10/16/2020 Antipsychotics - AMBOSS

Antipsychotics
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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 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.

Overview

Mechanism of action Indications Side effects

First- High-potency Haloperidol Dopamine- Schizophrenia Hyperprolactinemia

generation antipsychotics Fluphenazine specific Bipolar
antipsychotics Perphenazine antagonism (D2 disorder Extrapyramidal
(FGAs) Trifluoperazine receptor) Acute symptoms most
Pimozide psychosis common in high-
Delirium potency FGAs
Acute Prolonged QT
agitated interval
states Neuroleptic
malignant
Tourette syndrome
syndrome Metabolic and
OCD anticholinergic
(concomitant effects less
therapy) pronounced

Low-potency Chlorpromazine Dopamine Acute Anticholinergic

antipsychotics Thioridazine antagonism agitation effects,
Promethazine Anticholinergic Delirium sympatholytic
Antihistaminergic effects, metabolic
(primarily effects, and
sedative) sedation dominate
EPS less common

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Mechanism of action Indications Side effects

Second-generation Clozapine D2 receptor Schizophrenia Metabolic effects

antipsychotics (SGAs) Olanzapine antagonism (less Bipolar (usually weight
Risperidone pronounced than disorder gain,
Quetiapine that of typical Acute hyperglycemia,
Amisulpride antipsychotics) psychosis dyslipidemia) most
Ziprasidone 5-HT2A receptor Postpartum prominent
Aripiprazole antagonism psychosis Sedation,
Lurasidone Interaction with MDD with somnolence
Asenapine several other psychotic Prolonged QT
Iloperidone receptors (i.e., features interval
Paliperidone D3, D4, α- OCD Hyperprolactinemia
adrenergic, and (concomitant (less pronounced
H1 receptors) medication) than in FGAs)
Aripiprazole is a Tourette EPS less common
partial D2 syndrome Anticholinergic and
agonist Huntington sympatholytic
disease effects
Neuroleptic
malignant
syndrome
Clozapine can
cause
agranulocytosis.

Adverse effects

First-generation Second-generation
Details antipsychotics antipsychotics

Extrapyramidal See EPS below for details. High-potency FGAs Significantly fewer
symptoms (EPS) have the highest motor side effects
incidence of EPS. (EPS) due to
Low-potency FGAs reduced D2
have a rate of EPS receptor
similar to that of antagonism;
SGA. greater affinity for
5HT2A receptors
and interaction
with other
receptors

Hyperprolactinemia
Elevated prolactin levels: Dopamine All FGAs cause Smaller increase
inhibits the release of prolactin via elevated prolactin in prolactin levels
the D2 receptor in the levels. compared to
tuberoinfundibular pathway. Annual monitoring of typical
Therefore, dopamine antagonists symptoms is antipsychotics
increase the effects of prolactin. recommended. Most common in
In men: gynecomastia, risperidone,
galactorrhea, hypogonadotropic amisulpride,
hypogonadism (erectile dysfunction, and paliperidone
reduced libido, infertility)
In women: galactorrhea,
hypogonadotropic hypogonadism
(amenorrhea, reduced libido,
infertility)

Prolonged QT Potassium channel-mediated effect All FGAs All SGAs

interval Can lead to life-threatening Most common in (particularly
arrhythmias (torsades de pointes intravenous iloperidone,
and ventricular fibrillation) haloperidol and ziprasidone)
thioridazine

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First-generation Second-generation
Details antipsychotics antipsychotics

Anticholinergic Dry mouth, blurred vision, More common in low- Uncommon in

effects mydriasis, constipation, urinary potency FGAs most agents
retention, and tachycardia Mild in high-potency Clozapine,
FGAs olanzapine, and
quetiapine have
the highest
incidence of
anticholinergic
effects.
Clozapine
commonly causes
sialorrhea.

Metabolic effects Usually weight gain, hyperglycemia, More common in low- Prominent in most
dyslipidemia potency FGAs SGA
Occasionally loss of appetite and Clozapine,
weight loss olanzapine,
quetiapine carry
the highest risk of
metabolic
syndrome
(hyperglycemia,
dyslipidemia,
weight gain).

Olanzapine also
causes an
asymptomatic
increase of liver
enzymes.

Sympatholytic Orthostatic hypotension (due to α1- More common in low- Common during
effect adrenergic blockade) potency FGAs treatment initiation
Rare in high-potency and dose
FGAs adjustments
Particularly
olanzapine

Sedation Mediated via histamine H1 receptor Prominent in low- All SGAs

antagonism potency FGAs (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 Extremely rare Clozapine carries

first 4 months of therapy) a high risk of
agranulocytosis
(usually within the
first 4 months of
therapy).

Other cardiac side Myocarditis, cardiomyopathy, sinus Not reported Clozapine

effects tachycardia

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First-generation Second-generation
Details antipsychotics antipsychotics

Ocular effects Lenticular and corneal deposits Associated with low- Not reported
Cataracts potency FGAs
Epithelial keratopathy Chlorpromazine
Retinitis pigmentosa Thioridazine
carries the
highest risk of
retinitis
pigmentosa.

Thermoregulation Hyperthermia or hypothermia Associated with Most commonly

phenothiazines (e.g., associated
fluphenazine) olanzapine and
risperidone
Patients receiving
these medications
should avoid extreme
temperatures. [3]

Neuroleptic Life-threatening side effect All antipsychotics

malignant See NMS below for details.
syndrome

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

Hours to Painful and lasting muscle Acute treatment: anticholinergics or

days spasms predominantly
affecting the head, neck, and
tongue
Facial grimacing,
torticollis
Tongue protrusion or
twisting
Oculogyric crisis
Opisthotonus of the
back
Acute dystonia (also
see dystonia)
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).

Week 1 Cogwheel rigidity, stiff gait, Dose reduction or switch to an

tremor antipsychotic drug with lower risk of EPS
(SGA)
Anticholinergic (e.g., benztropine) or a
dopamine agonist (e.g., amantadine)
Pseudoparkinsonism

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EPS subtype Onset Symptoms Treatment

Weeks Restlessness/compelling Dose reduction or switch to an

1–8 urge to move antipsychotic drug with lower risk of EPS
Inability to sit or stand still (SGA)
First-line: propranolol
Alternative
Benztropine
Benzodiazepines
Akathisia

Months– Involuntary movements of the Discontinuation of antipsychotic drug

years mouth and tongue; limbs, Switch to SGA (less EPS)
face, and respiratory muscles Anticholinergics or antipsychotic
caused by chronic use of dose reduction may initially worsen
antipsychotic drugs the condition.
Repetitive chewing and Treatment: valbenazine and
lip smacking tetrabenazine [4]
Choreic movements
Tardive dyskinesia

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.

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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.

Indications

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 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 Clozapine

for Parkinson disease (dopamine agonists)

Psychosis during pregnancy First-line: FGAs (e.g., haloperidol)

Acute Postpartum psychosis

therapy

Long- Schizophrenia and other chronic psychotic SGAs

term disorders
therapy In cases of treatment failure, switch to high-potency
antipsychotics (primarily effective for positive
symptoms).

Concomitant medication for patients with SGAs

obsessive-compulsive disorders

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Important indications Preferred agents

Treatment-resistant schizophrenia and Clozapine

schizophrenia associated with persistent
suicidality

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!

References

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