Genetic Risk Factors for the Lack of Response to Clinical Treatment in Mental Disorders: an Approach from Pharmacogenetics

Abstract

Severe mental disorders, such as Major Depressive Disorder (MDD), Bipolar Disorder (BD) and Schizophrenia (SCZ), represent a huge burden to society, reflecting the limited efficacy of current drug treatments. Although the progress in development of pharmacological treatments is one of the great successes of modern psychiatry, it should not be forgotten that a very high percentage of patients do not receive and/or seek the proper treatment for their disease. Individual differences in clinical response to psychotropic drugs have long been recognized as a fundamental problem in the treatment of the seriously mentally ill patient. This variability in individual response ranges from patients who experience complete symptom remission to a subset of patients often describes as “treatment refractory”, as well as a marked variability in susceptibility to adverse drug effects. In this sense, the overall objective of pharmacogenetics is to determine the genetic basis of the variability in drug efficacy and safety, and to use this information to benefit the patient detecting a priori those patients that could not respond to a drug and/or present drug side effects. The present dissertation hypothesizes that lack of response to psychotropic drugs will be associated to genetic variability at genes coding for proteins involved directly or indirectly in the mechanism of action of these drugs. In this sense three different studies have been carried out. The first study analyses genetic variability at genes of the endocannabinoid system in clinical response and/or remission to citalopram treatment in MDD patients. The second study analyses genetic variability at genes related to phosphoinositide (PI), glycogen synthetase kinase-3 (GSK3), hypothalamic-pituitary-adrenal (HPA) and glutamatergic pathways in clinical response to lithium in BD patients. The third study analyses genetic variability at genes related to neurotrophic factors and HPA in clinical response to clozapine in patients with SCZ. Our results focused in the analyses of genetic variability at genes coding for proteins involved in the mechanism of action of psychotropic drugs let us to detect some minor and moderate effects of genetic variants that could explain, at least, part of the lack of response to these drugs. The results of our study in relation to citalopram response in MDD showed that genetic variability at genes related to the endocannabinoid system could play a role in the understanding of clinical response to this drug treatment. Specifically, we found an association between CNR1 gene and clinical remission at 12th week and an effect of CNR1 gene on longitudinal response (along the 12th week follow-up). The results of our study in relation to lithium response in BD showed that genetic variability at INPP1, IMPA2, GSK3B and GRIK2 genes could play a role in the understanding of lithium response. Finally, the results in relation to clozapine response in SCZ showed that genetic variants at FKBP5 and NTRK2 genes may play a role in clozapine response. The detection of individual genetic differences in the response to psychotropic drugs may provide new strategies for the treatment of mental disorders, as well as, new knowledge about the aetiology of these disorders.

Los trastornos mentales graves, como son la depresión mayor (DM), el trastorno bipolar (TB) y la esquizofrenia (SCZ), se han convertido en los últimos años en un importante problema de salud en los países desarrollados. Aunque el avance alcanzado en el desarrollo de tratamientos farmacológicos ha constituido uno de los grandes logros de la psiquiatría moderna, no debemos olvidar que hay un porcentaje muy alto de pacientes que no reciben el tratamiento adecuado para su enfermedad. En este sentido, la farmacogenética tiene como objetivo identificar y caracterizar los factores genéticos que se encuentran en la base de las diferencias existentes entre individuos en la respuesta clínica al tratamiento farmacológico. La presente tesis pretende estudiar variación genética basada en genes que codifican para moléculas implicadas directamente o indirectamente en los mecanismos de acción del tratamiento con citalopram (DM), carbonato de litio (TB) y clozapina (SCZ) que nos explicará parte del riesgo para la no respuesta clínica y la no remisión del episodio tratado farmacológicamente. Los resultados nos permitieron identificar variación genética asociada a la respuesta al tratamiento. Concretamente, nuestros resultados indicaron que variabilidad genética relacionada con el sistema endocannabinoide se asociaba con la respuesta a citalopram en DM. Por otro lado, genes involucrados con el sistema de fosfoinositoles podrían explican parte de la variación en la respuesta al litio en el TB. En referencia al estudio de la respuesta a clozapina en pacientes con SCZ, los resultados sugieren que variantes genéticas en los genes FKBP5 y NTRK2 pueden jugar un papel en la respuesta. En este sentido, nuestro estudio proporciona evidencia de la implicación del eje hipotálamo-pituitario-adrenal (HPA) y de factores neurotróficos en la modulación de la respuesta a clozapina. La detección de diferencias genéticas individuales en la respuesta a los fármacos psicotrópicos puede proporcionar nuevas estrategias para el tratamiento de trastornos mentales, así como, nuevos conocimientos sobre la etiología de estos trastornos.