How do antidepressants work? - Neil R. Jeyasingam
In the 1950s,
the discovery of two new drugs
sparked what would become a multibillion
dollar market for antidepressants.
Neither drug was intended
to treat depression at all—
in fact, at the time, many doctors
and scientists believed psychotherapy
was the only approach
to treating depression.
The decades-long journey of discovery
that followed
revolutionized our understanding
of depression—
and raised questions
we hadn’t considered before.
One of those first two antidepressant
drugs was ipronaizid,
which was intended to treat tuberculosis.
In a 1952 trial,
it not only treated tuberculosis,
it also improved the moods of patients
who had previously been diagnosed
with depression.
In 1956, a Swiss clinician observed
a similar effect when running a trial
for imipramine,
a drug for allergic reactions.
Both drugs affected a class
of neurotransmitters called monoamines.
The discovery of these
antidepressant drugs
gave rise
to the chemical imbalance theory,
the idea that depression is caused
by having insufficient monoamines
in the brain’s synapses.
Ipronaizid, imipramine,
and other drugs like them
were thought to restore that balance
by increasing the availability
of monoamines in the brain.
These drugs targeted several
different monoamines,
each of which acted on a wide range
of receptors in the brain.
This often meant a lot of side effects,
including headaches, grogginess,
and cognitive impairments
including difficulty with memory,
thinking, and judgment.
Hoping to make the drugs more targeted
and reduce side effects,
scientists began studying existing
antidepressants
to figure out which specific monoamines
were most associated
with improvements in depression.
In the 1970s, several different
researchers converged on an answer:
the most effective antidepressants
all seemed to act on one monoamine
called serotonin.
This discovery led to the production
of fluoxetine, or Prozac, in 1988.
It was the first of a new class of drugs
called Selective Serotonin
Reuptake Inhibitors, or SSRI’s,
which block the reabsorption of serotonin,
leaving more available in the brain.
Prozac worked well
and had fewer side effects
than older, less targeted antidepressants.
The makers of Prozac also worked
to market the drug
by raising awareness
of the dangers of depression
to both the public
and the medical community.
More people came to see depression
as a disease
caused by mechanisms beyond
an individual’s control,
which reduced the culture of blame
and stigmatization surrounding depression,
and more people sought help.
In the 1990s, the number of people being
treated for depression skyrocketed.
Psychotherapy and other treatments
fell by the wayside,
and most people were treated
solely with antidepressant drugs.
Since then, we’ve developed a more nuanced
view of how to treat depression—
and of what causes it.
Not everyone with depression responds
to SSRIs like Prozac—
some respond better to drugs
that act on other neurotransmitters,
or don't respond to medication at all.
For many, a combination
of psychotherapy and antidepressant drugs
is more effective than either alone.
We’re also not sure why antidepressants
work the way they do:
they change monoamine levels within
a few hours of taking the medication,
but patients usually don’t feel
the benefit until weeks later.
And after they stop
taking antidepressants,
some patients never experience
depression again, while others relapse.
We now recognize that we don’t
know what causes depression,
or why anti-depressants work.
The chemical imbalance theory
is at best an incomplete explanation.
It can’t be a coincidence that almost all
the antidepressants
happen to act on serotonin,
but that doesn’t mean serotonin deficiency
is the cause of depression.
If that sounds odd,
consider a more straightforward example:
steroid creams can treat rashes
caused by poison ivy—
the fact that they work doesn’t mean
steroid deficiency
was the cause of the rash.
We still have a ways to go in terms
of understanding this disease.
Fortunately, in the meantime,
we have effective tools to treat it.
