'Substance P' Antagonist Relieves Depression

An investigational compound that blocks the neurokinin "substance P" has demonstrated robust antidepressant effect in preliminary clinical testing against paroxetine (Paxil) and placebo. For several years, Merck & Co. researchers have been searching for such a compound useful for the migraine or general pain conditions suggested by substance P distribution in the nervous system. This finding has been described by Edward Scolnick, M.D., president of Merck Research Laboratories, as "a breakthrough discovery" in mental health care.

Experts outside Merck Research have concurred that this is an important discovery. James Krause, Ph.D., vice-president of Neurogen Corp., told Wall Street Journal reporter Robert Langreth, "The Merck finding will stimulate a whole new avenue of research into understanding the biology of depression."

Steven Hyman, M.D., director of the National Institute of Mental Health (NIMH), found the results of the phase II trial "an extraordinary surprise." If the findings hold up in subsequent, larger phase III trials, "it gives researchers a whole new target for developing depression treatments," Hyman said.

In the Sept. 11 issue of Science, Mark Kramer, M.D., senior research physician at Merck, Nadia Rupniak, Ph.D., senior research fellow at Merck in the United Kingdom, and colleagues reported preclinical indications that substance P antagonists affect stress response and emotion. They rapidly progressed to a phase II clinical test in patients with depression (Kramer et al.,1998).

The randomized double-blind, placebo-controlled study comprised 210 patients with major depressive disorder and "moderately high" anxiety. Subjects given single 300 mg daily doses of the agent, designated MK-869, and 20 mg of paroxetine produced similar reductions in total Hamilton Depression Rating Scale (HAM-D-21) scores from baseline to week 6 that were significantly superior to placebo response.

The substance P neuropeptide was first identified by Swedish researchers in 1931. It has been investigated extensively since 1970, when its chemical structure was characterized and a synthesized form became available. Its function has remained elusive.

"Substance P was considered a neurotransmitter in search of a disease," was the comment made to Langreth by Alan Metz, M.D., director of medical affairs for the central nervous system (CNS) section of Glaxo Wellcome, where substance P antagonists have been investigated for possible benefit in nausea and other conditions.

Kramer is credited for positing that substance P might be more closely linked to "psychic pain" than to the previously investigated headache or general pain. He noted that while substance P has been determined to be the most abundant neurokinin in the mammalian CNS, it is particularly concentrated in the amygdala and other regions thought critical for regulation of affective behavior and neurochemical responses to stress.

His hypothesis was taken up by Rupniak, whose group subjected the neurokinin and two antagonists to a series of preclinical evaluations of their effects on stress and emotion. In common with traditional anxiolytic and antidepressant medications, the substance P antagonists were found to inhibit stress-induced vocalizations in guinea pigs. In one of several studies they conducted, the substance P antagonists were comparable to these traditional medications in reducing vocalizations in guinea pig pups separated from their mother and littermates. The audible cries they made in this circumstance were similar to those evoked by central infusion of substance P.

The investigators reported, "These studies demonstrate that selective pharmacological blockade of substance P receptors is capable of inhibiting behavioral responses to psychological stress in a manner resembling the effect of clinically used psychotherapeutic agents."

Subsequent studies by this group have shown that substance P antagonists do not act by augmenting norepinephrine or serotonin in a manner occurring with established antidepressants; but a mechanism of action remains to be elucidated. The investigators indicate only that the atypical profile emerging from their evaluations, "supports the proposal that the antidepressant activity of substance P antagonists is mediated via a novel mechanism."

Although mechanisms of action remain unknown, the investigators suspect that the amygdala is a principal site of action, not only for MK-869, but for traditional antidepressants as well. They note that focal injection of the tricyclic antidepressant imipramine (Tofranil) into the amygdala has produced similar responses in psychological stress evaluations as those produced after systemic administration. A major output projection from the amygdala is to the hypothalamus, and the investigators have demonstrated that electrical stimulation of the amygdala produces the same defensive rage syndrome in cats as direct stimulation of the hypothalamus. They hypothesize that substance P enhancement of transmission from the medial amygdala to the hypothalamus mediates emotional response to stress.

Alleviating Pain of Depression

The substance P antagonist MK-869 was developed to be orally bioavailable with good CNS penetration and receptor specificity, and is sufficiently long-acting for single daily dosing. In the 6-week evaluation of its safety and efficacy in humans, the HAM-D-21 was applied at weeks 1, 2, 4 and 6 as the primary measure of efficacy. An antidepressant effect of MK-869 was apparent at all intervals, and was corroborated by Clinical Global Impression Severity Scale ratings.

Fifty-four percent of patients receiving MK-869 achieved a 50% or greater reduction in baseline HAM-D score by week 6, compared to 43% of those receiving paroxetine and 28% with placebo. Further, 43% of the patients receiving MK-869 achieved HAM-D scores below 10, which the investigators regarded as a "complete" response, compared to 33% of those on paroxetine and 17% of patients receiving placebo. The anxiolytic effects of the active drugs, assessed with the Hamilton Anxiety Scale, were similar through week 4, with somewhat greater effect evidenced with paroxetine by week 6.

Differences in specific HAM-D item results were assessed to further distinguish the active agents. Patients receiving MK-869 had more improvement with insomnia than did patients on paroxetine, while those receiving paroxetine demonstrated greater improved insight.

The investigators characterized the adverse effects from MK-869 as "generally similar to placebo," except for somnolence and asthenia, which occurred with both active agents and were described as "mild and typically transient." There were notably fewer patients experiencing sexual dysfunction with MK-869 (3% compared to 4% on placebo) than the 26% of patients receiving paroxetine.

Adverse effects prompted 19% of those receiving paroxetine to discontinue treatment, compared to 9% of those on MK-869 and 9% of those on placebo. Nausea, occurring in 29% of patients receiving paroxetine compared to 10% of those receiving MK-869, was the principal cause for patients discontinuing treatment with paroxetine. No specific side effect emerged as a principal cause for discontinuing either MK-869 or placebo. Treatment with MK-869 was not associated with drug-seeking behavior, or clinically significant changes in physical examination findings, including vital signs, weight or heart rate (measured by electrocardiogram).

NIMH director Hyman has urged the researchers to go forward in their clinical testing to include patients who have not improved on traditional antidepressants, and Kramer commented that he is excited about the therapeutic potential of this product. "We are dealing with a new system that is probably closer to the source of depression," he said.

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Reference

1.

Kramer MS, Cutler N, Feighner J et al. (1998), Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640-1645.