In patients experiencing a major depressive episode, elevated levels of the
brain enzyme responsible for breaking down the monoamine neurotransmitters may
be responsible for a wide variety of presenting symptoms, a new imaging study
Researchers at the University of Toronto and Canada's Center for Addiction
and Mental Health (CAMH) reported in the November Archives of General
Psychiatry that levels of monoamine oxidase A (MAO-A) appear to be
significantly elevated throughout multiple brain regions in patients who are
in the midst of a major depressive episode and have not taken antidepressant
The increased levels of the enzyme could explain a putative reduction in
available monoamines—serotonin, norepinephrine, and
dopamine—thought for more than three decades to be at the root of mood
The team of researchers, led by Jeffrey Meyer, M.D., Ph.D., an associate
professor of psychiatry at the University of Toronto and lead researcher in
CAMH's Neurochemistry of Depression Program, used positron emission tomography
imaging to determine whether brain MAO-A, the enzyme responsible for breaking
down serotonin, norepinephrine, and dopamine in preparation for reuptake was
higher in those with untreated depression than in healthy control
The brain-imaging technique showed that in the patients experiencing a
major depressive episode, MAO-A was significantly higher in every brain region
that the researchers investigated. On average, MAO-A was 34 percent higher in
patients with untreated depression than in matched control subjects.
"In major depression," Meyer said in a press release,"
higher levels of MAO-A is the primary process that lowers monoamine
levels. Having more MAO-A leads to greater breakdown of key chemicals like
The report includes a detailed new monoamine model of depression, based on
the current imaging study and four previously published studies from Meyer and
his collaborators at CAMH.
Meyer emphasized that the lack of a clear and precise disease model has
long been a key barrier to making advances in depression treatment."
Having a disease model is like having a map," he said."
Once you have that map, you can really begin to understand how an
illness like depression works and offer more targeted and effective
Meyer's model of depression (see
FIG1 below) hypothesizes that
in addition to elevated levels of MAO-A, monoamine transporters also play an
important role in removing monoamines from active binding sites across the
synapse. Elevated levels of a particular transporter may aggravate already
lowered levels of a monoamine due to increased Mao-a by increasing
"An important aspect of our advanced monoamine model is that
individuals with depression lose chemicals like serotonin and dopamine at
different rates based upon transporter density," Meyer explained."
This helps explain why one person with depression may experience
[certain symptoms] while another may not, and [why] some people have more
severe symptoms than others."
The next step for researchers, Meyer and his team said, will be to
investigate why MAO-A levels are elevated in the brain of people with
depression. With this understanding, it might be possible to develop targeted
preventive therapies as well as more specific therapies for acute
"Elevated Monoamine Oxidase A Levels in the Brain: An
Explanation for the Monoamine Imbalance of Major Depression" is posted
PET imaging data suggest increased activity of monoamine oxidase A
(MAO-A) during a major depressive episode (B), resulting in reduced monoamine
activity in the synapse, compared with healthy subjects (A). This elevation,
paired with fewer monoamine transporters during a mood episode, only modestly
reduces available monoamine and leads to mild-to-moderate symptoms (C).
However, if increased MAO-A activity occurs with increased numbers of
transporters, a severe depletion in available monoamines could occur, possibly
leading to more severe symptoms (D).