The Corpus Callosum

Many ScienceBloggers, and some science bloggers, are writing posts
about basic concepts.  I thought that was a good idea, but could
not think of one that would be interesting and that I felt like writing
about and that I was particularly well-suited to write.

Psychiatry is not a basic science.  It is a medical practice that
is derived from several basic sciences: psychology, pharmacology,
physiology, anatomy, epidemiology, and so forth.  So this is not
really a basic concept, in the sense of explaining something
fundamental about nature.  Rather, it explains something that is
fundamental in the course of psychiatric practice: the selection of
antidepressant medication.

PART ONE (below the fold)


One of the most common questions that arises in the course of
prescribing antidepressants is this: “How do you decide what to
prescribe?”  The question may come from the patient, or from a
family member.  Either way, the answer is not as simple as the
person asking the question usually assumes.  Unfortunately, the
full answer is both very long, and very incomplete. 

This qualifies as a basic concept, because it is one of the most common
scenarios in clinical practice, both among specialists (psychiatrists)
but also among primary care providers.  It is still true that more
antidepressant prescriptions are written by PCPs than by
psychiatrists.  Neurologists and OB/GYNs write for these fairly
often as well. 

Often, when patients learn how little is known about the rational basis
for selecting medications, they are surprised.  In part, this is
because of media reports.  Many times people will see media
reports about genetic testing or neuroimaging studies that seem to
indicate that there are tests that can be done to figure out what
antidepressant to prescribe.  Or, patients have seen drug company
ads that talk about a “chemical imbalance.”  This seems to imply
that there ought to be some way to test the chemicals that are
imbalanced, to find out what the imbalance is and how to correct
it.  Or, they assume that some medication are more effective than
others, so naturally they want the one that is going to be most
effective.  Or, they assume that some are milder than others, or
some are more potent than others.

To start, let us put those misconceptions behind us.  While it is
true that there are various genetic tests, neuroimaging studies, blood
tests, and cerebrospinal fluid tests that can be done, all showing
various discrepancies between persons with depression and those
without, none of these has any clinical utility whatsoever.  They
are of interest in research settings, but not in the clinic.

To understand why this is so, it is necessary to understand what is
learned from the results of these studies.  Generally, each study
includes several patients, and several “normal” controls.  This
generates a bunch of numbers.  Then, the numbers are averaged for
each group, and the two averages are compared.  If they are
significantly different, that is considered to be a positive
finding.  “Ah, depressed people have less gibblefoo in the left
medial foopart.”   But if you look and the data for the individuals
within that population, some depressed people will have more gibblefoo,
and some nondepressed people will have less.  So although there is
a significant difference between the two populations, there is a lot of
scatter within each population, and a lot of overlap. 
Consequently, doing the test on any individual does not tell you very
much. [Gibblefoo and foopart are made-up words, in case you were
wondering.]

A similar situation exists with regard to the relative effectiveness of
various antidepressants.  There are a few special cases involved
in this, which I am going to disregard for the sake of
simplicity.  Instead, I will discuss only the most common clinical
scenarios.  In general, all antidepressants are equally likely to
help, in any randomly selected depressed individual.  That is,
there is no systematic difference in effectiveness.  Occasionally
you will see a report that one is better than another, but usually
those findings do not hold up when disinterested parties try to
replicate them.  While it may be true that one really is better
than the others, if so, the difference is so small that it is hard to
demonstrate consistently.  As a rule of thumb, the differences
between patients are much greater than the differences between drugs.

As a corollary of the point above, you can ignore all the talk about
neurotransmitters.  Drug advertisements and other publications
will refer to the fact that Drug A acts on transmitter A, or
Drug B acts on transmitter B, or drug C ands on both A
and B.  That is all true.  But if you read the fine
print, invariably you will find the phrase “the clinical significance
of this has not been established.”  That is also true.  What
they do not tell you is that there is substantial evidence to the
contrary.  In other words, not only is there an absence of
data showing relevance; there is a presence of data
showing irrelevance.  I happen to believe that the
knowledge we have about neurotransmitters will be clinically relevant
someday, but in early 2007, we are still waiting for this to be
demonstrated.

Occasionally, a patient will ask for a “mild” antidepressant.  It
is fine for them to ask for this, and when they do, it is important to
take their request into account.  However, it is equally important
to explain that this:  since all antidepressants are equally
efficacious, there is no way to put them on a scale from stronger to
milder, with regard to efficacy.  However, it is possible to put
them on a scale wherein one considers the probability of causing
unacceptable adverse effects.  Some are distinctly more likely to
cause adverse effects; others, less so.  But again, we are talking
about differences between populations.  Individual results vary
considerably. 

I’ve seen people who take 300mg of clomipramine, who could win a
spitting contest.  I’ve also seen people take 50mg, who have such
bad dry mouth they can hardly talk.  I’ve seen people take 80mg of
fluoxetine who have perfectly intact sexual functioning, and others
take 10mg and complain bitterly about loss of libido.  The vast
majority of people will tolerate fluoxetine much better than
clomipramine, but there are a few individuals for whom the opposite is
true.

So if someone asks for a mild antidepressant, I usual tell them that I
understand their request, and will start them on a low dose of
something with a relatively low probability of adverse effects. 
In practical terms, that is really what they are asking for. 

If people ask about the “potency” of a drug, it is necessary to clarify
what that means.  Potency, in a technical sense, means how strong
the effect is, per milligram of drug administered.  When it comes
to antidepressants, potency probably is irrelevant.  The reason it
is irrelevant, is that the doses administered are already scaled to the
potency.  For example, milligram-for-milligram, fluoxetine is more
potent that sertraline.  The usual starting dose of fluoxetine is
20mg; the usual starting dose of sertraline is 50mg.  So although
one is more potent than another, in clinical practice, it doesn’t
matter.

If someone asks for a “potent” antidepressant, I usually translate that
into a request for a more aggressive dosing schedule.   That
request may or may not be clinically appropriate, but that is a
different topic.  It has nothing to do with the  decision
about what drug to prescribe. 

At this point, all I’ve done is dispel misconceptions.  I’ve
explained what factors are not important, rather than what factors are
important.  The reason for explaining things in that order, is
that when one is trying to learn about what is really important, but
has a bunch of misconceptions interfering with their learning process,
it is harder for them to understand what they are trying to
learn.  This is especially true when the subject material is
complex and involves many important distinctions between similar
concepts.

Next, we get to the heart of the matter: how does one decide what
antidepressant to prescribe?

That will appear in another day or two…

Comments

  1. #1 Martin R
    February 10, 2007

    Great stuff! Although I am myself blessed with an unusually buoyant spirit, these issues are strongly relevant to me.

  2. #2 Shelley
    June 1, 2007

    Don’t know how I missed this series the first time around, but enjoying it a lot now that I found it.

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