SnrI Mechanism

Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another 22 MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary restrictions, and possibility of fatal drug interactions.22,28 There is some evidence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,22,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.33... 

In the past decade, other antidepressants have been introduced. Many of these act, at least in part, via serotonin-mediated mechanisms and, as such, have been tested in the treatment of one or more anxiety disorders. These additional antidepressants include two dual serotonin-norepinephrine reuptake inhibitors (SNRIs),... 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30-2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT antagonists and mirtazapine). Ultimately, the increased availability of monoamines for... 

Duloxetine has recently been marketed as an antidepressant in Europe. It inhibits the re-uptake of serotonin and noradrenaline, with minimal effects on other neurotransmitter mechanisms. It is therefore classified as a serotonin and noradrenaline re-uptake inhibitor (SNRI) and is grouped with venlafaxine. The adverse effect profile of duloxetine appears to be similar to that of the SSRIs and venlafaxine. In placebo-controlled trials the most common adverse effects were nausea (37%), dry mouth (32%), dizziness (22%), somnolence (20%), insomnia (20%), and diarrhea (14%). Sexual dysfunction has also been reported. Current data suggest that, unlike venlafaxine, duloxetine does not increase the blood pressure, but further post-marketing surveillance studies will be needed to confirm this (1). 

Mechanism of action as SNRI suggests it may be effective in some patients who fail to respond to SSRis... 

NA has its action terminated by uptake. The tricyclic drug desipramine is an example of a potent inhibitor of this uptake mechanism as well as the newer SNRIs (venlafaxine) and cocaine (5). NA or DA present in a free state within the presynaptic terminal can be degraded by the enzyme MAO, which appears to be located in the outer membrane of mitochondria. Pargyline is an effective inhibitor of MAO (6). NA can be inactivated by the membrane-bound enzyme catechol-O-methyltransferase (COMT). Tropolone is an inhibitor of COMT. The normetanephrine (NM) formed by the action of COMT on NE can be further metabolised by MAO to... 

Mirtazapine is a potent antagonist of central a2-adrenergic auto- and heteroreceptors (see Section 2.5). Hence, like the SNRIs (although via a different mechanism), it enhances the release of both norepinephrine and serotonin to the synaptic cleft. Mirtazapine also antagonizes post-synaptic 5-HT2a and 5-HT3 serotonergic receptors and it indirectly activates the postsynaptic 5-HTia receptor. - ... 

Reboxetine is a nontricyclic SNRI in which the propylamine side chain of the TCAs is constrained into a morpholine ring (Fig. 21.8). It is a potent and selective ligand for the NET, with a mechanism of action is similar to that of desipramine. Reboxetine is used for the treatment of major depressive disorders. It is a chiral compound that is marketed as a racemic mixture of R,R- and S,S-reboxetine. The antidepressant activity for reboxetine appears to reside with the S,S-(+)-enantiomer, which has approximately twofold the inhibition potency of the R,R-enantiomer (42). It is well tolerated, with different adverse-event profiles, and it appears to be at least as effective as the SSRIs in the treatment of depressive illness. Currently, it is available only in Europe and is under U.S. FDA review. It preferentially inhibits the reuptake of NE (5-FIT NE ratio, 8). Reboxetine is not metabolized by the polymorphic isoforms, CYP2D6 or CYP2C19, and may offer a valuable alternative to the secondary amine TCAs in the treatment of major depression. Reboxetine is likely to become a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants. Reboxetine has been shown to be effective and well tolerated in the treatment of panic... 

For the most part, the therapeutic uses for the tertiary amine TCAs are very simiiar as a group, but these TCAs may be used in different cases of depression because of their variabiiity in their duai mechanism of aotion as SNRis and SSRis. Their efficacy in treating depression suggests that mixed inhibition of NET and SERT infiuence depression by paraiiei and independent pathways. The tertiary TCAs may offer an option in the treatment of major depression for patients who have faiied treatment with or who do not toierate SNRis or SSRis. 

Falls SSRIs and serotonin and noradrenalin reuptake inhibitors (SNRIs) have long been linked with an increased risk of osteopenia/osteoporosis potentiating falls and fractures, especially in tiie elderly. A biological mechanism for these risks associated with SSRIs has been idenhfied. Studies have demonstrated a reduction in osteoblast proliferation and activity following treatment with SSRIs, the magnitude of such effects being linked to affinity to the serotonin transporter. In addition, recent research examining serotonin receptor expression in human osteoblasts and osteoclasts has found that SSRIs differentially inhibit bone cells via apoptosis [10 ]. 

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