Clinical science

Antipsychotics (Neuroleptic)

Abstract

Antipsychotics are a heterogeneous group of substances used primarily to treat schizophrenia, 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 (lead compound: haloperidol) is based on D2 antagonism, while second-generation antipsychotics (atypical) 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 effect 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 potential side effect of both first-generation and second-generation antipsychotics is neuroleptic malignant syndrome, which presents with fever, hypertension, rigor, tremor, and psychopathological symptoms.

Agents and dosages

Active ingredient	Haloperidol (e.g., Haldol^®)
Administration	Oral Intramuscular
Standard dosage	1–3 mg orally, 3 times a day; maximum daily dose of 20–30 mg
Indications	Acute psychotic symptoms Acute schizophrenia Paranoid and hallucinatory syndromes Mania, hypermanic, or hypomanic states Psychomotor agitation In elderly people During alcohol withdrawal treatment Chronic schizophrenia Hyperkinesia , nervous tic, Tourette syndrome Huntington's disease, chorea minor Nausea and vomiting: e.g., after surgery or during cytostatic therapy
Special consideration	Initially, gradual dose increase followed by dose reduction during maintenance therapy The goal is to find the minimum effective maintenance dose. Not for children younger than 3 years Treatment should gradually be phased out. EPS may be treated with biperiden (antidote for early tardive dyskinesia).
Contraindications	Hypersensitivity to the active substance or adjuvants Acute intoxication with alcohol, sleeping pills, analgesics, opioid, or psychotherapeutic drugs; comatose patients Parkinson syndromes, lesions in the basal ganglia, EPS
Dose adjustment in renal impairment	Dose adjustment is not necessary.
Dose adjustment in hepatic impairment	Cautious dosing and continuous monitoring of liver parameters
Pregnancy/breastfeeding	Pregnancy: limited use only after careful assessment of the risks and benefits Breastfeeding: Haloperidol is not recommended during the lactation period.

Active ingredient	Levomepromazine (e.g. Levoprome^®)
Administration	Oral
Standard dosage	Initial dose of 25–50 mg orally; gradual dose increase up to 150–250 mg per day
Indications	Psychomotor agitation Schizophrenic psychosis Chronic psychosis with hallucinations Manic agitation Aggressive, intellectually challenged individuals
Special considerations	Dosage requires individual assessment and gradual adjustment.
Contraindications	Hypersensitivity to the active substance or adjuvants Angle-closure glaucoma Micturition disorders with residual urine History of agranulocytosis Porphyria Leukopenia Neurological disorders, e.g.: Multiple sclerosis Myasthenia Hemiplegia Acute intoxication with CNS depressants substances or alcohol Shock Coma
Dose adjustment in renal impairment	Cautious dosing and continuous monitoring of renal parameters
Dose adjustment in hepatic impairment	Cautious dosing and continuous monitoring of liver parameters
Pregnancy/breastfeeding	Pregnancy 1^st trimester: contraindicated 2^nd and 3^rd trimesters: limited use only after careful assessment of the risks and benefits Breastfeeding: Substance not recommended during lactation period.

Active ingredient	Pipamperone (e.g., Dipiperon^®)
Application	Oral
Standard dosage	Initial dose: 40 mg orally 3 times a day Dose increase up to 120 mg orally 3 times a day (within 2–3 weeks)
Indications	Chronic psychosis
Attention	Gradual dose increase Continuous dose adjustment to determine the minimum effective dose for maintenance therapy Initially, low-dose administration to elderly individuals (e.g., half of the recommended starting dose) followed by gradual dose increase, if necessary.
Contraindications	Hypersensitivity to the active substance or adjuvants CNS depression (e.g., coma, acute intoxication of alcohol, sleeping pills, analgesics, or psychotherapeutic drugs) Parkinson's disease Hepatic impairment Renal impairment
Dose adjustment in renal impairment	Contraindicated
Dose adjustment in hepatic impairment	Contraindicated
Pregnancy/breastfeeding	Pregnancy: limited use only after careful assessment of the risks and benefits Breastfeeding: Levomepromazine is not recommended during the lactation period.

