Antidepressants

Abstract

This chapter reviews the 26 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 The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by compounds that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake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 generation of antidepressants are serotonin‐selective reuptake inhibitors, which possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions. 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 antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain derived neurotrophic factor). New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, or corticotrophin releasing factor receptors.

Antidepressant specificity of serotonin transporter suggested by three LeuT–SSRI structures

“…As an important drug component, fluorine substituents in various drugs have been shown to be critical for the drugs’ affinity and selectivity by undergoing multipolar interactions with protein backbone in a hydrophobic environment as well as with the positively charged guanidinium side chain of arginine 33. Not restricted to the aforementioned aminotetraline and phenoxyphenylpropylamine derivatives, substitutions with an electronegative halogen at the 4th position in the phenyl or phenoxy ring are found in every other SSRI currently on the market — CF 3 - in fluvoxamine, and F- in paroxetine and citalopram 5,7,34. Strikingly, halogen substitutions at the same ring positions are also found in serotonin-norepinephrine reuptake inhibitors (sibutramine and nefazodone) 35,36 as well as the recently discovered serotonin-norepinephrine-dopamine triple reuptake inhibitors (brasofensine, tesofensine, indatraline and DOV21,947) 37-40 but, in stark contrast, not in NRIs 8,34.…”

Substrate and drug binding sites in LeuT

“…It is this halogen substitution and this characteristic dipole moment that appears to be largely responsible for the drugs’ specificity to SERT over NET [39,40]. Similar halogen substitutions also exist in serotonin-norepinephrine reuptake inhibitors [41,42] as well as in serotonin-norepinephrine-dopamine triple reuptake inhibitors [43–46] but not in norepinephrine selective reuptake inhibitors (NRIs) [32,37]. Strikingly, in fluoxetine-related antidepressants, [35,36] substitutions with CH 3 - or OCH 3 - at the 2nd ( ortho ) position in the phenoxy ring yield NRIs like tomoxetine and nisoxetine (Figures 2b & 2c).…”

Neurotransmitter transporters and their impact on the development of psychopharmacology

“…The monoamine uptake inhibitors have proved very effective in the treatment not only of major depression but also for a series of other psychiatric illnesses. The SSRIs expanded the approved indications for the use of these drugs to include obsessive compulsive disorder, bulimia nervosa, panic disorder, post‐traumatic stress syndrome, premenstrual tension and social anxiety syndrome ( Iversen & Glennon, 2003 ). They have also proved hugely successful commercially, with worldwide sales in excess of $17 billion in 2003.…”

“…The molecular mechanisms in the brain that are triggered by the antidepressants, however, remain obscure ( Iversen & Glennon, 2003 ). The fact that all drugs require a period of several weeks before they become fully effective suggest that they modify gene expression in the brain and that the resulting altered biochemical state takes a long time to become stabilized.…”

“…The fact that all drugs require a period of several weeks before they become fully effective suggest that they modify gene expression in the brain and that the resulting altered biochemical state takes a long time to become stabilized. Many theories have been proposed, including alterations in the expression of alpha and beta‐adrenergic receptors, changes in transcription factors and/or neurotrophic factors, and even morphological alterations in the connectivity of monoaminergic nerves and the promotion of new nerve cell formation ( Iversen & Glennon, 2003 ).…”