Behind the new study changing how doctors view depression

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You’ve seen the pharma ads saying depression may be caused by a chemical imbalance in the brain.

For years, that's what the public was led to believe about how antidepressants work.

That they corrected a serotonin imbalance in the brain. But a big, new study debunks that theory.

It's not that antidepressants don't work — for millions of people, they do. It's just that:

"Doctors don't know exactly how they work. Patients do want to know that there is an explanation out there," Daniel Carlat says. "And there are times when we do have to give them a shorthand explanation, even if it's not entirely accurate."

Today, On Point: Inside the new study changing how doctors view depression.

Daniel Carlat, chair of psychiatry at Melrose Wakefield hospital and publisher of the Carlat Psychiatry Report, part of the TuftsMedicine network. Author of Unhinged: The Trouble with Psychiatry. (@CarlatPsych)

Joanna Moncrieff, professor of psychiatry at University College, London. Co-author of a new metastudy confirming that the ‘serotonin theory’ of depression is wrong. (@joannamoncrieff)

Anne Harrington, professor of the history of science at Harvard University. Author of Mind Fixers: Psychiatry's Troubled Search for the Biology of Mental Illness.

How many psychiatric drugs can we say, with confidence, we know exactly how the drugs work?   

Daniel Carlat: "That's a good question. I mean, there are relatively few psychiatric drugs where we say we really know how they work. And those would be drugs that, for example, are used for alcoholism, for opiate use disorder, some of the anti-anxiety drugs, some of the insomnia drugs, which is to be sure, that's a minority of the psychiatric drugs. It is true that while the drugs do work and you know, I certainly as a practicing psychiatrist, I see them working all the time. It is true that we are humbled when it comes to our actual knowledge of the mechanisms, especially of the antidepressants."

On the study confirming the ‘serotonin theory’ of depression is wrong

Carlat: "I think it's a very nice paper that she and her colleagues created. I mean, it's nice to see all of this information pulled together in one place in a way that gets people talking about my favorite topic, psychiatry. So I applaud her group. I mean, why is this causing such a stir? You know, it's kind of hard to know. I think that, yes, people have been led to believe that there is a chemical imbalance theory of depression, that they are convinced is real and that it has to do with serotonin.

"But the fact is that for years now, and you mentioned the book that I wrote, I mean, so when I was doing research for that book, I remember reading the same studies that I'm sure Dr. Moncrieff and her colleagues read, which were basically saying that there's no direct evidence of a serotonin deficiency. So it's not really new. I think, again, they were able to pull the data together in a nice way. That makes it very clear. So maybe that's why it's caused such a reaction."

On major findings about depression from the study

Carlat: "The finding is really an artifact in a sense of how complicated the brain is. I mean, we have a brain with about 100 billion neurons and with many connections between them. And it really isn't possible to just put a syringe in the brain and pull out fluid. So they had to use indirect measures, such as spinal fluid. Some of the studies that she reviewed actually were post autopsy studies, where kind of gruesomely they would take brains out of people who had depression in their lifetime and do those analyses. So there were a lot of findings.

"But the fact is that, you know, in psychiatry in general, the medications that we use were really discovered by accident, usually in the 1940 and 1950s. And those antidepressants were based on looking for a better antihistamine. They were tried on various patients. They were found to be extremely effective. And it was after the fact that researchers then went into the lab and tried to figure out how old drugs like imipramine or amitriptyline worked.

"And they found out, hey, you know, these drugs do, in fact, increase levels of serotonin, and norepinephrine and several other neurotransmitters. So the natural conclusion of that would be, if these drugs work and if this is what the drugs do, then depression may be related to a chemical imbalance. And I don't think that's a wrongheaded, you know, sort of conclusion that they made. The fact is that it really hasn't panned out, that we've been able to come up with the direct evidence that we need."

On a history of our understanding of the serotonin theory of depression

Carlat: "The 1950s and 1960s were a time when these medications that we knew were very helpful were brought into the lab, and they were able to do experiments to show that they did seem to operate on neurotransmitters. That didn't mean that we understood that depression was caused by low serotonin, but we knew that the drugs seemed to work that way. So therefore, they thought there must be a chemical imbalance.

"But I remember I did my residency at Mass General in the early 1990s, and I remember being in seminars with really the top figures in psychopharmacology at the time. And we were all extremely skeptical of this theory. And one of the reasons is that when you give an antidepressant, and anybody who's been on one knows this, famously there's a delay of about two weeks before the medication works. And so if it were a simple matter of a chemical imbalance and righting that imbalance, you would think it would work pretty much right away, but it doesn't.

"So we knew that there were some downstream effects that we knew nothing about. And more recently, you know, there's been newer research on brain derived neurotropic factor, and changing the architecture of the brain, and changing connections between brain structures. And we're thinking that that may have something to do with how these drugs work, but you never know. It's such a complicated research topic, that in ten years we could be having this conversation about another paper, debunking all of those theories as well."

On decreasing the stigma around depression

Carlat: "Biochemically, we do not know what the cause of depression is. I mean, I think one of the things that I do talk to some of my patients about and I've been very, very honest in my writing, is that I, too, have suffered from depression. And I remember having a very, very amazing experience taking some of these SSRI's.

"And that two week gap that I talked about, I remember waking up two weeks after I started. I think in this case, it was Celexa many years ago, actually feeling better. And sort of the weight of the world was lifted from my shoulders. So when people wonder to me whether these medications really work, one of the things I do is, you know, to decrease stigma, and to let people know that I have had the actual experience, is to tell them that story."

For those who haven't received help, or are unable to receive help, what should they do?

Carlat: "They should be encouraged by the fact that there's a lot of research going on in other modalities. So I talked about the ketamine and the psychedelics, but there's also brain modulation techniques like transcranial magnetic stimulation, that is also very helpful. And a number of therapies. You mentioned insomnia in adolescents.

"One of the big success stories in psychotherapy is cognitive behavioral therapy for chronic insomnia. And that can be delivered actually just as effectively via an app and online as it can in person. So we're using the newer technologies to augment the already effective methods that we're using to help people."