Antipsychotics , also called neuroleptics , are a class of psychotropic medications used primarily in the treatment of psychotic disorders such as schizophrenia , bipolar disorder , and drug-induced psychosis . They are also used off-label for agitation , delirium , and behavioral disturbances in dementia .
High-Yield : Antipsychotics manage positive symptoms (hallucinations, delusions) and some negative symptoms (apathy, social withdrawal) of schizophrenia.
Mechanism of Action
Antipsychotics act primarily by blocking dopamine D2 receptors in various brain regions. Additional effects on serotonin (5-HT) , acetylcholine (muscarinic) , histamine (H1) , and adrenergic (α1) receptors explain their therapeutic effects and side effects.
Dopamine Receptor Subtypes:
- D1 and D5 : Primarily involved in motor activity and cognitive function.
- D2, D3, D4 : Implicated in psychosis; D2 blockade is most strongly correlated with antipsychotic efficacy.
Classification
First-Generation (Typical) Antipsychotics
- Mechanism : Potent D2 receptor antagonists
- Primary use : Positive symptoms of schizophrenia
- Examples :
- Haloperidol
- Fluphenazine
- Chlorpromazine
- Thioridazine
- Side Effects :
- Extrapyramidal symptoms (EPS) : dystonia, akathisia, parkinsonism, tardive dyskinesia
- Hyperprolactinemia
- Neuroleptic Malignant Syndrome (NMS)
- Sedation, orthostatic hypotension (α1 blockade)
- Anticholinergic effects (especially low-potency agents)
High-Yield : Potency ≠ effectiveness, but high-potency agents (e.g., haloperidol) cause more EPS , while low-potency agents (e.g., chlorpromazine) cause more anticholinergic and sedative effects.
Second-Generation (Atypical) Antipsychotics
- Mechanism : D2 antagonism + 5-HT2A antagonism (dual action)
- Use : Positive and negative symptoms , mood disorders
- Examples :
- Risperidone
- Olanzapine
- Clozapine
- Quetiapine
- Aripiprazole (partial D2 agonist)
- Ziprasidone
- Advantages :
- Lower risk of EPS
- Better for negative symptoms
- Lower risk of hyperprolactinemia (except risperidone)
- Major Side Effects :
- Weight gain , diabetes mellitus , dyslipidemia (especially with clozapine and olanzapine)
- Agranulocytosis (clozapine)
- QT prolongation (ziprasidone)
- Sedation
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia , but requires WBC monitoring due to risk of agranulocytosis.
Depot (Long-Acting Injectable) Antipsychotics
Depot formulations improve adherence and are useful in maintenance therapy after stabilization with oral antipsychotics.
| Drug | Duration | Vehicle |
|---|---|---|
| Fluphenazine decanoate | 7–28 days | Sesame oil |
| Haloperidol decanoate | Up to 4 weeks | Sesame oil |
| Risperidone microspheres | 2 weeks | Water-based |
| Paliperidone palmitate | 1–3 months | Aqueous suspension |
| Aripiprazole monohydrate | Monthly | Aqueous suspension |
Key Point : Use IM depot after initial stabilization with oral meds. The depot helps maintain therapeutic plasma levels and prevent relapse.
Clinical Uses of Antipsychotics
- Schizophrenia
- Schizoaffective disorder
- Bipolar mania
- Acute psychosis (including substance-induced)
- Tourette syndrome
- Delirium and agitation
- Psychosis in dementia (cautious use)
Boxed Warning : Antipsychotics in elderly patients with dementia-related psychosis are associated with increased risk of death (mostly due to cardiovascular events and infections).
Important Adverse Effects by System
| System | Effect |
|---|---|
| Neurological | EPS, NMS, tardive dyskinesia |
| Endocrine | Hyperprolactinemia, galactorrhea |
| Cardiac | QT prolongation (risk of torsades) |
| Metabolic | Weight gain, diabetes, dyslipidemia |
| Hematologic | Agranulocytosis (clozapine) |
| Anticholinergic | Dry mouth, urinary retention, constipation |
Extrapyramidal Symptoms (EPS) Timeline
| Time | EPS Type | Treatment |
|---|---|---|
| Hours–days | Acute dystonia | Benztropine or diphenhydramine |
| Days–weeks | Akathisia (restlessness) | β-blockers or benzodiazepines |
| Weeks–months | Parkinsonism | Anticholinergics (benztropine) |
| Months–years | Tardive dyskinesia | Switch to atypical (e.g., clozapine), consider VMAT2 inhibitors |
Neuroleptic Malignant Syndrome (NMS)
- Life-threatening reaction
- Features: Fever, muscle rigidity, autonomic instability, elevated CPK
- Treatment:
- Discontinue drug
- Dantrolene or bromocriptine
- Supportive care
Clinical Pearls
- Use haloperidol or risperidone for acute agitation (often IM in emergency settings).
- Clozapine is reserved for treatment-resistant schizophrenia .
- Monitor weight, glucose, and lipids regularly with atypicals.
- Depot antipsychotics improve compliance in chronic psychotic disorders.
- For elderly with dementia-related psychosis, non-pharmacological interventions are preferred.
