Modèle in vivo de risque suicidaire dans un contexte de schizophrénie

Les mécanismes impliqués dans le phénomène du risque suicidaire chez les patients schizophrènes ne semblent pas impliquer la neurotransmission sérotonergique et demeurent incompris jusqu’à maintenant. Nous avons ainsi développé un modèle in vivo à double atteinte impliquant l’activation immunitaire prénatale, avec le polyIC, suivie d’un isolement social dès le sevrage. Le lithium, un régulateur de l’humeur connu pour ses effets de « prévention de suicide » dans la population générale, a un effet principalement chez les souris soumises seulement à l’isolement social, alors que la clozapine, un ADG ayant l’effet de « prévention de suicide » le plus efficace, a des effets principalement chez les souris exposées au polyIC en période prénatale et à l’isolement social. Ces résultats permettent de suggérer que l’isolement social seul, dont l’IPP et les anomalies des comportements reliés au risque suicidaire sont prévenus que par le lithium, implique des mécanismes potentiellement associés à un phénotype de « population générale », alors que le modèle à double atteinte, dans lequel le déficit d’IPP et les comportements associés au risque suicidaire sont améliorés par la clozapine, implique des mécanismes spécifiques à un contexte de type schizophrénique.

Diagnostiquer le risque suicidaire chez les patients schizophrènes demeure un véritable défi pour les psychiatres. Dans le modèle in vivo à double atteinte, nous

démontrons des effets potentiateurs de l’activation immunitaire gestationnelle et de l’isolement social après le sevrage. De plus, le chlorure de lithium et la clozapine ont des effets distincts sur les comportements de type schizophrénique et associés au risque suicidaire, suggérant ainsi que le modèle à double atteinte implique un mécanisme distinct qui se différencie du phénotype dans le modèle d’isolement social. Le modèle in vivo à double atteinte pourra aider à mieux comprendre les mécanismes impliqués dans le risque suicidaire dans un contexte de schizophrénie et, à long-terme, une meilleure compréhension de la pathophysiologie du risque suicidaire chez les patients schizophrènes pourra favoriser le développement de nouvelles alternatives thérapeutiques visant les patients schizophrènes vulnérables.

9.2.2. Perspectives

Plus de travail sera nécessaire pour évaluer les paramètres sérotonergiques (principalement les concentrations de 5-HT et son métabolite, le 5-HIAA) afin de confirmer une absence d’implication de la neurotransmission sérotonergique dans le modèle à double atteinte, s’apparentant ainsi à l’absence de variation de 5-HIAA dans le liquide céphalo- rachidien des patients schizophrènes ayant effectué une tentative de suicide (Carlborg et al., 2009). De plus, l’effet du polyIC, en période prénatale, sur les neurones sérotonergiques, qui pourrait expliquer l’absence d’effet du lithium dans le modèle à double atteinte, devra être étudié. Enfin, l’implication de la synthèse des neurostéroïdes dans le modèle à double atteinte et dans l’action thérapeutique de la clozapine dans le même modèle devra être vérifié.

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