L. Sher^{1, 2}; M. S. Milak^{1, 2}; R. V. Parsey^{1, 2}; T. B. Cooper^{1, 3}; J. J. Carballo ^{1, 2}; M. A. Oquendo^{1, 2}; J. J. Mann^{1, 2}
1. Department of Psychiatry, Columbia University, New York, NY, USA.
2. Department of Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
3. Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.

Major depression (MDD) and alcohol dependence (alcoholism) are often comorbid. Depressed subjects with alcoholism have more chronic morbidity and mortality than individuals with either diagnosis alone. The serotonergic system is involved in the pathophysiology of both depression and alcoholism. Studies have used fenfluramine challenge to elucidate regional serotonergic function in addition to measures of resting regional glucose metabolic rate responses (rCMRglu). Fenfluramine causes a release of serotonin, consequent changes in rCMRglu can be measured by 18FDG and positron emission tomography (PET). This is the first study contrasting these changes in responses to a serotonergic challenge in major depressive disorder with and without comorbid alcoholism.

Twenty-eight patients with MDD without a history of alcoholism and 15 patients with MDD and comorbid of alcoholism were enrolled in this study. All met DSM-IV criteria for a current major depressive episode in the context of major depressive disorder. Subjects received placebo on the first day and fenfluramine on the second in a single blind design. A bolus injection of approximately 5 mCi 18FDG was administered three hours after the administration of placebo/fenfluramine. A Siemens ECAT EXACT 47 scanner was used to acquire a 60-min emission scan in 2D mode as a series of twelve 5-min frames. Regions of significant differences in rCMRglu between depressed subjects with and without a history of alcoholism on placebo day and fenfluramine day were evaluated using Statistical Parametric Mapping.

Patients with MDD without comorbid alcoholism had lower aggression and hostility scale scores compared to individuals with MDD and comorbid alcoholism. Prolactin levels rose significantly after fenfluramine administration compared to after placebo but there was no difference in prolactin responses to fenfluramine administration between the two groups. We found no difference in rCMRglu between the two groups after placebo or fenfluramine administration. Because our previous study suggested that there were differences in rCMRglu between MDD patients with and without comorbid borderline personality disorder (BPD), we were also interested in reanalyzing the data only for MDD subjects without BPD (MDD/no BPD). When we repeated the analysis excluding patients with BPD from both groups, patients without comorbid alcoholism still had lower aggression and hostility scale scores compared to their counterparts. When comparing rCMRglu after placebo administration in MDD/no BPD patients with and without comorbid alcoholism, we found an anterior medial prefrontal cortical area where MDD/no BPD patients with comorbid alcoholism had more severe hypofrontality than MDD/no BPD patients without alcoholism. This area encompassed the left medial frontal and left and right anterior cingulate gyri. This group difference disappeared after fenfluramine administration.

Higher aggression and hostility in MDD patients with alcoholism may be related to greater hypofrontality in this patient group. The fact that the observed group difference disappeared after the fenfluramine challenge suggests that serotonergic mechanisms play a role in the observed differences between the groups. It also suggests that serotonergic antidepressants may be useful in the treatment of MDD patients with comorbid alcoholism.