Antipsychotics (Neuroleptics)

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 (typical) antipsychotics (e.g., haloperidol) is based on D₂ antagonism, while second-generation (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.

			Mechanism of action	Indications	Side effects
First-generation antipsychotics (FGAs)	High-potency antipsychotics	Haloperidol Fluphenazine Perphenazine Trifluoperazine Pimozide	Dopamine-specific antagonism (D2 receptor)	Schizophrenia Bipolar disorder Acute psychosis Delirium Acute agitated states Tourette syndrome OCD (concomitant therapy)	Hyperprolactinemia Extrapyramidal symptoms most common in high-potency FGAs Prolonged QT interval Neuroleptic malignant syndrome Metabolic and anticholinergic effects less pronounced
	Low-potency antipsychotics	Chlorpromazine Thioridazine Promethazine	Dopamine antagonism Anticholinergic Antihistaminergic (primarily sedative)	Acute agitation Delirium	Anticholinergic effects, sympatholytic effects, metabolic effects, and sedation dominate EPS less common
Second-generation antipsychotics (SGAs)		Clozapine Olanzapine Risperidone Quetiapine Amisulpride Ziprasidone Aripiprazole Lurasidone Asenapine Iloperidone Paliperidone	D2 receptor antagonism (less pronounced than that of typical antipsychotics) 5-HT2A receptor antagonism Interaction with several other receptors (i.e., D3, D4, α-adrenergic, and H1 receptors) Aripiprazole is a partial D2 agonist	Schizophrenia Bipolar disorder Acute psychosis Postpartum psychosis MDD with psychotic features OCD (concomitant medication) Tourette syndrome Huntington disease	Metabolic effects (usually weight gain, hyperglycemia, dyslipidemia) most prominent Sedation, somnolence Prolonged QT interval Hyperprolactinemia (less pronounced than in FGAs) EPS less common Anticholinergic and sympatholytic effects Neuroleptic malignant syndrome Clozapine can cause agranulocytosis.

References:^[1][2]

	Details	First-generation antipsychotics	Second-generation antipsychotics
Extrapyramidal symptoms (EPS)	See EPS below for details.	High-potency FGAs have the highest incidence of EPS. Low-potency FGAs have a rate of EPS similar to that of SGA.	Significantly fewer motor side effects (EPS) due to reduced D2 receptor antagonism; greater affinity for 5HT2A receptors and interaction with other receptors
Hyperprolactinemia	Elevated prolactin levels: Dopamine inhibits the release of prolactin via the D2 receptor in the tuberoinfundibular pathway. Therefore, dopamine antagonists increase the effects of prolactin. In men: gynecomastia, galactorrhea, hypogonadotropic hypogonadism (erectile dysfunction, reduced libido, infertility) In women: galactorrhea, hypogonadotropic hypogonadism (amenorrhea, reduced libido, infertility)	All FGAs cause elevated prolactin levels. Annual monitoring of symptoms is recommended.	Smaller increase in prolactin levels compared to typical antipsychotics Most common in risperidone, amisulpride, and paliperidone
Prolonged QT interval	Potassium channel-mediated effect Can lead to life-threatening arrhythmias (torsades de pointes and ventricular fibrillation)	All FGAs Most common in intravenous haloperidol and thioridazine	All SGAs (particularly iloperidone, ziprasidone)
Anticholinergic effects	Dry mouth, blurred vision, mydriasis, constipation, urinary retention, and tachycardia	More common in low-potency FGAs Mild in high-potency FGAs	Uncommon in most agents Clozapine, olanzapine, and quetiapine have the highest incidence of anticholinergic effects. Clozapine commonly causes sialorrhea.
Metabolic effects	Usually weight gain, hyperglycemia, dyslipidemia Occasionally loss of appetite and weight loss	More common in low-potency FGAs	Prominent in most SGA Clozapine, olanzapine, quetiapine carry the highest risk of metabolic syndrome (hyperglycemia, dyslipidemia, weight gain). Olanzapine also causes an asymptomatic increase of liver enzymes.
Sympatholytic effect	Orthostatic hypotension (due to α1-adrenergic blockade)	More common in low-potency FGAs Rare in high-potency FGAs	Common during treatment initiation and dose adjustments Particularly olanzapine
Sedation	Mediated via histamine H1 receptor antagonism	Prominent in low-potency FGAs	All SGAs (tolerance usually develops within a few days of treatment) Quetiapine is often used as a sleep aid in low doses.
Hematologic	Agranulocytosis (usually within the first 4 months of therapy)	Extremely rare	Clozapine carries a high risk of agranulocytosis (usually within the first 4 months of therapy).
Other cardiac side effects	Myocarditis, cardiomyopathy, sinus tachycardia	Not reported	Clozapine
Ocular effects	Lenticular and corneal deposits Cataracts Epithelial keratopathy Retinitis pigmentosa	Associated with low-potency FGAs Chlorpromazine Thioridazine carries the highest risk of retinitis pigmentosa.	Not reported
Thermoregulation	Hyperthermia or hypothermia	Associated with phenothiazines (e.g., fluphenazine) Patients receiving these medications should avoid extreme temperatures. [3]	Most commonly associated olanzapine and risperidone
Neuroleptic malignant syndrome	Life-threatening side effect See NMS below for details.	All antipsychotics

