Reboxetine fluoxetine

Many currently used antidepressants are chiral drugs (for example, tricyclic antidepressants, mianserin, mirtazepine, venlafaxine, reboxetine, fluoxetine, paroxetine, sertraline, citalopram), some of which are administered as racemates (such as the tricyclics, mianserin, mirtazepine, fluoxetine, reboxetine, venlafaxine, citalopram) while others are given as single isomers (paroxetine and sertraline). 

Massana, J. (1998). Reboxetine versus fluoxetine an overview of efficacy and tolerability. J. Clin. 

Shen, Y. F., Li, H. F., Ma, C. et al. (2005). Comparison of reboxetine with fluoxetine in treatment of depressions randomized double-blind multicenter study. Chinese Journal of New Drugs and Clinical Remedies, 24(8), 619-23. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

As a results of these studies, clinicians have proposed that switching to reboxetine or bupropion might a useful strategy given that these antidepressants share the ability with desipramine and imipramine to block NE uptake. Nevertheless, only one small open label study has been done to test this possibility ( 365). If bupropion is to be used in patients switched from an ineffective trial of fluoxetine, the dose should be kept low for several weeks to allow for the clearance of fluoxetine and norfluoxetine. Case reports indicate that fluoxetine can elevate levels of the active metabolites of bupropion, which, in turn, could mediate an increase risk of adverse effects (366). 

Because reboxetine and bupropion share with desipramine the ability to block the NE uptake pump, some clinician may want to combine them with an SSRI. Bupropion, however, should be used cautiously with fluvoxamine, fluoxetine, and paroxetine because these three antidepressants inhibit one or more CYP enzymes to a substantial degree at their lowest, usually effective antidepressant dose. Therefore, the dose of bupropion should be kept low and TDM could be used to ensure that unusually high levels of bupropion or its active metabolites do not develop. 

In terms of comparative adverse effects, imipramine produces more dry mouth than reboxetine probably because imipramine blocks muscarinic cholinergic receptors as well as inhibiting NE uptake (47,5). Imipramine also produces more tremulousness and hypotension than reboxetine. Consistent with their pharmacology, fluoxetine produces more serotonin-mediated adverse effects than does reboxetine (i.e., nausea, loose stools, and somnolence), whereas reboxetine causes more sympathomimetic adverse effects (476). To date, reboxetine has not been reported to cause an increased incidence of laboratory abnormalities. 

FIGURE 7—54. Heroic combo 10 SSRI plus NRI. Here, 5HT and NE are both single-boosted. The preferred NRI is selective reboxetine, as there are no drug interactions. Nonselective TCAs that are preferential NRIs such as desipramine, maprotilene, nortriptyline, or protriptyline can be combined if plasma drug levels of the TCA are monitored, especially if fluoxetine or paroxetine is the SSRI chosen. 

Reboxetine, was the first antidepressant to be developed to work specifically on noradrenaline (Wong et al., 2000). It is a specific noradrenergic reuptake inhibitor (NARI) and in a clinical study, it was found to improve the psycho-social functioning of depressed patients, as measured by the Social Adaptation Self-evaluation Scale (SASS), more than fluoxetine, a specific serotonergic reuptake inhibitor (SSRI) antidepressant (Dubini, Bose, and Polin, 1997). It has been suggested that social adaptation as measured on the scale used (SASS) is associated with the concept of social motivation (Charles et al., 1999). The improvement, thus, appeared to be associated with enhancement of social motivation which might be important for the therapeutic recovery process (Hirschfeld, et al., 2000). However, the mechanism by which the changes in noradrenaline induced by reboxetine led to improvement on the SASS is unknown. 

Imipramine, desipramine, amitriptyline, nortriptyline, trimipramine, clomipramine, lofepramine, amoxapine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipram, sulpiride, tandspirone, methylpheni-date, melitracen Amitriptyline, imipramine, trimipramine, clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, reboxetine, viloxazine, doxepin, maprotiline, mianserine, mirtazapine, moclobemide, trazodone, opipramol (and some metabolites)... 

Substrates Alosetron8 Coumarin0 Bupropion0 Amodiaquine Diclofenac0 Fluoxetine Aniline Atomoxetine0 Alfentanil a-Dihydroergocriptine Itraconazole Reboxetine... 

Propranolol Nisoxetine Reboxetine Duloxetine Viloxazine Fluoxetine Atomoxetine... 

These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5HT neurotransmission. This notion is supported by the results of a 6-week doubleblind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (4). In a randomized, 8-week, double-blind, placebo-controlled study in 450 patients with major depression, fluoxetine (20 -0 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (5). 

Fleishaker JC, Herman BD, Pearson LK, Ionita A, Mucci M. Evaluation of the potential pharmacokinetic/ pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999 18 141-50. 

Bupropion, mirtazapine, reboxetine, or atomoxetine (add with caution and at lower doses since fluoxetine could theoretically raise atomoxetine levels) use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation... 

In the 1980s an entirely new class of antidepressant arrived with the SSRIs, firstly fluvoxamine immediately followed by fluoxetine (Prozac). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the United Kingdom. Further developments in the evolution of the antidepressants have been novel compounds such as venlafaxine, reboxetine, nefazodone and mirtazapine, and a reversible monoamine oxidase inhibitor, moclobemide. 

Cataplexy is most effectively treated with 5HT uptake-blocking drugs such as clomipramine or fluoxetine, or some other antidepressant drugs, e.g. reboxetine. 

Reboxetine. Most of the activity of rehoxetine resides in the 5.5 isomer (The marketed compound is RR and 55.) It is claimed to he superior to fluoxetine in severe depression. It is marketed in Europe. At least three tricyclic compounds, desipramine. nortriptyline, and the technically tetracyclic maprotiline are SNERIs. They, of course, have typical characteristic TCA side effects but lower anticholinergic and H -antihistaminic (sedative) effects than dimethyl compounds. SNERIs arc clinically effective antidepressants. 

Figure 8. Structures of the SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), the NSRI reboxetine, and the SNRI venlafaxine.

The potency of sertraline and its N-demethylated metabolite, desmethylsertraline, and paroxetine for inhibiting P-gp was comparable with that of quinidine (35). Fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and 0-demethylparoxetine showed intermediate inhibition, and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine showed only weak inhibition. No inhibition was found for 0-desmethylvenlafaxine. 

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