics can be used alone as an adjunct and 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 treat acute agitation in patients with schizophrenia or bipolar I disorder.

Before starting an atypical antipsychotic, the patient should be assessed for the presence of the following conditions:

  • Congenital long QT syndrome
  • Diabetes
  • Cardiovascular, hepatic, or renal disease
  • Electrolyte abnormalities
  • Medical conditions that might cause electrolyte abnormalities
  • Medications that would affect the metabolism of the atypical antipsychotic
  • Family history of torsades de pointes
  • A prolonged QTc
  • Fall risk
  • History of seizures or risk of seizures

Adverse Effects Caused by Atypical Antipsychotics

Atypical Antipsychotics and Patients with Dementia: Cerebrovascular Events and Sudden Death. Behavioral and psychological problems are common in elderly patients with dementia (Press & Alexander, 2018). Non-pharmacologic treatment is preferred for controlling the behavioral and psychological problems of dementia (Press & Alexander, 2018). 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 or the level of effectiveness is not significant (Press & Alexander, 2018).

Second, the atypical antipsychotics have been associated with increased mortality in elderly patients who have dementia-related psychosis (Press & Alexander, 2018). 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 (Press & Alexander, 2018). Later data analysis by the FDA confirmed these findings. The prescribing information for the atypical antipsychotics contains a US Boxed Warning that states (Maust et al., 2015): 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 (Press & Alexander, 2018). 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 (Press & Alexander, 2018). Despite these risks and the US Boxed warning, many elderly patients are prescribed atypical antipsychotics (Sturm et al., 2018).

The mechanism of actions - or mechanisms – that underpin these risks are not fully known or understood (Press & Alexander, 2018). The drugs may cause the mortality, stroke, and myocardial infarction associated with these drugs (e.g., QTc prolongation and arrhythmias, complications of excessive sedation), by independent patient risk factors or a combination of those two.

Movement Disorders

The atypical antipsychotics can cause 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 (Stepnicki et al., 2018).

Extrapyramidal symptoms are a well-known adverse effect of all antipsychotics. Still, 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 (Stepnicki et al., 2018). 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 (Katzung, 2019). 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 (Pringsheim et al., 2018). Antipsychotic-induced akathisia usually starts several days after therapy with the drug or when the dose is increased (Pringsheim et al., 2018). It may also occur when the dose is decreased or when the patient discontinues use, and late-onset akathisia is possible (Pringsheim et al., 2018).

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 can occur in any part of the body. Dystonias present as rhythmic, repetitive contractions characterized by twisting body parts, abnormal movements, and abnormal postures. They usually begin several hours after taking the first dose. Still, delayed onset of several days is also possible, and antipsychotic-induced dystonia can occur if a second antipsychotic is prescribed or when therapy with the drug is stopped (Pringsheim et al., 2018). Dystonias are uncomfortable and frightening for the patient, but they are not dangerous aside from laryngeal dystonia, which can cause airway obstruction. 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's disease, including (but not limited to) bradykinesia, cogwheel rigidity, gait disturbances, and neuropsychiatric problems (Pringsheim et al., 2018). Parkinsonism usually begins within a day to weeks after therapy begins or when the dose is increased. However, the onset of several months is possible, and parkinsonism may begin:

  • When therapy with the drug is stopped;
  • If the anticholinergic medication used to prevent EPS is stopped, or the dose is changed, or;
  • Another dopamine receptor antagonist is added to the regimen (Pringsheim et al., 2018).

The incidence of antipsychotic-induced parkinsonism has been reported to be 20%-40% (Pieters et al., 2018). 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 (Ward & Citrome, 2018).

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, and even if therapy with the drug is stopped, complete remission may take months or years (Tarsy, 2018). The true incidence of tardive dyskinesia caused by antipsychotics is unknown, but it has been reported to be between 20%-32%. The atypical antipsychotics are much less likely than the first-generation drugs to cause this adverse effect (Carbon et al., 2018).

Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect of the atypical antipsychotics that are characterized by hyperthermia (>38° C), a "lead-pipe" muscular rigidity, mental status changes, and autonomic dysfunction reflected by hypertension and tachycardia (Lommel et al., 2017). 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%, and the fatality rate is between 5%-20% (Wijdicks, 2019). The neuroleptic malignant syndrome typically occurs 2-10 days after administration of a drug (a later onset can occur). It is thought to be caused by an abrupt blockage of the D2 receptors.

Extrapyramidal symptoms are less likely to occur with the atypical antipsychotics than 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 (Wang et al., 2017). However, less likely and low are relative terms, and the atypical antipsychotics do present what could reasonably be called a significant risk for EPS (Riberio et al., 2017).

Metabolic Disorders

The atypical antipsychotics can cause hyperglycemia and hyperglycemic complications, hyperlipidemia, hyperprolactinemia, and weight gain (Jibson, 2018).

