New SNRI Versus SSRI for Social Functioning

A New Drug Application was submitted to the U.S. Food and Drug Administration in May for the selective norepinephrine reuptake inhibitor (SNRI) antidepressant, reboxetine. The manufacturer, Pharmacia & Upjohn, has marketed the antidepressant as Edronax in the United Kingdom since July 1997, and in October 1997 received approval through the European Mutual Recognition Procedure to distribute it in 11 other European Union Countries during 1998.

According to manufacturer data, reboxetine has low affinity for adrenergic and muscarinic receptors. It has evidenced low toxicity in animal studies and low liability for significant drug interactions (Dostert et al., 1997). Stuart Montgomery, M.D., of the Imperial College of Medicine at St. Mary's Hospital in London, summarized these data and the results from clinical studies at the 1997 meeting of the European College of Neuropsychopharmacology (ECNP) in Vienna.

Montgomery reported that fewer adverse events occurred in the reboxetine-treated population than in those receiving a tricyclic antidepressant (TCA) in placebo-controlled comparisons. The proportion of patients experiencing adverse events with reboxetine (67%) was similar to those receiving fluoxetine (Prozac) (65%) in two comparative studies with this selective serotonin reuptake inhibitor (SSRI), although the type of adverse events was different with these agents.

"The good tolerability of reboxetine is reflected in the low numbers of patients who withdrew from the trials due to adverse events," Montgomery said. "Reboxetine is also demonstrated to be well-tolerated over the long term, as there was no difference from placebo in the proportion of patients who experienced adverse events over a one-year study period [28.0% versus 22.8% in the reboxetine and placebo groups, respectively]."

Another nontricyclic, noradrenergic antidepressant-nomifensine (Merital) from Hoechst-was available briefly in the United States over a decade ago, before being recalled for causing fatal immune hemolysis. Nomifensine was marketed with the tag, "vive la difference!" to emphasize its distinction from the prevalent TCAs. It is anticipated that promotion of reboxetine, once approved by the FDA, will also distinguish the agent from the currently prevailing SSRI antidepressants.

Considering the comparative trials with reboxetine conducted in Europe (in which it is referred to as an NARI or noradrenaline reuptake inhibitor), it may well be promoted as superior for particular outcomes and for specific populations of patients with depression.

In addition to the studies demonstrating that reboxetine antidepressant efficacy is superior to placebo and comparable to a TCA, a head-to-head and a placebo-controlled study were conducted to compare reboxetine to fluoxetine. Montgomery related that a post hoc analysis of the two studies showed reboxetine superior to fluoxetine in the subset of patients having the most severe depression. In a review article, Montgomery (1997) wrote, "This superiority of reboxetine over fluoxetine is consistent with the reports of other potentially superior antidepressants, such as venlafaxine [Effexor] and clomipramine [Anafranil] which have been found to be significantly better than fluoxetine in treating severe depression."

Reboxetine's superiority was vigorously debated (Sackeim, 1996), however, as have the reasons for disparate findings between antidepressant trials conducted in Europe and in the United States (Ackenheil et al., 1996). Methodology issues raised about the Danish University Antidepressant Group (1990) comparison of clomipramine to an SSRI (paroxetine [Paxil], not fluoxetine), for example, included the choice of the predominately serotonergic clomipramine as the representative TCA, patient selection, and the dose and duration of the antidepressant treatments.

For the placebo-controlled comparison of reboxetine with fluoxetine, Pharmacia & Upjohn-sponsored investigators developed a self-reporting scale to assess changes in social motivation and behavior. They chose not to utilize any of the existing instruments, which, they commented, "were considered too complex to be used in a multicentre, multinational clinical trial" (Dubini et al., 1997).

The new 21-item instrument, the Social Adaptation Self-evaluation Scale (SASS) underwent a validation procedure based on data from a general population survey in 4,000 individuals and from two of the reboxetine comparative trials (against, respectively, placebo and fluoxetine in a total of 549 patients with major depression). The developers of the scale reported the SASS to be "valid, reliable and sensitive to change" (Bosc et al., 1997). They elaborated, "In view of its simplicity of use, and of its peculiar characteristic of investigating patient perspective on self and environmental perception, and on social motivation and behaviour, the scale represents a useful additional tool for the evaluation of social functioning in depression."

In describing the use of the SASS scale to compare effects of reboxetine and fluoxetine, David Healy, M.D., of the University of Wales College of Medicine, Bangor, U.K., commented at the 1997 ECNP meeting, "Information using SASS may provide a means of balancing the benefits and drawbacks of treatment in a way that conventional side-effect profiling of antidepressants doesn't." He posed the question, "If SASS is a useful outcome measure, then should it be adopted in all studies of antidepressants?"

To discern differences in improved social function between patients receiving fluoxetine and reboxetine, the researchers administered the SASS scale to 302 patients with major depression, ages 18 to 65, in 33 centers in Europe and Brazil (Dubini et al., 1997). All patients presented with an episode of depression of between one to four months and with a pretreatment Hamilton Depression Rating Scale total score greater than 22. After a minimum washout period of four days from prior antidepressant treatment, patients were randomized to receive eight weeks of treatment with either 8 mg/day reboxetine, 20 mg/day fluoxetine or placebo. At the end of the fourth week, dosage was increased, depending on therapeutic response, to 10 mg/day of reboxetine or 40 mg/day fluoxetine.

Dubini et al. reported that the mean SASS total score at last assessment was superior to placebo for both reboxetine and fluoxetine. The investigators noted that in the 91 patients who achieved remission in depressive symptoms, the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo.In their direct comparison of the two active agents, the investigators reported "a significant correlation between change in item score and treatment for nine items, in favour of reboxetine." Six of these nine items having maximal association with reboxetine rather than fluoxetine were related to improvement in negative self-perception and to active social behavior.

Dubini and colleagues concluded, "While social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment, noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action, resulting in a better quality of remission in terms of social functioning."

It is likely that as the relative efficacy of antidepressants for patients with severe depression continues to be argued, so too will the conclusion from this single study that reboxetine offers a superior effect on social functioning. If that debate prompts additional investigation of such therapeutic outcomes, however, the scope of future antidepressant clinical trials will be beneficially widened from quantifying effects on depressive symptoms to evaluating changes in the quality of life.

References:

References

1.

Ackenheil M, Lecrubier Y, panel co-chairs (1996), Clinical Trials in Depressed Patients: Differences between Europe and the United States. Presented at the 35th Annual Meeting of the American College of Neuropsychopharmacology. December; San Juan, Puerto Rico.

2.

Bosc M, Dubini A, Polin V (1997), Development and validation of a social functioning scale, the Social Adaptation Self-evaluation Scale. Eur Neuropsychopharmacol 7(suppl 1):S57-S70. Discussion S71-S73.

3.

Danish University Antidepressant Group (1990), Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord 18(4):289-299.

4.

Dostert P, Benedetti MS, Poggesi I (1997), Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol 7(suppl 1):S23-S35. Discussion S71-S73.

5.

Dubini A, Bosc M, Polin V (1997), Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning. J Psychopharmacology 11(4 suppl):S17-S23.

6.

Montgomery S (1997), Reboxetine: Additional benefits to the depressed patient. J Psychopharmacology 11(4 suppl):S9-S15.

7.

Sackeim HA, panel chair (1996), Are TCAs more effective than SSRIs in severe depression? Presented at the 35th Annual Meeting of the American College of Neuropsychopharmacology. December; San Juan, Puerto Rico.