- 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®) | |||||
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Special consideration |
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Contraindications |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding |
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Active ingredient | Levomepromazine (e.g. Levoprome®) | |||||
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Special considerations |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding |
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Active ingredient | Pipamperone (e.g., Dipiperon®) | |||||
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Attention |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding |
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Active ingredient | Clozapine (e.g., Clozaril®) | |||||
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Special considerations |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding | ||||||
Active ingredient | Olanzapine (e.g., Zyprexa®) | |||||
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Special considerations |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding |
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Active ingredient | Risperidone (e.g., Risperidal®) | |||||
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Administration |
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Indications and standard dosage |
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Contraindications |
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Dose adjustment in renal impairment |
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Dose adjustment in hepatic impairment |
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Pregnancy/breastfeeding |
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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)
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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 | |
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High-potency antipsychotics | ↑↑↑ | ↑ | |
Medium-potency antipsychotics | ↑↑ | ↑↑ | |
Low-potency antipsychotics | ↑ | ↑↑↑ |
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
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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 | |
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High-potency | Low-potency | ||
EPS | ↑↑↑ | ↑ | ↑ |
Hyperprolactinemia | ↑↑↑ | ↑ | ↑ |
Prolonged QT interval | ↑↑ | ↑↑ | - |
Antihistaminergic (sedation) | ↑ | ↑↑ | ↑↑ |
Anticholinergic | ↑ | ↑↑ | ↑↑ |
Metabolic | ↑ | ↑↑ | ↑↑↑ |
Agranulocytosis | - | - | ↑ |
Side effects
Nonspecific
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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.
- 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 |
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Acute dystonia (see also the learning card on dystonia) | Hours to days |
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Pseudoparkinsonism | Week 1 |
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Akathisia | Week 1–8 |
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Tardive dyskinesia | Months–years |
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Neuroleptic malignant syndrome (NMS)
- Description: life-threatening neurological disorder usually associated with antipsychotics
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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
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Diagnostics
- ↑↑ Creatinine kinase
- ↑ Transaminases
- Leukocytosis
- Metabolic acidosis
- Myoglobinuria
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Differential diagnosis
- Lethal catatonia (see also catatonic dilemma )
- Serotonin syndrome
- Malignant hyperthermia
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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
- Electroconvulsive therapy
FALTER: Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatinine kinase, transaminases), Rigor
Side effects of select second-generation antipsychotics
Active ingredient | Side effects |
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Clozapine |
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Olanzapine |
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Quetiapine |
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Risperidone |
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Amisulpride |
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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 | |
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Acute therapy | Acute delusions |
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Bipolar affective disorder or manic syndrome | ||
Delirium | ||
Delusional or agitated states |
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Psychotic symptoms caused by medication for Parkinson's disease (dopamine agonists) | ||
Long-term therapy | Paranoid schizophrenia and delusional disorders |
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Concomitant medication for patients with obsessive-compulsive disorders |
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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!