Depression: Have We Got It Wrong?

Questions about the serotonin hypothesis

Depression: Have We Got It Wrong?

This article first appeared in the March/April 2006 issue.

Today it seems almost anyone will tell you that a lack of the brain chemical serotonin is responsible for depression and a host of other mental and emotional problems, and that the way to boost depleted serotonin supplies is by taking antidepressants like Prozac, Paxil, Zoloft, or Celexa. Not only doctors and therapists, but even many patients have become so sophisticated that they can describe how selective serotonin reuptake inhibitors (SSRIs) work to keep more serotonin floating around in the brain, facilitating synaptic connections.

And how do they know all this? Because they’ve seen advertisements saying, for instance, “Paxil can help restore the balance of serotonin” in order to treat “depression, which is believed to be caused by deficits in certain neurotransmitters.” Or that Celexa “helps to restore the brain’s chemical balance by increasing the supply of a chemical messenger in the brain called serotonin.”

But now, two new studies suggest that the conventional wisdom fostered by drug companies about what causes depression and how both the brain and the Prozac generation of antidepressants actually work is overly simplistic, if not wrong. Taken together, the studies suggest that, while serotonin and other neurotransmitters may well affect mood and behavior, the mechanism by which they do so is far more complex than the “boost serotonin, elevate mood” equation embraced by popular culture.

“There is no scientifically established ideal Çchemical balance’ of serotonin, let alone an identifiable pathological imbalance,” says the first paper, published in the December 2005 issue of the journal PLoS Medicine. “There is not a single peer-reviewed article that directly support[s] claims of serotonin deficiency in any mental disorder.”

The idea that deficiencies of one or more brain chemical causes depression was first proposed in a 1965 paper by Joseph Schildkraut, a former researcher at the National Institute of Mental Health, who is now emeritus professor of psychiatry at Harvard. Researchers have been following that trail ever since, but the hunt has been anything but straightforward.

For one thing, it’s impossible to measure serotonin in the brains of living people. Instead, researchers have measured levels of a serotonin breakdown product in cerebrospinal fluid, finding in some studies that depressed, aggressive, or suicidal people have lower levels of it than do healthy, nondepressed people. The fact that serotonin-boosting drugs reduce the symptoms of some depressed people seemed to bolster the connection between serotonin levels and depression.

But other studies have found just the opposite, and a 2002 review of the research as a whole determined that the “seemingly robust association” between low serotonin and suicidal or aggressive behavior was “in fact rather weak.” As a result, in recent years, most researchers have moved away from understanding depression through the paradigm of serotonin deficiency. “I never use the term Çchemical imbalance,'” says Vassilis Koliatsos, a psychiatrist and researcher at Johns Hopkins University School of Medicine. “It’s unacceptable reductionism. It doesn’t have any explanatory power, and it doesn’t reflect the truth. The fact that Prozac works in depression doesn’t mean that depression is a deficit in serotonin. That was the way of thinking in the ’60s and ’70s. It’s time to move beyond the psychopharmacology of the ’60s and ’70s.”

Nevertheless, drug advertisements continue to use such terms and to promote a mechanistic role for serotonin. As a result, says Jonathan Leo, one of the authors of the PLoS Medicine paper, “people who don’t know the science think that this chemical-imbalance theory has more credence than it really does.” Good for drug sales, he says, but not good science.

Leo, it should be noted, is a longtime critic of the pharmaceutical industry, and as a professor of anatomy at Lake Erie College of Osteopathic Medicine in Bradenton, Florida, he’s outside the American biomedical research establishment. That isn’t the case with Koliatsos, the Johns Hopkins researcher and lead author of the second study, published in the Journal of Neurochemistry, who holds joint appointments to the university’s departments of neurology, neuroscience, pathology, and psychiatry.

For Koliatsos, one of the problems with the notion of depression as essentially a disease of serotonin deficiency–which SSRIs can correct–is one of timing. The active ingredients of SSRIs bind to key receptors in the brain within hours and appear to quickly increase serotonin levels, yet beneficial therapeutic effects, when they occur, generally take weeks. Why?

Partly to answer that question, Koliatsos looked at the impact on the brains of mice of both Prozac, which increases the supply of serotonin in the brain, and tianeptine, an antidepressant available only in France, which decreases it. He found that both drugs caused new axons, the tail-like extension of neurons, to sprout and grow in parts of the neocortex and limbic brain.

This is big news. It supports a radical shift in thinking that’s emerged in recent years about the ability of the adult brain to grow new brain cells. Previously, it had been an article of faith that after the early years of life, both animals and humans had all the brain cells they’d ever have. More recently, however, evidence has mounted that neurogenesis–the growth of new neurons–can take place in species ranging from rats to higher primates and humans, and that this process can either be enhanced or inhibited in a number of ways.

One way to enhance it, according to Koliatsos, may be with antidepressants. His study suggests that they don’t work by altering chemical levels directly, but by stimulating the growth of neurons, a more complex and gradual process. These are “structural, rather than biochemical, changes,” he says. “It appears that SSRI antidepressants rewire areas of the brain that are important for thinking and feeling, as well as operating the autonomic nervous system.”

Koliatsos believes the process may happen something like this: When serotonin levels either rise or fall, this turns on a protein critical for the survival of neurons called brain-derived neurotrophic factor (BDNF). This factor, in turn, signals neurons to start sprouting new axons.

Koliatsos’s work builds on other recent research, which found, for instance, that mice that live socially, spending quality time with other mice, grow neurons in the hippocampus more rapidly than mice that live in isolation. So do mice that work out on a running wheel. Once again, this may happen as a result of increased release of the BDNF peptide, according to Ronald Duman, a researcher in the division of molecular psychiatry at Yale University School of Medicine. Duman further says that while no one has yet proven this empirically, the animal studies “are consistent with the hypothesis that exercise and enrichment would enhance neurogenesis in humans.”

Chronic stress, by contrast, seems to slow the process of neural growth by triggering the release of stress hormones such as cortisol. Marmoset monkeys and tree shrews that are placed on the home turf of other animals, inducing a state scientists call intruder stress, suffer a drop in the rate of neurogenesis in their hippocampus. So do rodents that are exposed to the smell of foxes, their natural predators.

Duman suggests that the same thing may happen with humans. People who are exposed to severe stress, and thus chronically high levels of cortisol, may have reduced rates of neurogenesis, and this could contribute to their developing depression or post-traumatic stress disorder.

Could exercise, psychotherapy, or stress-reduction techniques like yoga or meditation help reverse the damage caused by high levels of cortisol? Duman says it’s “reasonable” to suggest that such interventions “could reduce stress [and] allow basal rates of neurogenesis to return to control levels, although there are no data to support this possibility.”

The interplay between life experience, drugs, and brain chemistry is far more complex than the simplistic explanations of pharmaceutical company advertisements. It’s also not a process that operates in just one direction, with chemical imbalances causing depression. Life experience influences brain chemistry; brain chemistry influences life experience; and the two combined help regulate the growth and survival of neurons, which, in turn, influence both life and chemistry.

What’s exciting about Koliatsos’s work, like much of the new brain research, is that it demonstrates once again that brain change, and therefore behavior change, isn’t exclusively the province of biochemists. “This is a new paradigm,” says Koliatsos, “and it opens up new possibilities.”

Rob Waters

Rob Waters is the former editor of the men’s health channel at WebMD and a former contributing editor to the Psychotherapy Networker.