Sunday, April 22, 2012

Yet More on the Broken Serotonin Model of Depression

A psychiatrist colleague sent me, with his endorsement, an article in the New York Times Magazine on the science of depression:
--whose author is Dr. Siddhartha Mukherjee of Columbia, whose recent book, Emperor of All Maladies: A Biography of Cancer was very well reviewed.

Since I have previously been dismissive of the serotonin theory of depression, Dr. Mukherjee's account of the history of the science of depression provides some potential balance. Dr. Mukherjee's basic hypothesis is that while it's clear that the idea that serotonin is a sort of magic bullet for depression is deeply flawed, two things are probably true--first, that serotonin plays an important role in at least some cases of depression in one way or another; and second, that drugs that change depression levels have been extremely helpful in our understanding of depression, not as cures, but as chemical probes that help us better understand what's going on in the brain--so long as we understand properly what the probes are telling us.

So I recommend the article, but I did find myself hiccuping at two places where I thought the author deviated from the careful and balanced tone he had established. The first such passage that caught my attention was: "But such a line of inquiry can’t tell us whether the absence of serotonin causes depression. For that, we need to know if depressed men and women have measurably lower levels of serotonin or serotonin-metabolites (byproducts of serotonin breakdown), in their brains."

Now, asking that question gets us a part of the way to an answer, but it's quite misleading if taken to represent the full answer. This is the old confusion between association and causation. Answering this question might reveal an association between serotonin levels and depression, but tells us nothing about whether that association plays a causal role, or whether some other thing is causing both the depression and the serotonin variations. Getting us messed up between association and causation is one of the primary ways that Pharma marketing manages to sell us a lot of ineffective and potentially harmful drugs.

The other passage that disturbed me relates to the newer theory of depression that excites Dr. Mukherjee the most, though he admits that depression is still very complicated and there may be no single "answer." The new theory is that while in most of the adult brain, no new cells grow, there seems to be an exception and new cells can grow slowly in one portion of the hippocampus, which seems to be related to mood. Experiments in mice show that behavior changes that are depression-related can be caused by enhancing or blocking the growth of these cells; and in humans, brain scans seem to indicate some similar function for cell growth in this region. Dr. Mukherjee then states about this cell-growth theory: "Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. It is very unlikely that we can “talk” our brains into growing cells."

This passage seems a retreat back into another mode of flawed thinking that Pharma marketing exploits to mislead us--the old-fashioned mind/body dualism, which persists in treating the mind as foreign from the body and made up of different sorts of stuff, so that things that influence the body cannot affect the mind and vice versa. Dr. Mukherjee had just finished explaining to us that when mice are put in an enhanced environment with fun new stuff to explore, they become more adverturous and less depressed-seeming, and their brains also grow new cells in the hippocampus. He apparently forgets for a moment that if an enhanced environment can grow new brain cells in mice, then the enhanced environment provided by "talk therapy" in humans might have the same effect.

Despite these bumps in the road the article seems thoughtful and I commend it to your attention. I'll await the comments of more expert readers than I as to how good the science is that Dr. Mukherjee refers to.


Bernard Carroll said...

Before there was a serotonin model of depression there was a norepinephrine model of depression and for a while there was a cholinergic-adrenergic hypothesis, too. Not to mention a trace amine model and an electrolyte model, and, and, and. Models are supposed to be heuristic, not to stick around forever. As in the tale of the three blind men and the elephant, all of them are partly right and all of them are wrong.

The serotonin model did stick around, not because of its intrinsic scientific merit but because it was hijacked by Pharma marketers. They insinuated themselves into the scientific conversation through various key opinion leaders, some of whom were not really aware of how they were being used. A key strategy was the invention of cute labels for the new drugs: once the SSRI meme took off then the selling was easier. SSRI didn’t explain anything, of course, and neither did ‘serotonin deficiency.’ Indeed, these labels gave the appearance of scientific closure without the substance.

Bernard Carroll said...

Now that I have read through the NYT article, I have a further comment, regarding the hippocampal neurogenesis theory of antidepressant drug action. It strikes me as a case of the drunk looking for his lost keys under the lamp post. Had you asked clinical researchers in mood disorders how the hippocampus was relevant to depression before around 1990, they would have been puzzled, because that region of the brain has no known relationship to the core, defining features of depression. That is still true. Moreover, the experimental work that Mukherjee mentions is based on an animal model of dubious validity. I call it a pretend model. Also, this line of work is not going anywhere… it is just drifting, though the grant renewals may pay the bills in various laboratories.

Alexis said...

Bernard Carroll I must say, you said some very true and some things I didn't knew. Do you have a blog?

Bernard Carroll said...

Alexis, thank you for the compliment. I am not a regular blogger, though I do post just a few times each year on Health Care Renewal. You can access those posts by searching here: