Study On Duloxetine Combined With TAAR1/5-HT_1A Dual Agonist SEP-363856 In The Treatment Of Depression

Backgrounds: Patients with major depressive disorder(MDD)tend to have a severe course and are at higher risk for suicide.However,more than one-third of MDD patients do not respond adequately to first-line antidepressant therapy,i.e.,they suffer from treatment-resistant depression(TRD).In addition,existing antidepressant drugs also produce more adverse reactions.Existing solutions include using a new antidepressant,combining multiple antidepressants,or combining one antidepressant with another(non-antidepressant).Objective: In this study,the first-line antidepressant duloxetine combined with the anti-schizophrenia drug trace amine-related receptor 1(TAAR1)/serotonin 1A receptor(5-HT1A)dual agonist SEP-363856(SEP-856)was investigated in the treatment of Antidepressant-like effects in obsessive-compulsive stress and chronic unpredictable mild stress(CUMS)mouse model of depression,to observe whether the multi-target therapeutic composition could produce better effects than duloxetine,in order to provide a new solution for the treatment of MDD Program.Methods:(1)Mouse forced stress model: including forced swimming test(FST)and tail suspension test(TST),and the open field test(OFT)to investigate the effect of combined medication on motor activity;(2)Mouse chronic stress model: The CUMS model was first established,and then the sugar water preference test(SPT),OFT and Morris water maze(MWM)experiments were performed;(3)Mice fatigue rotarod test: The effect of duloxetine combined with SEP-856 on motor coordination in mice was evaluated by the fall latency of mice in the fatigue rotarod test.Results:(1)In the obsessive stress model,duloxetine and SEP-856 could significantly shorten the immobility time of mice in FST and TST,and played an antidepressant effect,and the effect of combined medication was more significant and does not affect motor activity of mice in OFT;(2)In the chronic stress model,duloxetine and SEP-856 could significantly increase the sugar water preference rate in SPT mice,and played an antidepressant effect to improve anhedonia-like state,and the combined effect was more significant;Duloxetine and SEP-856 could improve the activity time,frequency and distance in the central area of mice in OFT,and played an antidepressant effect that improves anxiety-like state,and the combined effect was better;Duloxetine and SEP-856 had no effect on the swimming time and distance of mice in the escape target quadrant in MWM,and did not show the effect of improving memory and cognitive function;the combination of duloxetine and SEP-856 was effective in fatigue The rotarod experiment did not affect the motor coordination of mice;(3)The combination of duloxetine and SEP-856 did not affect the motor coordination of mice in the fatigue rotarod test.Conclusion: Duloxetine combined with the dual TAAR1/5-HT1 A agonist SEP-856 significantly improved depression-like behavior in mice,and compared with duloxetine alone,the effect was better,and it might be a better treatment for MDD.There are 6 pictures,5 tables and 133 references in this thesis.