By: Roaa Almusleh

Antipsychotic drugs, once called major tranquilizers and neuroleptics, have the capacity to diminish or alleviate symptoms of psychosis, like delusions (false beliefs) and hallucinations (perceiving things that aren’t present). This class of medication, now known as antipsychotics, serves as a primary treatment for individuals diagnosed with schizophrenia. Additionally, they are employed in managing psychosis associated with bipolar disorder, depression, and Alzheimer’s disease. Beyond this, antipsychotics prove valuable in stabilizing moods for those with bipolar disorder, alleviating anxiety in anxiety disorders, and mitigating tics in Tourette syndrome.[1

Mechanism of action 

Antipsychotics can’t cure psychosis but they can help to reduce many symptoms[2] by blocking the action of dopamine and acetylcholine or dopamine and serotonin receptors[3]. Ones of these cases:[2]

• delusions and hallucinations.
• anxiety.
• Serious agitation.
• incoherent speech.
• Confusion.
• violent or disruptive behaviour.
• Mania.

Types of antipsychotics 

There are two primary categories of antipsychotic medications:

1. First-generation antipsychotics, also known as “typical antipsychotics,” were the initial medications developed for psychosis treatment. While they were once prevalent, they are now less commonly prescribed due to their associated side effects.

   – Chlorpromazine (Thorazine)

   – Fluphenazine (Prolixin, Permitil)

   – Haloperidol (Haldol®)

   – Loxapine (Adusuve®) (previously known as Loxitane)

   – Molindone (Moban)

   – Perphenazine (Trilafon)

   – Pimozide (Orap*)

   – Prochlorperazine (Compro®) (previously known as Compazine)

   – Thiothixene (previously known as Navane)

   – Thoridazine (previously known as Mellaril)

   – Trifluoperazine (previously known as Stelazine)

2. Second-generation antipsychotics, or “atypical antipsychotics,” have become the primary drugs for treating psychosis due to their reduced side effects.

   – Aripiprazole (Abilify®, Aristada®)

   – Asenapine (Secuado®, Saphris®)

   – Brexpiprazole (Rexulti®)

   – Cariprazine (Vraylar®)

   – Clozapine (Clozaril®, Versacloz®) (previously known as Fazaclo)

   – Iloperidone (Fanapt®)

   – Lumateperone (Caplyta®)

   – Lurasidone (Latuda®)

   – Olanzapine (Zyprexa®, Lybalvi®, Symbyax®)

   – Quetiapine (Seroquel®)

   – Paliperidone (Invega®)

   – Pimavanserin (Nuplazid®)

   – Risperidone (Perseris®, Risperdal®)

   – Ziprasidone (Geodon®)

3. Long-acting antipsychotic medications, including both conventional and second-generation antipsychotics (SGAs), are formulated as depot preparations, as outlined in the Depot Antipsychotic Drugs table. These depot preparations serve a crucial role in addressing issues of medication nonadherence. Additionally, they offer support to patients who may struggle with consistent oral medication intake due to factors such as disorganization, indifference, or denial of their illness.

The uses of Antipsychotics drugs

There are many uses of the Antipsychotics drugs such as:

• Schizophrenia and Schizoaffective Disorders:

– First and second-generation antipsychotics (except clozapine) are recommended for treating acute episodes and maintenance therapy of schizophrenia and schizoaffective disorders.

– First-generation antipsychotics are particularly effective against positive symptoms like hallucinations and delusions, also reducing the risk of relapse.

– Second-generation antipsychotics address both positive and negative symptoms and are known to reduce relapse rates.

• Acute Mania:

– First-generation antipsychotics are effective in treating acute mania with psychotic symptoms.

– Second-generation antipsychotics (excluding clozapine) are also suitable for treating acute mania.

– They are typically used alongside mood stabilizers initially, with gradual withdrawal after symptom stabilization.

• Major Depressive Disorder with Psychotic Features:

– Either first or second-generation antipsychotics, combined with an antidepressant, is the preferred treatment.

– Olanzapine and fluoxetine combination therapy holds FDA approval for treatment-resistant depression.

• Delusional Disorder:

– First-generation antipsychotics are indicated for treating delusional disorder and paranoia associated with personality disorders.

• Severe Agitation:

– Short-term courses of first-generation antipsychotics are effective in managing severe agitation.

– Second-generation antipsychotics can also be used for acute agitation.

– Their use in children with severe autism exhibiting behavioral disturbances should be approached cautiously.

• Tourette Disorder:

– Haloperidol and pimozide are commonly used antipsychotics for Tourette disorder.

– Second-generation antipsychotics can be considered, although off-label.

• Borderline Personality Disorder:

– Both first and second-generation antipsychotics are utilized to treat symptoms of psychosis and paranoia associated with borderline personality disorder.

