Depression Traced to Overactive Brain Circuit
A brain imaging study by the NIH's National Institute of Mental
Health (NIMH) has found that an emotion-regulating brain circuit
is overactive in people prone to depression even when they are
not depressed. Researchers discovered the abnormality in brains
of those whose depressions relapsed when a key brain chemical messenger
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 sapped of tryptophan,
the chemical precursor of serotonin, the neurotransmitter that is
boosted by antidepressants.
Neither a placebo procedure in patients nor tryptophan depletion
in healthy volunteers triggered the mood and brain activity changes.
Brain scans revealed that a key emotion-processing circuit was overactive
only in patients in remission whether or not they had re-experienced
symptoms and not in controls. Since the abnormal activity did
not reflect mood state, the finding suggests that tryptophan depletion
unmasks an inborn trait associated with depression.
Alexander Neumeister, M.D., Dennis Charney, M.D., Wayne Drevets,
M.D., NIMH Mood and Anxiety Disorders Program, and colleagues, report
on their positron emission tomography (PET) scan study in the August
2004 Archives of General Psychiatry.
The NIMH researchers and others 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 even in healthy people from depression-prone
families. This added to evidence that a genetic predisposition that
renders some people vulnerable to inadequate serotonin activity
may be at the root of the mood disorder.
The researchers scanned subjects after their blood tryptophan levels
were reduced by about three-fourths, using a radioactive tracer
(a form of glucose, the brain's fuel) which reveals where the brain
is active during a particular experimental condition.
They randomly gave 27 unmedicated depressed patients-in-remission
and 19 controls either pills containing seven essential amino acids,
such as lysine and valine, or identical-looking placebo pills. Subjects
received either the active pills or placebos in repeated trials
over several days in a blind, crossover design.
Sixteen (59 percent) of the patients experienced a transient return
of symptoms under tryptophan depletion; their mood lifted to normal
by the next day. Compared to controls, the 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 the circuit activation as a
transient, mood-dependent phenomenon, the new evidence suggests
that circuit over-activation is likely an underlying vulnerability
trait, say 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
"Since brain function appears to be disregulated even when
patients are in remission, they need to continue long-term treatment
beyond the symptomatic phase of their illness," noted Neumeister,
who recently moved to the Yale University psychiatry department.
Also participating in the research were: Drs. Allison Nugent, Tracy
Waldeck, Omer Bonne, Earl Bain and Marilla Geraci, David Luckenbaugh,
NIMH; Dr. Markus Schwarz, Munich University Hospital of Psychiatry,
Dr. Peter Herscovitch, NIH Clinical Center PET Department.
NIMH is part of the National Institutes of Health (NIH), the Federal
Government's primary agency for biomedical and behavioral research.
NIH is a component of the U.S. Department of Health and Human Services.