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Antidepressants and “Stress” Revisited

April 13, 2011

If you have even the slightest interest in the biology of depression (or if you’ve spent any time treating depression), you’ve heard about the connection between stress and depressive illness.  There does seem to be a biological—maybe even a causative—link, and in many ways, this seems intuitive:  Stressful situations make us feel sad, hopeless, helpless, etc—many of the features of major depression—and the physiological changes associated with stress probably increase the likelihood that we will, in fact, become clinically depressed.

To cite a specific example, a steroid hormone called cortisol is elevated during stress, and—probably not coincidentally—is also usually elevated in depression.  Some researchers have attempted to treat depression by blocking the effects of cortisol in the brain.  Although we don’t (yet) treat depression this way, it is a tantalizing hypothesis, if for no reason other than the fact that it makes more intuitive sense than the “serotonin hypothesis” of depression, which has little evidence to back it up.

A recent article in Molecular Psychiatry (pdf here) adds another wrinkle to the stress hormone/depression story.  Researchers from King’s College London, led by Christoph Anacker, show that antidepressants actually promote the growth and development of new nerve cells in the hippocampus, and both processes depend on the stress hormone receptor (also known as the glucocorticoid receptor or GR).

Specifically, the group performed their experiments in a cell culture system using human hippocampal progenitor cells (this avoids some of the complications of doing such experiments in animals or humans).  They found that neither sertraline (Zoloft) alone, nor stress steroids (in this case, dexamethasone or DEX) alone, caused cells to proliferate, but when given together, proliferation occurred—in other words, the hippocampal progenitor cells started to divide rapidly.  [see figure above]

Furthermore, when they continued to incubate the cells with Zoloft, the cells “differentiated”—i.e., they turned into cells with all the characteristics of mature nerve cells.  But in this case, differentiation was inhibited by dexamethasone. [see figure at right]

To make matters more complicated, the differentiation process was also inhibited by RU486, a blocker of the receptor for dexamethasone (and other stress hormones).  What’s amazing is that RU486 prevented Zoloft-induced cell differentiation even in the absence of stress hormones.  (However, it did prevent the damaging effects of dexamethasone, consistent with what we might predict.) [see figure at left]

The take-home message here is that antidepressants and dexamethasone (i.e., stress hormones) are required for cell proliferation (first figure), but only antidepressants cause cell differentiation and maturation (second figure).  Furthermore, both processes can be inhibited by RU486, a stress hormone antagonist (third figure).

All in all, this research makes antidepressants look “good.”  (Incidentally, the researchers also got the same results with amitripytline and clomipramine, two tricyclic antidepressants, so the effect is not unique to SSRIs like Zoloft.)  However, it raises serious questions about the relationship between stress hormones and depression.  If antidepressants work by promoting the growth and development of hippocampal neurons, then this research also says that stress hormones (like dexamethasone) might be required, too—at least for part of this process (i.e., they’re required for growth/proliferation, but not for differentiation).

This also raises questions about the effects of RU486.  Readers may recall the enthusiasm surrounding RU486 a few years ago as a potential treatment for psychotic depression, promoted by Alan Schatzberg and his colleagues at Corcept Pharmaceuticals.  Their argument (a convincing one, at the time) was that if we could block the unusually high levels of cortisol seen in severe, psychotic depression, we might treat the disease more effectively.  However, clinical trials of their drug Corlux (= RU486) were unsuccessful.  The experiments in this paper show one possible explanation why:   Instead of simply blocking stress hormones, RU486 blocks the stress hormone receptor, which seems to be the key intermediary for the positive effects of antidepressants (see the third figure).

The Big Picture:   I’m well aware that this is how science progresses:  we continually refine our hypotheses as we collect new data, and sometimes we learn how medications work only after we’ve been using them successfully for many years.  (How long did it take to learn the precise mechanism of salicylic acid, also known as aspirin?  More than two millennia, at least.)  But here we have a case in which antidepressants seem to work in a fashion that is so different from what we originally thought (incidentally, the word “serotonin” is used only three times in their 13-page article!!).  Moreover, the new mechanism (making new brain cells!!) is quite significant.  And the involvement of stress hormones in this new mechanism doesn’t seem very intuitive or “clean” either.

It makes me wonder (yet again) what the heck these drugs are doing.  I’m not suggesting we call a moratorium on the further use of antidepressants until we learn exactly how they work, but I do suggest that we practice a bit of caution when using them.  At the very least, we need to change our “models” of depression.  Fast.

