Depression-Serotonin Link: Many Mysteries Remain

“Challenge” studies testing the effects of serotonin depletion in healthy and depressed subjects continue to suggest a role for the neurotransmitter in depression that is far more complex than the simple deficiency assumed by researchers in the past.

Instead, researchers say, those studies—in combination with neuroimaging and genetic studies—point to a complex neuronal circuitry regulated by many different neurotransmitters and neuropeptides, including serotonin, that interact with each other.

“Our understanding of how serotonin works in depression is much more refined than a simple deficiency hypothesis,” said Dennis Charney, M.D., chief of the mood and anxiety disorder research program at the National Institute of Mental Health. “However, there continues to be an enormous amount of evidence that points to an abnormal regulation of the serotonin system in depression. The job now is to look at the different receptor systems and different genes to be more precise about how serotonin interacts. There are many roads to depression, and the circuits are complex.”

Pedro Delgado, M.D., chair of psychiatry at University Hospitals (UH) of Cleveland and Case Western Reserve University School of Medicine, has been involved for nearly two decades in serotonin-challenge studies—in which levels of serotonin are depleted or stimulated—to study the effects and their relation to depressive symptoms.

Delgado said that he believes those studies show that serotonin deficiency alone cannot account for depression and that in many cases the actual causes are likely to be “downstream” in some as-yet-undiscovered dysfunction within the very cells of that neuronal circuit.

“One of the summary points is that people who don’t have a history of depression don’t develop depression during serotonin depletion,” he said. Moreover, depressed people who are not treated with antidepressants don’t get any worse when challenged with depletion.

More to Relationship

Importantly, however, it appears that depressed patients taking SSRIs—which selectively block the reuptake of serotonin—are affected by depletion. “Whatever the illness of depression is, it is not due to a deficiency of neuroepinephrine, dopamine, or serotonin,” said Delgado. “But at the same time the research strongly supports their importance in the mechanism of antidepressants that block reuptake of those neurotransmitters. The unanswered question is, Why do some people become depressed when serotonin is low, while others with low serotonin levels remain depression free?”

Delgado and colleagues at UH are extending the work of serotonin-challenge studies with an eye toward using them to identify those individuals for whom serotonin levels are influencing mood regulation—much like a glucose tolerance or treadmill test to identify patients at risk for diabetes or heart disease.

“We believe that the serotonin-depletion procedure might be used to predict when patients no longer need medication,” Delgado told Psychiatric News. “We also hope to identify those people who, though they never had depression, are at increased risk for it in the future.”

Tryptophan Depleted

In the study at University Hospitals of Cleveland, Delgado and colleagues will induce a reduction in serotonin levels in healthy participants and in individuals who have previously suffered from depression by depleting natural stores of the amino acid tryptophan.

Delgado explained that a considerable body of research has shown a correlation between levels of tryptophan—one of the naturally occurring amino acids essential to the building of protein—and levels of serotonin. “Serotonin levels change within 30 minutes to two hours of tryptophan depletion,” he said. “There is a very tight correlation.”

Depletion of the body’s store of tryptophan is accomplished ingeniously. Subjects imbibe a drink consisting of 16 essential amino acids but lacking in tryptophan. When the amino acids are ingested, the body begins to put them together into proteins.

“You are actually driving the synthesis of protein,” he said. “But if you leave out any one of the essential amino acids, the body will extract the missing amino acid from its own serum.”

Thus, the body’s own stores of tryptophan are depleted, causing a concomitant depletion of serotonin. “You can reliably cause a depletion of tryptophan by 90 percent within five hours,” he said.

But can researchers ethically induce in volunteers the depletion of a naturally occurring chemical believed to be involved—however indirectly—with depression?

Such questions invariably adhere to challenge studies, which came under increasing scrutiny in the last decade when safety issues arose around studies looking at the effects of medication-abatement in schizophrenia. But Delgado says that 20 years of serotonin-challenge studies—and their results essentially refuting the hypothesis that diminished serotonin levels alone are the cause of depression—have proven the tryptophan-depletion strategy to be hazard free.

“From an ethical perspective, this procedure is relatively safe and well tolerated. Tryptophan depletion most often doesn’t cause any clinical change in mood, and when it does, the symptoms are quickly and easily reversible,” Delgado said.

In a study published in the May 1990 Archives of General Psychiatry looking at the effects of serotonin depletion, Delgado said he and colleagues at Yale University looked at 100 patients who had been treated successfully with antidepressant medication of different kinds. They found that following serotonin depletion nearly 80 percent of those patients became transiently depressed, which was quickly and easily reversible.

Curiously, too, they found that the depressive symptoms were highly idiosyncratic. “The symptom profile that re-emerged during the depletion was unique to the person,” Delgado said. “It wasn’t as though they had some nonspecific syndrome.”

The observation seemed to suggest that serotonin depletion wasn’t the cause of depression per se, but likely had some role in the regulation of mood in individuals being treated for depression.

The findings were underscored in a study published in the November 1994 Archives of General Psychiatry. This time the researchers looked at a much larger sample of patients with depression who had never been treated with antidepressants.

And what they found was that depletion of serotonin did not make depression worse—though there did appear to be a “day after” effect in which a small subset felt somewhat worse. The import of the studies was clear: though serotonin level had something to do with regulating mood, it wasn’t the cause of depression.

Delgado likens the flaw in the serotonin-deficiency hypothesis to the error in reasoning that assumes the sun rises because the cock crows. “If you have a rash,” he said, “and use some corticosteroid cream and it gets better, [using the same reasoning] you would come to the conclusion that it was a deficiency in corticosteroid that causes a rash.”

But Charney noted that serotonin-challenge studies combined with genetic research and neuroimaging do underscore a central role for serotonin in depression. And he said that in at least some patients a reduced number of certain receptor subtypes for serotonin might be crucial.

“Depression is a heterogeneous disease,” Charney told Psychiatric News. “We are identifying a circuitry that involves different brain regions that mediate different facets of depression. And we are identifying how different transmitters and neuropeptides regulate those circuits.”

Charney said that positron emission tomography scans of the brain have shown that one serotonin receptor subtype in particular—the 1A receptor—appears to be prominent. “A number of imaging studies have shown that depressed patients have a reduced number of 1A receptors,” he said. “Even patients in remission seem to have a lower number.”

Preclinical studies also bear out the hypothesis. “If you take away the serotonin 1A receptor in mice using genetic techniques, the animals develop a phenotype of depression,” Charney said.

Researchers agree that what once appeared to be a straightforward correlation between serotonin levels and depression now presents itself as a far more richly nuanced and dynamic process.

Delgado believes that in many cases science will have to look for the causes of depression in the intracellular dysfunctions of neurons themselves. “Whatever the illness of depression is, in many cases it has to do with cellular dysfunction in neurons that make up the circuits that regulate mood,” he said. “The neurotransmitters may help to modulate those circuits and seem to be important in sustaining their connectedness.” ▪