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.

FDA Considers Classification of ECT

CNS Spectrums ◽  
2009 ◽  
Vol 14 (12) ◽  
pp. 668-670 ◽  
Author(s):  
S.H. Lisanby ◽  
Stefano Pallanti ◽  
Thomas E. Schlaepfer
Keyword(s):  
Brain Stimulation ◽  
The United States ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
United States Food ◽  
Recent Developments ◽  
States Food ◽  
Resistant Depression ◽  
Deep Brain

With the increasing number of new brain stimulation techniques now available and on the horizon, does electroconvulsive therapy (ECT) still have a role? As clinicians and researchers we say most definitely “yes”. ECT is the most effective and rapidly acting treatment for severe forms of depression and other disorders. Transcranial magnetic stimulation has shown promise but mainly for less severely ill and less treatment resistant patients. Deep brain stimulation (DBS) has shown promise for the more resistant cases but its invasiveness limits its use. Results from only ∼50 patients treated worldwide are available and at present it is not approved by the United States Food and Drug Administration for depression. Vagus nerve stimulation, less invasive than DBS but still a surgical procedure, is presently FDA approved for acute treatment resistant depression but published efficacy rates fall short of those seen with ECT. Therefore, there continues to be an important role for ECT in the treatment of severe psychiatric disorders. But will ECT always be there when our patients need it? Somewhat unexpected recent developments at the FDA may impact the future availability of ECT to severely depressed patients. Here we provide background on the classification of ECT devices, the FDA reclassification process, and the process for providing FDA input in these critical deliberations.

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 Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR)

BMJ ◽  
2018 ◽  
pp. k4218 ◽  
Author(s):  
David S Kessler ◽  
Stephanie J MacNeill ◽  
Deborah Tallon ◽  
Glyn Lewis ◽  
Tim J Peters ◽  
...  
Keyword(s):  
Primary Care ◽  
Adverse Effects ◽  
Confidence Interval ◽  
Beck Depression Inventory ◽  
Reuptake Inhibitor ◽  
Controlled Trial ◽  
Phase Iii ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

AbstractObjectiveTo investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.DesignTwo parallel group multicentre phase III randomised placebo controlled trial.Setting106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015.Participants480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up.Main outcome measuresDepressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks.ResultsBeck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.ConclusionThis study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited.Trial registrationCurrent Controlled TrialsISRCTN06653773.

scholarly journals Neuromodulation Intervention in Resistant Depression

2020 ◽  
Vol 8 (2) ◽  
pp. 39
Author(s):  
Era Catur Prasetya ◽  
Lestari Basoeki
Keyword(s):  
Functional Disability ◽  
Antidepressant Drugs ◽  
The United States ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Duration Of Treatment ◽  
Non Invasive ◽  
Disability Rate ◽  
Resistant Depression ◽  
Interventional Therapies

Treatment-resistant depression occurs in about 20% of all Major Deppresion Disorder patients. In addition to the high cost of treatment to be borne, the high functional disability rate, the suicide rate triggered by the disorder is also quite large. Various efforts were made to overcome this, including dose optimization and duration of treatment, substitution of drug selection, combination therapy and augmentation using non-antidepressant drugs and bilateral electroconvulsion therapy. Current pharmacological options according to some experts are no more efficacious than the 1950s. Clearly, a novel therapeutic approach to treatment - resistant depression disorders is urgently needed. Over the last few decades, there has been a renewed interest in focal neuromodulation as a treatment approach for neuropsychiatric conditions. The neuromodulation-based interventions discussed include Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), which are non invasive intervention therapy and Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS), which are invasive interventional therapies. This literature review proves that, although today only TMS and VNS have been approved for use by the Food and Drug Administration (FDA) in the United States, but neuromodilation-based intervention therapy has proven to be promising as a more effective and efficient resistant depression therapy in the future.

scholarly journals Ketamine: A tale of two enantiomers

2020 ◽  
pp. 026988112095964
Author(s):  
Luke A Jelen ◽  
Allan H Young ◽  
James M Stone
Keyword(s):  
Side Effects ◽  
Receptor Antagonist ◽  
The United States ◽  
Receptor Activation ◽  
Racemic Mixture ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Resistant Depression

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

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