Novel antidepressant drugs: Beyond monoamine targets

CNS Spectrums ◽  
2021 ◽  
pp. 1-10
Author(s):  
Xenia Gonda ◽  
Peter Dome ◽  
Joanna C. Neill ◽  
Frank I. Tarazi
Keyword(s):  
Side Effects ◽  
Unmet Need ◽  
Antidepressant Drugs ◽  
Treatment Resistant ◽  
Monoamine Neurotransmitters ◽  
Major Depressive ◽  
Superior Efficacy ◽  
Psychedelic Drugs ◽  
Resistant Depression ◽  
Clinical Trial Results

Abstract Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

scholarly journals Development of Pharmacophore Model and Asymmetric Synthesis of Novel Tetrahydrofuran Derivatives Enroute to Triple Uptake Inhibitors As Anti-Depressant Agents

2014 ◽  
Author(s):  
aloke dutta ◽  
Horrick Sharma ◽  
Soumava Santra ◽  
Joy Debnath ◽  
Maarten EA Reith
Keyword(s):  
Side Effects ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Tricyclic Antidepressants ◽  
Unmet Need ◽  
Antidepressant Drugs ◽  
Pharmacophore Model ◽  
Unipolar Depression ◽  
Current Treatment ◽  
Monoamine Neurotransmitters ◽  
Norepinephrine Reuptake

Unipolar depression, caused by an imbalance of monoamine neurotransmitters in brain, is ranked as the most prevalent of all somatic and psychiatric illness. It is estimated that about 40 % of patients remains refractory to treatment thereby limiting the use of current antidepressant drugs. Moreover, because of relapse and unwanted side effects of existing drugs there is an unmet need to discover novel agents for the treatment of this devastating mental disorder. Current treatment aims at alleviating extraneuronal concentration of serotonin (5-HT) and /or norepinephrine (NE) (Figure 1). Tricyclic antidepressants were among the first class to have been discovered but due to their nonspecific side effects they have limited use in clinics. They have been largely replaced by second-generation antidepressants including selective serotonin reuptake inhibitors (SSRI, e.g., fluoxetine, Figure 2), selective norepinephrine reuptake inhibitors (NRI, e.g. reboxetine, Figure 2), and serotonin and norepinephrine reuptake inhibitors (SNRI, venlafexine, Figure 2).

scholarly journals Could ketamine be the answer to treating treatment-resistant major depressive disorder?

2020 ◽  
Vol 33 (5) ◽  
pp. e100227
Author(s):  
Abdullah Mohammed Ramadan ◽  
Islam Ahmed Mansour
Keyword(s):  
Major Depressive Disorder ◽  
Side Effects ◽  
Depressive Disorder ◽  
Receptor Antagonist ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Nmda Receptor Antagonist ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Major Depressive ◽  
Resistant Depression

Major depressive disorder (MDD) is a common, serious, debilitating condition affecting 350 million people worldwide, which remains to be unsatisfactorily treated with 53% of patients still complaining of symptoms after completing their courses with the correct dosage. Ketamine, which was approved by the Food and Drug Administration in 2019, is a potential treatment option for those recalcitrant cases. The mechanism of ketamine is not fully understood, but as type it is classified as an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, and can be given intravenously, intranasally and orally. It is used to treat treatment-resistant depression, depression associated with suicidal ideation, mood and anxiety disorders and depressions associated with either type of bipolar disorder. Although ketamine is considered relatively safe, several side effects have been reported with the major ones being psychiatric in the form of worsening mood, anxiety and agitation; psychotomimetic in the form of dissociation, perceptual disturbance and abnormal sensations; cardiovascular in the form of increased blood pressure and increased heart rate; and neurological in the form of headache and dizziness. Ketamine is still not approved worldwide for usage in patients with treatment-resistant MDD, but if it is approved sometime in the future with relatively fewer side effects, it is expected to significantly save millions of dollars spent yearly on patients with treatment-resistant depression and that will lift this major burden off the shoulders of healthcare professionals. This study was designed to measure the effects of ketamine, an NMDA receptor antagonist, on patients with treatment-resistant MDD and to analyse the concept that makes it different and relatively safer than other major antidepressants like selective serotonin reuptake inhibitors, monoamine oxidase inhibitors and TCAs (tricyclic antidepressants).

scholarly journals Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression

2020 ◽  
Vol 263 ◽  
pp. 568-575 ◽  
Author(s):  
Elia E. Acevedo-Diaz ◽  
Grace W. Cavanaugh ◽  
Dede Greenstein ◽  
Christoph Kraus ◽  
Bashkim Kadriu ◽  
...  
Keyword(s):  
Single Dose ◽  
Side Effects ◽  
Comprehensive Assessment ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression

scholarly journals Using Oral and Intranasal Dosage Forms of Ketamine for Managing Treatment-Resistant Depression: A Review of the Literature

2016 ◽  
Vol 4 (2) ◽  
pp. 64-71 ◽  
Author(s):  
Patrick Arthur Twohig ◽  
Vaughn Huckfeldt
Keyword(s):  
Health Care ◽  
Side Effects ◽  
Care Setting ◽  
Dosage Forms ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Similar Reduction ◽  
Aspartate Receptor ◽  
Pubmed Database ◽  
Resistant Depression

A lack of effective treatment for patients with treatment-resistant depression (TRD) has led to the evaluation of ketamine, an N-methyl- D-aspartate receptor antagonist. Despite the demonstrated short-term benefits of using intravenous (IV) ketamine, side effects and the difficulty in administering ketamine outside the health-care setting has raised interest in alternative dosage forms. Research articles evaluating oral or intranasal (IN) ketamine were retrieved from the PubMed database. Patients who received oral or IN ketamine experienced a similar reduction in depressive symptoms within 24 hours of treatment and fewer side effects compared to patients who received IV ketamine. Novel administration forms of ketamine provide an opportunity for patients with TRD to achieve remission with fewer adverse side effects. Future studies should continue to evaluate these administration strategies in the hope of promoting ketamine’s use outside health-care settings and for longer time periods.

