Researchers Explore Link Between Smoking, Depression

Researchers at the University of Mississippi have discovered that chemicals inhaled in cigarette smoke may act pharmacologically in the brain just like antidepressants. The new report in the September Archives of General Psychiatry may help to explain why smoking is more prevalent in persons with major depression than in the general population.

“People who have depression have a very difficult time quitting smoking,” said Gregory Ordway, Ph.D., a professor of psychiatry and human behavior and director of the division of neurobiology and behavior research at the University of Mississippi Medical Center in Jackson. “And those people who have recovered from major depression and then stop smoking have a greater likelihood of having their depressive symptoms recur when they stop smoking,” Ordway told Psychiatric News.

Ordway said that he and his colleagues looked at previous data that have documented several compounds in cigarette smoke that inhibit monoamine oxidase (MAO) A and B, which researchers know has antidepressant action. Recently, adding to these findings, a report showed that chronic smokers have lower brain levels of MAO A and B in their brains.

However, what specific components of inhaled cigarette smoke are linked to this change is not yet clear, Ordway explained. Researchers do know that nicotine is not an MAO inhibitor. It is also clear that whatever component of cigarette smoke is causing the biochemical changes in the brain requires tobacco to be burned. Tobacco extracts themselves do not appear to cause the same effects.

“There is an old hypothesis that people who are depressed and who smoke,” Ordway said, “do so as a means of self-medication. This led us to examine the biology of the brain in long-term smokers to compare them with nonsmokers and look at specific proteins that we feel are important to the pathophysiology of depression.”

In a three-year study funded by grants from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression, Ordway joined principal investigator Violetta Klimak, Ph.D., assistant professor of psychiatry at the University of Mississippi, to examine the brains of 20 human cadavers—10 from smokers, 10 from nonsmokers—all of whom were free of any history of major depression.

Brain tissues were supplied by Craig Stockmeier, Ph.D., also at the University of Mississippi, from a collection at the Cleveland Clinic. Stockmeier also provided Ordway and Klimek with psychiatric autopsies for the 20 individuals studied.

Noradrenergic Cells Studied

The team studied noradrenergic cells in the locus coeruleus, a collection of neurons in the brain stem, of each of the brains and measured the amounts of the enzyme tyrosine hydroxylase as well as the total quantity of alpha-2 adrenoreceptors in those neurons. Tyrosine hydroxylase, Ordway explained, is the rate-limiting enzyme in the synthesis of the neurotransmitter norepinephrine. When levels of the enzyme increase, more neurotransmitter is produced, and vice versa. Norepinephrine, in turn, binds to the alpha-2 receptors, modulating activity of nerve endings reaching out from the locus coeruleus to most parts of the brain.

Previous research has shown these particular neurons and tyrosine hydroxylase, as well as alpha-2 receptors, to be important in the pathophysiology of depression, Ordway told Psychiatric News. In the brains of persons with major depression or who committed suicide, tyrosine hydroxylase is elevated, and there are increased numbers of alpha-2 receptors. However, both have been found to be reduced by chronic administration of antidepressant medications in laboratory animals.

In the current study, the team found that in individuals who had a history of heavy, long-term smoking (between one and five packs a day for 27 to 50 years), tyrosine hydoxylase was lower, and there were fewer alpha-2 receptors in the smokers than in the nonsmokers.

“So the data suggest,” Ordway said, “that chronic smoking creates an antidepressant-like effect in these neurons, and that would lead us to speculate that individuals who are depressed and are smoking may be getting some benefit in terms of the pathophysiology of their illness from their smoking.

“Our data indicate that chronic smokers have an adjustment of the level of tyrosine hydroxylase that reflects a difference in the level of activity of the locus coeruleus,” Ordway said. By smoking, they have pharmacologically reduced that increase in activity, probably as a downward adjustment to their responsiveness to stress, he explained.

Reaction to Stress

“At this point, of course, it is speculation, but think about why a person picks up a cigarette,” Ordway explained. “The anecdotal evidence certainly adds up, and it’s up to the scientists to prove or disprove it. Our data are consistent with the anecdotal evidence that suggests that smoking can be a response to stress.”

The data, however, are not absolutely conclusive, Ordway said, so the team is conducting additional research. In particular, the researchers wonder whether people who have a genetic predisposition to lower levels of tyrosine hydroxylase and/or alpha-2 receptors would be more susceptible to developing a smoking habit. “In other words, are the decreased levels of the enzyme and the receptor really a cause or an effect of smoking?,” Ordway asked.

Smokeless Tobacco

The researchers are also interested in whether individuals who use smokeless tobacco products also have changes in the level of enzyme and receptor in the locus coeruleus. “Simple extracts of tobacco do not appear to be effectively altering the levels in the lab,” Ordway pointed out. “But it is possible that something could be ingested and then metabolized that is active in changing the levels.”

Ordway believes it would “obviously be ludicrous” to say that people who are depressed should smoke. But the team does recommend looking at smoking cessation differently in people either with current or a history of depression.

“There is enough evidence that people with depressive symptoms—not just major depression—should strongly be considered for antidepressant therapy to help them stop smoking,” Ordway told Psychiatric News. “And drugs in particular that modulate norepinephrine rather than serotonin have been shown to be useful.”

An abstract of “Effects of Long-Term Cigarette Smoking on the Human Locus Coeruleus” is posted on the Web at http://archpsyc.ama-assn.org/issues/v58n9/abs/yoa20275.html. ▪