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

Vitor Silva Pereira, Sâmia R L Joca, Brian H Harvey, Betina Elfving, Gregers Wegener

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Abstract

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.

Original languageEnglish
JournalActa Neuropsychiatrica
Volume31
Issue5
Pages (from-to)258-265
Number of pages8
ISSN0924-2708
DOIs
Publication statusPublished - Oct 2019

Keywords

  • Adrenocorticotropic Hormone
  • Depression
  • GLYX-13 peptide
  • esketamine
  • rat

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