Depression

2018 ◽  
Author(s):  
Raymond W. Lam
Keyword(s):  
Depressive Disorders ◽  
Special Populations ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Major Depressive ◽  
Basic Principles ◽  
Medically Ill ◽  
Dsm 5 ◽  
Resistant Depression

Depression, Third Edition provides a succinct clinical guide for the recognition, diagnosis, management, and modalities of treatment of depressive disorders. This new edition includes the DSM-5 diagnostic criteria, updates the latest neurobiological and psychological findings, and summarizes the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder. The initial chapters deal with the epidemiology, pathogenesis, clinical features, and diagnosis of depression. Basic principles of clinical management are provided, as well as individual chapters dealing with the spectrum of available treatments for depression, including pharmacological, psychological, somatic, and complementary medicine approaches. A final chapter focuses on treatment-resistant depression (TRD) and other special populations including peripartum, elderly and medically ill, and children and adolescents.

scholarly journals Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

2019 ◽  
Author(s):  
Eleanor J. Cole ◽  
Katy H. Stimpson ◽  
Brandon S. Bentzley ◽  
Merve Gulser ◽  
Kirsten Cherian ◽  
...  
Keyword(s):  
Side Effects ◽  
Rating Scale ◽  
Neuropsychological Testing ◽  
Anterior Cingulate ◽  
High Dose ◽  
Delayed Response ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resting Motor Threshold ◽  
Resistant Depression

AbstractBackgroundCurrent treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed ‘Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)’.MethodsTwenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.ResultsNineteen of 21 participants (90.48%) met criteria for remission (≤10 on the Montgomery-Åsberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events.DiscussionOur accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study.Trial registrationClinicalTrials.gov NCT03240692

scholarly journals Esketamine in Treatment Resistant Depression: The Way to Remission

2021 ◽  
pp. 35-39
Author(s):  
João Facucho-Oliveira ◽  
Daniel Esteves-Sousa ◽  
Bruno Prates ◽  
Rui Neves ◽  
Pedro Varandas
Keyword(s):  
Depressive Symptoms ◽  
Behavioral Therapy ◽  
Symptomatic Relief ◽  
European Medicines Agency ◽  
Caucasian Woman ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Major Depressive ◽  
Aspartate Receptor ◽  
Resistant Depression

Major depressive disorder affects an estimate of 5% of the population with nearly 1‑third of patients failing to achieve remission with conventional pharmacological treatment. Esketamine, a novel rapid‑acting antidepressant, with a noncompetitive antagonism on N‑methyl‑D‑Aspartate receptor, have been recently approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment‑resistant depression. Here, we report a clinical case of a 42‑year‑old Caucasian woman who endured many years with severe depressive symptoms and high functional impairment. Previous treatments included cognitive behavioral therapy, numerous pharmacological trials with antidepressants and augmentation agents, and neurostimulation approaches. Upon treatment with esketamine, the patient presented remarkable clinical recovery. Psychometric assessments determined an acute reduction on the MADRS score after 1 week and progressive recovery of the depressive symptoms on the following weeks. Likewise, PHQ‑9 scale assessments, evaluating the relative frequency of depressive symptoms. and the Sheehan scale, assessing functional recovery, also determined a pronounced symptomatic relief.

scholarly journals Treatment-Resistant Depression in a Real-World Setting: First Interim Analysis of Characteristics, Healthcare Resource Use, and Utility Values of the FondaMental Cohort

2020 ◽  
Vol 10 (12) ◽  
pp. 962
Author(s):  
Antoine Yrondi ◽  
Djamila Bennabi ◽  
Emmanuel Haffen ◽  
Delphine Quelard ◽  
Ludovic Samalin ◽  
...  
Keyword(s):  
Resource Use ◽  
Healthcare Resource ◽  
The Other ◽  
Health State ◽  
Treatment Resistant Depression ◽  
Healthcare Resource Use ◽  
Treatment Resistant ◽  
Utility Value ◽  
Major Depressive ◽  
Resistant Depression

Background: Major depressive disorder (MDD) is among the most common psychiatric disorders. One-third of patients are usually unresponsive to several lines of treatment. This study aimed to describe the FondaMental French cohort of patients with treatment-resistant depression (TRD) and to estimate utility and healthcare resource use outcomes. Methods: Patients with TRD were evaluated prospectively over four years (baseline, 6, 12, 18, 24, 36 and 48 months) in a real-world clinical setting. Interim analyses focused on the first two consecutive years. Four MDD-related states (major depressive episode (MDE), response, remission, recovery) were defined based on the MADRS (Montgomery–Åsberg depression rating scale) and other clinical events. Health status was assessed with the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) questionnaire. Utility values were estimated as preference measures that the patients assigned to their overall health status. Results: This study was based on 252 patients with TRD. The mean utility value by health state was 0.41, 0.63, 0.80, and 0.90, for MDE, response, remission, and recovery, respectively. At baseline, 59% of patients had an MADRS score of at least 28. Their baseline average utility value was lower compared to the other patients (0.43 versus 0.58, p < 0.001). This significant difference persisted at the following visits. The rate of patients in MDEs having at least one hospitalisation for depression or other reasons than depression was generally higher than that in the other health states. Conclusion: This study documented patterns in healthcare resource consumption, quality of life, and other characteristics in patients with TRD, both globally and by health state and depression severity.

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