New Antidepressants Target Aches and Pains, Too

Studies have documented that nearly 80 percent of patients with depression first present solely with physical symptoms, not emotional complaints.

Indeed, according to John Greden, M.D., chair of APA’s Council on Research and director of the University of Michigan’s Depression Center, in studies of patients treated for depression, 90 percent of those with residual symptoms after receiving antidepressants had mild to moderate physical complaints, such as fatigue, headache, or pack pain—even though their mood symptoms may have improved. Research shows that patients with residual symptoms are three times more likely to relapse than those who have no residual symptoms.

How to effectively treat patients for those residual, especially physical, symptoms has been the topic of discussion at numerous psychiatric and other clinical meetings the world over, including last month’s meeting of the American Association for Geriatric Psychiatry. Now, clinicians may get a little help from antidepressants in development and at least one medication that is very close to market approval.

Research has indicated that an antidepressant that causes a change in the metabolism of both serotonin and norepinephrine could be far more effective at relieving both emotional and physical complaints in depression (Psychiatric News, April 4).

The first “dual reuptake inhibitor,” or serotonin-norepinephrine reuptake inhibitor to be released in the U.S. market was venlafaxine (Effexor XR). There is at least one report—an unpublished study presented at the annual meeting of the American College of Neuropsychopharmacology last December—that venlafaxine is more effective than several SSRIs (fluoxetine, paroxetine, and fluvoxamine) in relieving both emotional and physical symptoms due to depression and anxiety disorders.

Clinicians, however, have seen numerous patients who experience significant side effects with the drug, including nausea, dizziness, excessive sweating, and nervousness. In addition, there have been rare reports of significant increases in blood pressure associated with the drug.

Most of venlafaxine’s side effects occur with higher doses, which many patients need to get good control of their emotional symptoms, said Steven Roose, M.D., a professor of clinical psychiatry and director of the Neuropsychiatric Research Clinic at the New York State Psychiatric Institute at Columbia University, at the AAGP meeting.

“At higher doses, venlafaxine has a stronger effect on norepinephrine, which is where many of the side effects come from, but is also has more of an effect on physical symptoms like pain.”

In fact, studies have shown that while venlafaxine does inhibit reuptake of both serotonin and norepinephrine, its effect on serotonin is 30 times stronger than on norepinephrine.

That strong preference for one neurotransmitter over another is just one reason drug researchers have been searching for a “more balanced” dual reuptake inhibitor.

Duloxetine, developed by Eli Lilly and Co., received its approvable letter from the FDA last fall, and Lilly hopes to receive final approval for marketing by the end of 2003. The new drug, which will be marketed under the trade name Cymbalta, is more equally balanced in its inhibition of serotonin vs. norepinephrine reuptake than venlafaxine, although it still favors serotonin 9 to 1 over norepinephrine.

Roose said that the clinical data with duloxetine so far are impressive, especially its ability to relieve both emotional and physical symptoms associated with depression. In depressed patients with aches and pains, a 60-mg, once-daily regimen achieved statistically significant reductions in ratings for headache, backache, shoulder pain, pain while awake, interference with activities of daily living, and overall feeling of well-being using the Visual Analogue Scale. In addition, significant reductions in both emotional and physical symptoms occur in days rather than weeks, and all ratings were significantly improved by the second week of medication therapy, as measured by the 17-item Hamilton Depression Rating Scale and Clinical Global Impression Scale change and improvement subscales.

In clinical trials to date, Lilly reported that the only adverse events that occurred at a rate higher than 1 percent that led to discontinuation of the medication were nausea (1.5 percent) and somnolence (1.4 percent). Other side effects not associated with discontinuation included dry mouth, constipation, decreased appetite, insomnia, fatigue, and blurry vision.

Other potential medications in development as antidepressants include drugs that antagonize substance-P, or its receptor NK-1, and antagonists of corticotrophin-releasing hormone. Although substance-P is known to modulate certain pain pathways, early study results have so far not addressed physical symptoms as opposed to emotional symptoms. ▪