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Table of Contents

Magill’s Medical Guide, 9th Edition

Antipsychotic medications

by Michael A. Buratovich, , PhD

Category: Medication

Anatomy or system affected: Brain

Specialties and related fields: Neurology, pharmacology, psychiatry

Definition: a class of psychotropic medications used to manage psychosis, principally in schizophrenia but also with mood stabilizers, to treat bipolar disorder

Key terms:

atypical antipsychotics: also known as second-generation antipsychotics; serotonin-dopamine antagonists, largely introduced after the 1970s and used to treat psychiatric conditions

neuroleptics: psychotropic drugs that depress nerve functions

phenothiazines: chemical derivatives of phenothiazine with tranquilizing properties, used to treat mental illness.

psychosis: a severe mental disorder in which thought and emotions are so impaired that contact is lost with external reality

typical antipsychotics: a class of antipsychotic drugs first developed in the 1950s to treat psychosis.

INTRODUCTION

Psychiatrists first used antipsychotic medications to treat people who were out of touch with reality (psychotic) in the 1950s with the development of chlorpromazine (Thorazine). Originally developed for surgical patients, chlorpromazine was used on patients with psychiatric problems because of its calming effects. Its antipsychotic effect went well beyond calming, affecting the nervous system, especially the anticholinergic, antidopaminergic, and antihistamine receptors. Chlorpromazine became the model for the class of drugs known as phenothiazines, the early antipsychotics. These and the other early antipsychotics (first-generation antipsychotic agents) are typical antipsychotics or major tranquilizers. When Jean Delay and Pierre Deniker, working at St Anne’s Hospital in Paris, developed these drugs, people deemed psychotic had traditionally been treated with brain surgery (lobotomies). Hence, medications provided a great advance in treatment modalities.

The second class of typical antipsychotics is the phenylbutylpiperadines. This category of drugs includes haloperidol (Haldol), first developed in the late 1950s but not approved for use in the United States until 1988. Haloperidol is routinely used to treat delirium and acute psychotic states. It is also used to treat Tourette syndrome. Because of the effect of these drugs on the central nervous system, antipsychotic agents are also referred to as neuroleptics. They can cause a decrease in delusions, hallucinations, confusion, and agitation in psychiatric patients and may normalize their motor activity. Such medications have been widely used to treat schizophrenia and bipolar disorder disorders.

Ad from 1962 for Thorazine (tradename of chlorpromazine in the U.S.). Unknown author, via Wikimedia Commons. [Public domain.]

MMG2022_p199_001.tif

However, in many patients, treatment with first-generation antipsychotics has been stopped because of adverse side effects. Common side effects are extrapyramidal reactions, including low blood pressure, impotence, lethargy, and tardive dyskinesia (movement disorders involving involuntary, purposeless movements, typically of the face, legs, or torso).

MODE OF ACTION

Schizophrenia results, in part, from excessive dopamine neurotransmission in the brain. First, Illicit drugs that increase dopamine neurotransmission in the brain can cause some of the positive symptoms of schizophrenia. Second, PET (positron emission tomography) studies have identified differences in dopamine neurotransmission in the prefrontal cortex, cingulate cortex, and hippocampus between schizophrenia patients and healthy control subjects. Third, all antipsychotic drugs decrease dopamine neurotransmission through the D2 receptor. However, the so-called dopamine hypothesis of schizophrenia is incomplete since it fails to explain the cognitive defects of schizophrenia-alogia, flat effect, etc. It cannot account for the effects of psychoactive drugs, such as LSD (lysergic acid diethylamide), that cause schizophrenic symptoms but do not affect the D2 receptor.

Typical antipsychotics bind the D2 receptor very strongly and decrease dopamine neurotransmission in all four main dopamine pathways of the brain:

  • Mesolimbic pathway: regulates motivation cognition, motivation, emotions, and reward.

  • Nigrostriatal pathway: motor planning and purposeful movement.

  • Mesocortical pathway involves cognition and executive function, emotions, and affect.

  • Tuberoinfundibular pathway: negatively regulates the secretion of prolactin by the anterior pituitary.

Inhibition of D2 receptors in the nigrostriatal pathway induces extrapyramidal symptoms. Extrapyramidal symptoms consist of continuous muscle spasms (dystonia), a restlessness that results in constant motion (akathisia), and symptoms more commonly observed in patients with Parkinson’s disease (parkinsonism), such as rigidity, slowness of movement (bradykinesia), tremor, and irregular, jerky movements (tardive dyskinesia). Typical antipsychotics, which strongly bind and antagonize the D2 receptor, such as haloperidol, frequently cause “pseudoparkinsonism.”

SECOND-GENERATION ANTIPSYCHOTICS

To avoid the extrapyramidal side effects of the typical antipsychotic agents, drug companies developed medications known as second-generation or atypical antipsychotics. Atypical antipsychotics do not bind the D2 receptor as strongly as typical antipsychotics and antagonize some serotonin receptors (specifically, the serotonin 5HT2A receptor). The first atypical antipsychotic, clozapine (Clozaril), was developed in 1970 but not approved for use until 1989 to treat schizophrenia. This medication, a debenzapine derivative, was found to have a potentially deadly side effect, agranulocytosis (a decrease in the white blood cells circulating in the bloodstream), in one percent of patients and was voluntarily withdrawn from the market. In 1989, after further testing, it was approved for use by the Food and Drug Administration (FDA) for individuals with treatment-resistant schizophrenia. Clozapine also causes heart inflammation (myocarditis) in 0.5 to 3 percent of patients. It only occurs within the first one to six weeks of treatment. It is one of the few medications shown to decrease suicidality in severely schizophrenic patients.

