Esketamine and Rapastinel, but not Imipramine, have antidepressant-like effect in a treatment-resistant animal model of depression

TY - JOUR

T1 - Esketamine and Rapastinel, but not Imipramine, have antidepressant-like effect in a treatment-resistant animal model of depression

AU - Pereira, Vitor Silva

AU - Joca, Sâmia R L

AU - Harvey, Brian H

AU - Elfving, Betina

AU - Wegener, Gregers

PY - 2019/10

Y1 - 2019/10

N2 - Objectives: Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals.Methods: Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 g/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out.Results: We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment.Conclusion: The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.

AB - Objectives: Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals.Methods: Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 g/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out.Results: We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment.Conclusion: The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.

KW - Adrenocorticotropic Hormone

KW - Depression

KW - GLYX-13 peptide

KW - esketamine

KW - rat

U2 - 10.1017/neu.2019.25

DO - 10.1017/neu.2019.25

M3 - Journal article

C2 - 31230597

SN - 0924-2708

VL - 31

SP - 258

EP - 265

JO - Acta Neuropsychiatrica

JF - Acta Neuropsychiatrica

IS - 5

ER -