Continuing Education Activity

In recent years, the atypical antipsychotics or second-generation antipsychotics have become the drugs of choice for acute psychoses. They are “atypical” as they are differentiated from “conventional” or first-generation antipsychotics based on their clinical profile. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of atypical antipsychotics in psychosis management.

Objectives:

• Summarize the indications for using atypical antipsychotic agents.
• Identify the mechanism of action of the atypical antipsychotic class of drugs.
• Review the adverse event and interaction profile for atypical antipsychotics.
• Explain interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with atypical antipsychotics leading to optimal patient outcomes.

Indications

In recent years, atypical antipsychotics or second-generation antipsychotics have become the drugs of choice for acute psychoses. They are “atypical” as they are differentiated from “conventional” or first-generation antipsychotics based on their clinical profile. They have fewer side effects regarding extrapyramidal symptoms when compared to typical antipsychotics. Atypical antipsychotics have transformed the treatment of psychoses as they are prescribed for acute psychoses and in the management of schizophrenia, affective disorders (depression and mania), and geriatric agitation. They are becoming the treatment of choice for patients during their first psychotic break and indicated through their lifetime.[1][2][3]

Mechanism of Action

Second-generation antipsychotics such as risperidone, ziprasidone, paliperidone, and aripiprazole are all potent antagonists of dopamine D2 receptors, while clozapine and quetiapine are weak D2 antagonists. These antipsychotics also have additional properties such as 5-HT2A antagonism and 5-HT1A agonism. Atypical antipsychotics also have antidepressant properties in combination with other antidepressants and when administered alone. Mechanisms linked to antidepressant actions include serotonin and/or norepinephrine reuptake inhibition. Quetiapine and ziprasidone have weak binding at these sites. Alpha2 antagonism is the mechanism with quetiapine, clozapine, risperidone, and aripiprazole with variable degrees of potency.

Atypical antipsychotics with D2 antagonism and partial agonism combined with 5HT2A antagonism have greater efficacy for mania, and these include aripiprazole, quetiapine, olanzapine, risperidone, and asenapine. Antipsychotics also have histamine, muscarinic (cholinergic), and alpha-adrenergic antagonism. Almost all atypical antipsychotics bind to alpha-adrenergic receptors, but the most potent are clozapine, risperidone, iloperidone, and clozapine. Quetiapine, clozapine, and olanzapine have high anticholinergic properties, whereas other atypical antipsychotics very weakly bind to muscarinic cholinergic receptors.[4][5][6]

Administration

Atypical antipsychotics are available in a variety of formulations such as immediate-release injectable (IM), long-acting injectable (IM), and orally disintegrating tablets in addition to the customary oral tablets.  None of the atypical antipsychotics are available for intravenous use. The immediate-release injectables are used in emergencies when a patient is highly agitated or acutely psychotic, including olanzapine and ziprasidone. The long-acting injectables include aripiprazole, olanzapine, paliperidone, and risperidone, which are administered at two to four-week intervals. Oral dosing is the preferred course of administration in most patients. The orally disintegrating tablets include aripiprazole, asenapine, clozapine, olanzapine, and risperidone, which are identical to the standard tablets in terms of absorption and bioavailability. 

Adverse Effects

Atypical antipsychotics can cause adverse effects of weight gain, hyperlipidemia, diabetes mellitus, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual side effects, which this activity will discuss here. Treatment with second-generation antipsychotics can contribute to weight gain and, subsequently, metabolic syndrome with high blood sugar, hypertension, abnormal cholesterol, and triglyceride concentrations, posing a patient at risk for stroke, myocardial disease, and diabetes mellitus. The mean increase in weight over a ten-week period for patients treated with standard doses of atypical antipsychotics was 4.45 kg with clozapine and 4.15 kg with olanzapine. Weight gain was not as significant with other antipsychotics; however, data on quetiapine has been variable. Olanzapine was associated with an increased and significant adverse effect on triglycerides and lipids in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, while ziprasidone was the only second-generation antipsychotic that was not associated with metabolic syndrome. Numerous studies suggest that certain atypical antipsychotics, especially clozapine and olanzapine, are associated with diabetes mellitus. Patients can also demonstrate increased serum triglyceride and cholesterol concentrations with clozapine, olanzapine, and quetiapine.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, ziprasidone was the only antipsychotic associated with improvement in triglyceride and cholesterol concentrations, while olanzapine was associated with greater and adverse effects of these metabolic variables. QTc prolongation is another adverse effect of antipsychotics. In the CATIE study, there was no difference in the effects of olanzapine, risperidone, quetiapine, and ziprasidone. However, a recent focus is on ziprasidone and its impact on QTc prolongation, especially when the medication administration takes place with a drug that inhibits its metabolism.[7]

Myocarditis is another adverse effect, especially associated with the use of clozapine. Evidence suggests that clozapine is associated with a low risk of fatal myocarditis, and the medication would require discontinuation, and the patient monitored closely for any signs and symptoms of cardiomyopathy or myocarditis. Sexual side effects are also common because of the drug's effect on dopaminergic, alpha1 and alpha2 adrenergic, and H1 histamine receptors. Antipsychotic-induced sexual dysfunction is mainly related to the D2 receptor blockade in the pituitary gland leading to an excess of prolactin. Hyperprolactinemia is associated with menstrual and sexual dysfunction, and therefore consideration should be given to switching to a medication that is prolactin sparing, such as aripiprazole. Atypical antipsychotics are typically associated with fewer extrapyramidal side effects when compared to typical antipsychotics. Antipsychotics have an FDA boxed warning of increased death in geriatric patients with psychoses related to dementia.[8][4][9]

