Posted by Eddie Sylvano on April 16, 2003, at 10:42:53
In reply to substance-P antagonists, posted by Elizabeth on April 15, 2003, at 20:40:31
Here's commentary on the topic from the Medscape editor. Pretty interesting stuff, particularly the intestinal motility bit. I always seem to get bad GI cramping during depressive flare ups, so maybe this will be good for a specific depressive subtype with such features...
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Sidebar: Letter from the Editor
Von Euler and Gaddum reported in 1931 that a powdered extract of horse brain and intestine could lower blood pressure and stimulate muscle contractions in rabbit duodenum. Forty years elapsed before the active agent, deemed substance P (for "powder") (SP), was shown to be an 11-amino acid neuropeptide, one of a larger class of tachykinins having vasodepressor and intestinal stimulatory effects. If you remember anything about SP from your training (and don't be embarrassed if you don't), it's probably that it had something to do with pain modulation. So what does that have to do with depression?That was my thought five years ago when Kramer and colleagues (1998) published a ground-breaking study in Science involving the SP receptor antagonist (SPA) MK-869. They compared MK-869 with the selective serotonin reuptake inhibitor (SSRI) paroxetine and placebo in a six-week clinical trial involving 213 outpatients with major depression. The SPA was equal in efficacy to paroxetine and superior to placebo, but with a side-effect profile better than that of the SSRI. The implications were startling: a new compound with clinical properties as good or better than those of a first-line antidepressant, but acting via a completely novel mechanism. Moreover, that mechanism appeared to be independent of monoamine neurotransmission, distinguishing it from the effects of every other proven antidepressant treatment.
It turns out that SP-containing neurons occur in many brain regions that have been implicated in the pathogenesis of depression, including basal ganglia, midbrain, hypothalamus, amygdala and hippocampus. Moreover, SP is co-localized with other neurotransmitters that are relevant to the pathophysiology and treatment of affective disorders, including serotonin, dopamine and corticotropin releasing hormone (CRH). Good studies of SP in humans have been limited, which is why those highlighted in our lead article this month are worth noting. It's been shown that SP levels are high in anxious parachutists (but aren't affected by the stress of the jump itself) (Schedlowski et al. 1995) and in civilians under threat of missile attack during wartime (Weiss et al. 1996). The implication is that SP may be involved in more lasting anxiety states rather than in the response to acute stress, but little is known about SP in patients diagnosed with psychiatric disorders.
Meanwhile, it's been five years since the Kramer et al. paper was published. The major pharmaceutical manufacturers have been working hard to bring SPAs forward in clinical trials. Rumors abound in this area, with reports of successes in some indications and failures in others. One especially intriguing report using positron emission tomography (PET) suggested that very high levels of brain SP receptor binding were associated with therapeutically significant antidepressant and antiemetic effects (Hargreaves 2002). However the facts on SPAs are closely held proprietary information, so it's difficult to know just how close we are to seeing these compounds in the clinic. If they are ultimately found to be safe and effective in depression or anxiety, they will end up turning all those pharmacologic treatment algorithms you've memorized into scratch paper. In the meantime, we should learn as much as we can about what SP is really about in humans.
— Lawrence H. Price, M.D., Editor
poster:Eddie Sylvano
thread:219669
URL: http://www.dr-bob.org/babble/20030411/msgs/219808.html