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Cited by 1,140Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorReceptor Mechanisms and Signaling

Does Fast Dissociation From the Dopamine D 2 Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis

Kapur, Shitij, Seeman, Philip·2001·American Journal of Psychiatry
DOI 10.1176/appi.ajp.158.3.360
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Abstract

OBJECTIVE: Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics. METHOD: Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT(2) and dopamine D(4) receptors in atypicality. RESULTS: Neuroimaging data show that optimal dopamine D(2) occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D(2) occupancy, not from high 5-HT(2) occupancy. If D(2) occupancy is excessive, atypicality is lost even in the presence of high 5-HT(2) occupancy. Animal data show that a rapid dissociation from the D(2) receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D(2) receptor, not its high affinity at 5-HT(2), D(4), or another receptor. CONCLUSIONS: The authors propose that fast dissociation from the D(2) receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.

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Crossref · 10.1176/appi.ajp.158.3.360

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  • For drugs with short half-lives or "fast off" characteristics, like clozapine or quetiapine, more caution may be required and it may be necessary to reduce doses by 2.5-5 percentage points of D2 (or cholinergic or histaminergic) occupancy every 6-12 weeks, depending on individual responses.

    “For drugs with short half-lives or “fast off” characteristics, like clozapine or quetiapine (supplementary table S12),105 with reputations for quicker onset of psychosis following withdrawal, more caution may be required and it may be necessary to reduce doses by 2.5–5 percentage points of D2 (or cholinergic or histaminergic) occupancy every 6–12 weeks, depending on individual responses (see”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [105]

  • The FDA reported that safety concerns for esketamine are misuse, abuse, dissociation, and sedation, for which a Risk Evaluation and Mitigation Strategy was planned.

    “Additionally, the FDA reported that the safety concerns for esketamine are misuse, abuse, dissociation, and sedation, for which a Risk Evaluation and Mitigation Strategy was planned [143, 144].”

    From Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications (2020) · cites this paper as [143]

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Authors
Kapur, S., & Seeman, P.
Affiliations
Centre for Addiction and Mental Health (CA)
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2001-03-01
Volume
158
Issue
3
Pages
360-369
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.158.3.360
OpenAlex
W2099576957
Cited by
1,140
References
81
Citations by year
2026: 16 · 2025: 21 · 2024: 27 · 2023: 20 · 2022: 25 · 2021: 37 · 2020: 26 · 2019: 27 · 2018: 32 · 2017: 27 · 2016: 38 · 2015: 39 · 2014: 50 · 2013: 55 · 2012: 58
FWCI
14.16
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
atypical antipsychotics, dopamine D2 receptor, receptor dissociation kinetics, 5-HT2 receptor, dopamine D4 receptor, mechanism of action, schizophrenia, motor side effects, prolactin elevation, negative symptoms
MeSH terms
Olanzapine, Benzodiazepines, Brain, Clozapine, Haloperidol, Humans, Terminology as Topic, Pirenzepine, Psychotic Disorders, Receptors, Serotonin, Schizophrenia, Tomography, Emission-Computed, Antipsychotic Agents, Receptors, Dopamine D2, Risperidone, Receptors, Dopamine D4, Dopamine D2 Receptor Antagonists

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