Behind the new study changing the way doctors think about depression

You’ve seen the pharmaceutical ads say the Depression can be caused by a chemical imbalance in the brain.

For years, that’s what the public has been led to believe about how antidepressants work.

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

It’s not that antidepressants don’t work – for millions of people, they do. It’s just this:

“Doctors don’t know exactly how they work. Patients want to know there’s an explanation out there,” says Daniel Carlat. “And there are times when we have to give them an abbreviated explanation, even if it’s not entirely accurate.”

Today, About: Inside the new study changing the way 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 Unbalanced: the problem with psychiatry. (@CarlatPsych)

Also Featured

Joanna Moncrieff, Professor of Psychiatry at University College London. Co-author of a new meta-study confirming that the ‘serotonin theory‘ of depression is wrong. (@joannamoncrieff)

Anne Harington, professor of the history of science at Harvard University. Author of Mind Fixers: Psychiatry’s Troubled Research on the Biology of Mental Illness.

Interview Highlights

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

Daniel Carlat: “That’s a good question. I mean, there are relatively few psychiatric drugs that we say we really know how they work for. And those are drugs that, for example, are used for alcoholism, for opioid use disorders, some of the anti-anxiety drugs, some of the insomnia drugs, sure enough, that’s a minority of psychiatric drugs. drugs work and you know, as a practicing psychiatrist, I see them working all the time. It’s true that we are humbled by our real knowledge of the mechanisms, especially antidepressants.

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

Carlat: “I think it’s a really good article that she and her colleagues have put together. I mean, it’s nice to see all of this information put together in one place in a way that gets people talking about my favorite subject, psychiatry So I applaud his band I mean why is this causing such a stir You know, it’s kinda hard to know I think, yeah, people were brought up to believe that there is a chemical imbalance theory of depression, which they are convinced is real and 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 this book, I remember reading the same studies that I’m sure Dr. Moncrieff and colleagues read , which basically said there was no direct evidence of a serotonin deficiency, so it’s not really new. I think, again, they have been able to put the data together in a nice way. It makes things very clear. Maybe that’s why it’s caused such a reaction.”

On the main results of the study on depression

Carlat: “The discovery is really an artifact in the sense of the complexity of the brain. I mean, we have a brain with about 100 billion neurons and with many connections between them. And it’s really not possible to just put a syringe into the brain and extract fluid, so they had to use indirect measures, such as cerebrospinal fluid.Some of the studies she looked at were actually post-autopsy studies, where horribly, they removed the brains of people who had suffered from depression in their lifetime and do these analyses, so there were a lot of conclusions.

“But the thing is, you know, in psychiatry in general, the drugs that we use were really discovered by accident, usually in the 1940s and 1950s. And these antidepressants were based on the search for a better antihistamine. They They were tried on various They proved to be extremely effective, and it was after the fact that researchers went into the laboratory and tried to understand how old drugs like imipramine or amitriptyline worked.

“And they found, hey, you know, these drugs actually increase the levels of serotonin, norepinephrine, and several other neurotransmitters. So the natural conclusion would be, if these drugs work and if that’s what the drugs do , then the depression may be related to a chemical imbalance. And I don’t think that’s an erroneous conclusion, you know, that they came to. The thing is, it really didn’t work, that we were able to for find the direct evidence we need.”

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

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

“But I remember doing my residency at Mass General in the early 1990s, and I remember going to seminars with really the biggest 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 anyone who has taken one knows this, there is a delay of about two weeks before the drug works. And so if it was just a chemical imbalance and correcting that imbalance you would think works pretty much right away, but it doesn’t.

“So we knew there were downstream effects that we didn’t know about. And more recently, you know, there’s been new research being done on brain-derived neurotropic factor, altering brain architecture, and changing the connections between brain structures And we I think it 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 we could have this conversation on another article, debunking all these theories as well.

On reducing the stigma around depression

Carlat: “Biochemically, we don’t know what causes depression. I mean, I think one of the things that I talk to some of my patients that I’ve been very, very honest about in my writing, is is that I, too, suffered from depression. And I remember having a very, very amazing experience taking some of these SSRIs.

“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, I felt better. And kind of the weight of the world has been lifted off my So when people ask me if these drugs really work, one of the things I do is, you know, reduce the stigma and let people know that I’ve had the real experience of telling them that story.

For those who have not received help or who cannot receive it, what should they do?

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

“One of the great success stories of psychotherapy is cognitive behavioral therapy for chronic insomnia. And that can be delivered just as effectively via an app and online as it is in person. So we’re using new technologies to augment the already effective methods we use to help people.”

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