Why this work is in the frame
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Bibliographic record
Abstract
Back to table of contents Previous article Next article Clinical & Research NewsFull AccessClozapine Study Zeroes In On Dopamine ReceptorsJim RosackJim RosackPublished Online:17 Sep 2004https://doi.org/10.1176/pn.39.18.0390024Clozapine (Clozaril) stands alone in its effectiveness in the treatment of patients with refractory schizophrenia. As new antipsychotic medications have come (and some gone), researchers have continued their attempts to discover the molecular secrets of the drug, hoping to tease out and exploit those properties that contribute to its effectiveness, while discarding those properties responsible for significant adverse effects.In a new study using positron emission tomography (PET), researchers have determined that clozapine alone among the newer generation antipsychotics has a relatively balanced affinity for dopamine type 1 (D1) receptors and dopamine type 2 (D2) receptors. This balanced D1/D2 ratio, they noted, may be the answer to the question. The research, led by Johannes Tauscher, M.D., a professor of psychiatry at the Medical University of Vienna, Austria, along with a group of researchers at the University of Toronto, appears in the September issue of the American Journal of Psychiatry. The work was funded by Eli Lilly Canada.Many have put forth theories for clozapine's relative superiority in treating schizophrenia patients who have not responded to other medications. It has been noted, for example, that the medication's low propensity to induce extrapyramidal symptoms (EPS) is explained by its combined antagonism of both 5HT-2A and D2 receptors, and possibly also its relatively quick dissociation from the D2 receptor after binding. But while these pharmacologic factors could explain its low EPS profile, researchers believe they do not contribute to an explanation of the drug's greater efficacy in certain patient populations.Other theories have been put forward, including clozapine's affinity to bind to the D4 receptor; however, to date, Tauscher and his colleagues stressed, "none of these theories has held so far." The team set out to determine whether the medication's affinity for the D1 receptor—previously documented in animal studies—could play a role.Tauscher's team studied 25 patients with schizophrenia or schizoaffective disorder who were receiving ongoing antipsychotic therapy either as inpatients or outpatients. Patients had been on stable doses of second-generation antipsychotics for at least 14 days prior to PET scanning. Seven patients were on clozapine, six on olanzapine (Zyprexa), five on quetiapine (Seroquel), and seven on risperidone (Risperdal). Using two radioligands—specific for either D1 receptors or D2 receptors—each patient was scanned using standard PET protocols to determine receptor binding, specifically to dopamine receptors in the striatum.The affinities for the four antipsychotic medications varied greatly. Clozapine was found to bind the strongest to D1 receptors (55 percent of D1 receptors bound), followed in decreasing order by olanzapine (43 percent), risperidone (25 percent), and quetiapine (12 percent). In contrast, risperidone bound most tightly to D2 (81 percent of receptors bound), followed by olanzapine (79 percent), clozapine (61 percent), and quetiapine (30 percent).Significantly, Tauscher and his colleagues noted, clozapine is the only one of the four medications to even come close to a ratio of 1. Clozapine's D1/D2 binding ratio specifically was 0.88, while olanzapine exhibited a binding ratio of 0.54, quetiapine a ratio of 0.41, and risperidone a ratio of 0.31.Tausher and his colleagues suggested that their pilot study provides" a strong impetus for prospective clinical studies focusing on the role of dopamine D1 receptors," while they cautioned that" it is still unclear whether agonistic or antagonistic properties are desirable."Determining the second half of the equation, they said, could lead to advances in efforts to develop new antipsychotic medications with enhanced therapeutic efficacy.The study, "Equivalent Occupancy of Dopamine D1and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics," is posted online at<http://ajp.psychiatryonline.org/cgi/content/full/161/9/1620>.▪ Am J Psychiatry 2004 161 1620 ISSUES NewArchived
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.001 |
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 it