So That’s How Antidepressants Work (in mice)!

By Rama via Wikimedia Commons

In the September 17 of Science, a new mouse study of SSRI effects finds that there is a microRNA that is upregulated by SSRIs, and which affects expression of serotonin transporters. This is presumably in addition to the direct inhibition of the reuptake pumps by the drug itself. It’s an interesting new piece of info that helps explain how these drugs work, which is surprisingly mysterious given how widely they are used.

Most people, even many psychiatrists, will tell you that they work by increasing the amount of serotonin in the brain (or if they’re really trying to be smart, the amount of serotonin in the synapse). It’s true that these drugs do in fact do this (in the synapse): it makes basic sense that if you stop reuptake, there will be more serotonin left in the synapse. But does this treat depression and anxiety? Are these maladies simply caused by a lack of serotonin in synapses, or perhaps an insensitivity of the post-synaptic cell which then requires extra serotonin to be activated? These common explanations, again, even by some psychiatrists. But they are wrong. If all we needed was more serotonin in the synapses, then these drugs would work immediately. SSRIs would work just as fast as Tensilon and amphetamine, which increase acetylcholine and dopamine in synapses respectively. It’s well-known that SSRIs take 4-6 weeks or more to take effect, and it’s even more well-known that amphetamine works immediately. So it should be obvious that SSRIs have effects that depend on something besides dumping serotonin into our synapses.

I’m not going to tell you exactly how SSRIs work, because I don’t know. And I don’t know anyone who does. It is likely that by increasing the amount of serotonin in the synapse they affect the sensitivity and/or expression of presynaptic receptors (autoreceptors), thereby effecting subtle changes in the sensitivity and overall reactivity of the serotonin networks. This kind of response would in fact be expected to take a few weeks.

But then there’s norepinephrine.

Image courtesy of Odile Kellermann via AAAS

To me, the interesting thing about the current study, even if it’s just in mice, is that the researchers have demonstrated that SSRIs appear to have downstream effects that include promoting expression of serotonin reuptake in noradrenergic neurons. This is mapped out in the cartoon here. I’m not a molecular biologist, so I can’t and won’t get too deep here, but in this mouse model fluoxetine (Prozac) sensitizes noradrenergic neurons this way, and also inhibits GSK3β. Before today I had never heard of GSK3β, and I don’t know if this is truly meaningful, but Dr. Wikipedia says that another drug that inhibits GSK3β is lithium! Another effective drug that we really don’t know what it’s doing. GSK3β appears to have a number of activities, and one that is interesting is phosphorylation of Tau, the protein that is found in the “tangles” of Alzheimer’s.

I once asked an experienced psychiatrist why he prescribed so much Cymbalta. (Cymbalta is an SNRI, so it works directly on both serotonin and norepinephrine.) His answer was that, although he continues to use SSRIs extensively, he feels that the responses from patients are not as robust as he used to see in the days when he prescribed mostly tricyclics. He thought this might have been from the noradrenergic effect of TCAs that was presumably missing from SSRIs. Now that he has Cymbalta available, he often uses it as a first choice and feels the response is better than from SSRIs.

So maybe the effect from SSRIs is really due to this other effect, however weak, on the noradrenergic system. This would be a blow to the Serotonin Hypothesis purists, but not to the utility of the medications and the patients who benefit from them. It’s unlikely, however, that SSRIs work in only this way. There remains abundant evidence that serotonin itself is somehow implicated in mood and anxiety, so norepinephrine can’t be the whole story. Perhaps, however, it’s been serotonin’s silent partner all along. And maybe these mice brains and their microRNA-16s will help norepinephrine get the co-star billing it deserves.

“Medical School Sucks”

Wellcome Images

While I was in medical school, near the end of second year, I was burnt out. We were all preparing for USMLE Step 1 and final exams for Pathology, Pharmacology, etc.  at the same time. I had the distinct feeling that if the school had for some reason added two more courses to our workload it would have been unnoticeable. I was already fully overwhelmed, stressed, and worn out. Having more work to do might have lowered my test scores, but it couldn’t feel any worse. I was discussing this with an attending physician with whom I had a friendly relationship, and he said: “Look, medical school sucks. Second year really sucks. Third year sucks in a different way. Fourth year is fantastic, and that’s good, because the year after that, internship, sucks more than anything that came before.” I didn’t find this discouraging, but oddly reassuring. Not only did I know that I wasn’t alone, but I knew that I was right on schedule, and that things were tough because they had to be, not because I was wildly off track or over my head.

The current issue of JAMA is devoted to medical education, with a few articles about the mental health and attitudes of medical students. In the past, medical students have been popular research subjects, and all manner of experimental procedures and treatments were done on them. There’s not a good history of this research (hello, Lawrence K. Altman, maybe this is your next book?), and it’s now fairly rare as IRBs are very protective of students as a “disempowered” population. But medical students continue to fascinate doctors, and a fair amount of research has been done into the mental states of medical students.

The results are fairly consistent, and not very surprising to anyone who has been or known a medical student or resident.  Medical students are more prone to depression, anxiety, suicidality, and more likely to die by suicide than others of the same age. The study in JAMA notes that depressed medical students are more likely than their non-depressed classmates to think that seeking treatment would be more stigmatizing or more likely to damage their academic reputation. This is most likely a combination of the facts that depressed people have a more negative outlook than the nondepressed but also a more realistic one. One reassuring finding in the depression study was that the depressed students reported that they were less professional and made more errors than their peers, but there was no evidence that they actually did so.

Mostly, these findings demonstrate that medical students, and therefore doctors (even your doctor) are human beings. Residents who felt that self-sacrifice was no excuse to accept inappropriate gifts were more likely to state they would accept gifts from drug companies after they were asked to reflect on the sacrifices they have made for their job. Another article discusses pervasive “presenteeism” among residents, coming to work despite illness, that is likely part of that perceived hardship.

There’s no doubt that medical trainees face difficult situations, extreme stresses, and significant barriers to mental health treatment. There seems to be a persistent interest by medical educators to address these issues, and as the system becomes more humanized (continuing adjustment of work hours rules, etc.) they may actually make some progress. There continues to be a perception, however, among medical students and residents, that they should work as many hours as possible, consistently do excellent work, never complain (except to each other), and never get ill. And the inability to be superhuman, or the desire not to attempt it, can lead to guilt, depression, and resentment. This is a complex problem, and with the social and economic status of doctors remaining in flux, it does not appear it will become simpler any time soon.