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...