Dopamine supersensitivity psychosis

Dopamine supersensitivity psychosis is a hypothesis that attempts to explain the phenomenon in which psychosis (e.g. having hallucinations, which can mean hearing or seeing things that other people do not see or hear) occurs despite treatment with escalating doses of antipsychotics.[1] Dopamine supersensitivity may be caused by the dopamine receptor D2 antagonizing effect of antipsychotics, causing a compensatory increase in D2 receptors within the brain that sensitizes neurons to endogenous release of the neurotransmitter dopamine. Because psychosis is thought to be mediated—at least in part—by the activity of dopamine at D2 receptors, the activity of dopamine in the presence of supersensitivity may paradoxically give rise to worsening psychotic symptoms despite antipsychotic treatment at a given dose. This phenomenon may co-occur with tardive dyskinesia, a rare movement disorder that may also be due to dopamine supersensitivity.


Dopamine supersensitivity psychosis may occur due to upregulation of dopamine 2 receptors (D2). The D2 receptor is the primary target of almost all antipsychotics, which oppose the action of the neurotransmitter dopamine at this receptor. The antagonizing or "blockade" of D2 by antipsychotics may cause neurons, a type of cell within the brain, to undergo compensatory changes to make up for the loss of activity at D2 receptors. The D2 signaling pathway within neurons is complex, and involves multiple enzymes and other secondary messengers. It may be the case that, in response to antipsychotics, neurons increase the production of D2 receptors (upregulation), thereby sensitizing the neuron to dopamine.[2] However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically, there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia).[3] Other hypotheses include increases in the "active" D2 receptors (termed D2High) relative to the "inactive" conformation (D2Low).[3]

The end result is dopamine supersensitivity. It is thought that the psychotic symptoms within schizophrenia are primarily due to overactive dopamine activity in the mesolimbic area of the brain.[4] Therefore, dopamine supersensitivity may reduce the effect of antipsychotics and increase the brain's response to endogenous dopamine, leading to worsening psychosis.[4]

Tardive dyskinesia, a type of rare movement disorder that can be caused by antipsychotics, may also be caused by dopamine receptor sensitization. This may explain why, for people with tardive dyskinesia, increasing the dose of the antipsychotic may temporarily improve symptoms.[5]


The original criteria for dopamine supersensitivity psychosis were the following:[1]

  • A. Continuous use of antipsychotics for at least 3 months.
  • B. One of the following:
  • 1. Rebound psychosis within 6 weeks of a change (e.g. dose reduction, or antipsychotic switching) in an oral antipsychotic regimen or 3 months for long-acting injectable antipsychotics
  • 2. Tolerance to antipsychotic effects (requiring escalating doses, even beyond what has controlled symptoms in the past)
  • 3. Presence of tardive dyskinesia (which should occur when antipsychotics are withdrawn, and improve or disappear when antipsychotics are restarted)

Differential diagnosisEdit

It may sometimes be impossible to distinguish dopamine supersensitivity psychosis from psychosis that occurs "naturally" in the course of a primary psychotic disorder like schizophrenia, including cases in which the person was not taking their antipsychotic medication.[1] Even in the presence of an alternative etiology, or when it is impossible to determine the precise etiology for a psychotic episode, it is possible that dopamine supersensitivity psychosis can play a role in the presentation.[1] Recognizing the possible role of dopamine supersensitivity psychosis in a psychotic episode has implications for how to best manage someone's antipsychotic therapy.[1]


When supersensitivity psychosis was explored in 1978,[6] a featured concern was increasing resistance to medication, requiring higher doses or not responding to higher doses. Some articles use the term tardive psychosis to reference to this specific concept.[7] However, articles have disputed its validity.[7][8] The condition has been discovered in very few people.[7][9] Palmstierna asserts that tardive psychosis is a combination of "several different and not necessarily correlated phenomena related to neuroleptic treatment of schizophrenia."[7]

Society and cultureEdit

Dopamine supersensitivity is often dismissed as an inconsequential factor in the progression of psychotic disorders by psychiatrists in the medical literature.[2] The dopamine supersensitivity hypothesis was discussed by investigative journalist and author Robert Whitaker in his book Anatomy of an Epidemic, published in 2010.[a]


As of 2017, much of the evidence for dopamine supersensitivity psychosis comes from studies performed in animals. There is still a need for robust, human research.[2]

In a cohort study of people taking chronic antipsychotic therapy with either schizophrenia or schizoaffective disorder that presented for psychiatric care due to a relapse of their psychotic symptoms without a clear precipitating cause (e.g. new or worsening substance abuse, evidence of nonadherence to antipsychotics), 39% of the sample met the authors' checklist for dopamine supersensitivity psychosis. The people that met the criteria were more likely than others to have worse symptoms when their psychosis returned (relapsed), have residual psychotic symptoms, had overall worse health outcomes at 6 month follow-up, and were more likely to live in residential care.[14]

