An Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine

2020 ◽  
Vol 20 (7) ◽  
pp. 554-584 ◽  
Author(s):  
Domenico De Berardis ◽  
Carmine Tomasetti ◽  
Maurizio Pompili ◽  
Gianluca Serafini ◽  
Federica Vellante ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Depressive Symptomatology ◽  
Phase Iii ◽  
Glutamatergic Neurotransmission ◽  
Treatment Resistant Depression ◽  
Glutamatergic System ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Imminent Risk

Background: A research on mood disorder pathophysiology has hypothesized abnormalities in glutamatergic neurotransmission, by suggesting further investigation on glutamatergic N-methyl-Daspartate (NMDA) receptor modulators in treating Major Depressive Disorder (MDD). Esketamine (ESK), an NMDA receptor antagonist able to modulate glutamatergic neurotransmission has been recently developed as an intranasal formulation for treatment-resistant depression (TRD) and for rapid reduction of depressive symptomatology, including suicidal ideation in MDD patients at imminent risk for suicide. Objective: The present study aims at investigating recent clinical findings on research on the role of the glutamatergic system and ESK in treating suicidal depression in MDD and TRD. Methods: A systematic review was here carried out on PubMed/Medline, Scopus and the database on U.S. N.I.H. Clinical Trials (https://clinicaltrials.gov) and the European Medical Agency (EMA) (https://clinicaltrialsregister.eu) from inception until October 2019. Results: Intravenous infusion of ESK is reported to elicit rapid-acting and sustained antidepressant activity in refractory patients with MDD and TRD. In phase II studies, intranasal ESK demonstrated a rapid onset and a persistent efficacy in patients with TRD as well as in MDD patients at imminent risk for suicide. However, some data discrepancies have emerged in phase III studies. Conclusion: The U.S. Food and Drug Administration (FDA) granted fast track and Breakthrough Therapy Designation to Janssen Pharmaceuticals®, Inc. for intranasal ESK in 2013 for treatment-resistant depression (TRD) and in 2016 for the treatment of MDD with an imminent risk of suicide. However, further studies should be implemented to investigate the long-term efficacy and safety of intranasal ESK.

scholarly journals Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

2020 ◽  
Vol 11 ◽  
pp. 204209862093789 ◽  
Author(s):  
Mohammed S Salahudeen ◽  
Cameron M Wright ◽  
Gregory M Peterson
Keyword(s):  
Literature Search ◽  
Product Information ◽  
The United States ◽  
Narrative Review ◽  
Phase Iii ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Frequency Of Use ◽  
Phase Iii Trials ◽  
Resistant Depression

This narrative review aims to provide an overview of the current literature on the pharmacology, safety, efficacy and tolerability of intranasal esketamine, the S-enantiomer of ketamine, for the treatment of treatment-resistant depression (TRD). A literature search using Medline, Embase, PsycINFO and Cochrane Central was conducted (January 2000 to July 2019). Product information and www.clinicaltrials.gov were also reviewed. The literature search was limited to human studies published in English. Phase I, II, and III studies of intranasal esketamine for TRD were reviewed. About a third of patients with major depressive disorder fail to achieve remission despite treatment with multiple antidepressants. This article examines the trials that led to the approval of esketamine in the United States, as well as other recent studies of esketamine for TRD. The findings from limited phase III trials illustrate that intranasal esketamine is effective and safe in reducing depressive symptoms and achieving clinical response in patients with TRD. The optimum duration and frequency of use are not fully understood. Although the nasal spray is a convenient dosage form, its use in practice may be limited by cost and administrative regulation. While it may prove beneficial to many patients who suffer from TRD, further long-term data are required, along with comparative trials with the R-isomer (arketamine). In the interim, care and monitoring should be exercised in its use in clinical practice.

The Role of Transcranial Magnetic Stimulation in Treatment-Resistant Depression: A Review

2012 ◽  
Vol 18 (36) ◽  
pp. 5846-5852 ◽  
Author(s):  
Jonathan C. Lee ◽  
Daniel M. Blumberger ◽  
Paul B. Fitzgerald ◽  
Zafiris J. Daskalakis ◽  
Andrea J. Levinson
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

scholarly journals PAX-D: study protocol for a randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression

2021 ◽  
pp. ebmental-2021-300282
Author(s):  
Sheena Kristine Au-Yeung ◽  
James Griffiths ◽  
Sophie Roberts ◽  
Chloe Edwards ◽  
Ly-Mee Yu ◽  
...  
Keyword(s):  
Decision Making ◽  
Depressive Symptomatology ◽  
Bipolar Depression ◽  
Antidepressant Medication ◽  
Well Being ◽  
Reward Processing ◽  
Self Report ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

IntroductionClinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task.Methods and analysisPAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties.DiscussionPramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD.Trial registration numberISRCTN84666271

scholarly journals Role of the serotonergic system in subcallosal DBS for treatment-resistant depression

2021 ◽  
Author(s):  
A. Ghaderi ◽  
E.C. Brown ◽  
D.L. Clark ◽  
R. Ramasubbu ◽  
Z.H.T. Kiss ◽  
...  
Keyword(s):  
Serotonergic System ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

Deep Brain Stimulation for Treatment Resistant Depression: The Role of the Ventral Capsule/Ventral Striatum

2010 ◽  
Vol 40 (10) ◽  
pp. 477-484 ◽  
Author(s):  
Cristina Cusin ◽  
Karleyton C. Evans ◽  
Linda L. Carpenter ◽  
Benjamin D. Greenberg ◽  
Donald A. Malone ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Ventral Striatum ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Deep Brain

scholarly journals Treatment-Resistant Depression Revisited: A Glimmer of Hope

2021 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Angelos Halaris ◽  
Emilie Sohl ◽  
Elizabeth A. Whitham
Keyword(s):  
Significant Risk ◽  
Treatment Resistance ◽  
Contributory Factor ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Test Procedures ◽  
Gonadal Dysfunction ◽  
Immune Biomarkers ◽  
Resistant Depression

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.

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