Antidepressants

Abstract

This article reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g. phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g. moclobemide) or by inhibitors of serotonin/norepinephrine monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g. reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All approved antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This, although perhaps somewhat agent‐specific, might be attributable to drug‐induced alterations in the expression of receptors in brain and/or alterations in the expression of neurotrophic factors (e.g. brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include triple reuptake inhibitors, antagonists for glutamate NMDA receptors, corticotrophin‐releasing factor receptors, or agonists/antagonists for galanin receptors. There is particular interest in ketamine analogs and certain other agents (considered as drugs of abuse) because of their rapid and persistent antidepressant effects, especially in treatment‐resistant depression. Agents with mixed mechanisms also are being pursued.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review

“…147 However, relocation of the methoxy substituents of DOPP actually enhanced affinity by as much as an order of magnitude. For example, the 2,3-, 3,5-, and 2,6dimethoxy positional isomers of DOPP (11) bind with K i values of 3−4 nM. In fact, the presence of a methoxy group is not essential for binding (i.e., 15).…”

“…e.g.1−10 A broad structural and mechanistic variety of antidepressants are currently being explored but, as a group, serotonergic psychedelic agents represent a large class of agents with psychotherapeutic potential. 11 In fact, recognizing their potential therapeutic utility, the U.S. Food and Drug Administration has recently published recommended guidelines for the investigation of such agents. 12 These agents can be broadly divided into two large structural classes: (i) indolealkylamines, exemplified by N,N-dimethyltryptamine-related (or DMT-related) analogues and lysergic acid diethylamide (LSD) that possess a tryptaminergic backbone, and (ii) phenylalkylamines (see below for examples); together, these agents can be collectively referred to as arylalkylamines.…”

“…e.g. − A broad structural and mechanistic variety of antidepressants are currently being explored but, as a group, serotonergic psychedelic agents represent a large class of agents with psychotherapeutic potential . In fact, recognizing their potential therapeutic utility, the U.S. Food and Drug Administration has recently published recommended guidelines for the investigation of such agents .…”

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

“…Although medications have existed for many years (antidepressants) [ 9 , 11 ], there are multiple reasons that led to the 2019 U.S. FDA approval of ( S )-ketamine for the treatment of patients when given in conjunction with standard-of-care (SOC) antidepressants like monoamine uptake inhibitors. One pressing reason for the approval of ( S )-ketamine is that about 30% of MDD patients do not respond to SOC antidepressants—treatment-resistant depression (TRD).…”