Contraindications

The few contraindications to the use of antipsychotic drugs include tardive dyskinesia, parkinsonism, and previous neuroleptic malignant syndrome. In elderly patients diagnosed with dementia, there is an FDA  boxed warning describing a severe reaction to antipsychotics leading to death. Caution is necessary when using antipsychotics in the presence of a prolactinoma as there is a significant concern that a dopamine antagonist can cause a pituitary prolactinoma to enlarge. In patients with Tay Sachs disease (hexosaminidase-A deficiency), findings suggest that antipsychotic drugs deplete hexosaminidase-A and worsen the course of the disease. Some other contraindications to the use of antipsychotics are glaucoma, liver disease, severe neutropenia, or bone marrow depression.[10][11][12]

Monitoring

The patient should be closely monitored for adverse effects mentioned above when starting on atypical antipsychotics. The baseline body mass index should be recorded before treatment with atypical antipsychotics and at every visit for at least six months. The patient’s weight circumference also needs monitoring, and intervention may be necessary if there is an increase in one body mass index unit. The patient should receive counseling in nutrition, possible initiation of a weight loss program, use of medication to help with weight loss, and/or consider switching to another antipsychotic with less weight gain. Monitoring weight gain alone may not be sufficient for assessing diabetes mellitus risk. Some of the tests used to assess the risk of diabetes mellitus include random glucose, fasting plasma glucose, glycated hemoglobin, and oral glucose tolerance test. A baseline lipid panel and EKG are also necessary before the initiation of atypical antipsychotics. Clozapine can cause severe neutropenia, and thus neutrophil count (ANC) needs to be monitored.[13][14][15]

Toxicity

Atypical antipsychotics block a variety of neurotransmitter receptors, which varies from one drug to another regarding which is responsible for any toxic effects from an overdose. By blocking dopamine receptors, second-generation antipsychotics can cause extrapyramidal symptoms and neuroleptic malignant syndrome, although to a lesser extent, compared to a typical antipsychotic, e.g., haloperidol. Alpha-adrenergic blockade causes orthostatic hypotension and tachycardia via vasodilation. Olanzapine, clozapine, aripiprazole, and quetiapine cause significant anti-alpha-adrenergic effects. Almost all atypical agents block serotonin receptors, and several of them inhibit muscarinic receptors. Quetiapine, clozapine, and olanzapine are powerful anti-muscarinic agents, and toxicity can cause urinary retention, tachycardia, hyperthermia, and delirium. Many second-generation antipsychotics also cause significant sedation by antihistamine activity; these agents are aripiprazole, quetiapine, clozapine, and olanzapine. Olanzapine causes central nervous system depression, hypotension, sedation, sometimes agitation and is rarely lethal in monotherapy overdose.

On the other hand, clozapine can sometimes be lethal in overdose by causing respiratory depression, myocarditis, cardiomyopathy, changes in heart rhythm, and altered mental status. In overdose, quetiapine is rarely fatal; however, it correlates with the highest mortality rate of all antipsychotics as it successfully blocks muscarinic, alpha-adrenergic, and histamine receptors. Toxicity with quetiapine presents with tachycardia, delirium, central nervous system depression, and rarely fatal ventricular arrhythmia. There are no reported fatalities with aripiprazole, and symptoms of overdose with ziprasidone include tachycardia and central nervous system depression, and toxicity is seldom lethal.

Enhancing Healthcare Team Outcomes

Over the past two decades, many novel antipsychotic agents have undergone development, but so far, there is little solid evidence to suggest that one is better than the other. The decision to choose one atypical antipsychotic over another requires clinical judgment, patient's prior response, tolerability, affordability, and personal preferences. Plus, the adverse effects of these drugs merit consideration, as some are more likely than others to cause weight gain, dyskinesias, or sedation. The latest atypical antipsychotics are reputed to cause fewer adverse effects compared to the first generation of atypical antipsychotics, but as yet, there are no long-term data on these novel agents. All patients who receive atypical antipsychotics need to understand their adverse effects, including weight gain, prolonged QTc interval, diabetes mellitus, sedation, and the risk of dyskinesias. Patients also need to comprehend that to treat their symptoms, they must remain adherent to their drug therapy. Unfortunately, frequently, those individuals prescribed antipsychotics are also present with more complex management challenges. Many have other comorbidities like smoking, the use of illicit drugs, alcohol misuse, and personality disorders, all of which interfere with pharmacotherapy adherence. Most patients drop out of follow-up as soon as their symptoms improve and only return to therapy when forced by the family or the legal system.[16][17] [Level 5]

Given the above, it is evident that prescribing and managing therapy with atypical antipsychotics requires an interprofessional team effort; the more eyes on patients who require these medications, the better chance for therapeutic success. While the clinician will initially prescribe one of these agents, they would do well to consult with a psychiatric specialty pharmacist, who can go over the patient's medication record, assist in agent selection, and verify appropriate dosing. Nurses, as well as the clinician and the pharmacist, can offer counsel, monitor adherence (which is often a challenge with these patients, as already covered above), and assess for potential adverse effects from the drugs. Any mental health providers involved should also be included in the team approach, and the lines of communication between all disciplines must be open so that everyone on the interprofessional healthcare team has the same information and can offer assistance or evaluate the patient as the case progresses, leading to better patient outcomes. [Level 5]