CYP2D6 and CYP2C19 ultrarapid metabolisms are associated with suicide attempts in schizophrenia
Bibliographic record
Abstract
• Suicides are a major cause of reduced life expectancy in schizophrenia. • UM CYP2D6 metabolization increases the risk of suicide attempt in schizophrenia. • UM CYP2C19 metabolization increases the risk of suicide attempt in schizophrenia. Genetic polymorphisms in genes encoding enzymes metabolizing psychotropics drugs result in various isoenzymes with different catalytic efficacies. Of particular interest, some of these isoenzymes are highly catalytic leading to an ultrarapid metabolism (UM) of their substrate medication, which in turn results in lower medication concentrations and possibly poor clinical outcomes, including a higher risk for suicidal behavior. In this study, we investigate the role of CYP2D6 (metabolizing most antidepressant medications) and CYP2C19 (important in metabolizing antipsychotics) UM isoenzymes on suicidal behavior among a cohort of patients with schizophrenia. One hundred and seventy-eight patients diagnosed with schizophrenia were recruited from the day hospital of a regional psychiatric academic hospital. Lifetime suicide attempts were compared between groups of patients stratified according to their enzymatic profile. Several socio-demographics and clinical covariates were controlled for. Among the 178 patients, 16 and 44 were UM as determined by their CYP2D6 and CYP2C19 genotype respectively. Univariate analysis showed a significant association between suicidal attempts and CYP2D6 and CYP2C19 UM status ( P = 0.041 and P = 0.029 respectively). These associations remained significant in multivariate analyses (adjusted for age, sex, dose exposure and antidepressant use…) for both CYP2D6 ( P = 0.020, OR = 4.096, 95% CI [1.25–13.48]) and CYP2C19 ( P = 0.016, OR = 2.680, 95% CI [1.21–5.95]). This study suggests that the UM phenotypes for both CYP2D6 and CYP2C19 are associated with an increased risk for suicide attempts in patients with schizophrenia. Les polymorphismes génétiques dans les gènes codant pour les enzymes métabolisant les médicaments psychotropes donnent naissance à diverses isoenzymes dont l’efficacité catalytique varie. Il est particulièrement intéressant de noter que certaines de ces isoenzymes ont une efficacité catalytique élevée, ce qui entraîne un métabolisme ultrarapide (UM) de leur substrat médicamenteux, qui se traduit à son tour par des concentrations médicamenteuses plus faibles et éventuellement par de mauvais résultats cliniques, y compris un risque plus élevé de comportement suicidaire. Dans cette étude, nous étudions le rôle des isoenzymes CYP2C19 (qui métabolisent la plupart des antidépresseurs) et CYP2D6 (important dans le métabolisme des antipsychotiques) sur le comportement suicidaire d’une cohorte de patients atteints de schizophrénie. Cent soixante-dix-huit patients diagnostiqués avec une schizophrénie ont été recrutés dans l’hôpital de jour d’un hôpital universitaire psychiatrique régional. Les tentatives de suicide au cours de la vie ont été comparées entre des groupes de patients stratifiés en fonction de leur profil enzymatique. Plusieurs facteurs sociodémographiques et covariants cliniques ont été pris en compte. Parmi les 178 patients, 16 et 44 étaient UM selon leur génotype CYP2D6 et CYP2C19 respectivement. L’analyse univariée a montré une association significative entre les tentatives de suicide et les statuts CYP2D6 et CYP2C19 UM ( p = 0,041 et p = 0,029 respectivement). Ces associations sont restées significatives dans les analyses multivariées (ajustées sur l’âge, le sexe, la dose d’exposition et l’utilisation d’antidépresseurs) à la fois pour le CYP2D6 ( p = 0,020, OR = 4,096, IC 95 % [1,25–13,48]) et le CYP2C19 ( p = 0,016, OR = 2,680, IC 95 % [1,21–5,95]). Cette étude suggère que les phénotypes UM pour CYP2D6 ou CYP2C19 sont associés à un risque accru de tentatives de suicide chez les patients atteints de schizophrénie.
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How this classification was reachedexpand
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 | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 teacher head, 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".