Antipsychotics

Last updated: January 3, 2024

Summary

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 have a decreased risk of 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.

Overview

Description

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	Haloperidol Fluphenazine Perphenazine Trifluoperazine Pimozide	Dopamine-specific antagonism (D₂ receptor)	Schizophrenia Bipolar disorder Acute psychosis Delirium Acute agitated states (e.g., patients who are agitated and aggressive due to alcohol and/or illicit drug use) Tourette syndrome OCD (concomitant therapy) Huntington disease	Hyperprolactinemia Extrapyramidal symptoms most common in high-potency FGAs Prolonged QT interval Neuroleptic malignant syndrome Metabolic and anticholinergic effects less pronounced
First-generation antipsychotics (FGAs)	Low-potency antipsychotics	Chlorpromazine Thioridazine	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 FGAs) 5-HT_2A 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 Anxiety disorders Huntington disease	Metabolic effects (usually weight gain, hyperglycemia, new-onset diabetes mellitus, dyslipidemia) most prominent Prolonged QT interval ^[1] Hyperprolactinemia Less pronounced than in FGAs Exception: aripiprazole does not cause hyperprolactinemia ^[2] Neuroleptic malignant syndrome Clozapine can cause agranulocytosis and lowers the seizure threshold ^[3] Sedation, somnolence EPS less common Anticholinergic and sympatholytic effects

HAL TRIed to FLy high: HALoperidol, TRIfluoperazine, and FLuphenazine are high potency antipsychotics.

CHarlatans and THIeves are lowlifes: CHlorpromazine and THIoridazine are low potency antipsychotics.

Indications

All antipsychotics, except for 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.

Overview of indications of antipsychotics
	Important indications	Preferred agents
Acute therapy	Acute psychosis	First-line: SGAs (e.g., aripiprazole for acute delusions; risperidone for acute mania or hypomania) Alternative: high-potency antipsychotics (e.g., haloperidol)
	Bipolar affective disorder or acute mania
	Delirium	High-potency antipsychotics (alternatively, low-potency antipsychotics)
	Delusional or agitated states (e.g., patients who are agitated and aggressive due to alcohol and/or illicit drug use)	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)
	Dementia (should be reserved for severe symptoms only)	Risperidone
Long-term therapy	Schizophrenia and other chronic psychotic disorders	SGAs (effective for positive and negative symptoms) In cases of treatment failure Switch to high-potency antipsychotics (primarily effective for positive symptoms). Or clozapine
	Concomitant medication for patients with obsessive-compulsive disorders	SGAs
	Treatment-resistant schizophrenia and schizophrenia associated with persistent suicidality	Clozapine
	Tic disorders, Tourette syndrome Huntington disease	Tiapride

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

Adverse effects

For the management of toxic effects due to overdose, see “Antipsychotic overdose.”

Overview

Overview of adverse effects of antipsychotics
		Characteristics	First-generation antipsychotics	Second-generation antipsychotics
Extrapyramidal symptoms (EPS)		See “Extrapyramidal symptoms.”	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 5HT_2Areceptors 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, oligomenorrhea, 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
Cardiac adverse effects	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)
Cardiac adverse effects	Other	Myocarditis Cardiomyopathy Sinus tachycardia	Not reported	Clozapine
Anticholinergic adverse effects		Dry mouth Constipation Blurred vision, mydriasis Urinary retention Tachycardia	More common in low-potency FGAs than in SGAs 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 adverse 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, and quetiapine carry the highest risk of metabolic syndrome (hyperglycemia, new-onset diabetes mellitus, dyslipidemia, weight gain). Olanzapine: asymptomatic increase of liver enzymes.
Sympatholytic adverse 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).
Ocular effects		Lenticular and corneal deposits (especially chlorpromazine) Cataracts Epithelial keratopathy Retinitis pigmentosa (especially thioridazine)	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) ^[4] Patients receiving these medications should avoid extreme temperatures. ^[5]	Most commonly associated olanzapine and risperidone
Neuroleptic malignant syndrome		Life-threatening side effect See “Neuroleptic malignant syndrome.”	All antipsychotics

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 agranulocytosis.

Management of antipsychotic adverse effects and associated comorbidities

These recommendations are consistent with the 2020 American Psychiatric Association guidelines for the management of schizophrenia but may also guide management of other conditions treated with antipsychotics. Consult psychiatry if an adjustment of psychiatric medications is required.

