Antipsychotics are a heterogeneous group of substances used primarily to treat schizophrenia, psychosis, mania, delusions, and states of agitation. The term neuroleptics was formerly used interchangeably with antipsychotics because early antipsychotic drugs induced apathy, quiescence, and reduced psychomotor activity, but newer antipsychotic drugs no longer have these effects. The antipsychotic effect of first-generation antipsychotics (also called typical antipsychotics, e.g., haloperidol) is based on D2 antagonism, while second-generation antipsychotics (also called atypical antipsychotics) interact with several receptors (e.g., D2, D3, D4, 5-HT). Extrapyramidal symptoms, which include acute dystonia, akathisia, and tardive dyskinesia, are the most common side effects of first-generation antipsychotics. Metabolic side effects (e.g., weight gain, insulin resistance), on the other hand, are more typical of second-generation antipsychotics. A potentially life-threatening side effect of both first-generation and second-generation antipsychotics is neuroleptic malignant syndrome, which manifests with fever, muscle rigidity, autonomic instability, and mental status changes.
First-generation antipsychotics (also called typical antipsychotics): block D2 receptor → ↑ cAMP
- High-potency antipsychotics have a strong antipsychotic effect even at relatively low doses, but they also more commonly cause neurologic side effects (e.g., extrapyramidal symptoms) than low-potency antipsychotics.
- Low-potency antipsychotics more commonly cause anticholinergic, antihistamine, and sympathetic α1-blockade effects.
- Stored in fat tissue (lipid soluble) and, therefore, only slowly eliminated from the body.
- Second-generation antipsychotics: (also called atypical antipsychotics): most are 5-HT2 and D2 antagonists with varying α and H1 receptor effects
|Overview of antipsychotics|
|Mechanism of action||Indications||Side effects|
|First-generation antipsychotics (FGAs)||High-potency antipsychotics|| || |
|Low-potency antipsychotics|| || |
|Second-generation antipsychotics (SGAs)|| || || |
HAL TRIed to FLy high: HALoperidol, TRIfluoperazine, and FLuphenazine are high potency antipsychotics.
- All antipsychotics, except for clozapine (used for ), have similar clinical effectiveness.
- The choice of drug depends on the side effect profile of the antipsychotic drugs and the patient's clinical status.
- SGAs are preferred in many cases because they carry a lower risk of EPS; however, in some patients (e.g., those with significant metabolic risk factors), FGAs may be more suitable.
|Overview of indications|
|Important indications||Preferred agents|
|Acute therapy|| |
| || |
|Overview of adverse effects|
|Characteristics||First-generation antipsychotics||Second-generation antipsychotics|
|Hyperprolactinemia|| || |
|Cardiac adverse effects||Prolonged QT interval|
|Anticholinergic adverse effects|
|Metabolic adverse effects|| |
|Sympatholytic adverse effect|| || |
|Hematologic|| || |
|Ocular effects|| |
|Neuroleptic malignant syndrome|| || |
Chlorpromazine causes Corneal deposits; Thioridazine causes reTinal deposits.
cRISPy PINEapple chips will make you fat: olanzaPINE/clozaPINE and RISPeridone cause weight gain.
When administering CLOzapine, check the bone marrow CLOsely due to risk of agranlocytosis.
Extrapyramidal symptoms (EPS)
- Definition: : a collection of movement disorders that are typically due to disruption of dopaminergic pathways in the basal ganglia, resulting in bradykinesia, rigidity, dystonia, athetosis, chorea, ballismus, akathisia, tics, and tremors
- All antipsychotics that interact with the D2 receptor may cause EPS, but the probability of this side effect is significantly higher with high-potency (typical) antipsychotics than with SGAs
- extrapyramidal symptoms., although not an antipsychotic, may also cause
- Anticonvulsants (e.g., carbamazepine)
- Pathophysiology: Inhibition of the nigrostriatal dopaminergic pathways results in EPS.
|Overview of extrapyramidal symptoms|
Acute dystonia (also see “ ”) 
| || |
|Akathisia|| || |
|Tardive dyskinesia|| || || |
Neuroleptic malignant syndrome (NMS) 
- Description: life-threatening neurological disorder usually associated with antipsychotics; that is characterized by a tetrad of features (fever, muscle rigidity, autonomic instability, and mental status changes) as well as rhabdomyolysis and elevated creatine kinase
- Reaction to antipsychotic drugs (more common with high-potency FGAs than with SGAs)
- Agents that affect the CNS (e.g., carbamazepine, lithium, venlafaxine)
- Certain antiemetics (e.g., metoclopramide, promethazine)
- Genetic predisposition
- A connection between NMS and the duration of therapy or therapeutic dose has not been established.
Pathophysiology: The underlying mechanism is not well understood; disruption of numerous neurotransmitter pathways is suspected.
- Central D2 receptor blockade in the nigrostriatal pathway and hypothalamus, resulting in movement disorders and impaired thermoregulation
- Increased sympathetic tone disrupts autonomic regulation and increases muscle tone and metabolism.
- Increased release of calcium from the SR of striated muscle cells, resulting in increased contractility and muscle breakdown
- Clinical features: Onset usually occurs within 2 weeks of the first dose.
- See “.”
We list the most important adverse effects. The selection is not exhaustive.