Catecholamine depletion in first-degree relatives of individuals with mood disorders: An [(18)F]fluorodeoxyglucose positron emission tomography study()

Catecholamine depletion with alpha-methylparatyrosine (AMPT) has previously been shown to induce depressive symptoms in currently remitted patients with major depressive disorder (MDD) but not healthy controls. Thus sensitivity to catecholamine depletion has been hypothesized to be an endophenotype of MDD. Here we tested this hypothesis in the context of a randomized, double-blinded, placebo-controlled design by measuring changes in mood in a group of psychiatrically-healthy individuals at risk of mood disorders by virtue of family history (high-risk subjects, HRs). In addition, we tested whether HRs differed from healthy controls with no family-history of mood disorders (low-risk controls, LRs) in their cerebral metabolic response when undergoing catecholamine depletion. Eight healthy LRs (6 males, mean age = 34.1 ± 7.1) and 6 healthy HRs (3 males, mean age = 29.3 ± 4.6) participated in two, 3-day-long identical sessions during which they completed standardized measures of depression, anxiety and fatigue and an [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scan. On one occasion participants received 4 weight-adjusted doses of AMPT and on the other occasion participants received 4 doses of placebo. The LR and HR groups did not differ from each other in their mood during sham depletion. However, during the period of peak catecholamine depletion, the HR group reported significantly more depression, anxiety and fatigue than the LR group. A region-of-interest analysis showed that during catecholamine depletion versus placebo the combined LR and HR groups displayed a significant increase in cerebral metabolic rate in the left and right ventral striata, left and right amygdalae, and left and right hippocampi (FWE-corrected p < 0.05). Whole brain voxel-wise analyses indicated significantly increased glucose metabolism in the left and right putamina (FWE-corrected p < 0.05) in the combined LR and HR groups in the AMPT versus the placebo session. In the LR group, alone, no significant elevation in glucose metabolism was observed in the regions-of-interest in the catecholamine depletion versus placebo condition. In the HR group, alone, the region-of-interest analysis showed a significant increase in cerebral metabolic rate in the left and right ventral striata (FWE-corrected p < 0.05). No regions-of-interest showed significantly different metabolism in the HR group versus the LR group in the placebo condition, however compared with the LR group, the HR group displayed nominally increased glucose metabolism in the left amygdala during catecholamine depletion (SVC-corrected p = 0.05). A region-of-interest analysis for the interaction contrast confirmed that catecholamine depletion had differential effects on HR and LR participants. Compared with the LR group, the HR group displayed significantly increased glucose metabolism in the left ventral striatum, left amygdala, and left lateral orbitofrontal cortex (OFC) (FWE-corrected p < 0.05). Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic–cortical–striatal–pallidal–thalamic circuitry.