Further readingEdit

  • Chouinard G, Jones BD (1980). "Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics". Am J Psychiatry. 137 (1): 16–21. doi:10.1176/ajp.137.1.16. PMID 6101522.
  • Steiner W, Laporta M, Chouinard G (1990). "Neuroleptic-induced supersensitivity psychosis in patients with bipolar affective disorder". Acta Psychiatr Scand. 81 (5): 437–40. doi:10.1111/j.1600-0447.1990.tb05477.x. PMID 1972608. S2CID 36082613.CS1 maint: multiple names: authors list (link)
  • Moncrieff J (2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatr Scand. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. S2CID 6267180.
  • Miller R, Chouinard G (1993). "Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia". Biol Psychiatry. 34 (10): 713–38. doi:10.1016/0006-3223(93)90044-e. PMID 7904833. S2CID 2405709.


  1. ^ Whitaker's book, a New York Times bestseller, discusses the work of Chouinard and Jones in the section "Supersensitivity Psychosis". Whitaker comments that "In the late 1970s, two physicians at McGill University, Guy Chouinard and Barry Jones, stepped forward with a biological explanation for why the drugs made schizophrenia patients more biologically vulnerable to psychosis". Paraphrasing their work he says: "The severe relapse suffered by many patients withdrawn from antipsychotics was not necessarily the result of the "disease" returning, but rather was drug-related", and "In short, initial exposure to neuroleptics put patients onto a path where they would likely need the drugs for life."[10] This book was reviewed in Time,[11] Scientific American,[12] and the New York Review of Books.[13]


  1. ^ a b c d e Nakata, Y; Kanahara, N; Iyo, M (December 2017). "Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice". Journal of Psychopharmacology (Oxford, England). 31 (12): 1511–1518. doi:10.1177/0269881117728428. PMID 28925317. S2CID 1957881.
  2. ^ a b c Yin, John; Barr, Alasdair; Ramos-Miguel, Alfredo; Procyshyn, Ric (14 December 2016). "Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review". Current Neuropharmacology. 15 (1): 174–183. doi:10.2174/1570159X14666160606093602. PMC 5327459. PMID 27264948.
  3. ^ a b Seeman, Philip (April 2011). "All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2High Receptors". CNS Neuroscience & Therapeutics. 17 (2): 118–132. doi:10.1111/j.1755-5949.2010.00162.x. PMC 6493870. PMID 20560996.
  4. ^ a b Brisch, Ralf; Saniotis, Arthur; Wolf, Rainer; Bielau, Hendrik; Bernstein, Hans-Gert; Steiner, Johann; Bogerts, Bernhard; Braun, Anna Katharina; Jankowski, Zbigniew; Kumaritlake, Jaliya; Henneberg, Maciej; Gos, Tomasz (19 May 2014). "The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue". Frontiers in Psychiatry. 5: 47. doi:10.3389/fpsyt.2014.00047. PMC 4032934. PMID 24904434.
  5. ^ Katzung, BG; Kruidering-Hall, M; Trevor, AJ (eds.). "Chapter 29: Antipsychotic Agents & Lithium". Katzung & Trevor's Pharmacology: Examination & Board Review (12 ed.). McGraw-Hill.
  6. ^ Chouinard G, Jones BD, Annable L (1978). "Neuroleptic-induced supersensitivity psychosis". Am J Psychiatry. 135 (11): 1409–10. doi:10.1176/ajp.135.11.1409. PMID 30291.CS1 maint: multiple names: authors list (link)
  7. ^ a b c d Palmstierna, T; Wistedt, B (1988). "Tardive psychosis: Does it exist?". Psychopharmacology. 94 (1): 144–5. doi:10.1007/BF00735897. PMID 2894699. S2CID 29048614.
  8. ^ Kirkpatrick B, Alphs L, Buchanan RW (1992). "The concept of supersensitivity psychosis". J Nerv Ment Dis. 180 (4): 265–70. doi:10.1097/00005053-199204000-00009. PMID 1348269. S2CID 29597822.CS1 maint: multiple names: authors list (link)
  9. ^ Chouinard G (1991). "Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment". Schizophr Res. 5 (1): 21–33. doi:10.1016/0920-9964(91)90050-2. PMID 1677263. S2CID 38211914.
  10. ^ Whitaker, Robert (2015). Anatomy of an epidemic: magic bullets, psychiatric drugs, and the astonishing rise of mental illness in America (1st ed.). Crown Publishers. pp. 105–107. ISBN 9780307452429.
  11. ^ Time Magazine. "Book review: Anatomy of an Epidemic by Robert Whitaker".
  12. ^ "Are Psychiatric Medications Making Us Sicker?".
  13. ^ "The Epidemic of Mental Illness: Why?".
  14. ^ Fallon, P; Dursun, S; Deakin, B (February 2012). "Drug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients". Therapeutic Advances in Psychopharmacology. 2 (1): 13–22. doi:10.1177/2045125311431105. PMC 3736929. PMID 23983951.