What are Antipsychotic Medications?


What are Antipsychotics?

Antipsychotics are a class of medication used to treat the following disorders:

Psychotic disorders (e.g., Schizophrenia and Schizoaffective Disorder)

Bipolar Disorders

Acute Agitation

Tourette’s Syndrome (Tic Disorder)

Major Depressive Disorder (as add-on treatment)

A Brief History of Antipsychotics

Antipsychotics were discovered by accident. During the early to mid 1900s, surgeons began searching for sedatives to administer to their patients before surgery. Researchers at Rhone Poulenc, a French Pharmaceutical company, were working to improve recently synthesized antihistamines such as diphenhydramine (i.e. Benadryl) as sedatives for surgery.  Paul Charpentier, a Chemist, synthesized  chlorpromazine, also known as Thorazine. Jean Delay and Pierre Deniker were psychiatrists interested in Chlorpromazine’s sedative effects and began studying it’s use for patients with psychotic disorders. Delay and Deniker’s work was published in 1952 in a landmark paper describing Chlorpromazine’s ability to reduce psychotic symptoms. It would later became the first widely used antipsychotic medication. It wasn’t until later that antipsychotics were found to produce their effects, at least partially, by blocking dopamine receptors in the brain. The first antipsychotics were called “first generation” antipsychotics or “typical” antipsychotics and were classified based upon how strongly they block dopamine receptors. Although blocking dopamine in specific areas of the brain has beneficial antipsychotic effects, blocking dopamine receptors in other areas causes many side effects. This limited their use until new medications were synthesized with newer mechanisms that reduced these side effects. These newer agents were called “second generation” or “Atypical” antipsychotics. 

Classification and Naming

Antipsychotic medications are divided into two classes:

Typical Antipsychotics (also termed 1st Generation or Conventional antipsychotics)

Atypical Antipsychotics (also termed 2nd Generation antipsychotics)

Typical antipsychotics are the older class of medications that are subdivided based on potency at the dopamine 2 receptor (D2R). That is, typical antipsychotics may be considered high potency, medium potency, or low potency depending on how strongly they bind to, and inhibit the activity of, the dopamine 2 receptor. Haloperidol (Haldol) is an example of high potency typical antipsychotic. Chlorpromazine (Thorazine) is an example of a low potency typical antipsychotic. 

Atypical antipsychotics are a more recent class of medications that have some additional properties that render them “Atypical.” Antagonism of 5HT-2A receptors and the resulting decrease in the risk of abnormal movements is the primary reason we call them atypical. That is, the addition of potent serotonin receptor binding reduces some of the side effects that were problematic with the typical antipsychotics. For example, antagonism (or blockade) of the 5HT-2A serotonin receptor causes an increase in dopamine release in certain dopamine projections such as the mesocortical, nigrostriatal, and infundibular-pituitary dopamine tracts (but not in the mesolimbic tract as dopamine neurons in this circuit appear to have minimal, if any, 5-HT-2A receptors). Atypical antipsychotics are about ten-fold less likely to cause extrapyramidal symptoms (abnormal involuntary muscle movements) or tardive dyskinesia compared to typical antipsychotics. The first reason for this is that atypical antipsychotics dissociate from the dopamine (D-2) receptor more rapidly than typical antipsychotics.  The second reason is because of the additional property of antagonism at (5HT-2A) receptors mentioned previously.

Are all Antipsychotics equally effective?

Probably not, but we don’t know for certain. While there is ongoing debate about the comparative efficacy of antipsychotics, there is little empirical evidence that any one antipsychotic, with the exception of Clozapine (Clozaril), is superior to the rest in terms of efficacy.

Typical Antipsychotics

Generic NameBrand Name

Side Effects

The Typical (first-generation) antipsychotics are derived from a number of chemical classes but differ in their affinity (or potency) for binding to dopamine (D2) receptors in the brain. High Potency antipsychotics include Haloperidol and Fluphenazine whereas Low Potency antipsychotics include Chlorpromazine. Unfortunately, the lower potency antipsychotics such as chlorpromazine (Thorazine) target more than just dopamine receptors which means they also cause a lot of other side effects. They block Histamine (H1) receptors causing sedation and weight gain, Adrenergic (α1) receptors causing sedation and blood pressure changes, and Muscarinic cholinergic (M1) receptors causing dry mouth, urinary retention, constipation, blurry vision, and cognitive impairment/memory impairment. High-potency antipsychotics such as fluphenazine and haloperidol show far less sedation, hypotension, and anticholinergic side effects, but ebcause they are strong dopamine blockers, they are more likely to cause side effects from blocking dopamine (slowed movements, cognitive problems, emotional flattening, dystonic reactions, prolactin elevations, and tardive dyskinesia).


Weight Gain

Increased Appetite

Blood Pressure Changes and Lightheadedness

Dry Mouth

Urinary Retention/Difficulty Urinating


Blurry Vision

Cognitive Impairment

Slowed Movements (Parkinsonism)

Emotional “Blunting” or “Flattening”

Seizures (rare)

Cardiac Arrhythmias (rare)

Tardive Dyskinesia


Extrapyramidal Symptoms (EPS)

High-potency antipsychotics such as fluphenazine and haloperidol show far less sedation, hypotension, and anticholinergic side effects, but are more likely to induce extrapyramidal symptoms (EPS) such as acute dystonia, acute akathisia, and/or acute pseudo-Parkinsonism due to robust dopamine antagonism in the pars compacta-striatal dopamine circuit.