Active ingredient	Clozapine (e.g., Clozaril^®)
Administration	Oral
Standard dosage	Initial dose on the first day of 12.5 mg orally once or twice daily, followed by 25 mg once to twice daily on the second day May be increased in increments of 25 mg–50 mg per day for 2–3 weeks until target dose of 300 mg per day is achieved If necessary, the dose can be increased (preferably) once or twice weekly in increments of 50 mg–100 mg per day up to a maximum daily dose of 900 mg.
Indications	Treatment of refractory schizophrenia Long-term reduction of suicidal behavior associated with schizophrenia and schizoaffective disorders Psychosis in patients with Parkinson's disease
Special considerations	Doses have to be assessed individually. The goal is to determine the lowest effective dose for each patient. Cautious dose titration and splitting of the daily dose into several individual doses are necessary to minimize the risk of hypertonia, seizures, and sedative effects. Treatment should be continued for at least 6 months after onset of the antipsychotic effect. Gradual dose reduction for 1–2 weeks to discontinue treatment
Contraindications	Hypersensitivity to the active substance or adjuvants If the patient's blood cannot be checked regularly Medical history of granulocytopenia or agranulocytosis (except of granulocytopenia/agranulocytosis caused by previous chemotherapy) Impaired bone marrow function Uncontrolled epilepsy Alcohol-related psychosis, psychosis caused by intoxication or medication , or comatose states Circulatory collapse and/or CNS depression Severe renal or cardiac impairment Myocarditis Acute liver disease associated with nausea, anorexia or jaundice, advanced liver disease, liver failure Paralytic ileus Concomitant medication that may cause agranulocytosis Concomitant antipsychotics that can be administered as d.i.
Dose adjustment in renal impairment	Dose adjustment required
Dose adjustment in hepatic impairment	Cautious dosing and continuous monitoring of liver parameters
Pregnancy/breastfeeding	Pregnancy: limited use only after careful assessment of the risks and benefits Breastfeeding: Clozapine is not recommended during the lactation period.

Active ingredient	Olanzapine (e.g., Zyprexa^®)
Administration	Oral
Standard dosage	Initial dose of 10 mg orally per day Maintenance dose of 5–20 mg orally per day
Indications	Schizophrenia Monotherapy or combination therapy with lithium or valproate to treat acute manic episodes in patients with bipolar disorders
Special considerations	Treatment of elderly individuals should start with an initial dose of 5 mg orally per day. Gradual dose reduction to discontinue treatment
Contraindications	Hypersensitivity to the active substance or adjuvants Risk of angle-closure glaucoma Children and adolescents younger than 18 years
Dose adjustment in renal impairment	Dose adjustment not necessary
Dose adjustment in hepatic impairment	Dose reduction required
Pregnancy/breastfeeding	Pregnancy: limited use only after careful assessment of the risks and benefits Breastfeeding: Olanzapine is not recommended during the lactation period.

Active ingredient	Risperidone (e.g., Risperidal^®)
Administration	Oral Intramuscular
Indications and standard dosage	Schizophrenia and other psychotic disorders Patients with Alzheimer's disease or dementia who are highly aggressive or present with severe psychotic symptoms Manic episodes associated with bipolar disorders Conduct disorders, oppositional defiant disorders, or other socially disruptive behavior in children, adolescents, or adults associated with below-average mental abilities or retardation and destructive behavior, e.g., aggression, impulsivity, and self-harm Autism spectrum disorders characterized by hyperactivity and irritability (including aggression, self-harm, anxiety, and repetitive behavior) in children and adolescents older then 5 years.
Contraindications	Patients with dementia and symptoms of Parkinson's disease such as rigor, bradykinesia, and postural abnormalities Patients with dementia most probably caused by dementia with Lewy bodies
Dose adjustment in renal impairment	Begin with half the recommended dose, then cautiously increase it.
Dose adjustment in hepatic impairment	Begin with half the recommended dose, then cautiously increase it.
Pregnancy/breastfeeding	Pregnancy: Risperidone is not recommended during pregnancy. Breastfeeding: Risperidone is not recommended during the lactation period.

