Atypical Antipsychotic Agents

Article Author:
Keith Willner
Article Author (Archived):
Sarayu Vasan
Article Editor:
Sara Abdijadid
7/17/2019 3:09:47 PM
PubMed Link:
Atypical Antipsychotic Agents


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. 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 not only during their first psychotic break but also indicated through their lifetime.[1][2][3]

Mechanism of Action

The 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-HT 2A antagonism and 5-HT 1A 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. Alpha 2 antagonism is seen with quetiapine, clozapine, risperidone, and aripiprazole with variable degrees of potency. Atypical antipsychotics with D2 antagonism and partial agonism combined with 5HT2A antagonism have a 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 do not bind muscarinic cholinergic receptors.[4][5][6]


Atypical antipsychotics are available in a variety of formulations such as immediate release injectable, long-acting injectable, 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 emergency situations when a patient is extremely agitated or acutely psychotic, and these include 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 will be discussed here. Treatment with second-generation antipsychotics can contribute to weight gain and subsequently metabolic syndrome with high blood sugar, hypertension, abnormal cholesterol and triglyceride levels 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 were 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 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. There have been numerous studies suggesting that certain atypical antipsychotics, especially clozapine and olanzapine, are associated with diabetes mellitus. There is also increased serum triglyceride and cholesterol levels with clozapine, olanzapine, and quetiapine. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, ziprasidone was the only antipsychotic that was associated with improvement in triglyceride and cholesterol levels 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 effects of olanzapine, risperidone, quetiapine, and ziprasidone. However, there is a recent focus on ziprasidone and its effect on QTc prolongation especially when the medication is administered with a drug that inhibits its metabolism. 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 need to be discontinued, and the patient monitored closely for any signs and symptoms of cardiomyopathy or myocarditis. Sexual side effects are also common because of the drugs effect on dopaminergic, alpha 1 and alpha 2 adrenergic, and H1 Histamine receptors. Antipsychotic-induced sexual dysfunction is particularly related to 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 less extrapyramidal side effects when compared to typical antipsychotics.[7][4][8]


The few contraindications to the use of antipsychotic drugs include tardive dyskinesia, parkinsonism, and previous neuroleptic malignant syndrome. In patients diagnosed with dementia, there is a black box warning describing a severe reaction to antipsychotics leading to death. Caution is indicated 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), there are findings suggesting 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.[9][10][11]


The patient should be closely monitored for adverse effects mentioned above when they are initiated 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. Patient’s weight circumference should also be monitored, and intervention may be required if there is an increase of one body mass index unit. The patient should be counseled 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 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 indicated before initiation of atypical antipsychotics.[12][13][14]


Atypical antipsychotics block a variety of neurotransmitter receptors, and this varies from one drug to another which is responsible for any toxic effects from overdose. By blocking dopamine receptors, second-generation antipsychotics can cause extrapyramidal symptoms and neuroleptic malignant syndrome although to a lesser extent when compared to a typical antipsychotic. 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 very strong anti-muscarinic agents and in toxicity can cause urinary retention, tachycardia, hyperthermia, and delirium. Many of the 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 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 lethal however it is associated 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. No fatalities have been reported with aripiprazole, and symptoms of overdose with ziprasidone include tachycardia and central nervous system depression, and toxicity is seldom lethal.

Enhancing Healthcare Team Outcomes

An evidence-based approach to atypical antipsychotics

Over the past 2 decades, many novel antipsychotic agents have been developed 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 must be considered 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 are prescribed atypical antipsychotics have to be educated on their adverse effects like weight gain, prolonged Qt interval, diabetes, sedation and the risk of dyskinesias. Patients have to be educated that in order to treat their symptoms, they must remain compliant with drug therapy. Unfortunately, that frequently is prescribed antipsychotics is also more complex to deal with. Many have other comorbidities like smoking, use of illicit drugs, alcohol abuse, and personality disorders; all of which interfere with compliance. Most patients do 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.[15][16] (Level V)


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