Findings from a brain imaging study may provide clues for why some individuals with heavy cigarette-smoking habits experience depressed mood upon withdrawal from smoking, according to a report in the August issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Cigarette smoking is the second leading cause of preventable death and is an important risk factor for coronary artery disease, lung disease, suicide and cancer, according to background information in the article. "Although many people who smoke cigarettes would like to quit, the effects of withdrawal frequently lead to relapse," write the authors. "Relapse is particularly problematic in early withdrawal because 50 percent of people relapse within the first 3 days of quitting."

Previous research into early cigarette withdrawal has focused on nicotine's modulation of dopamine-releasing neurons. "However, other neural targets that may be important in cigarette withdrawal are affected by cigarette smoke," write the authors. For instance, the enzyme monoamine oxidase A (MAO-A), which metabolizes mood-enhancing chemicals, has been shown to be affected by cigarette smoke. In regions of the brain that modulate affect, such as the prefrontal cortex and anterior cingulate cortex, elevations in MAO-A binding are associated with depressive episodes. "The main hypothesis of this study," the authors explain, "is that MAO-A binding increases during acute cigarette withdrawal in regions implicated in affect regulation, such as the prefrontal cortex and the anterior cingulate cortex."

Ingrid Bacher, Ph.D., and colleagues from the Centre for Addiction and Mental Health, Toronto, and the University of Toronto, conducted a study of 24 healthy, nonsmoking individuals and 24 otherwise healthy cigarette-smoking individuals. Among the latter group, 12 were moderate smokers (15 to 24 cigarettes per day) and 12 were heavy smokers (25 or more cigarettes per day). Positron emission tomography (PET) scans were performed once in nonsmokers and twice in smokers (once after active cigarette smoking and once after acute withdrawal). Before scans were conducted, participants also completed an assessment of their mood, energy level, anxiety level and urge to smoke.

An elevation in MAO-A density during cigarette withdrawal was found in the heavy-smoking subgroup but not the moderate-smoking subgroup, with a magnitude of change of 23.7 percent and 33.3 percent in the prefrontal and anterior cingulate cortices, respectively. A highly significant interaction between smoking severity and condition (measurement of MAO-A density during active smoking and withdrawal) was noticed among participants who smoked heavily. The MAO-A density levels in the prefrontal and anterior cingulate cortex were also significantly greater during heavy smokers' withdrawal period compared with healthy nonsmoking controls. In heavy-smoking individuals, researchers also noticed a change in depressed mood self-report between the withdrawal day and the active smoking day.

"These results have significant implications for quitting heavy smoking and for understanding what has previously appeared to be a paradoxical association of cigarette smoking with major depressive disorder and suicide," state the authors. "Understanding the neurobiology of heavy cigarette smoking is important because those who smoke heavily are much more likely to have major depressive disorder and to experience medical complications resulting from cigarette smoking." The researchers also call for clinical trials of MAO-A inhibiting drugs among individuals in the earliest stages of quitting heavy cigarette smoking.