Healthy Skepticism Library item: 2777

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Publication type: news

Begley S.
Some Drugs Work To Treat Depression, But It Isn't Clear How
THE WALL STREET JOURNAL 2005 Nov 18
http://online.wsj.com/public/article/SB113226807554400588-tRyDenS6jsMJ1_bOOLqdQQPzAgo_20051218.html?mod=tff_article

Keywords:
depression serotonin

Notes:

Ralph Faggotter’s Comments:

“ The hegemony of the serotonin hypothesis may be keeping patients from a therapy that will help them more in the long term. The relapse rate for patients on pills is higher than for those getting
cognitive-behavior psychotherapy.”

This very telling paragraph from near the end of this excellent article provides one of the reasons why the ‘chemical imbalance’ theory of depression is not only inaccurate but dangerous.

Full text:

The Wall Street Journal

November 18, 2005; Page B1

SCIENCE JOURNAL

By SHARON BEGLEY

Some Drugs Work To Treat Depression,
But It Isn’t Clear How

Hardly any patients know how Lipitor
lowers cholesterol, how Lotensin
reduces blood pressure, or even how
ibuprofen erases headaches. But when
it comes to Prozac, Zoloft and Paxil,
ads and glowing accounts in the press
have turned patients with depression
into veritable pharmacologists, able
to rattle off how these “selective
serotonin reuptake inhibitors” keep
more of the brain chemical serotonin
hanging around in synapses,
correcting the neurochemical
imbalance that causes depression.

There is only one problem. “Not a
single peer-reviewed article …
support[s] claims of serotonin
deficiency in any mental disorder,”
scientists write in the December
issue of the journal PLoS Medicine.

Indeed, a steady drip of studies have
challenged the “serotonin did it”
hypothesis. A 2003 mouse experiment
suggested that SSRIs work by inducing
the birth and growth of new brain
neurons, not by monkeying with
serotonin. In March, a review of
decades of research concluded that
something other than “changes in
chemical balance might underlie
depression.” And as Jeffrey Lacasse
and Jonathan Leo write in PLoS
Medicine, although ads for SSRIs say
they correct a chemical imbalance,
“there is no such thing as a
scientifically correct ‘balance’ of
serotonin.”

How did so many smart people get it
so wrong? Medicinal chemist Derek
Lowe, who works in drug development
for a pharmaceutical firm, offered an
explanation in his “In the Pipeline”
blog. “I worked on central nervous
system drugs for eight years, and I
can confidently state that we know
just slightly more than jack” about
how antidepressants work.

It is not for lack of trying. In
1965, psychiatrist Joseph Schildkraut
of Harvard University suggested that a
deficiency of a brain chemical causes
depression. With the success of drugs
that block the reuptake of these
chemicals, that idea started to look
pretty good.

Yet the evidence was always
circumstantial. You can’t measure
serotonin in the brains of living
human beings. The next best thing,
measuring the compounds that
serotonin breaks down to in
cerebrospinal fluid, suggested that
clinically depressed patients had
less of it than healthy people did.
But it was never clear whether
depression caused those low levels,
or vice versa. A 2002 review of these
early experiments took them to task
for such flaws.

There had always been data that don’t
fit the serotonin-imbalance theory.
Depleting people’s serotonin levels
sometimes changed their mood for the
worse and sometimes didn’t. Sending
serotonin levels through the roof
didn’t help depression, a study found
as early as 1975.

There is little doubt that the SSRIs
do what their name says, keeping more
serotonin in the brain’s synapses. But
the fact “that SSRIs act on the
serotonin system does not mean that
clinical depression results from a
shortage of serotonin,” says Dr. Leo,
professor of anatomy at Lake Erie
College of Osteopathic Medicine,
Bradenton, Fla. No more so, anyway,
than the fact that steroid creams
help rashes means that rashes are
caused by a steroid shortage.

A clue to how SSRIs do work comes
from how long they take to have any
effect. They rarely make a dent in
depression before three weeks, and
sometimes take eight weeks to kick
in. But they affect serotonin levels
right away. If depression doesn’t
lift despite that serotonin hit, the
drugs must be doing something else;
it’s the something else that eases
depression.

The best evidence so far is that the
something else is neurogenesis — the
birth of new neurons. When scientists
led by Rene Hen of Columbia
University and Ronald Duman of Yale
blocked neurogenesis in mice, SSRIs
had no effect. When neurogenesis was
unimpeded, SSRIs made the mice less
anxious and depressed — for rodents.
As best scientists can tell, SSRIs
first activate the serotonin system,
which is somehow necessary for
neurogenesis. That is what takes
weeks.

Claiming that depression results from
a brain-chemical imbalance, as ads do,
is problematic on several fronts.
Patients who believe this are more
likely to demand a prescription. If
you have a disease caused by too
little insulin, you take insulin; if
you have one caused by too little
serotonin, you take serotonin
boosters.

Most people treated for depression
get pills rather than psychotherapy,
and this week a study from Stanford
University reported that drugs have
been supplanting psychotherapy for
depressed adolescents. Clinical
guidelines call for using both, and
for psychotherapy to be the
first-line treatment for most kids.
Psychotherapy “can be as effective as
medications” for major depression,
concluded a study in April of 240
patients, in the Archives of General
Psychiatry. Numerous other studies
find the same.

The hegemony of the serotonin
hypothesis may be keeping patients
from a therapy that will help them
more in the long term. The relapse
rate for patients on pills is higher
than for those getting
cognitive-behavior psychotherapy.

Some 19 million people in the U.S.
suffer from depression in any given
year. For many, SSRIs help little, if
at all. To do better, we have to get
the science right.

Write to Sharon Begley at
sciencejournal@wsj.com