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Antipsychotics

Last updated: March 4, 2021

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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 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.

Description

Overview of antipsychotics
Mechanism of action Indications Side effects
First-generation antipsychotics (FGAs) High-potency antipsychotics
  • Haloperidol
  • Fluphenazine
  • Perphenazine
  • Trifluoperazine
  • Pimozide
Low-potency antipsychotics
  • Chlorpromazine
  • Thioridazine
Second-generation antipsychotics (SGAs)
  • Clozapine
  • Olanzapine
  • Risperidone
  • Quetiapine
  • Amisulpride
  • Ziprasidone
  • Aripiprazole
  • Lurasidone
  • Asenapine
  • Iloperidone
  • Paliperidone

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

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

  • 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
Important indications Preferred agents
Acute therapy
  • Delusional or agitated states (e.g., patients who are agitated and aggressive due to alcohol and/or illicit drug use)
  • Dementia (should be reserved for severe symptoms only)
Long-term therapy
  • Tiapride

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

Overview of adverse effects
Characteristics First-generation antipsychotics Second-generation antipsychotics
Extrapyramidal symptoms (EPS)
  • Significantly fewer motor side effects (EPS) due to reduced D2 receptor antagonism; greater affinity for 5HT2A receptors and interaction with other receptors
Hyperprolactinemia
  • All FGAs cause elevated prolactin levels.
  • Annual monitoring of symptoms is recommended.
Cardiac adverse effects Prolonged QT interval
Other
  • Not reported
Anticholinergic adverse effects
Metabolic adverse effects
Sympatholytic adverse effect
  • Common during treatment initiation and dose adjustments
  • Particularly olanzapine
Sedation
  • All SGAs (tolerance usually develops within a few days of treatment)
  • Quetiapine is often used as a sleep aid in low doses.
Hematologic
  • Extremely rare
Ocular effects
  • Not reported
Thermoregulation
  • Associated with phenothiazines (e.g., fluphenazine) [3]
  • Patients receiving these medications should avoid extreme temperatures. [4]
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 agranlocytosis.

Extrapyramidal symptoms (EPS)

Overview of extrapyramidal symptoms
EPS subtype Onset Symptoms Treatment

Acute dystonia (also see “Dystonia”) [5]

  • Hours to days
Pseudoparkinsonism
  • Week 1
Akathisia
  • Weeks 1–8
  • Restlessness/compelling urge to move
  • Inability to sit or stand still
Tardive dyskinesia
  • Months–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
  • First-line: discontinuation of antipsychotic drug
  • Second-line: VMAT inhibitors
    • Valbenazine and deutetrabenazine [7]
    • Tetrabenazine (more side effects, e.g., aggravation of depressive symptoms)

ADAPT: extrapyramidal symptoms include Acute Dystonia, Akathisia, Parkinsonism, and Tardive dyskinesia.

Neuroleptic malignant syndrome (NMS) [8][9][10]

To remember the different symptoms of neuroleptic malignant syndrome, think FALTER: Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatine kinase, transaminases), Rigor

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

  1. Polcwiartek C, Sneider B, Graff C, et al. The cardiac safety of aripiprazole treatment in patients at high risk for torsade: a systematic review with a meta-analytic approach. Psychopharmacology (Berl). 2015; 232 (18): p.3297-3308. doi: 10.1007/s00213-015-4024-9 . | Open in Read by QxMD
  2. Jason Wong, Nicholas Delva. Clozapine-Induced Seizures: Recognition and Treatment. The Canadian Journal of Psychiatry. 2007; 52 (7): p.457-463. doi: 10.1177/070674370705200708 . | Open in Read by QxMD
  3. Fluphenazine. https://pubchem.ncbi.nlm.nih.gov/compound/fluphenazine#section=Top. . Accessed: May 18, 2017.
  4. Zonnenberg C, Bueno-de-Mesquita JM, Ramlal D, Blom JD. Hypothermia due to Antipsychotic Medication: A Systematic Review. Front Psychiatry. 2017; 8 . doi: 10.3389/fpsyt.2017.00165 . | Open in Read by QxMD
  5. Life in the fast lane - Acute Dystonic Reaction (Stiff and Twisted). https://lifeinthefastlane.com/toxicology-conundrum-030/. Updated: April 20, 2010. Accessed: May 18, 2017.
  6. Cloud LJ, Jinnah HA. Treatment strategies for dystonia. Expert Opin Pharmacother. 2010; 11 (1): p.5-15. doi: 10.1517/14656560903426171 . | Open in Read by QxMD
  7. Uhlyar S, Rey JA. Valbenazine (Ingrezza): The First FDA-Approved Treatment for Tardive Dyskinesia.. P T. 2018; 43 (6): p.328-331.
  8. Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management.. Ann Clin Psychiatry. 2012; 24 (2): p.155-162.
  9. Sahoo MK, Agarwal S, Biswas H. Catatonia versus neuroleptic malignant syndrome: the diagnostic dilemma and treatment. Ind Psychiatry J. 2014; 23 (2): p.163-165. doi: 10.4103/0972-6748.151703 . | Open in Read by QxMD
  10. Lang F, Lang S, Becker T, Jäger M. Neuroleptic malignant syndrome or catatonia? Trying to solve the catatonic dilemma. Psychopharmacology. 2015; 232 (1): p.1.