How antipsychotics work - From receptors to reality

Shitij Kapur, Ofer Agid, Romina Mizrahi, Ming Li

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

How does a small molecule blocking a few receptors change a patients' passionately held paranoid belief that the FBI is out to get him? To address this central puzzle of antipsychotic action, we review a framework linking dopamine neurochemistry to psychosis, and then link this framework to the mechanism of action of antipsychotics. Normal dopamine transmission has a role in predicting novel rewards and in marking and responding to motivationally salient stimuli. Abnormal dopamine transmission alters these processes and results in an aberrant sense of novelty and inappropriate assignment of salience leading to the experience of psychosis. Antipsychotics improve psychosis by diminishing this abnormal transmission by blocking the dopamine D2/3 receptor (not D1 or D4), and although several brain regions may be involved, it is suggested that the ventral striatal regions (analog of the nucleus accumbens in animals) may have a particularly critical role. Contrary to popular belief, the antipsychotic effect is not delayed in its onset, but starts within the first few days. There is more improvement in the first 2 weeks, than in any subsequent 2-week period thereafter. However, a simple organic molecule cannot target the complex phenomenology of the individual psychotic experience. Antipsychotics diminish dopamine transmission and thereby dampen the salience of the preoccupying symptoms. Therefore, in the initial stage of an antipsychotic response, the patients experience a detachment from symptoms, a relegation of the delusions and hallucinations to the back of their minds, rather than a complete erasure of the symptoms. Only with time, and only in some, via the mediation of new learning and plasticity, is there a complete resolution of symptoms. The implications of these findings for clinical care, animal models, future target discovery and drug development are discussed.

Original languageEnglish (US)
Pages (from-to)10-21
Number of pages12
JournalNeuroRx
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2006

Fingerprint

Antipsychotic Agents
Dopamine
Psychotic Disorders
Neurochemistry
Corpus Striatum
Delusions
Dopamine D2 Receptors
Hallucinations
Nucleus Accumbens
Drug Discovery
Reward
Animal Models
Learning
Brain

Keywords

  • Antipsychotics
  • D2/3 receptors
  • Dopamine
  • Salience
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

How antipsychotics work - From receptors to reality. / Kapur, Shitij; Agid, Ofer; Mizrahi, Romina; Li, Ming.

In: NeuroRx, Vol. 3, No. 1, 01.01.2006, p. 10-21.

Research output: Contribution to journalArticle

Kapur, Shitij ; Agid, Ofer ; Mizrahi, Romina ; Li, Ming. / How antipsychotics work - From receptors to reality. In: NeuroRx. 2006 ; Vol. 3, No. 1. pp. 10-21.
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