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Effects of Major Depressive Episodes and Severity of Dysfunctional Attitudes

Jeffrey H. Meyer, MD, PhD, FRCPC; Sylvain Houle, MD, PhD, FRCPC; Sandra Sagrati, MEd; Anna Carella, BSc; Doug F. Hussey, BSc; Nathalie Ginovart, PhD; Verdell Goulding, BSc; James Kennedy, MD, PhD, FRCPC; Alan A. Wilson, PhD

Arch Gen Psychiatry. 2004;61:1271-1279.

Background  Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin₂ BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin.

Methods  Regional 5-HTT BP was measured in 20 nonsmoking medication-free (3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [¹¹C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale.

Results  No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F_1,26, 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]).

Conclusions  Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.

Author Affiliations: Vivian M. Rakoff PET Imaging Centre (Drs Meyer, Houle, Ginovart, and Wilson; Mss Sagrati and Carella; and Messrs Hussey and Goulding), the Neurogenetics Section (Dr Kennedy), and the Mood Disorders Division (Dr Meyer), Centre for Addiction and Mental Health, and Department of Psychiatry (Drs Meyer, Houle, Ginovart, Kennedy, and Wilson; Mss Sagrati and Carella; and Messrs Hussey and Goulding), University of Toronto, Toronto, Ontario.