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 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.
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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1017/neu.2019.25 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis.
Mol Psychiatry
November 2024
Molecular Psychiatry Lab, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Article Synopsis
- A meta-analysis was conducted to evaluate whether psychoplastogens like ketamine and psychedelics increase peripheral BDNF levels in humans, which have been suggested as biomarkers for neuroplasticity.
- The analysis included data from 29 studies and found no significant evidence that these substances elevate peripheral BDNF levels, regardless of various factors such as drug type, dosage, or participant characteristics.
- The findings imply that peripheral BDNF may not be a reliable marker for assessing neuroplasticity changes in humans after psychoplastogen administration, highlighting potential discrepancies between preclinical and human studies.
Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder.
Cochrane Database Syst Rev
September 2021
Oxford Health NHS Foundation Trust, Oxford, UK.
Background: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.
Objectives: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.
Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders.
Chronic Stress (Thousand Oaks)
June 2021
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
Article Synopsis
- * Recent research highlights the importance of amino acid neurotransmitters as potential targets for new mood disorder treatments, moving beyond the monoamine hypothesis.
- * The article reviews several drugs aimed at glutamate and GABA systems, discussing their progress in phase II and III clinical trials, emphasizing their potential as innovative therapies.
Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status.
CNS Drugs
May 2021
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg 10 CRC, Unit 7 Southeast, Room 7-5342, Bethesda, MD, 20892, USA.
The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders.
View Article and Find Full Text PDFRapid acting antidepressants in the mTOR pathway: Current evidence.
Brain Res Bull
October 2020
Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, India. Electronic address:
Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!