Overall, I’m glad this research is being done so that we can learn more about the mechanisms of antidepressant action (and develop new, more specific ones… maybe ones that target the glucocorticoid receptor).  In the meantime, we ought to pause and recognize that what we think we’re doing may be entirely wrong.  Practicing a little humility is good every once in a while, even especially for a psychopharmacologist.

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How Lithium Works (Maybe)

February 17, 2011

“Half of what we have taught you is wrong.  Unfortunately, we don’t know which half.”

— attributed to a Harvard Medical School dean at commencement, sometime in the 20th century

The above, possibly apocryphal, statement is often invoked to illustrate how dynamic the field of medicine can be, and how what we thought we once knew beyond a shadow of a doubt, sometimes turns out to be dead wrong.  It’s also a celebration of scientific progress; as we revise our pathophysiological models, we can develop more targeted therapeutics.

In this regard, psychiatry is no different from any other field of medicine.  We don’t know (yet) what we don’t know, but once we do, our treatments will improve.  At the same time, we need to be careful how we use this new information, lest it give us a false sense that we “know” something we don’t.

I thought of this question when I encountered a headline earlier today at psychcentral.com“How Lithium Works Finally Explained.” Talk about a tantalizing headline!  First used clinically in the late 1800s (and later “rediscovered” in the 1940s), and still used extensively as a mood stabilizer in bipolar disorder and as adjunctive treatment for major depression, lithium is one of the most widely prescribed medications in all of medicine.  Many patients report a very good response to lithium, and its efficacy has not been surpassed by the multitude of other mood stabilizing agents introduced in the last 40 years.

But there’s just one problem.  Nobody really knows how lithium works.  It’s an ion (similar to sodium), so it doesn’t bind to a receptor or transporter, like most other psychiatric drugs.  It doesn’t seem to affect membrane potential (and therefore neuron excitability), and it doesn’t seem to target any particular region of the brain, much less those thought to be involved in mood disorders.  It may inhibit intracellular messengers (the phosphatidylinositol pathway) or it might inhibit cellular differentiation (via the Wnt signaling pathway).  Maybe it blocks sodium ion transport.  Maybe it interacts with nitric oxide.  No one knows.  And yet it works.

So it was with great interest that I read the original paper cited in the Psychcentral article.  It’s a “mega-analysis,” published in the February 15 issue of Biological Psychiatry, of 321 bipolar patients in 11 centers worldwide who underwent MRI scans and were compared to non-bipolar controls.  Half of the bipolar patients were taking lithium.  To summarize the results, patients taking lithium had larger hippocampal and amygdala volumes than those not taking lithium, and patients with a longer history of bipolar disorder had reduced cerebral volumes.

The data, then, seem to be consistent with the idea of lithium as having a “trophic” effect—i.e., as a promoter of neuronal growth, at least in some brain structures.  But that’s about all we can say.  Whether this has anything to do with intracellular signaling or the Wnt pathway, or with any known nerve growth factors, is beyond the scope of this study.

So despite the exciting headline claiming to identify the “mechanism of lithium,” this is simply an observation, much like the observation about how antipsychotics may decrease brain volumes, about which I wrote last week.  It suggests further research to understand lithium’s effect on these regions.  But it may not be clinically relevant.

Lithium is a widely used drug because it works.  Period.  These new data add to our knowledge about bipolar disorder, but to assume that they help us understand bipolar patients any better than we did before, is incorrect.  Moreover, it may lead us to draw false conclusions about our patients (i.e., “he’s not responding to lithium so his hippocampus must be atrophied”) or, worse, reject or disregard data that don’t fit with our hypothesis.  I’d much rather prescribe a drug because I have years of experience using it, and have heard hundreds of patients endorse its benefit, rather than adhere to an incorrect theory, even a theory with “face validity” like lithium promoting nerve cell growth and differentiation.  In fact it’s not too hard to find arguments against this theory:  for starters, consider lithium’s teratogenic effects during human embryonic development.

Anyone who wants an accurate explanation for how a psychiatric drug works is, unfortunately, out of luck.  The serotonin hypothesis is a perfect example:  SSRIs work in a lot of patients, and the serotonin hypothesis helps to guide treatment, but it might be absolutely incorrect.  How many alternate explanations have we ignored because we want to believe that our model must be right?

We can, and should, continue to use SSRIs to treat depression, and lithium to treat bipolar disorder.  But we should be aware that our explanations of their mechanisms are mere hypotheses—nothing more.  And, moreover, that these hypotheses may be contradicted or proven wrong.  Because we don’t know which half of our knowledge is the correct half.


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