Reboxetine action

Although its mechanism of action is similar to that of desipramine and maprotiline, reboxetine is not a TCA, and, in contrast, does not inhibit electrically excitable membranes. For this reason, overdose of reboxetine should not carry a significant risk of cardiotoxicity or seizures. Although a distinct advantage, the aforementioned is based on preclinical data because there is minimal clinical experience with overdoses of this drug. 

This antidepressant can interact with other drugs via its two mechanisms of action serotonin and NE uptake inhibition. The former action means that the same pharmacodynamic interactions will occur with venlafaxine as with SSRIs, including the serotonin syndrome. At higher doses, venlafaxine is also prone to the same pharmacodynamic interactions as NSRIs such as secondary amine TCAs like desipramine and with newer NSRIs such reboxetine. Thus, the combination of high-dose venlafaxine plus an MAOl could produce a hypertensive crisis as well as the serotonin syndrome. 

Consistent with its most potent known mechanism of action, bupropion is an indirect dopamine agonist via its inhibition of the neuronal uptake pump for dopamine (503, 504). Hence, bupropion can potentiate the effects of other dopamine agonists. This interaction does not typically cause serious problems and may even be advantageous in specific instances such as patients with Parkinson s disease plus a depressive disorder. Because of its ability to inhibit NE uptake, bupropion would be prone to the same interactions as NSRIs such as desipramine and reboxetine. 

FIGURE 7—40. Adrenergic combo 1 Bupropion plus norepinephrine reuptake inhibitor (NRI). Here the NE actions of bupropion are double-boosted by the NRI (either selective reboxetine or nonselective desipramine, maprotilene, nortriptyline, or protriptyline). Dopamine is single-boosted by bupropion only. 

Newer antidepressants. Although the SSRIs are the only antidepressants formally approved for the treatment of panic disorder, recent evidence suggests that several other antidepressants are promising treatments for panic disorder as well. These include nefazodone, venlafaxine XR, mirtazapine, and reboxetine. Bupropion, however, does not seem to have apparent antipanic actions. Since the documentation of efficacy of these newer antidepressants in panic disorder is still emerging, they tend to be used as second-line therapy after SSRIs foil to improve panic or in patients who cannot tolerate them. 

The therapeutic action of reboxetine is mediated in part via direct interactions with serotonergic neurotransmission. 

CNS and cardiovascular actions of d,l-methylphenidate could theoretically be enhanced by combination with agents that block norepinephrine reuptake, such as the tricyclic antidepressants desipramine or protriptyline, venlafaxine, duloxetine, atomoxetine, milnacipran, and reboxetine... 

Bupropion, reboxetine, nortriptyline, desipramlne, maprotlllne, atomoxetine (all potentially powerful enhancers of noradrenergic action, but observe for activation of bipolar disorder and suicidal Ideation)... 

Via CYP450 2D6 inhibition, reboxetine could theoretically interfere with the analgesic actions of codeine, and increase the plasma levels of some beta blockers and of atomoxetine and TCAs... 

Novel use of reboxetine may be for attention deficit disorder, analogous to the actions of another norepinephrine selective reuptake inhibitor, atomoxetine, but few controiied studies... 

Several findings support the view that antidepressants that enhance both serotonin and norepinephrine (dual-acting antidepressants) have greater therapeutic efficacy compared with antidepressants that enhance either neurotransmitter alone (e.g. SSRIs enhance mainly serotonin, while reboxetine and desipramine enhance predominantly norepinephrine). It is specifically proposed that the dual-acting SNRIs may display faster onset of action and can be more efficacious in cases of severe depression. There are four new-generation dual-acting antidepressants duloxetine, milnacipran, mirtazapine, and venlafaxine. ... 

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... 

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