Unveiling a Novel Molecular Biotype of Depression - Effects of Dysregulated microRNA Biogenesis in Treatment Resistance Depression
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Document Type
Document Version
Author
Director
Martínez Sirés, Anna
Dierssen, Mara
Perera Bel, Júlia
Dierssen, Mara
Perera Bel, Júlia
Tutor
Dierssen, Mara
Other authors
Publication Date
Pages
207 p.
Embargo date
Citation
Lorenzon, N. Unveiling a Novel Molecular Biotype of Depression - Effects of Dysregulated microRNA Biogenesis in Treatment Resistance Depression. Universitat Pompeu Fabra; 2025. handle: http://hdl.handle.net/10803/695334
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Citation
Doctoral program
Universitat Pompeu Fabra. Doctorat en Biomedicina
Abstract
El Trastorno Depresivo Mayor (TDM) es uno de los trastornos psiquiátricos más frecuentes e invalidantes, con más de 300 millones de personas afectadas en todo el mundo. Las estrategias de tratamiento actuales se basan en tratamientos de "ensayo y error", siguiendo directrices universales con diferentes grupos de medicamentos que actúan sobre los pocos mecanismos patogénicos conocidos. En consecuencia, más de dos tercios de los pacientes diagnosticados con TDM no responden a la primera línea de tratamiento, y más de un tercio pasará a ser considerado con un TDM "resistente al tratamiento". En este proyecto, investigamos la hipótesis de que existen mecanismos etiopatogénicos de este trastorno aún inexplorados, y que, sobre todo, van más allá del clásico enfoque en neurotransmisión, estrés o inflamación, dictados por la visión reduccionista actual. Además, creemos que lo que comúnmente llamamos "depresión resistente al tratamiento" (DRT) se trate de un distinto biotipo molecular de depresión, que comparte elementos de la sintomatología clínica, a pesar de tener otro origen etiopatológico. Para comprobar esta teoría, comparamos pacientes con DRT y no-DRT a través de un método multiómico, con el objetivo de investigar a un nivel de regulación molecular inexplorado en psiquiatría: los microRNAs (miRNAs). De hecho, se sabe que los miRNAs juegan un papel crucial en la regulación del sistema nervioso central, y se han observado cambios en sus concentraciones en diferentes trastornos psiquiátricos, especialmente según la respuesta al tratamiento. Nuestros resultados demuestran que la DRT se asocia a marcas de miRNA específicas y a una desregulación de la maquinaria de biogénesis de los miRNAs. Creemos que este fenómeno desencadene alteraciones funcionales en varios procesos biológicos, ayudando al desarrollo de fenotipo depresivo, o incluso de DRT. Además, validamos un subgrupo de candidatos de miRNAs en un modelo murino a través de una inyección intraventricular de antagomires, obteniendo fenotipos compatibles con depresión. Nuestros descubrimientos abren la puerta al uso de los miRNAs como biomarcadores predictivos para una identificación precoz de DRT y para el desarrollo de nuevas estrategias terapéuticas enfocadas en restablecer la maquinaria de los miRNAs.
Major Depressive Disorder (MDD) is one of the most prevalent and invalidating psychiatric disorders, affecting more than 300 million people worldwide. Current therapeutic strategies rely on a trial-and-error approach, based on one-size-fits-all guidelines describing an ordered list of drugs targeting the recognized pathogenic pathways of MDD. However, more than two-thirds of MDD patients do not respond to first-line treatments, while over one-third are eventually deemed as “treatment-resistant”. In this project, we investigated our hypothesis that these oversimplistic views of depression, which focus on neurotransmission, stress and inflammation, disregard pivotal unexplored molecular etiologies of the disorder. Moreover, we believe that what we commonly refer to as "treatment resistant depression” (TRD) is a different molecular biotype of depression, with shared clinical symptomatology but an alternative etiopathogenic origin. To test this hypothesis, we compared TRD and non-TRD patients using a multi-omics approach to investigate an unexplored molecular regulatory layer in psychiatry, microRNAs (miRNAs). In fact, miRNAs are known to play a pivotal role in the central nervous system and changes in their levels have been observed in several psychiatric disorders, especially in response to treatment. Our results showed that TRD is associated with specific miRNA signatures and the dysregulation of the miRNA biogenesis machinery. We believe that this alteration might lead to changes in several biological processes, and in turn, to the depressive/TRD phenotype. We validated in mice a subset of those miRNAs by intracerebroventricular injection of antagomirs and recapitulated depressive-like phenotypes. Our findings pave the way for the use of miRNAs as predictive biomarkers for the early identification of TRD and for the development of novel therapeutic strategies targeting the miRNA machinery.
Major Depressive Disorder (MDD) is one of the most prevalent and invalidating psychiatric disorders, affecting more than 300 million people worldwide. Current therapeutic strategies rely on a trial-and-error approach, based on one-size-fits-all guidelines describing an ordered list of drugs targeting the recognized pathogenic pathways of MDD. However, more than two-thirds of MDD patients do not respond to first-line treatments, while over one-third are eventually deemed as “treatment-resistant”. In this project, we investigated our hypothesis that these oversimplistic views of depression, which focus on neurotransmission, stress and inflammation, disregard pivotal unexplored molecular etiologies of the disorder. Moreover, we believe that what we commonly refer to as "treatment resistant depression” (TRD) is a different molecular biotype of depression, with shared clinical symptomatology but an alternative etiopathogenic origin. To test this hypothesis, we compared TRD and non-TRD patients using a multi-omics approach to investigate an unexplored molecular regulatory layer in psychiatry, microRNAs (miRNAs). In fact, miRNAs are known to play a pivotal role in the central nervous system and changes in their levels have been observed in several psychiatric disorders, especially in response to treatment. Our results showed that TRD is associated with specific miRNA signatures and the dysregulation of the miRNA biogenesis machinery. We believe that this alteration might lead to changes in several biological processes, and in turn, to the depressive/TRD phenotype. We validated in mice a subset of those miRNAs by intracerebroventricular injection of antagomirs and recapitulated depressive-like phenotypes. Our findings pave the way for the use of miRNAs as predictive biomarkers for the early identification of TRD and for the development of novel therapeutic strategies targeting the miRNA machinery.
Keywords
Treatment resistant depression, MiRNAs, MicroARNs, Depression, Depresión, Multiomics, Multiómicas, Precision psychiatry, Psiquiatría de precisión
Subjects
616.89 - Psychiatry. Psychopathology
Publisher
Universitat Pompeu Fabra
