Antipsychotics are a class of medication used to treat the following disorders:
Psychotic disorders (e.g., Schizophrenia and Schizoaffective Disorder)
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.
Antipsychotics are classified into two categories:
Typical Antipsychotics (also termed 1st Generation or Conventional antipsychotics)
Atypical Antipsychotics (also termed 2nd Generation antipsychotics)
Are all Antipsychotics Equal In Terms of Efficacy?
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.
|Generic Name||Brand Name|
Side Effects of Typical Antipsychotics
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).
Blood Pressure Changes and Lightheadedness
Urinary Retention/Difficulty Urinating
Slowed Movements (Parkinsonism)
Emotional “Blunting” or “Flattening”
Cardiac Arrhythmias (rare)
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. 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), fever, seizures, and renal failure. 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).
|Generic Name||Brand Name|
|Quetiapine||Seroquel, Seroquel XR|
|Olanzapine||Zyprexa, 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.”
The clozapine family (the -“pines”) includes clozapine, olanzapine, etc.
The risperidone family (or the -“dones”) includes risperidone, ziprasidone, etc
The rest include aripiprazole, brexpiprazole and cariprazine.
What Makes An Antipsychotic “Atypical”
The reasons we call these agents “Atypical” is beyond the scope of this discussion but is related to the fact that these agents are less likely to cause many of the side effects associate with Typical antipsychotics due to their ability to interact with serotonin and other neurotransmitter systems.
Glucose Regulation and Metabolic Side Effects
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 their effects at α-adrenergic (α1) Receptors
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.
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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