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Antipsychotics

Last updated: October 26, 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 have a decreased risk of 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.

CHarlatans 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 of antipsychotics
Important indications Preferred agents
Acute therapy
  • 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 of antipsychotics
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 agranulocytosis.

Extrapyramidal symptoms (EPS) [5]

Recommendations in this section are consistent with the 2020 American Psychiatric Association (APA) guidelines for the management of schizophrenia. Consult psychiatry if an adjustment of psychiatric medications is required. [6]

Overview of extrapyramidal symptoms [6][10][11]
EPS subtype Onset Symptoms Treatment

Acute dystonia (see also “Dystonia”) [12]

  • Hours to days
Pseudoparkinsonism [13]
  • ∼ 1–4 weeks
Akathisia [5]
  • 1–8 weeks
  • Restlessness/compelling urge to move
  • Inability to sit or stand still
Tardive dyskinesia [16]
  • Months to 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

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

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

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  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. Muench J, Hamer AM. Adverse effects of antipsychotic medications.. Am Fam Physician. 2010; 81 (5): p.617-22.
  6. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. American Psychiatric Association Publishing ; 2020
  7. Zadikoff C, Munhoz RP, Asante AN, et al. Movement disorders in patients taking anticonvulsants. Journal of Neurology, Neurosurgery & Psychiatry. 2007; 78 (2): p.147-151. doi: 10.1136/jnnp.2006.100222 . | Open in Read by QxMD
  8. Madhusoodanan S, Alexeenko L, Sanders R, Brenner R. Extrapyramidal symptoms associated with antidepressants--a review of the literature and an analysis of spontaneous reports.. Ann Clin Psychiatry. 2010; 22 (3): p.148-56.
  9. Sykes DA, Moore H, Stott L, et al. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat Com. 2017; 8 (1). doi: 10.1038/s41467-017-00716-z . | Open in Read by QxMD
  10. Brunton L. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition. McGraw-Hill Education / Medical ; 2017
  11. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018; 17 (3): p.341-356. doi: 10.1002/wps.20567 . | Open in Read by QxMD
  12. 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
  13. Kamin J, Manwani S, Hughes D. Emergency Psychiatry: Extrapyramidal Side Effects in the Psychiatric Emergency Service. Psychiatric Services. 2000; 51 (3): p.287-289. doi: 10.1176/appi.ps.51.3.287 . | Open in Read by QxMD
  14. Roppolo LP, Morris DW, Khan F, et al. Improving the management of acutely agitated patients in the emergency department through implementation of Project BETA (Best Practices in the Evaluation and Treatment of Agitation). J Am Coll Emerg Physicians Open. 2020; 1 (5): p.898-907. doi: 10.1002/emp2.12138 . | Open in Read by QxMD
  15. Pringsheim T, Gardner D, Addington D, et al. The Assessment and Treatment of Antipsychotic-Induced Akathisia. The Canadian Journal of Psychiatry. 2018; 63 (11): p.719-729. doi: 10.1177/0706743718760288 . | Open in Read by QxMD
  16. Waln O, Jankovic J. An Update on Tardive Dyskinesia: From Phenomenology to Treatment. Tremor Other Hyperkinet Move. 2013; 3 : p.03. doi: 10.5334/tohm.165 . | Open in Read by QxMD
  17. Uhlyar S, Rey JA. Valbenazine (Ingrezza): The First FDA-Approved Treatment for Tardive Dyskinesia.. P T. 2018; 43 (6): p.328-331.
  18. Ward KM, Citrome L. Antipsychotic-Related Movement Disorders: Drug-Induced Parkinsonism vs. Tardive Dyskinesia-Key Differences in Pathophysiology and Clinical Management.. Neurol Ther. 2018; 7 (2): p.233-248. doi: 10.1007/s40120-018-0105-0 . | Open in Read by QxMD