• Dementia and Delirium:

– Low doses of high-potency first-generation antipsychotics like haloperidol are recommended for agitation in delirium and dementia, with caution in elderly patients.

– Second-generation antipsychotics can also be used for behavioral disturbances in dementia, including off-label use in AIDS-related dementia.

• Substance-Induced Psychotic Disorder:

– Antipsychotics may be used to control severe psychosis secondary to substance use, with caution in specific situations such as alcohol withdrawal and phencyclidine intoxication.

• Childhood Schizophrenia:

– Clozapine has shown benefits in treating early-onset schizophrenia.

Side effects

First-generation antipsychotics (FGAs) are notorious for their extrapyramidal side effects. Low-potency dopamine receptor antagonists like chlorpromazine and thioridazine commonly induce anticholinergic adverse effects such as dry mouth, constipation, and urinary retention. Additionally, FGAs block H1 histamine receptors, leading to sedation, with chlorpromazine being the most sedating. These medications can also lower the seizure threshold, particularly chlorpromazine and thioridazine, which are more epileptogenic than others. Haloperidol, in particular, poses a risk of abnormal heart rhythm, ventricular arrhythmia, torsades de pointes, and sudden death if administered intravenously. Other FGAs may lead to QTc interval prolongation and cardiac conduction abnormalities, with thioridazine carrying an FDA-backed warning for sudden cardiac death.

Orthostatic hypotension, commonly caused by alpha-adrenergic block, is prevalent with low-potency FGAs like chlorpromazine or thioridazine, usually occurring at the beginning of treatment. Patients often develop tolerance, but epinephrine should be avoided in treating hypotension. Rare side effects of FGAs include leukopenia, thrombocytopenia, and blood dyscrasia. Elevated serum prolactin concentrations may result in galactorrhea, breast enlargement, amenorrhea, impotence in men, and anorgasmia in women due to dopamine receptor blockade in the tuberoinfundibular tract. Chlorpromazine is associated with allergic dermatitis and photosensitivity, along with blue-gray skin discoloration and benign pigmentation of the lens and cornea. Thioridazine may cause retinal pigmentation, persisting even after discontinuation.

Neuroleptic malignant syndrome, although rare, is a potentially fatal adverse effect of FGAs, characterized by increased temperature, severe muscular rigidity, confusion, agitation, and elevated laboratory markers. Immediate discontinuation of the antipsychotic and treatment with dantrolene are crucial, along with hydration, cooling, and close monitoring.

Second-generation antipsychotics (SGAs) exhibit reduced extrapyramidal side effects compared to FGAs but are associated with significant weight gain and metabolic syndrome. FDA guidelines recommend monitoring for metabolic abnormalities and personal and family history of related conditions. Each SGA has its unique side effect profile, ranging from dizziness and anxiety with risperidone to weight gain and somnolence with olanzapine. Clozapine stands out for its potential hypersalivation, tachycardia, hypotension, and agranulocytosis, necessitating regular monitoring of blood counts. Additionally, clozapine may suppress dyskinesia but carries a risk of cardiomyopathy and myocarditis. Both FGAs and SGAs may increase mortality risk in elderly patients with dementia-related psychosis, as indicated by FDA boxed warnings. Higher doses of antipsychotics amplify the risk of adverse effects.

Contraindecations 

• First-generation antipsychotics should not be used in the following circumstances:

1. History of severe allergy

2. Concurrent use of central nervous system (CNS) depressants such as barbiturates, benzodiazepines, or opioids

3. Use of anticholinergic medications like scopolamine or phencyclidine

4. Severe cardiac abnormalities

5. History of seizure disorder

6. Narrow-angle glaucoma or prostatic hypertrophy

7. History of or ongoing tardive dyskinesia

• Second-generation antipsychotics carry an FDA boxed warning regarding an increased incidence of stroke in elderly patients with dementia. It is recommended to avoid combining second-generation antipsychotics with other drugs that prolong the QTc interval.

Antipsychotics should be avoided during pregnancy, particularly in the first trimester, and should only be used if the benefits outweigh the risks. They are excreted in breast milk, so breastfeeding should be avoided when taking antipsychotics.

References

1. https://www.camh.ca/en/health-info/mental-illness-and-addiction-index/antipsychotic-medication
2. https://www.mind.org.uk/information-support/drugs-and-treatments/antipsychotics/about-antipsychotics/
3. https://my.clevelandclinic.org/health/treatments/24692-antipsychotic-medications
4. https://my.clevelandclinic.org/health/treatments/24692-antipsychotic-medications
5. https://www.merckmanuals.com/professional/psychiatric-disorders/schizophrenia-and-related-disorders/antipsychotic-drugs
6. https://www.ncbi.nlm.nih.gov/books/NBK519503/