CELECOXIB ADDED TO RISPERIDONE FOR DEPRESSIVE SYMPTOMS IN FIRST-EPISODE AND DRUG NAÏ VE SCHIZOPHRENIA: PHARMACOGENETIC IMPACT OF BDNF GENE POLYMORPHISMS

Abstract Background Although depressive symptoms are common in patients with schizophrenia (SCZ), depression is not successfully treated in most SCZ patients. SCZ patients with comorbid depression may have activated inflammatory responses, and celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can dampen inflammation and improve treatment of depression. Brain-derived neurotrophic factor (BDNF) may be associated with the treatment response to antidepressants and has an important role in inflammation associated with depression. Aims & Objectives Therefore, we intended to explore the efficacy of celecoxib augmentation for depressive symptoms in SCZ patients and its possible relationship with BDNF serum levels and two BDNF genotypes. Method In a case-control study, two BDNF polymorphisms (rs6265 and rs10835210) were genotyped in 308 first-episode and drug-naï ve (FEDN) SCZ patients and 422 healthy controls. Serum BDNF levels were measured in 239 patients and 259 healthy controls. Then 90 FEDN SCZ patients were entered a double- blind, randomized and placebo-control 12-week treatment with 400 mg per day of celecoxib. We assessed clinical efficacy with the Hamilton Depression Rating Scale (HAMD) and psychiatric symptoms with the Positive and Negative Syndrome Scale (PANSS). Results Our results showed that SCZ patients had lower BDNF levels than healthy controls. BDNF levels were associated with PANSS total score, positive symptoms, general psychopathology and HAMD total score. The BDNF gene rs10835210 was associated with SCZ susceptibility, positive symptoms and BDNF serum levels in SCZ patients. Celecoxib treatment significantly improved depressive symptoms compared to placebo treatment. Furthermore, patients in the BDNF rs10835210 CC group showed significantly more improvement in depressive symptoms than the A allele carrier group. Discussion & Conclusion Our findings suggest that COX2 inhibitors may be a promising therapeutic agent for the treatment of comorbid depressive symptoms in FEDN SCZ patients. The BDNF system may be involved in the pathogenesis of depressive symptoms in SCZ patients and forms the pharmacogenetic basis for improvement after treatment with COX2 inhibitor. References 1.Etchecopar-Etchart, D., Korchia, T., Loundou, A., Llorca, P.M., Auquier, P., Lanç on, C., Boyer, L. and Fond, G., 2021. Comorbid major depressive disorder in schizophrenia: a systematic review and meta-analysis. Schizophrenia Bulletin, 47, pp.298-308. 2.Mü ller, N., 2017. Immunological aspects of the treatment of depression and schizophrenia. Dialogues in clinical neuroscience, 19, pp.55-63. 3.Mü ller, N., Schwarz, M.J., Dehning, S., Douhe, A., Cerovecki, A., Goldstein-Mü ller, B., Spellmann, I., Hetzel, G., Maino, K., Kleindienst, N. and Mö ller, H.J., 2006. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add- on pilot study to reboxetine. Molecular psychiatry, 11, pp.680-684. 4.Mü ller, N., Riedel, M., Scheppach, C., Brandstä tter, B., Sokullu, S., Krampe, K., Ulmschneider, M., Engel, R.R., Mö ller, H.J. and Schwarz, M.J., 2002. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry, 159, pp.1029-1034. 5.Mü ller, N., Krause, D., Dehning, S., Musil, R., Schennach-Wolff, R., Obermeier, M., Mö ller, H.J., Klauss, V., Schwarz, M.J. and Riedel, M., 2010. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophrenia research, 121, pp.118-124. 6.Castré n, E. and Monteggia, L.M., 2021. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biological psychiatry, 90, pp.128-136. 7.Nieto, R.R., Carrasco, A., Corral, S., Castillo, R., Gaspar, P.A., Bustamante, M.L. and Silva, H., 2021. BDNF as a biomarker of cognition in schizophrenia/psychosis: an Updated review. Frontiers in Psychiatry, 12, p.662407.