MECHANISMS OF ACTIONS OF ANTIDEPRESSANTS

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The advent of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) has resulted, perhaps, in norepinephrine (NE) becoming the “forgotten” monoamine with respect to the mechanism of action of antidepressants. This is unfortunate as it has been clear for many years that drugs that acutely alter NE function selectively can be antidepressants (e.g., desipramine). This presentation focuses on the mechanisms of action of all types of antidepressants as well as the pharmacodynamic reasons for differences in their side-effect profile. For example, the improved side-effect and toxicity profile seen with the SSRIs, as well as newer drugs such as venlafaxine, is due, at least in part, to their inability to block muscarinic cholinergic, (1 adrenergic, or H1 histamine receptors, nor to inhibit myocardial conduction. With respect to mechanism of action, it is of interest that different types of antidepressants have comparable efficacy in treating heterogeneous groups of depressed patients. Drugs that selectively block the uptake of serotonin (e.g., fluoxetine, sertraline) or norepinephrine (desipramine, the investigational compound reboxetine) or both monoamines (imipramine, venlafaxine) cause a similar extent of improvement in nonselected depressed patients. Whether this holds true for subgroups of depressed patients is currently under investigation. Relevant to this issue is whether drugs that are selective in vitro retain their selectivity in vivo, especially under repeated administration. Both preclinical and clinical data will be presented that address this. For example, repeated administration of NE reuptake inhibitors to rats does not affect certain serotonergic parameters (e.g., 5-HT1A receptor sensitivity) in the same way as SSRIs. On the other hand, SSRIs do not downregulate β1 adrenergic receptors, but antidepressants that affect noradrenergic function do this. Also, the clinical efficacy of NE reuptake inhibitors does not seem to be dependent on the presence of 5-HT, nor is the efficacy of SSRIs dependent on the presence of NE. By contrast, new in vivo voltammetric data are presented demonstrating that NE reuptake inhibitors alter the clearance of 5-HT in certain brain areas. Also, treatment of depressed patients with desipramine causes, over time, a reduction of the content of 5-HT in their platelets. Thus, there is evidence for both selective and nonselective effects of various types of antidepressants on monoamine function in vivo.