The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile

Abstract

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets. Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8-10 mg/day) and that it exhibits minimal drug-drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo-controlled, active comparator-controlled and open-label uncontrolled studies in both short-term and long-term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short- or long-term placebo-controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active-controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side-effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.

The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

“…An analysis of the completers of the study alone, which showed a 49% improvement, revealed an efficacy of reboxetine, which would be expected during a clinical study using an antidepressant. 26 Additionally to this therapeutic effect of reboxetine, the data clearly show an advantage of the combined therapy of reboxetine and celecoxib compared to the therapy with reboxetine alone. The trend to significance regarding the patients showing response or remission supports this view.…”

“…Although the reduction of 8.1 HAMD scores in the reboxetine (and placebo-) group is relatively small regarding an active antidepressant, it is in accordance with four other clinical studies of reboxetine, which show a decrease of the HAMD scores between six and 10.9. 26 The small decrease is due to the high number of dropouts in the reboxetine-alone group. Partly, the patients dropped out due to side effects.…”

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

“…Their clinical efficacy is hypothesized to be linked mainly with potent inhibition of presynaptic norepinephrine transporters (Wong et al, 2000;Hajós et al, 2004;Simpson and Plosker, 2004). Furthermore, recent studies have suggested that the drugs are potentially useful for the treatment of several other psychiatric conditions, including anxiety disorders, eating disorders, substance use disorders, and narcolepsy (Kadhe et al, 2003;Hajós et al, 2004;Szerman et al, 2005;McElroy et al, 2007;Geller et al, 2007;Wilens et al, 2008).…”

“…Atomoxetine (originally named tomoxetine) and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/ hyperactivity disorder and depression, respectively (Hajós et al, 2004;Garland and Kirkpatrick 2004;Simpson and Plosker, 2004;Supplementary Figure S1). Their clinical efficacy is hypothesized to be linked mainly with potent inhibition of presynaptic norepinephrine transporters (Wong et al, 2000;Hajós et al, 2004;Simpson and Plosker, 2004).…”

A Case of Profound Weight Loss Secondary to use of Reboxetine

“…Reboxetine, the first selective norepinephrine re-uptake inhibitor used in the treatment of depression, mainly acts by binding to the norepinephrine transporter and blocking re-uptake of extracellular norepinephrine [1]. Increase in the appetite and weight gain are major problems in most of the psychiatric disorders either as a symptom or as a drug induced side effect.…”