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

doi:10.1017/neu.2019.25

Abstract

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. Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/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. 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. 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.

Highlights

Depression is a severe and debilitating disease that affects millions of people around the world and it is considered the leading cause of disability worldwide (WHO, 2018)
Experiment 1: Effects of s-ketamine and imipramine in animals exposed to chronic Adrenocorticotropic hormone (ACTH) and tested on the open field and forced swim: A two-way ANOVA analysis of the forced swim test (FST) data revealed no significant interaction between ACTH/no-ACTH and treatment [F (2,71) = 2.702, p = 0.0739], but a significant effect of ACTH/ no-ACTH [F (1,71) = 16.93, p < 0.0001] or treatment [F (2,71) = 12.22, p < 0.0001] alone (Fig. 1A)
Our results are in accordance with previous studies showing that repeated treatment with ACTH for 14 days induced a behavioural phenotype in the animals which is insensitive to treatment with conventional antidepressants and mood-stabilisers, such as desipramine, amitriptyline and lithium, when assessed in the FST or novelty suppressed feeding (Kitamura et al, 2002, 2008; Walker et al, 2013; Antunes et al, 2015)

Summary

Introduction

Depression is a severe and debilitating disease that affects millions of people around the world and it is considered the leading cause of disability worldwide (WHO, 2018). Animal models that help to identify drugs that can potentially overcome resistance to treatment and induce a rapid antidepressant response are of special importance

Objectives

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Results

Conclusion