Minor Depression: Dopaminergic/Noradrenergic Agents

By | February 5, 2015

Dual-mechanism dopaminergic/noradrenergic antidepressants are not a popular focus of drug development programs; only a small percentage of drugs in development are based on this mechanism. These compounds offer the promise of freedom from sexual side effects (bupropion [GSK’s Wellbutrin, Wellbutrin XR] is commonly praised for its freedom from sexual side effects), but they have poor efficacy in treating the anxiety associated with depression. Lack of anxiolytic effect essentially translates into lack of efficacy for antidepressant drugs because as many as 50% of depressive patients are at risk of an anxiety disorder. Several studies show that on a lifetime basis, 40-60% of people with major depression also have an anxiety disorder. Bupropion acts on the noradrenergic and dopaminergic system by inhibiting reuptake of norepinephrine and dopamine. Because it does not affect the serotonergic system, this drug has become a common alternative for patients unable to bear the side effects associated with serotonin-reuptake inhibition. However, its poor efficacy in managing comorbid anxiety often relegates the drug to adjunct use with serotonergic-acting drugs. GSK has a similar noradrenergic/dopaminergic agent, radafaxine, in Phase II development in Europe. Although no clinical trial data are publicly available, the results of any antidepressant trials evaluating radafaxine are expected to be similar to those of bupropion trials because of the drugs’ similar mechanisms of action. Solvay’s SLV-308 (SME-308), a partial D2 agonist and noradrenergic agonist with 5-HTia agonist properties, is also in Phase II development for major depression, but publicly available data concerning the drug are limited.

Mechanism Of Action

The symptoms of depression are presumed to result from poor uptake of monoamines (serotonin, norepinephrine, dopamine) by post-synaptic transporters. The leftover monoamines are reabsorbed by the presy-naptic cell; consequently, the presynaptic cell releases fewer monoamines into the synaptic cleft. The net result is a monoamine deficit in the synaptic cleft. Noradrenergic/dopaminergic-reuptake agents exert their antidepressant effects by blocking the reuptake of the monoamines noradrenaline and dopamine by presynaptic cells; these agents have no direct action on the serotonin system. The noradrenergic/dopaminergic-reuptake agents’ mechanism of action makes them more effective in managing the cognitive, psychomotor, and fatigue symptoms of minor depression than they are in managing the comorbid anxiety.

Radafaxine

GSK’s radafaxine (GW-353162) is in Phase II trials for the treatment of major depression in the United Kingdom, where the drug is also under investigation for neuropathic pain, obesity, and restless leg syndrome (Phase Italy). The drug was in development for bipolar disorder, but Phase Italy trials were discontinued in December 2003. In a November 2004 company presentation to investors and financial analysts, GSK reported that although results from Phase II depression trials that evaluated lower doses (60 mg) of radafaxine did not meet primary end points for efficacy, the results of secondary end point analysis provided a basis for undertaking further clinical studies at higher doses (100-120 mg).

Like bupropion, radafaxine inhibits both dopamine and norepinephrine reuptake and most likely will have only marginal effects on serotonin and no antagonism of either alpha-1 or muscarinic receptors. This characteristic is an advantage for radafaxine because muscarinic-receptor blockade can cause anticholinergic effects such as dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment; alpha-1-adrenergic blockade can lead to postural hypotension, reflex tachycardia, dizziness, and sexual dysfunction.

It is assumed that future trial results in depression will be similar to those of bupropion trials because of the drugs’ similar mechanism of action. Bupropion was shown to be as effective as the selective serotonin reuptake inhibitor sertraline, with reduced rates of sexual dysfunction, in a large, placebo-controlled study in major depression. Sustained-release bupropion, 150-400 mg/day, was compared with placebo and sertraline, 50-200 mg/day, in a randomized study with outpatients (n = 360) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. Response to treatment was evaluated using the HAM-D, HAM-A, and the CGIS. At the eight-week end point, scores on all scales measuring efficacy were statistically significant when compared with placebo scores, and there were no statistically significant differences between sustained-release bupropion and sertraline. However, differences were found in rates of sexual dysfunction as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: patients taking sertraline experienced more sexual dysfunction throughout the study than did patients taking sustained-release bupropion. Side effects experienced by patients taking sertraline were similar to those of selective serotonin reuptake inhibitors (e.g., constipation, dry mouth, nausea). The most common side effects associated with bupropion use were nausea, dry mouth, headache, and insomnia.

Radafaxine will be a welcome alternative for patients who are either unresponsive to serotonergic agents or unable to tolerate their side effects. Because the similar agent bupropion is already available in United States, radafaxine’s biggest impact will be on the European and Japanese markets, where bupropion is unavailable (bupropion is branded as Zyban, a smoking cessation agent, in Europe). A major limitation for radafaxine will be its relatively poor efficacy in treating anxiety; this handicap will relegate the drug to second-line adjunctive therapy for the more than 50% of patients with depression who suffer comorbid anxiety.

SLV-308

Solvay is developing SLV-308 (also called SME-308) for the treatment of Parkinson’s disease (panic disorder), panic disorder, and depression. By January 2001, SLV-308 had entered Phase II trials for panic disorder, anxiety, and depression. Meiji Seika was involved in the development of SLV-308; however, by June 2003, the company discontinued its development agreement with Solvay.

SLV-308 is a partial D2 agonist and noradrenergic agonist with 5-HTia agonist properties. The agent’s additional serotonergic mechanism differentiates it from other agents in this category. However, it is unclear whether this agent will offer the anxiolytic properties (combined with freedom from sexual side effects) that this drug class so sorely needs for blockbuster success.

Escitalopram is an antidepressant of the SSRI class. It is approved for the treatment of children over 12 years of age and adults with major depressive disorder and anxiety disorder.

Common brands (equivalents) of Escitalopram, which the pharmacists offer you to buy according to your prescription or without a prescription: Anxiset-E, Aramix, Celtium, Cipralex, Citalax, Ectiban, Entact, Esertia, Esipram, Ipran, Lexam, Lexamil, Lexapro, Lextor, Meridian, Neozentius, Recita, S-Citadep, Seroplex, Sipralexa, Zepaz.