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


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


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


METHODS
Psychiatric outpatient clinic.


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


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


METHODS
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.
Hasler
Gregor
G
Department of Psychiatry, University Hospital, Culmannstrasse 8, 8091 Zurich, Switzerland. g.hasler@bluewin.ch
Fromm
Stephen
S
Carlson
Paul J
PJ
Luckenbaugh
David A
DA
Waldeck
Tracy
T
Geraci
Marilla
M
Roiser
Jonathan P
JP
Neumeister
Alexander
A
Meyers
Noah
N
Charney
Dennis S
DS
Drevets
Wayne C
WC
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D002395:Catecholamines / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000378:metabolism* / Q000503:physiopathology*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D006304:Health Status; D006801:Humans; D008032:Limbic System / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D012074:Remission Induction; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D019805:alpha-Methyltyrosine / Q000008:administration & dosage / Q000494:pharmacology*
D002395:Catecholamines; D019805:alpha-Methyltyrosine; D005947:Glucose