Does Fast Dissociation From the Dopamine D<sub>2</sub>Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis
Bibliographic record
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.004 |
| Scholarly communication | 0.002 | 0.006 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.004 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".