Management of antipsychotic adverse effects ^[6]^[7]
Movement disorders	Use the lowest possible dose of antipsychotics. Consider switching to another agent. Consider starting an anticholinergic or benzodiazepine (see “Extrapyramidal disorders” below for further information).
Hyperprolactinemia	Consider switching to aripiprazole or ziprasidone, or starting bromocriptine. ^[8]
Obesity	Provide diet and exercise advice. Consider: Changing antipsychotics to one with fewer metabolic effects, e.g., aripiprazole ^[9] Starting metformin
Diabetes	Treatment does not vary from standard diabetes management.
Orthostatic hypotension	Divide doses. Reduce the speed of titration. Advise patients to avoid sudden changes in position. Consider fludrocortisone.
Hyperlipidemia	Start lipid-lowering agents.
Neutropenia ^[10]	Mild or moderate: Continue clozapine at increased screening intervals (see “Recommended screening for patients taking antipsychotics”). Severe Stop clozapine and consult hematology. Treat any associated infections. Consider granulocyte colony-stimulating factor.

The severity of most adverse effects can be reduced by using the lowest possible dose.

Extrapyramidal symptoms (EPS) ^[11]

These recommendations are consistent with the 2020 American Psychiatric Association guidelines for the management of schizophrenia. Consult psychiatry if an adjustment of psychiatric medications is required. ^[6]

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 FGAs than with SGAs; or low-potency FGAs.
- Metoclopramide, although not an antipsychotic, may also cause EPS.
- Anticonvulsants (e.g., carbamazepine) may also cause movement disorders. ^[12]
- Antidepressants ^[13]
Pathophysiology: Inhibition of the nigrostriatal dopaminergic pathways results in EPS. ; ^[14]^[15]
- First-generation high-potency antipsychotics: D₂antagonism → EPS
- Second-generation antipsychotics: weaker D₂antagonism → fewer EPS

Overview of extrapyramidal symptoms ^[6]^[15]^[16]
EPS subtype	Onset	Symptoms	Treatment
Acute dystonia (see also “Dystonia”) ^[17]	Hours to days	Painful and lasting muscle spasms and stiffness predominantly affecting the head, neck, and tongue Facial grimacing, torticollis Tongue protrusion or twisting Oculogyric crisis (upward deviation of the eyes) In severe cases: laryngospasm, opisthotonus of the back	Acute treatment with one of the following: ^[17] Anticholinergics (e.g. benztropine) ^[15] Antihistamines: diphenhydramine ^[15] Benzodiazepines ^[17] Switch to an antipsychotic drug with a lower risk of EPS (an SGA) or continue secondary prophylaxis, e.g., with benztropine. ^[16]^[18] Prophylaxis (e.g., with benztropine or diphenhydramine) is recommended for patients receiving intramuscular haloperidol (especially individuals with little prior exposure to FGAs). ^[16]^[19] Intubation in case of laryngospasm
Pseudoparkinsonism ^[18]	∼ 1–4 weeks	Cogwheel rigidity, stiff gait, tremor Bradykinesia	Preferred: Lower the dose or switch to an antipsychotic drug with a lower risk of EPS (an SGA). If dose reduction or switching is not possible or not tolerated: Anticholinergic (e.g. benztropine) ^[15] OR dopamine agonist (e.g., amantadine ) ^[15]
Akathisia ^[11]	1–8 weeks	Restlessness/compelling urge to move Inability to sit or stand still	Preferred: Lower the dose or switch to an antipsychotic drug with a lower risk of EPS (an SGA). First-line: beta blocker such as propranolol ^[11]^[20] Second-line: benzodiazepines, e.g., clonazepam ^[16]^[17]^[20] Consider benztropine (controversial) ^[6]
Tardive dyskinesia ^[21]	Months to 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	Consult psychiatry. Discontinue the causative drug if possible after slowly tapering the dose. ^[11] Switch to an SGA (associated with fewer EPS, especially clozapine and quetiapine). ^[21] Treatment with anticholinergics or a sudden reduction in the dose of antipsychotics may initially worsen the condition. ^[21] Start vesicular monoamine transporter-2 (VMAT) inhibitors for moderate or severe symptoms. Valbenazine ^[6]^[22] Deutetrabenazine ^[6]^[23] Tetrabenazine

ADAPT: Extrapyramidal symptoms include Acute Dystonia, Akathisia, Parkinsonism, and Tardive dyskinesia. Timeline of extrapyramidal symptoms induced by antipsychotics

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

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Antipsychotics

Summary

Overview

Description

Indications

Adverse effects

Overview

Management of antipsychotic adverse effects and associated comorbidities

Extrapyramidal symptoms (EPS) [11]

Extrapyramidal symptoms (EPS) ^[11]