Posted by Eddie Sylvano on April 16, 2003, at 10:36:51
In reply to substance-P antagonists, posted by Elizabeth on April 15, 2003, at 20:40:31
Medscape had a report on a recent substance P trial...
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Phase II Study of an SPA
A Phase II 6-week randomized double-blind study by Rupniak and Kramer of both men and women with depression compared safety/tolerability and efficacy of an SPA with the selective serotonin reuptake inhibitor (SSRI) paroxetine.The researchers randomly assigned 213 outpatients with major depressive disorder to aprepitant, an SPA; paroxetine; or plabeco. Patients were moderately depressed, had moderately high anxiety and were moderately ill according to the 17-item Hamilton Rating Scale for Depression (HAM-D-17), the Hamilton Rating Scale for Anxiety (HAM-A) and the Clinical Global Impressions-Severity of Illness scale (CGI-S), respectively. The mean baseline HAMD-17 score was 25 in all three groups.
The primary efficacy measure was the total score on the 21-item Hamilton Rating Scale for Depression (HAMD-21). Secondary measures included the Hamilton Rating Scale for Anxiety (HAM-A) total score and the Clinical Global Impressions-Severity of Illness scale (CGI-S) score.
After six weeks of treatment, improvement from baseline on the HAMD-21 was significantly greater (4.3 points, p=0.003) in patients taking aprepitant than in those taking placebo. Aprepitant showed similar efficacy to paroxetine in reducing symptoms of depression as measured by the HAM-D-21. The antidepressant effect of both drugs was evident as early as week one of the study, and continued to accrue throughout the course of the study. Patients receiving aprepitant had a higher rate of complete response than those receiving paroxetine and a significantly higher rate (p=0.001) than those in the placebo group.
Aprepitant also significantly reduced symptoms of anxiety in these patients. After six weeks of treatment patients taking aprepitant showed a larger decrease from baseline in their HAM-A scores than did those taking placebo (p=0.002).
The rate of adverse effects was the same in the aprepitant and placebo groups, causing 9 percent of the patients in each group to withdraw from the study. This adverse effect rate compared favorably with the 19 percent rate in the paroxetine group. Sexual dysfunction was significantly more frequent in patients taking paroxetine than in those taking aprepitant (p<0.001).
A subsequent dose-finding study by Rupniak and Kramer investigated the efficacy and tolerability of four dosages of aprepitant (10 mg, 30 mg, 100 mg and 300 mg, once daily) compared to active (fluoxetine 20 mg once daily) and placebo controls. This study was unable to draw any conclusions about aprepitant, as the improvement in the placebo group was equal to that in the active fluoxetine control group. "You couldn't tell whether they got better naturally," said Krishnan.
According to Krishnan, approximately 50-60 percent of all controlled trials with various antidepressants fail - i.e., show no difference between active drug and placebo.
"The dose-response trials have the highest failure rate because they have a lot of arms, so they end up being big studies," elaborated Dr. Krishnan. The larger studies have a greater risk of failure because there are more opportunities for variability between subjects, variability between sites, inconsistencies in expectations, etc., he explained.
Pfizer and other pharmaceutical companies are currently developing compounds similar to aprepitant, stated Krishnan. For example, the positive results seen in the Phase II trial were recently replicated with a structurally different SPA, known as Compound A.
"It is likely that these compounds will have more than one use," noted Krishnan. "SP antagonists will also be used in treating nausea."
He added that the clinical impact of the SPAs will depend on the side effects of each compound and how they compare to the side effects of existing drugs. Phase III trials will be instrumental in establishing the role of SPAs in the treatment of depression.
"As a class this will give another option for treating people with depression... an option that's sorely needed," concluded Krishnan. "Sixty percent of them [patients with depression] get better and another 30 to 40 percent clearly need another option."
poster:Eddie Sylvano
thread:219669
URL: http://www.dr-bob.org/babble/20030411/msgs/219806.html