The authors cannot be held responsible for the contents provided being exhaustive, correct, or up to date. The contents have been meticulously researched by our editors. Especially updates regarding warnings and recommendations must be considered. Unless otherwise noted, the recommendations provided apply to adults.

Effects

First-generation antipsychotics (FGA)

Mechanism of action: antagonism at the D2 receptor
- High-potency antipsychotics are dopamine-specific antagonists and have a strong antipsychotic effect even in relatively low doses.
- Low-potency antipsychotics are antidopaminergic, antihistaminergic, and anticholinergic (primarily sedative).
- In comparison to butyrophenones (e.g., melperone, benperidol, pipamperone), phenothiazines (e.g., chlorpromazine, levomepromazine, perphenazine) are not only sedative and antihistaminergic but may also have autonomic, anticholinergic side effects.

	Substances	Antipsychotic effects	Sedative and antiemetic effects
High-potency antipsychotics	Haloperidol Fluphenazine Perphenazine	↑↑↑	↑
Medium-potency antipsychotics	Chlorpromazine	↑↑	↑↑
Low-potency antipsychotics	Promethazine	↑	↑↑↑

Second-generation antipsychotics (SGA)

Studies have shown that some SGA are more effective regarding primary negative symptoms compared to equivalent FGA. However, no difference was detected regarding secondary negative symptoms (e.g., social withdrawal related to paranoid hallucinations).

Definition: substances with antipsychotic effects that have significantly fewer motor side effects and a smaller increase in prolactin levels compared to typical antipsychotics
Mechanism of action
- 5HT2A receptor antagonism and D2 receptor antagonism (less pronounced than that of typical antipsychotics) but also interaction with several other receptors (i.e., D3, D4, α-adrenergic, and H1 receptors)
- The greater affinity to 5HT2A receptors and the reduced D2 receptor antagonism, along with the interaction with other receptors, decreases the likelihood of extrapyramidal effects.
Common substances: clozapine, olanzapine, risperidone, quetiapine, amisulpride, ziprasidone, aripiprazole

References:^[1]^[2]

Side effects

Overview

Side effects	First Generation		Second Generation
Side effects	High-potency	Low-potency	Second Generation
EPS	↑↑↑	↑	↑
Hyperprolactinemia	↑↑↑	↑	↑
Prolonged QT interval	↑↑	↑↑	-
Antihistaminergic (sedation)	↑	↑↑	↑↑
Anticholinergic	↑	↑↑	↑↑
Metabolic	↑	↑↑	↑↑↑
Agranulocytosis	-	-	↑

Side effects

Nonspecific

Hyperprolactinemia (Dopamine inhibits the release of prolactin via the D2 receptor and the tuberoinfundibular pathway. Therefore, dopamine antagonists increase the effects of prolactin, which may lead to galactorrhea.)
- In men: gynecomastia, galactorrhea, hypogonadotropic hypogonadism (erectile dysfunction, reduced libido, infertility)
- In women: galactorrhea, hypogonadotropic hypogonadism (amenorrhea, reduced libido, infertility)
Prolonged QT interval
Anticholinergic effects (e.g., dry mouth, mydriasis, constipation, and tachycardia)
Sympatholytic effect (e.g., orthostatic intolerance)
Metabolic effects; (usually weight gain, occasionally loss of appetite and weight loss)
Hypothermia/hyperthermia: fluphenazine may disrupt thermoregulation; patients receiving antipsychotics should avoid extreme temperatures

Extrapyramidal symptoms (EPS)

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.
- First-generation high-potency antipsychotics: D2 antagonism → EPS
- Second-generation antipsychotics: weaker D2 antagonism → less frequently EPS
Metoclopramide, although not an antipsychotic, may also cause extrapyramidal symptoms.
Treatment
- In case of EPS (or in case of patient wish if longterm antipsyochotic therapy is likely), a typical antipsychotic can be replaced with an atypical (2^nd generation) antipsychotic
- In case of severe dyskinesia, tetrabenazine can be given