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
• Etiology: All antipsychotics that interact with the D₂ receptor may cause EPS, but the probability of this side effect is significantly higher with high-potency antipsychotics.
  • Metoclopramide, although not an antipsychotic, may also cause extrapyramidal symptoms.
• Pathophysiology: Inhibition of the nigrostriatal dopaminergic pathways results in EPS.
  • First-generation high-potency antipsychotics: D₂ antagonism → EPS
  • Second-generation antipsychotics: weaker D₂ antagonism → fewer EPS

EPS subtype	Onset	Symptoms	Treatment
Acute dystonia (also see dystonia)	Hours to days	Painful and lasting muscle spasms predominantly affecting the head, neck, and tongue Facial grimacing, torticollis Tongue protrusion or twisting Oculogyric crisis Opisthotonus of the back	Acute treatment: anticholinergics or antihistamines First-line: benztropine Alternatives Diphenhydramine Benzodiazepines (e.g., diazepam) Switch to an antipsychotic drug with lower risk of EPS (SGA) or begin secondary prophylaxis with benztropine Prophylaxis using benztropine or diphenhydramine is recommended for patients who receive intramuscular haloperidol (especially individuals with little prior exposure to FGA).
Pseudoparkinsonism	Week 1	Cogwheel rigidity, stiff gait, tremor	Dose reduction or switch to an antipsychotic drug with lower risk of EPS (SGA) Anticholinergic (e.g., benztropine) or a dopamine agonist (e.g., amantadine)
Akathisia	Weeks 1–8	Restlessness/compelling urge to move Inability to sit or stand still	Dose reduction or switch to an antipsychotic drug with lower risk of EPS (SGA) First-line: propranolol Alternative Benztropine Benzodiazepines
Tardive dyskinesia	Months–years	Involuntary movements of the mouth and tongue; limbs, face, and respiratory muscles caused by chronic use of antipsychotic drugs Repetitive chewing and lip smacking Choreic movements	Discontinuation of antipsychotic drug Switch to SGA (less EPS) Anticholinergics or antipsychotic dose reduction may initially worsen the condition. Treatment: valbenazine and tetrabenazine [4]

Neuroleptic malignant syndrome (NMS) ^[5]

• 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
• Etiology
  • Reaction to antipsychotic drugs (especially high-potency antipsychotics), other agents that affect the CNS (e.g., carbamazepine, lithium, venlafaxine), or 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.
  • Muscle rigidity, akinesia, tremor
  • Hyperthermia
  • Autonomic instability (tachycardia, labile blood pressure, tachypnea, diaphoresis, dysrhythmias)
  • Mental status change: confusion, delirium, reduced vigilance, stupor
• Diagnostics
  • ↑↑ Creatine kinase
  • Leukocytosis
  • ↑ Transaminases
  • Metabolic acidosis
  • Myoglobinuria
  • Electrolyte abnormalities (hypocalcemia, hyperkalemia, hyponatremia or hypernatremia)
  • Low serum iron concentration
• Differential diagnosis
  • Lethal catatonia (see also catatonic dilemma )
  • See differential diagnosis of drug-induced hyperthermia.
• Treatment
  • Discontinuation of the antipsychotic drug!
  • Supportive measures (e.g., ICU care)
  • Pharmacotherapy
    • Dantrolene (ryanodine receptor antagonist): prevents the release of calcium from the sarcoplasmic reticulum of striated muscle → reduced muscle rigidity and hyperthermia
    • Alternatives: bromocriptine, apomorphine, or amantadine
    • Benzodiazepines can be administered to treat psychomotor agitation.

To remember the different symptoms of neuroleptic malignant syndrome, think "FALTER": Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatine kinase, transaminases), Rigor

References:^{[6][7][8][9][10][11][12][13][14][15][5][4]}

We list the most important adverse effects. The selection is not exhaustive.

• All antipsychotics, with the exception of clozapine (used for treatment-resistant schizophrenia), 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.

	Important indications	Preferred agents
Acute therapy	Acute psychosis	First-line: SGAs Alternative: high-potency antipsychotics
	Bipolar affective disorder or acute mania
	Delirium	High-potency antipsychotics (alternatively, low-potency antipsychotics)
	Delusional or agitated states	High-potency antipsychotics Children and adolescents: risperidone Elderly: risperidone or melperone
	Psychotic symptoms caused by medication for Parkinson disease (dopamine agonists)	Clozapine
	Psychosis during pregnancy	First-line: FGAs (e.g., haloperidol)
	Postpartum psychosis	First-line: SGAs (e.g., quetiapine, risperidone, olanzapine)
Long-term therapy	Schizophrenia and other chronic psychotic disorders	SGAs In cases of treatment failure, switch to high-potency antipsychotics (primarily effective for positive symptoms).
	Concomitant medication for patients with obsessive-compulsive disorders	SGAs
	Treatment-resistant schizophrenia and schizophrenia associated with persistent suicidality	Clozapine
	Tic disorders, Tourette syndrome	Tiapride

To reduce/avoid anticholinergic side effects in patients of advanced age, high-potency substances (e.g., haloperidol, risperidone) or melperone are preferred!