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How to really treat depression
Exercise, Prozac and electroconvulsive therapy (ECT) may
ultimately relieve depression in the same way.
That’s what the latest research, conducted on mice,
suggests, and the scientists are encouraged that similar processes are at work
in the human brain as well. According to the findings, published in the
journals Cell Stem Cell and Molecular Psychiatry, all of these therapies can
spur the growth of brain cells. And it seems that such neurogenesis, which
perhaps results from changes in levels of brain chemicals like serotonin, can
lift the symptoms of depression.
Since the mid-1990s, researchers have been piecing together
a theory of depression that accounts for the seemingly disparate triggers of
the mental illness, as well as the variety of treatments that seem to
counteract the negative mood.
And so far, this is what they believe: extreme or
uncontrollable stress, particularly early in life, can lead to excessive
release of the neurotransmitter glutamate in the brain. At these high levels, glutamate can damage or
even kill certain cells in the hippocampus, a region known for its role in
memory. This can lead to a thinning of
the neural network in this area, which contributes to depression for reasons
that are not yet clear. But antidepressant treatments all seem to promote the
birth of new brain cells in that part of the brain.
Moreover, “It’s not just growth of new nerve cells [in this
region],” says Bruce McEwen, professor of neuroscience at Rockefeller
University, ”There’s also plasticity of nerve cells all over the brain that is ongoing and can be facilitated or
blocked.” These changes may start in the
hippocampus, where new cells can be born, but older cells can be revitalized
elsewhere as well, perhaps even changing the circuit of nerve activity that
keeps people stuck in depressive thoughts and feelings.
MORE: Antidepressants: Are They Effective or Just a Placebo?
Now, Hongjun Song, professor of neurology and neuroscience
at Johns Hopkins University, documents how disparate treatments, from exercise
to antidepressants that manipulate serotonin levels, and even electrical
stimulation of certain brain regions, can ultimately trigger this nerve growth
that fights depression.
The brain must maintain a delicate balance, with complex
chains of signals keeping various opposing processes in check. One protein that stymies the growth of brain
cells, sFRP3, is useful in controlling cell growth from getting out of hand,
but could be harmful if it hampers necessary growth. Working with mice, Song
and his colleagues showed that antidepressant medications, ECT and exercise all
affect levels of sFRP3.
“If you treat with different classes of antidepressants or
ECT, they all lead to changes in expression of sFRP3,” says Song, who studied
Prozac (fluoxetine), a selective serotonin reuptake inhibitor (SSRI) and
imipramine, an antidepressant in another class of drugs called tricyclics,
which regulate multiple neurotransmitters.
The research showed that these drugs reduced levels of sFRP3 levels in
the hippocampus, which allowed new cells and connections to grow.
To further confirm the effect of sFRP3 on depression, Song
and his colleagues also genetically engineered mice without the sFRP3 protein;
these animals were less likely to show depressive responses when they were
forced to swim until exhaustion, an indication that they were less prone to
experiencing the negative mood state.
The research also found that in human patients, genes
associated with the protein affected how long it took depressed people to
respond to medication. Taken together, the latest data suggests that presence
of elevated levels of sFRP3 protein may increase vulnerability to depression by
preventing new nerve cells from growing in the hippocampal region. Similarly,
mice given ECT, and those that exercised regularly, also showed lower levels of
sFRP3.
MORE: Ketamine: Leading the Way Toward Fast-Acting
Antidepressants
So how do things as different as ECT, drugs and exercise
change the same protein? They all affected a single type of cell in the
hippocampus, known as granule cells.
“What matters is that you want to activate [these] granule cells,” says
Song. “If the animals do running, that leads to firing of those neurons,” he
says, explaining that all of the other treatments did so as well.
Further studies are needed to confirm whether consistently
high levels of the protein increase the likelihood of depression in human
patients, but if that’s the case, then activating granule cells, by way of
suppressing the release of sFRP3, might be a promising new way of treating
depression. So far, “no drugs are known [to affect it directly],” says Song,
“The next step is trying to find an approach where we can modulate the function
of sFRP3 as an antidepressant.”
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