EPS subtype	Onset	Symptoms	Treatment
Acute dystonia (see also the learning card on dystonia)	Hours to days	Painful and lasting muscle spasms predominantly affecting the head, neck, and tongue Oculogyric crisis Tongue protrusion or twisting Facial grimacing, torticollis Opisthotonus of the back	Acute treatment: anticholinergics or antihistamines Common first-line: benztropine Alternatives: Diphenhydramine Benzodiazepines (e.g., diazepam) Prophylaxis using benztropine or diphenhydramine can be used in patients receiving parenteral haloperidol; especially those with little prior exposure to typical neuroleptics.
Pseudoparkinsonism	Week 1	Cogwheel rigidity, stiff gait, tremor	Anticholinergic (e.g., benztropine) or a dopamine agonist (e.g., amantadine) Dose reduction or discontinuation of antipsychotic drug
Akathisia	Week 1–8	Restlessness/compelling urge to move Inability to sit or stand still	Discontinuation or dose reduction of antipsychotic drug Propranolol
Tardive dyskinesia	Months–years	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.

Neuroleptic malignant syndrome (NMS)

Description: life-threatening neurological disorder usually associated with antipsychotics
Etiology
- Reaction to antipsychotic drugs (especially high-potency antipsychotics such as haloperidol), other agents that affect the CNS (e.g. carbamazepine, lithium, venlafaxine), or certain antiemetics (e.g., metoclopramide, promethazine)
- The underlying mechanism is not well understood. A connection between NMS and the duration of therapy or therapeutic dose has not been established.
Pathophysiology: Central D2 receptor blockade in the nigrostriatal pathway
Clinical features: onset usually within 2 weeks of the first dose
- Psychiatric symptoms: reduced vigilance, stupor, mental confusion, mutism
- Vegetative symptoms: high fever, tachycardia, tachypnea, diaphoresis
- Extrapyramidal symptoms: akinesia, tremor, rigor
Diagnostics
- ↑↑ Creatinine kinase
- ↑ Transaminases
- Leukocytosis
- Metabolic acidosis
- Myoglobinuria
Differential diagnosis
- Lethal catatonia (see also catatonic dilemma )
- Serotonin syndrome
- Malignant hyperthermia
Treatment
- Discontinuation of the antipsychotic drug!
- Supportive measures (e.g., ICU care)
- Pharmacotherapy
  - First line: Dantrolene (ryanodine receptor antagonist): prevents the release of calcium from the sarcoplasmic reticulum of striated muscle → reduced muscular activity
  - Alternatives: bromocriptine, apomorphine, or amantadine

FALTER: Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatinine kinase, transaminases), Rigor

Side effects of select second-generation antipsychotics

Active ingredient	Side effects
Clozapine	Agranulocytosis (usually within the first 4 months of therapy) Metabolic syndrome, hyperglycemia, hypercholesterolemia, weight gain Decreased risk of EPS compared to typical antipsychotics
Olanzapine	Metabolic syndrome, hyperglycemia, dyslipidemia, weight gain, asymptomatic increase of liver enzymes Anticholinergic side effects: dry mouth, constipation Orthostatic hypotension (due to α1-adrenergic blockade)
Quetiapine	Sedation Metabolic syndrome, hyperglycemia, hypercholesterolemia, weight gain
Risperidone	Elevated prolactin levels (may lead to amenorrhea)
Amisulpride	Elevated prolactin levels

References:^[3]^[4]^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12]

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

Indications

	Important indications	Preferred substances
Acute therapy	Acute delusions	First choice: SGA Alternative: high-potency antipsychotics
	Bipolar affective disorder or manic syndrome	First choice: SGA Alternative: high-potency antipsychotics
	Delirium	High-potency antipsychotics (alternatively medium or 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's disease (dopamine agonists)	Clozapine
Long-term therapy	Paranoid schizophrenia and delusional disorders	SGA (in cases of treatment failure, switch to high-potency antipsychotics)
	Concomitant medication for patients with obsessive-compulsive disorders	SGA
	Treatment-resistant schizophrenia and schizophrenia associated with persistent suicidality	Clozapine
	Tic disorders	Tiapride

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