Another category of second-generation antipsychotics includes the benzisoxidil group, typified by risperidone (Risperdal). This drug is often used to treat bipolar disorder. Each of the atypical antipsychotics also causes side effects. Still, in general, these drugs are better tolerated than first-generation antipsychotics. Second-generation antipsychotics include olanzapine, quetiapine, paliperidone, asenapine, iloperidone, and lurasidone. Whereas clozapine is the most effective antipsychotic, olanzapine is more effective than quetiapine, risperidone, or ziprasidone in reducing psychotic symptoms, and risperidone is more effective than quetiapine or ziprasidone.

A newer category of antipsychotics sometimes called the “third-generation antipsychotics,” does not inhibit the D2 receptor but instead partially activates it. These drugs are called “partial agonists,” and they include aripiprazole (Abilify), brexpiprazole (Rexulti), cariprazine (Vraylar), and the newer antipsychotic lumateperone (Caplyta). Cariprazine is FDA-approved for bipolar disorder.

Whereas second-generation antipsychotics have a lower risk of neurological side effects, some are associated with an increased risk of hyperglycemia, weight gain, dyslipidemia, and developing type 2 diabetes mellitus. Olanzapine has the worse side effect profile, followed by clozapine and quetiapine. Weight gain is problematic in patients who take olanzapine, clozapine, quetiapine, paliperidone, and risperidone. Cariprazine and paliperidone have the highest risk of causing extrapyramidal symptoms, and ziprasidone and iloperidone can cause abnormal heart rhythms. Paliperidone and risperidone can elevate prolactin levels, which can cause cessation of sperm production in men and menstruation abnormalities in women. Aripiprazole may cause akathisia.

A potential side effect of antipsychotics is tardive dyskinesia. This movement disorder consists of involuntary muscle movements in the face, neck, arms, and legs. Long-term antipsychotic use increases the risk of tardive dyskinesia. The risk of tardive dyskinesia is higher with first-generation antipsychotics but still occurs with second-generation antipsychotics. Those at higher risk for tardive dyskinesia include older patients, women, those with previous traumatic brain damage, diabetes mellitus, and those of African American ethnicity. Remission of tardive dyskinesia after discontinuing the medication is more likely in younger patients and may take months to years.

USE OF THESE DRUGS

Typically, when deciding which medication to prescribe, a physician will consider an individual’s symptoms, age, weight, and personal, family, and medication history. Research has shown that most antipsychotic drugs alter the brain’s structure. In some cases, these structural changes directly result from the treatment. In contrast, they are side effects of the medication in other cases. Researchers hope that some of these structural changes in the brain provide clues to how these antipsychotic drugs work.

For Further Information:

1 

Antipsychotic Medications. CAMH, n.d., www.camh.ca/en/health-info/mental-illness-and-addiction-i ndex/antipsychotic-medication. Accessed 1 Apr. 2022.

2 

Antipsychotics. Mind, Sept. 2020, www.mind.org.uk/media-a/6438/antipsychotics-2020.pdf. Accessed 1 Apr. 2022.

3 

Antipsychotics. Rethink Mental Health, May 2021, www.rethink.org/Factsheets/10036/Antipsychotics%20factsheet. Accessed 1 Apr. 2022.

4 

“Drugs for Psychotic Disorder.” Medical Letter on Drugs and Therapeutics, vol. 58, no. 1510, 2016, pp. 160-64.

5 

Psychosis. National Alliance on Mental Health, n.d., www.nami.org/About-Mental-Illness/Mental-Health-Conditions/Psychosis. Accessed 1 Apr. 2022.

6 

Psychotic Disorders. MedlinePlus, 10 Aug. 2021, medlineplus.gov/psychoticdisorders.html. Accessed 1 Apr. 2022.

7 

Mental Health Medicines. National Institute of Mental Health, Oct. 2016, www.nimh.nih.gov/health/topics/mental-health-medications. Accessed 1 Apr. 2022.

8 

Stahl, S. M. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 5th ed. Cambridge UP, 2021.

Citation Types

Type
Format
MLA 9th
Buratovich, Michael A. "Antipsychotic Medications." Magill’s Medical Guide, 9th Edition, edited by Anubhav Agarwal,, Salem Press, 2022. Salem Online, online.salempress.com/articleDetails.do?articleName=MMG2022_0085.
APA 7th
Buratovich, M. A. (2022). Antipsychotic medications. In A. Agarwal, (Ed.), Magill’s Medical Guide, 9th Edition. Salem Press. online.salempress.com.
CMOS 17th
Buratovich, Michael A. "Antipsychotic Medications." Edited by Anubhav Agarwal,. Magill’s Medical Guide, 9th Edition. Hackensack: Salem Press, 2022. Accessed December 14, 2025. online.salempress.com.