Serotonin Paucity May Predict Pessimism in Depression

If major depression is teased apart into its various deleterious components, it includes not just sad mood, sleep/wake disturbances, and weight change, but a pessimistic outlook on oneself, the world, and the future.

The evidence is fairly overwhelming that abnormalities involving the nerve transmitter serotonin underlie the sad mood associated with major depression. But do they also explain its pessimistic outlook—that is, the proclivity to expect the worst from oneself, one’s world, and one’s future? It seems so, a new study suggests.

The study was conducted by Jeffrey Meyer, M.D., Ph.D., of the Center for Addiction and Mental Health at the University of Toronto and colleagues and is reported in the January American Journal of Psychiatry.

The study included three experiments. In the first experiment, the researchers used an instrument called the Dysfunctional Attitude Scale to measure the levels of pessimism in 28 mentally healthy subjects, aged 18 to 40 years. One hour later 15 of the subjects received a single dose of the compound d-fenfluramine, which is known to provoke the release of serotonin from neurons in the cerebral cortex. The remaining 13 subjects received a single dose of a control compound, clonidine, which was chosen because its side-effect profile is similar to that of d-fenfluramine. Once again, an hour later, the researchers used the Dysfunctional Attitude Scale to measure pessimism in the subjects. Those subjects who had received d-fenfluramine were found to have a significantly less-negative outlook compared with their outlook at the start of the study than was the case for subjects who had received clonidine.

Since the unleashing of serotonin from brain neurons can alchemize a grim outlook into a more positive one, the researchers concluded, then a paucity of serotonin probably underlies pessimism in mentally healthy individuals, and if this is so in mentally healthy individuals, then it is probably so in depressed ones as well.

In their second experiment, Meyer and his coworkers used the Dysfunctional Attitude Scale to measure the levels of pessimistic outlooks in 22 subjects who were experiencing a major depressive episode secondary to a major depressive disorder. The researchers also measured, with positron emission tomography, the serotonin receptor binding potential in various areas of the subjects’ brains. The serotonin receptor binding potential reflects the density of serotonin receptors. The investigators then attempted to see whether they could find a statistically significant link between high pessimism levels and a high serotonin receptor binding potential. They found that the association was especially strong between elevated pessimism levels and an elevated serotonin receptor binding potential in the prefrontal cortex brain region.

Thus, it looks as though an abnormally large number of serotonin receptors in the brain, and especially in the prefrontal cortex, underlies the pessimism accompanying major depression, the researchers concluded.

In their third experiment, Meyer and his colleagues divided the 22 subjects from the previous one into two groups based on whether their Dysfunctional Attitude Scale score was above or below the median score for the entire group. The researchers then compared the serotonin receptor binding potential of those 11 subjects who had been found to have extremely grim outlooks with that of 22 mentally healthy subjects. The researchers found a significantly greater binding potential in the former than in the latter, especially in the prefrontal cortex area.

This finding, too, the investigators believe, adds ammunition to the argument that an abnormally large number of serotonin receptors in the brain, and especially in the prefrontal cortex area, underlies the pessimism accompanying a major depression.

Putting all these findings together, Meyer and company concluded that both a paucity of serotonin and too many serotonin receptors are at least part of the neurochemistry underlying the pessimism of major depression.

The study was funded by the Canadian Institutes of Health Research, the National Alliance for Research on Schizophrenia and Depression, and the Canadian Institutes of Health Research.

The study, “Dysfunctional Attitudes and 5-HT2 Receptors During Depression and Self-Harm,” is posted on the Web at http://ajp.psychiatryonline.org/cgi/content/full/160/1/90?. ▪

Am J Psychiatry 2003 160 90