Antipsychotic

Structural representation of phenothiazines, a class of antipsychotic drugs.

Antipsychotics, also known as neuroleptics or major tranquilizers, are a class of medications used primarily for the treatment of psychosis, including symptoms such as delusions, hallucinations, paranoia, and disorganized thinking. These medications are most commonly prescribed for individuals with schizophrenia and bipolar disorder, though they are also used in other psychiatric and neurological conditions.

Classification

Antipsychotic medications are broadly categorized into two main groups:

First-Generation Antipsychotics (FGAs)

Also known as typical antipsychotics, these medications were the first to be developed and are primarily dopamine (D₂) receptor antagonists. They are effective in treating positive symptoms of psychosis but are associated with a higher risk of extrapyramidal side effects (EPS). Examples include:

• Haloperidol – Frequently used in acute psychosis and agitation.
• Chlorpromazine – One of the first discovered antipsychotic drugs.
• Fluphenazine – Used for long-term management of schizophrenia.
• Thioridazine – Less commonly used due to cardiac side effects.

Second-Generation Antipsychotics (SGAs)

Also known as atypical antipsychotics, these drugs target both dopamine (D₂) and serotonin (5-HT2A) receptors, leading to improved efficacy for both positive and negative symptoms of schizophrenia and a lower risk of motor side effects. Common SGAs include:

• Risperidone – Used for schizophrenia, bipolar disorder, and autism-related irritability.
• Olanzapine – Effective in schizophrenia and acute mania.
• Quetiapine – Used for bipolar disorder, depression, and sleep disorders.
• Aripiprazole – A partial dopamine agonist with a lower risk of weight gain.
• Clozapine – Reserved for treatment-resistant schizophrenia due to its risk of agranulocytosis.

Mechanism of Action

Antipsychotic drugs function by modifying neurotransmitter activity in the brain, primarily affecting:

• Dopamine blockade: Most antipsychotics work by antagonizing dopamine D₂ receptors, reducing excessive dopamine transmission, which is believed to be responsible for psychotic symptoms.
• Serotonin modulation: Atypical antipsychotics also antagonize 5-HT2A receptors, contributing to improved efficacy in treating both positive and negative symptoms while reducing motor side effects.
• Other neurotransmitter effects: Some antipsychotics impact histamine (H1), adrenergic (α1), and muscarinic (M1) receptors, leading to variations in side effect profiles.

Indications

Antipsychotics are used in the treatment of various psychiatric and neurological disorders, including:

• Schizophrenia – Primary indication for both FGAs and SGAs.
• Bipolar disorder – Used in both manic and depressive phases.
• Major depressive disorder (MDD) – Some SGAs (e.g., aripiprazole, quetiapine) are approved as adjunctive treatments.
• Psychotic depression – Beneficial in severe cases with delusions or hallucinations.
• Tourette syndrome – Used to manage severe tics.
• Delirium – Short-term management of acute confusion states.
• Dementia-related aggression – Occasionally prescribed for severe agitation but with caution due to increased mortality risks in elderly patients.
• Autism spectrum disorder – Certain SGAs are used to reduce irritability and aggression.

Side Effects

Antipsychotic medications are associated with a range of potential side effects, which vary between typical and atypical antipsychotics.

Common Side Effects

• Sedation – Due to histamine H1 receptor antagonism.
• Weight gain – Particularly with SGAs like olanzapine and clozapine.
• Dizziness and hypotension – Resulting from alpha-adrenergic blockade.
• Dry mouth and constipation – Linked to muscarinic receptor antagonism.
• Increased prolactin levels – Leading to galactorrhea, gynecomastia, and menstrual irregularities.

Extrapyramidal Side Effects (EPS)

More common with FGAs due to strong dopamine antagonism:

• Tardive dyskinesia – Involuntary movements, often irreversible.
• Akathisia – Inner restlessness and urge to move.
• Dystonia – Sudden, painful muscle contractions.
• Parkinsonism – Tremors, rigidity, and bradykinesia.

Metabolic Side Effects

SGAs are linked to metabolic changes, including:

• Increased appetite and obesity
• Insulin resistance and type 2 diabetes
• Dyslipidemia – Elevated cholesterol and triglyceride levels.

Special Considerations

Some antipsychotics require close monitoring due to specific risks:

• Clozapine – Requires regular blood monitoring due to the risk of agranulocytosis.
• Ziprasidone and thioridazine – Can cause QT prolongation, increasing the risk of cardiac arrhythmias.
• Haloperidol – Can induce neuroleptic malignant syndrome (NMS), a life-threatening condition characterized by fever, rigidity, and altered mental status.

Long-Term Considerations

Chronic use of antipsychotics requires careful monitoring for:

• Tardive dyskinesia – Particularly with prolonged use of FGAs.
• Metabolic syndrome – Regular screening for weight, blood glucose, and lipid levels.
• Prolactin elevation – Some patients may develop sexual dysfunction, infertility, or osteoporosis.

Withdrawal and Discontinuation

Stopping antipsychotics should be done gradually under medical supervision to prevent:

• Withdrawal dyskinesia – Sudden discontinuation can cause rebound movement disorders.
• Psychotic relapse – Discontinuing medication increases the risk of symptom recurrence.
• Supersensitivity psychosis – Some patients may experience worsening symptoms due to dopamine receptor upregulation.

Future Developments

Research into novel antipsychotic drugs aims to:

• Reduce metabolic side effects.
• Improve negative and cognitive symptoms in schizophrenia.
• Develop partial dopamine agonists with fewer motor side effects.
• Investigate non-dopaminergic targets such as glutamate and GABA modulation.

See Also

• Psychosis – A symptom that antipsychotics help manage.
• Schizophrenia – A primary indication for antipsychotic treatment.
• Bipolar disorder – A condition often treated with SGAs.
• Mood stabilizers – Other drugs used in bipolar disorder.
• Neuroleptic malignant syndrome – A rare but serious complication of antipsychotics.

External Links

• World Health Organization - Essential Medicines
• American Psychiatric Association - Guidelines for Antipsychotic Use

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