Antipsychotics are a class of medication used to treat the following disorders:


  • Psychotic disorders (e.g., Schizophrenia and Schizoaffective Disorder)
  • Bipolar Disorders
  • Acute Agitation
  • Tourette’s Syndrome (Tic Disorder)
  • Major Depressive Disorder (as add-on treatment)


Antipsychotics can be divided into two categories based on pharmacological profile:


  1. Typical Antipsychotics (also termed 1st Generation or Conventional antipsychotics or Dopamine Antagonists)
  2. Atypical Antipsychotics (also termed 2nd Generation or Serotonin Dopamine Antagonists)

Atypical Antipsychotics


Second-generation antipsychotics (atypical antipsychotics) can be divided into three groups based on structural similarity:

  1. The clozapine family (the “pines”) is comprised of asenapine, clozapine, olanzapine, and quetiapine
  2. The risperidone family (the “dones”) is comprised of iloperidone, lurasidone, paliperidone, risperidone, and ziprasidone
  3. The partial dopamine agonist family includes aripiprazole, brexpiprazole and cariprazine.   


Atypical Antipsychotics



Are all Antipsychotics Equal In Terms of Efficacy?

  • There is ongoing debate about the relative efficacy of antipsychotics
  • There is little empirical evidence that any one antipsychotic, with the exception of Clozapine, is superior to the rest in terms of efficacy
  • NOTE: The CATIE trial was NOT an efficacy study


What Makes An Antipsychotic “Atypical”

  • Antagonism of 5HT-2A receptors and resulting decrease in EPS risk is thought to make these agents “atypical”
  • Antagonism of 5HT-2A receptors increases dopamine release in the meso-cortical, nigro-striatal, and infundibular-pituitary dopamine circuits, but not in the mesolimbic circuit, as the presynaptic dopamine neurons of this circuit appear to have minimal, if any, 5-HT-2A receptors. (See mechanism at bottom of this page)
  • Second-generation antipsychotics are about ten-fold less likely to induce extrapyramidal symptoms (EPS) or tardive dyskinesia when compared to typical antipsychotics. Why?
    • Theoretically, atypical antipsychotics carry a lower risk of EPS due to a more rapid dissociation from the dopamine (D-2) receptor and because of the additional property of antagonism at (5HT-2A) receptors (see proposed mechanism at the bottom of this page).


Side Effects


  • Metabolic: The second-generation antipsychotics, however, are more likely than the first-generation antipsychotics to induce metabolic syndrome by inducing resistance at insulin receptors by an unclear mechanism. This results in glucose intolerance and shunting of lipids toward central adipose stores
    • Highest Risk: clozapine and olanzapine
    • Lowest Risk: aripiprazole, asenapine, brexpiprazole, cariprazine, and lurasidone 
  • Sedation, Orthostatic Hypotension: Second generation antipsychotics are associated with sedation, weight gain, orthostatic hypotension, and anticholinergic side effects due to antagonism at
    1. Histamine (H1) Receptors (sedation, weight gain)
    2. α-adrenergic (α1) Receptors (sedation, hypotension)
    3. Muscarinic cholinergic (M1) Receptors (sedation, hypotension, and anticholinergic effects)
  • Cardiovascular: All antipsychotics have the potential to prolong the Q-T interval
    • QT interval on electrocardiogram represents the time it takes the ventricles of the heart to depolarize and then repolarize).
    • Q-T prolongation is a risk factor for the development of Torsades de Pointes, a life threatening cardiac arrhythmia.
    • See Tables and Illustrations in the “Gallery” Below
  • Seizures: All antipsychotics have the potential to lower the seizure threshold
    • See Tables and Illustrations in the “Gallery” Below

Typical Antipsychotics


Chlorpromazine Thorazine
Fluphenazine Prolixin
Haloperidol Haldol
Loxapine Loxatane
Perphenazine Trilafon
Pimozide Orap
Thiothixene Navane
Trifluoperazine Stellazine




  • The Typical (first-generation) antipsychotics are derived from a number of chemical classes but differ clinically in their affinity for dopamine (D2) receptors
  • Typical Antipsychotics are categorized by their relative potency at dopamine (D2) receptors
    • High Potency: Haloperidol, Fluphenazine
    • Low Potency: Chlorpromazine
  • Low-potency antipsychotics such as chlorpromazine (Thorazine) are also antagonists at the following receptors
    • Histamine (H1): Sedation, Weight gain
    • Adrenergic (α1): Sedation, Orthostatic hypotension
    • Muscarinic cholinergic (M1): Anticholinergic side effects (dry mouth, urinary retention, constipation, blurry vision, cognitive impairment/memory impairment)
  • All antipsychotics (both typical and atypical) reduce the seizure threshold and may predispose patients to seizures
    • See Gallery of Tables and Illustrations Below


  • Thioridazine has a unique, additional risk of retinal pigmentation.
  • High-potency antipsychotics such as fluphenazine and haloperidol show far less sedation, hypotension, and anticholinergic side effects, but are more likely to induce extrapyramidal symptoms (EPS) such as acute dystonia, acute akathisia, and/or acute pseudo-Parkinsonism due to robust dopamine antagonism in the pars compacta-striatal dopamine circuit.


Tardive Dyskinesia (TD)


  • All first-generation antipsychotics induce tardive dyskinesia (TD) at an incidence rate of about 3% to 5% per year of exposure up to 60% lifetime prevalence. 
    • TD is mild and non-progressive in majority of cases.
    • TD results from chronic antagonism of post-synaptic receptors in the basal ganglia. Chronic antagonism is thought to result in upregulation of post-synaptic dopamine receptors and therefore dopamine super sensitivity. Oxidative damage of these upregulated receptors is also thought to play a role in the pathophysiology of TD.
    • Once TD is well-established, withdrawal of the offending agent does not typically result in a return of the nigrostriatal pathway to baseline signal transduction, i.e. movements tend to persist.
    • TD is treated by reducing the dose of the antipsychotic, switching to an atypical antipsychotic, or using new medications such as Valbenazine (Ingrezza).
    • Clozapine has been shown to reduce TD symptoms in some patients
  • In general, extrapyramidal symptoms are treated by reducing the dose of antipsychotic, switching to an atypical antipsychotic, and/or administering an anticholinergic agent such as benztropine.
  • See Gallery of Tables and Illustrations Below



Neuroleptic Malignant Syndrome (NMS)

  • First generation antipsychotic medications, especially high-potency medications, may rarely induce neuroleptic malignant syndrome (NMS). 
  • Note that immediate withdrawal of dopamine agonists can also lead to NMS.
  • NMS is characterized by delirium, muscle rigidity, rhabdomyolysis/CK elevations (5,000-10,000+), extreme fever, febrile seizures, and renal failure due to myoglobinuria. 
  • The mortality rate is about 15% in well-managed cases.
  • Treatment usually involves supportive measures such as IV fluids, cooling blankets, dantrolene, and/or bromocriptine.


  • See Gallery of Tables and Illustrations Below



  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.

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