A research report from the University of North Carolina (UNC) at Chapel Hill has surprised investigators with its implications that some people with depression have a persistent biologically based abnormality in their brain’s serotonin system, even when the patients are in remission.
Ten years ago, Robert Golden, M.D., a professor and chair of psychiatry at UNC, and his colleagues discovered that people with clinical depression showed a blunted hormonal response to a test that boosts serotonin. The team showed that when subjects were administered clomipramine, a tricyclic antidepressant that is a potent serotonin reuptake inhibitor that would normally boost serotonin levels with an initial dose, the serotonin systems of those with depression were "sluggish in response and not working properly."
Their methodology involved measuring plasma prolactin levels in response to the clomipramine challenge test. Serotonin increases secretion of prolactin by the pituitary gland. Golden likened the finding to a serotonin system that needed a tune-up, because the blunted prolactin response in patients with depression indicated they were not getting "much gas mileage" from the increase in serotonin availability. Several other researchers have, in the decades since, repeated the findings.
In the new report, which appeared in the May Neuropsychopharmacology, Golden’s team showed that as a group, people with depression have a blunted prolactin response to the clomipramine challenge test, even when they are in remission.
"What we had thought was that this abnormal index of serotonin function would sort of be the equivalent of fever in strep throat," Golden told Psychiatric News, "in that when the patient got better, the response would normalize."
Golden said the team originally thought that the initial blunted response to clomipramine might normalize early on in treatment with antidepressant medication, signaling that the patient would respond to the treatment even before his or her symptoms improved.
"What we found was that for the group as a whole, both in those who did respond to treatment and those who didn’t respond, there was no normalization," Golden said. "Then, when we followed the responders longitudinally, to our surprise, even when they were completely well, medication free, and in a state of remission, the abnormal blunted response persisted."
Golden said that the team—in retrospect—should not have been surprised. Depression has long been thought to have genetic influences. It would stand to reason that the biological abnormality would not simply "go away with a little drug treatment."
Golden cautioned that the abnormal response to clomipramine was not a ubiquitous finding; some study patients who were depressed did show a normalized response to the drug.
"So what I think this might turn out to be," Golden suggested, "is a way of teasing out who is destined to have multiple recurrent episodes of depression without long-term treatment."
Golden hypothesized that the serotonin system in patients with a blunted response to the clomipramine challenge test is analogous to a car engine in need of a tune-up. Under normal conditions, the engine may not be running properly, but the car nonetheless gets riders to their destination. But, he told Psychiatric News, if the car is driven up a mountain road, the engine probably could not handle the additional stress. Everything the engine needs to run is still available, he said, but it isn’t able to function efficiently—it needs a tune-up.
"If you only look at serotonin levels in the brain—or for that matter, norepinephrine, which I think is just as important—you’re only getting part of the picture," Golden said. "If you just measure serotonin or norepinephrine receptors, and even if you see consistent findings, up or down, you don’t know how to interpret that. There’s an interplay between the neurotransmitter and the receptor that needs to be teased out."
With the clomipramine challenge test, "we give the serotonin system in the brain a known challenge [using a specific dose of clomipramine], and we let it show us how much mileage we can get," he explained.
By giving the clomipramine intravenously in low doses, Golden said, the team has minimized many potential problems, including bypassing "first-pass metabolism" of the drug through the liver after an oral dose and highly variable absorption from the stomach in different individuals.
Also by giving a low dose (12.5 mg, IV), Golden has achieved a "fairly clean" action of the drug. At that low dose, clomipramine is a potent serotonin reuptake inhibitor but has no detectable effects on norepinephrine or dopamine.
"The next exciting question," Golden said, "is why are the test results abnormal in these people? If we can figure out which component of the complicated serotonin system is responsible for this persistent laboratory abnormality, then that could be a target for developing new treatments."
The team is repeating the same study in a new group of people with depression and their first-degree relatives, as well as a control group of "super healthy" people—those with no personal or family history of depression, he explained.
"What we expect to see is that some family members of patients with depression will have an abnormally blunted test, though no symptoms of depression," Golden said.
The team will look for genetic polymorphisms in subjects’ serotonin system and try to relate these to results on the clomipramine challenge test.
"It might be a way," Golden postulated, "for this type of biological subtyping of depression—those with a blunted clomipramine challenge test as one subtype—to identify patients who need a particular intervention and/or to identify those patients who will need long-term treatment to prevent relapsing through multiple episodes."
An abstract of "A Longitudinal Study of Serotonergic Function in Depression" is posted on the Web at www.elsevier.com/gej-ng/10/33/33/show/. ▪