Low Serotonin, Depression Link a Myth?

Liam Davenport

April 27, 2015

The concept that depression is a result of low brain serotonin levels and, therefore, that selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for the disorder is a myth, says a UK psychiatrist.

Moreover, David Healy, MD, professor of psychiatry, Hergest Unit, Bangor, Wales, United Kingdom, believes that SSRIs were a treatment looking for a condition and that doctors and patients were co-opted into the myth by clever marketing, resulting in better treatments being sidelined.

"This history raises a question about the weight doctors and others put on biological and epidemiological plausibility. Does a plausible (but mythical) account of biology and treatment let everyone put aside clinical trial data that show no evidence of lives saved or restored function?," Dr Healy asks.

"In other areas of life the products we use, from computers to microwaves, improve year on year, but this is not the case for medicines, where this year's treatments may achieve blockbuster sales despite being less effective and less safe than yesterday's models," he adds.

The editorial was published online April 21 in the BMJ.

Doctors, Patients Co-opted

Outlining the history of SSRIs, Dr Healy says that in the 1960s, the notion that serotonin levels are lower in persons with depression was rejected, and SSRIs were shown to be less effective than tricyclic antidepressants. The SSRIs were then marketed as tranquilizers, for which they were equally unsuccessful.

They only found a place in the market when it was suggested that depression is the "deeper illness" behind anxiety. This notion was predicated on the idea that a there is "chemical imbalance" of serotonin levels in the brain that needs to be normalized.

Dr Healy suggests that this concept initially took root in the lay public and became co-opted first by the complementary health markets and then by psychologists, among others.

In his editorial, he says: "Above all, the myth co-opted doctors and patients."

"For doctors, it provided an easy short hand for communication with patients. For patients, the idea of correcting an abnormality has a moral force that can be expected to overcome the scruples some might have had about taking a tranquilliser, especially when packaged in the appealing form that distress is not a weakness."

The result is that there are now more prescriptions for antidepressants than there are people in the Western world, Dr Healy writes.

One of the main issues with the rise of SSRIs, he says, is that "more effective and less costly" treatments have been marginalized. Furthermore, research into other, more plausible explanations for depression ― as illustrated, for example, by the antidepressant potential of ketamine ― has been stifled.

"What we get instead is great marketing that doesn't have anything to do with clinical wisdom," Dr Healy told Medscape Medical News.

"They don't want a person like me to exercise any judgement about these drugs at all. They just want me to give it to everybody that walks in the door."

"Not only isn't there good evidence that this is going to save lives and get people back to work and to get them working better, but there's a great deal of evidence that these drugs cause a whole range of problems in that they impair the quality of your life," he added.

Dr Healy observed that an illustrative analogy for the utility of SSRIs is that of alcohol.

"The kind of data you get out of an SSRI trial is roughly the kind of data you might expect out of an alcohol trial," he said.

"If we put people on alcohol vs placebo alcohol for a 6-week period, you'd be able, because alcohol relaxes you a bit and gets you to fall asleep at night, to get exactly the same kind of changes on rating scales from an alcohol trial as you'd get with SSRIs," he added.

However, Dr Healy said: "We wouldn't go about the place saying, on the basis of a 6-week alcohol trial, that people should be taking alcohol for the next 10 years or that you're going to be doing your job better and you're going to be more effective because you're taking alcohol daily."

One Size Does Not Fit All

Commenting on the editorial for Medscape Medical News, Georgia Hodes, PhD, postdoctoral researcher in neuroscience at Icahn School of Medicine at Mount Sinai, in New York City, observed that, in effect, Dr Healy is saying that the idea that SSRIs are the "be all and end all" is incorrect and that "basically it's held the field back."

"Clearly there are a percentage of people in whom these [drugs] have been extremely helpful, but at the same time, there's a large percentage of the depressed patient population whom these drugs are just not effective for," she said.

She noted that, for example, the research on ketamine that Dr Healy pointed to suggests that there are potentially different mechanisms underlying different types of depression.

"I think it's pretty clear from the research that's been done for the past 50 years or so that it's a heterogeneous population...and that we need to start finding out what is actually wrong with these different types of people who suffer from depression," she said.

Dr Hodes believes that what is needed are "biologically relevant" tests for mental illness in general, and depression and anxiety in particular, to identify biomarkers that will indicate what kind of depression a person has and, consequently, the best treatment for them.

"Right now, it's all based on someone going in and talking about their symptomatology without there being any biological basis for this, and there's no biological basis even for what drug you give the person," she said.

Dr Hodes explained that this is partly due to an "inability of the field to move forward from SSRIs," adding: "They weren't looking for a mechanism of depression, because they figured that they had it."

Instead, she believes that there are probably cues that can be taken from the body as to how best to treat people, "rather than what drug is being pushed by the drug reps that week or what some doctor's favorite drug is to treat with."

Pointing to recent research indicating that depression is linked to both inflammation and glutamate signaling, Dr Hodes said: "One of the things that I think has held people back is that we always think about depression as being in the brain."

"So when they're looking for biomarkers, they're trying to look for biomarkers that are the same in the blood as in the brain, but we've done some research that suggests it's also a condition of the body."

She concluded: "Maybe we should just be focusing on what's happening in the body. This might be a way not only to treat people without having to get drugs into the brain but also to find better biomarkers."

Dr Healy is a founder member of RxISK and is on the advisory board of the Foundation for Excellence in Mental Health Care. He has acted as an expert witness in cases relating to suicide and violence and SSRIs.

BMJ. Published online April 21, 2015. Editorial


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