An emotion-regulating brain circuit is overactive in people vulnerable to depression even when they are not depressed, according to an imaging study published in the August issue of the Archives of General Psychiatry.

Researchers discovered the abnormality in brains of people whose depression
relapsed when serotonin level was experimentally reduced. Even when in remission, most subjects with a history of mood disorder experienced a temporary recurrence of symptoms when their brains were experimentally depleted of tryptophan, the chemical precursor of serotonin.

Neither a placebo procedure in patients nor tryptophan depletion in healthy volunteers triggered mood and brain activity changes. Positron emission tomographic scans revealed that a key emotion-processing circuit was overactive in patients in remission - whether or not they had re-experienced symptoms with tryptophan depletion- but not in controls.

Because the abnormal metabolic activity did not reflect perceived mood state, the finding suggests that tryptophan depletion unmasks an inborn trait associated with development of depression.

Alexander Neumeister, M.D., his colleagues, and other groups had previously shown that omitting tryptophan from a cocktail of several other essential amino acids washes out the precursor chemical from the blood and brain, depleting serotonin and often triggering symptoms in people with a history of depression--- and sometimes even in people with no history of personal depression but who come from families with a positive history for depression.

In the current study, American researchers scanned subjects with use of a radioactive glucose tracer after their blood tryptophan levels were reduced by about 75 percent: A total of 27 unmedicated depressed patients-in-remission and 19 healthy controls were randomized to pills containing seven essential amino acids or identical-appearing placebo pills. Subjects received either the active pills or placebos in repeated trials over several days in a blind, crossover design.

Of the 27 patients, 16 (59 percent) experienced a transient return of symptoms under tryptophan depletion; their mood lifted to normal by the next day. Compared with controls, patients showed increased brain activity in a circuit coursing through the front and center of the brain (orbitofrontal cortex, thalamus, anterior cingulate, and ventral striatum) - areas involved in regulating emotions and motivation that have been implicated in previous studies of depression. Whereas previous studies interpreted circuit activation as a transient, mood-dependent phenomenon, the new evidence suggests that circuit over-activation is likely an underlying vulnerability trait, according to the researchers.

Because of its ability to unmask what appears to be a trait marker for major depressive disorder, the researchers suggest that tryptophan depletion may be a useful tool for studying the genetic basis of depression.

"Since brain function appears to be dysregulated even when patients are in remission, they need to continue long-term treatment beyond the symptomatic phase of their illness," noted Neumeister, the lead author of the study.