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How Antidepressants Work

SSRIs and Newer Mechanisms

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Updated October 17, 2012

Selective Serotonin Reuptake Inhibitors

Claims of decreased side-effects and increased safety relative to the older medications have made this class of antidepressant very popular in recent years. Drugs belonging to this class include fluoxetine (Prozac), citalopram (Celexa) escitalopram (Lexapro), fluvoxamine (Luvox), sertraline (Zoloft) and paroxetine (Paxil). SSRI stands for Selective Serotonin Reuptake Inhibitor. These medications work, as the name implies, by blocking the presynaptic serotonin transporter receptor.8 This drug differs from the tricyclics in that its action is specific to serotonin only. Its effect on norepinephrine is indirect, through the fact that falling serotonin "permits" norepinephrine to fall so preserving serotonin preserves norepinephrine.9 SSRIs, through their specificity, have the advantage of not affecting histamine and acetylcholine. The implication is that although they are not without side-effects, they do not create the same bothersome side-effects as the tricyclics.

Newer Mechanisms

Five newer medications which do not fit into the above categories are: bupropion (Wellbutrin), nefazodone (Serzone), trazodone (Desyrel), venlafaxine (Effexor), and mirtazapine (Remeron). The mechanism of bupropion's antidepressant activity is poorly understood, but it is thought to be mediated through noradrenergic or dopaminergic pathways or both.10 This medication lacks the sexual side-effects so common to the SSRIs and is popular for patients who exhibit a lack of energy, psychomotor slowness and excessive sleep. Nefazodone and its precursor trazodone both inhibit neuronal reuptake of serotonin and, to a lesser extent, norepinephrine. They also block postsynaptic 5-HT2 receptors. Nefazodone has weak affinity for cholingeric and a1- adrenergic receptors and, therefore, is associated with less sedation and orthostasis than trazodone.11

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