Gene Association Studies of Clozapine Response: A Dopamine System Approach
Bibliographic record
Abstract
The antipsychotic clozapine (CLZ) is under-utilized due to its life-threatening side-effects despite superior efficacy for treatment-resistant schizophrenia (SCZ). Thus, predictors for response could help inform drug administration decisions. Given the genetic basis for response, we aimed to identify genetic predictors and build a preliminary genetic model for CLZ efficacy. Since CLZâ s targets the DA system, we investigated a DA D2 receptor (DRD2) gene variant implicated in SCZ risk in a recent genome-wide association study. We observed that the A-allele was associated with better CLZ response. We also examined the association between catechol-O-methyltransferase gene (COMT) polymorphism Val158Met and antipsychotic response, observing that Met/Met was associated with greater improvement. Lastly, we developed a genetic model for response, consisting of four polymorphisms from the DRD2, serotonin-6 receptor (5-HT6), brain-derived neurotrophic factor (BDNF), and neurexin-1 genes (NRXN1) (Adjusted R2=52%, sensitivity=70%, specificity=47%). While replication is required, our findings identify several potential genetic predictors of response.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".