• 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
Special consideration
  • Initially, gradual dose increase followed by dose reduction during maintenance therapy
  • 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

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
    • 1st trimester: contraindicated
    • 2nd and 3rd 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
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
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

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

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)

Substances Antipsychotic effects Sedative and antiemetic effects
High-potency antipsychotics

↑↑↑

Medium-potency antipsychotics

↑↑

↑↑
Low-potency antipsychotics

↑↑↑

Second-generation antipsychotics (SGA)

References:[1][2]

Side effects

Overview

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

Side effects

Nonspecific

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 antagonismEPS
    • 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 (2nd 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
Pseudoparkinsonism Week 1
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)

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

Side effects of select second-generation antipsychotics

Active ingredient Side effects
Clozapine
Olanzapine
Quetiapine
Risperidone
Amisulpride

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
Bipolar affective disorder or manic syndrome
Delirium
  • High-potency antipsychotics (alternatively medium or low-potency antipsychotics)
Delusional or agitated states
Psychotic symptoms caused by medication for Parkinson's disease (dopamine agonists)
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
Tic disorders

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