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Pharmacological management of depression in older people
Published in Stephen Curran, John P Wattis, Practical Management of Affective Disorders in Older People, 2018
Stephen Curran, Andrew Byrne, John P Wattis
A number of other drugs are currently in development but many are still at an early stage or not available in the UK. These include dopamine reuptake inhibitors, 5-HT3 receptor antagonists, corticotropin-releasing factor antagonists, neurokinin (substance P) receptor antagonists, melatonergic agonists and glutamatergic modulators. In addition, most of the focus to date has been on intrasynaptic function. In the future it is likely that developments will shift in part towards intracellular signalling pathways but the latter is still at an early stage. Our own view is that the monoamine hypothesis is very simplistic. The fact that there are multiple interactions between intra- and extra-cellular systems probably means that a drug or drugs which enhances several of these mechanisms is more likely to be beneficial than one which only enhances one. In our view, our understanding of the biological basis of depression remains very limited despite the successes to date.
The Management of Treatment-Resistant Depression
Published in Dr. Ather Muneer, Mood Disorders, 2018
Agomelatine is a drug that works through melatonergic agonism (on MT1 and MT2 receptors) and 5-HT2C antagonism. Agomelatine has been shown to be efficacious in MDD in several studies. Yet, there is no evidence of agomelatine’s efficacy, particularly in TRD, thus necessitating further studies.
Generalized Anxiety Disorder
Published in Stephen M. Stahl, Bret A. Moore, Anxiety Disorders: A Guide for Integrating Psychopharmacology and Psychotherapy, 2013
Joseph E. Comaty, Claire Advokat
One new approach is the drug agomelatine, an agonist at melatonergic (MT1, MT2) receptors and an antagonist at 5HT2C serotonergic receptors. It has no effect on monoamine uptake and no affinity for adrenergic, histaminergic, cholinergic, dopaminergic, BZD receptors, or other serotonergic receptors. During clinical trials in which it was tested for antidepressant efficacy, it showed some anxiolytic action and was assessed for GAD (at 25–50 mg/day) in a randomized, placebo-controlled 12-week study (D. J. Stein, Ahokas, & de Bodinat, 2008). Agomelatine decreased the HAM-A total score significantly more than placebo. Although both psychic and somatic scores declined, only the latter decline reached statistical significance relative to placebo. Significantly more patients responded to the drug than to placebo (66.7& vs. 46.6&, respectively), and significantly more remitted under the drug (41.3& vs. 22.4&). Very few patients withdrew from the study (three out of 55 from placebo and five out of 63 from agomelatine), and adverse events were minimal (mainly dizziness, 7.9& vs. 3.4&, and nausea, 4.8& vs. 1.7&, for agomelatine compared to placebo). Considering the high baseline HAM-A score of ≥22, the outcome indicates that agomelatine may have anxiolytic benefit.
In silico drug discovery of melatonin receptor ligands with therapeutic potential
Published in Expert Opinion on Drug Discovery, 2022
Gian Marco Elisi, Laura Scalvini, Alessio Lodola, Annalida Bedini, Gilberto Spadoni, Silvia Rivara
Unfortunately, only a few of these compounds have progressed to a thorough pharmacological characterization, to in vivo studies, and very few to clinical trials (e.g., piromelatine [87] and beta-methyl-6-chloromelatonin [88] in addition to the approved agonists). Nevertheless, some compounds, in particular subtype-selective ligands, have been successfully used to clarify the role of melatonergic receptors in certain tissues or processes, as happened, for example, with IIK7 and UCM765 in sleep induction and maintenance. Melatonergic ligands designed through a ligand-based approach have chemical structures reminiscent of that of melatonin, usually comprising an aromatic scaffold, an amide group, and a hydrogen bond acceptor mimicking the methoxy group, combined in such a way to mimic the steric and conformational properties of the natural ligand. For these compounds, we can expect an arrangement at the ligand binding site and interactions with receptor residues consistent with those of melatonin.
Alcohol and melatonin
Published in Chronobiology International, 2021
Mel is part of the body’s defense system against adverse effects, and, therefore, interference of its synthesis may be a cause and marker of pathological changes (Cipolla-Neto and Amaral 2018), for example, associated with alcohol consumption. The hormone stabilizes the activity of various endocrine systems disorganized by stress of different origin, including the elimination of excessive stress of adrenal hypercorticism. Oxidative stress generated by chronic immobilization and alcohol consumption causes severe neurotoxicity in the hippocampus region, which ultimately leads to cognitive dysfunction. Some data suggest that alcohol-dependent patients and alcohol-treated laboratory rats have reduced levels of Mel and a delay of its nocturnal peak concentration (Vengeliene et al. 2015). Therefore, it is important to establish whether the melatonergic system can be used as a novel tool to support the treatment of alcohol addiction (Sönmez et al. 2012).
Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials
Published in Expert Opinion on Emerging Drugs, 2021
Amna Majeed, Jiaqi Xiong, Kayla M. Teopiz, Jason Ng, Roger Ho, Joshua D. Rosenblat, Lee Phan, Bing Cao, Roger S. McIntyre
In recognition of the importance of examining other avenues of depression management (i.e. aside from traditional antidepressant drugs [e.g. SNRIs] that act through norepinephrine and serotonin receptors), various antidepressants with novel mechanisms of action have emerged in recent decades [13]. For example, agomelatine, a melatonergic receptor agonist and a 5-HT2C antagonist has been shown to be effective and well-tolerated in MDD patients [14]. Another novel molecule, neuropeptide Y (NPY), has also been reported to exert positive antidepressant effects in both preclinical and clinical studies [15,16]. The discovery that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, is capable of rapid-onset efficacy in adults with treatment resistant depression (TRD) provides proof of principle that pharmacologic agents that primarily target glutamate signaling may also be capable of symptom relief in MDD [17]. Indeed, intranasal esketamine has been approved and received Breakthrough Designation by the US Food and Drug Administration for adults with TRD as well as adults with MDD and suicidality [18–21].