Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects

Abstract

Context: The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD).

Objectives: To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD.

Design: Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial.

Setting: Psychiatric outpatient clinic.

Participants: Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls.

Intervention: Induction of CD by oral administration of alpha-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose.

Main outcome measures: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia).

Results: Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms.

Conclusions: This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Figure 1

Behavioral response to catecholamine depletion and relationship to brain metabolism in the ventromedial prefrontal cortex. A, Behavioral response to catecholamine depletion with α-methylparatyrosine (AMPT) and placebo in unmedicated subjects with major depressive disorder in remission (RMDD subjects) and healthy control subjects. BAI indicates Beck Anxiety Inventory; MADRS, Montgomery-Asberg Depression Rating Scale; and SHAPS, Snaith-Hamilton Pleasure Scale. *Significant diagnosis effect (RMDD subjects vs controls, P<.05). †Significant treatment effect for RMDD subjects. ‡Significant treatment effect for controls. B, Positive relationship between AMPT-induced changes in normalized metabolism (regional/global cerebral metabolic rates for glucose) in the ventromedial frontal polar cortex (at x=−4, y=54, z=−8) and the corresponding changes in depressive symptoms (r=0.77, P<.001). The difference between the within-session MADRS score change for each subject in the AMPT session vs the placebo session was calculated to reflect the magnitude of the AMPT-induced effect on depression ratings. The regression line (determined from the Pearson correlation coefficient) represents regression on data from RMDD subjects and control subjects together (N=28).

Figure 2

Image sections obtained with Statistical Parametric Mapping software (SPM2) (Wellcome Department of Imaging Neuroscience, London, England) illustrating α-methylparatyrosine (AMPT)-induced metabolic changes and correlations between AMPT-induced symptoms and regional metabolism displayed on an anatomic magnetic resonance image of the brain in the SPM2 analyses of the combined samples (N=28). A, Metabolism increased after AMPT treatment in the bilateral anteroventral striatum, as shown by voxel t values (in color bar) corresponding to P<.001; the crosshair of the lower images does not correspond to a particular peak. B, Reductions in metabolism after AMPT treatment in the left orbitofrontal cortex, as shown by voxels with t corresponding to P<.001 in the medial orbital gyrus. C, Area where changes in metabolism correlated with AMPT-induced depressive symptoms (rated by the Montgomery-Asberg Depression Rating Scale [MADRS]) in the ventromedial frontal polar cortex, as shown by voxel t values corresponding to P<.001 in the correlational analysis. D, Area where glucose utilization correlated with AMPT-induced anhedonia (rated by negative scores from the Snaith-Hamilton Pleasure Scale [SHAPS]) in the right accumbens area, shown as voxel t values corresponding to P<.005. Stereotaxic coordinates corresponding to the horizontal and vertical axes (shown in blue) are listed to the left of each image set and are interpreted as in Table 4.