Tardive Dyskinesia (TD)

Tardive Dyskinesia (TD) is a hyperkinetic movement disorder associated with long term use of antipsychotics and/or the rapid withdrawal of antipsychotic medications. Symptoms include involuntary movements such as lip smacking, eye blinking, grimacing, tongue movements, or writhing movements of the extremities or trunk. All first-generation antipsychotics induce tardive dyskinesia (TD) at an incidence rate of about 3% to 5% per year of exposure up to 60% lifetime prevalence. TD is mild and non-progressive in majority of cases. TD results from chronic blockade of dopamine receptors in the brain and the body’s response to such blockade over time.

TD results from chronic antagonism of post-synaptic receptors in the basal ganglia. Chronic antagonism is thought to result in upregulation of post-synaptic dopamine receptors and therefore dopamine super sensitivity. Oxidative damage of these upregulated receptors is also thought to play a role in the pathophysiology of TD.  

Once TD is well-established, withdrawal of the offending agent does not typically result in a return of the nigrostriatal pathway to baseline signal transduction, i.e. movements tend to persist. TD is treated by reducing the dose of the antipsychotic, switching to an atypical antipsychotic, or using new medications such as Valbenazine (Ingrezza). Clozapine has been shown to reduce TD symptoms in some patients. In general, extrapyramidal symptoms are treated by reducing the dose of antipsychotic, switching to an atypical antipsychotic with lower dopamine blocking properties, and/or administering an anticholinergic agent such as benztropine (Cogentin) or diphenhydramine (Benadryl). 

Neuroleptic Malignant Syndrome (NMS)

First generation antipsychotic medications, especially high-potency medications, may rarely induce a condition called neuroleptic malignant syndrome (NMS).  Note that immediate withdrawal of dopamine agonists (such as L-Dopa or Bromocriptine) can also lead to NMS. NMS is characterized by delirium/confusion, muscle rigidity, rhabdomyolysis (muscle break down), CK elevations (5,000-10,000+), fever, seizures, and renal failure due to myoglobinuria. The mortality rate is about 15% in well-managed cases. Treatment usually involves medical hospitalization with supportive measures such as intravenous fluids, cooling blankets, and specific medications (such as dantrolene and bromocriptine). 

Retinal Pigmentation

Thioridazine has a unique risk of this side effect. 

Atypical Antipsychotics

Generic NameBrand Name
ClozapineClozaril, FazaClo
QuetiapineSeroquel, Seroquel XR
OlanzapineZyprexa, Zydis, and Relprevv

Atypical antipsychotics are listed in the table below. We usually group the Atypical antipsychotic medications with similar structures and properties into “families” or “groups” just like we group apples and oranges as “fruits.”

Second-generation antipsychotics (atypical antipsychotics) can be divided into three groups based on structural similarity:

The clozapine family (the “pines”) is comprised of asenapine, clozapine, olanzapine, and quetiapine

The risperidone family(the “dones”) is comprised of iloperidone, lurasidone, paliperidone, risperidone, and ziprasidone

The partial dopamine agonist family includes aripiprazole, brexpiprazole and cariprazine. 

Side Effects

Metabolic Syndrome

The atypical antipsychotics are more likely than the typical antipsychotics to induce metabolic syndrome (insulin resistance, obesity, dyslipidemia) by inducing resistance at insulin receptors (mechanism remains unclear). This results in glucose intolerance and shunting of lipids toward central adipose stores (increased visceral fat). 

Highest Risk: clozapine and olanzapine
Lowest Risk: aripiprazole, asenapine, brexpiprazole, cariprazine, and lurasidone 

Sedation, Lightheadedness, and Blood Pressure Changes

Similar to Typical antipsychotics, Atypical antipsychotics are associated with sedation, lightheadedness, and orthostasis/blood pressure changes due to antagonism at α-adrenergic (α1) Receptors and cholinergic (M1) receptors 

Histamine (H1) Receptors (sedation, weight gain)

α-adrenergic (α1) Receptors (sedation, hypotension)

Muscarinic cholinergic (M1) Receptors (sedation, hypotension, and anticholinergic effects)

Dry Mouth, Constipation, Blurry Vision, and Urinary Retention

Similar to Typical antipsychotics, Atypical antipsychotics are associated with dry mouth, constipation, blurry vision, urinary retention, and tachycardia due to their effects at muscarinic cholinergic (M1) Receptors

Arrhythmias and QT Prolongation

The QT interval on electrocardiogram (EKG) represents the time it takes the ventricles of the heart to depolarize and then repolarize. This time can be prolonged by all antipsychotics and can increase the risk, albeit very small, of developing something called Torsades de Pointes, a life threatening cardiac arrhythmia. See Tables and Illustrations in the “Gallery” Below


All antipsychotics have the potential to lower the seizure threshold. It appears that low potency typical antipsychotics such as Chlorpromazine are at highest risk followed by the Atypical Antipsychotic Clozapine. 

List of Atypical Antipsychotics


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