Hyperglycemia: In 2003, the FDA issued a warning that the second-generation antipsychotics harm 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 ( Kowalchuk et al., 2018). A direct drug effect may cause abnormal glucose metabolism in patients who take atypical antipsychotics, but in part by weight gain and by the patient's psychiatric illness; people with schizophrenia are more likely than the general population to develop type 2 diabetes (Bent-Ennakhil et al., 2018). The incidence of hyperglycemia and the risk of developing type 2 diabetes from atypical antipsychotics are unknown. Some of these drugs are more likely than others to affect glucose metabolism (Kato et al., 2015). Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma are rare adverse effects of antipsychotics (Yuk et al., 2017). The atypical antipsychotics may cause hyperglycemia soon after therapy with the drug is started and even after a single dose (Bishara, 2016).

Hyperlipidemia: The atypical antipsychotics can cause hyperlipidemias like elevations of fasting serum cholesterol and serum triglycerides (Jibson, 2018). There are big differences between the atypical antipsychotics in the prevalence of dyslipidemias, e.g., dyslipidemias are common in patients taking olanzapine. Still, they are uncommon in patients taking aripiprazole, and the drugs that cause significant weight gain are associated with a higher risk of dyslipidemias (Riberio, 2018). 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 effects and patient variables (Jibson, 2018).

Hyperprolactinemia: Hyperprolactinemia is a well-known adverse effect of the typical antipsychotics 2, and as with the other metabolic effects, the prevalence of this adverse effect varies from drug to drug (Jibson, 2018). Hyperprolactinemia has been associated with sexual dysfunction and the development of certain cancers like breast cancer that may be prolactin-dependent. Still, according to clinical research and prescribing information, the use of atypical antipsychotics does not increase the risk of tumorigenesis (De Hert et al., 2016).

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 (Yang et al., 2018).

Other Adverse Effects

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(Slim et al., 2016). 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 unknown. Still, it is rare, and a prolonged QTc is only one of many factors that can precipitate torsades de pointes in a patient taking an atypical antipsychotic (Arunachalam et al., 2018).

Atypical Antipsychotics and Suicide

The atypical antipsychotics are not categorized as antidepressants, but some have a label for treating patients with a major depressive disorder. The prescribing information for these drugs has a US Boxed Warning that advises clinicians that children, adolescents, and adults 18-24 are at risk for suicidal behavior and ideation in the first few weeks of treatment. The role of medications in decreasing or increasing the risk for suicide is complex. Still, clozapine has a label for reducing the risk of suicide in patients with schizophrenia or schizo-affective disorder. There is evidence that some of the other atypical antipsychotics decrease the risk of suicide (Ma Ch et al., 2018).

Nursing Considerations

Patient Safety

Drowsiness and orthostatic hypotension are common adverse effects of atypical antipsychotics, and these medications are associated with a risk for falls. Patients receiving an atypical antipsychotic should have a routine ambulatory status/ability assessment, neurological status, and vital orthostatic signs.

Extrapyramidal Syndromes

Extrapyramidal symptoms cannot be completely prevented, but assessing their presence and early detection may help lessen the consequences. Two important points to remember:

  1. The signs and symptoms of EPS syndrome may be subtle and non-specific, and;
  2. The onset of EPS can be very delayed, and;
  3. EPS can occur when the use of the drug is stopped, the dose is increased, or when another medication has been added to the patient's regimen.

Metabolic Considerations

Weight, serum glucose, serum cholesterol, serum lipids, and serum prolactin should be periodically checked.

QTc Prolongation and Torsades de Pointes

If the patient has hypocalcemia, hypokalemia, or hypomagnesemia, the physician should be notified if the QTc > 500 msec or > (Ma Ch et al., 2018). 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.

Discontinuing Therapy

Abruptly stopping the use of an atypical antipsychotic may cause a discontinuation syndrome that can have significant clinical effects 3 Therapy with an atypical antipsychotic should be discontinued slowly, and the dose should be gradually tapered (Jibson, 2018).

Patient Education

The patient receiving an atypical antipsychotic should be informed about the signs and symptoms of metabolic disturbances, EPS, CNS depression, and orthostatic hypotension. The patient may detect subtle, early symptoms of these adverse effects before the nurse notices them. Second, these adverse effects are often the reason for non-compliance with and discontinuation, so early detection is important.

Case Study #1

A 15-year-old male, S.L., has been diagnosed with type I bipolar disorder, and he was prescribed lithium carbonate (Ma Ch et al., 2018).0 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 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. Still, he has gained 15 pounds, 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 prescribe aripiprazole; this drug is 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.

Case Study #2

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. Still, she has had intermittent episodes of agitation and several severe emotional outbursts for the past week. 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. Before 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 vital orthostatic 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. Still, they continued to monitor the patient for adverse effects, and routine ECG and laboratory assessments were continued.

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