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Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects.
Arch Gen Psychiatry. 2008 May; 65(5):521-31.AG

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.

Authors+Show Affiliations

Department of Psychiatry, University Hospital, Culmannstrasse 8, 8091 Zurich, Switzerland. g.hasler@bluewin.chNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

18458204

Citation

Hasler, Gregor, et al. "Neural Response to Catecholamine Depletion in Unmedicated Subjects With Major Depressive Disorder in Remission and Healthy Subjects." Archives of General Psychiatry, vol. 65, no. 5, 2008, pp. 521-31.
Hasler G, Fromm S, Carlson PJ, et al. Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Arch Gen Psychiatry. 2008;65(5):521-31.
Hasler, G., Fromm, S., Carlson, P. J., Luckenbaugh, D. A., Waldeck, T., Geraci, M., Roiser, J. P., Neumeister, A., Meyers, N., Charney, D. S., & Drevets, W. C. (2008). Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Archives of General Psychiatry, 65(5), 521-31. https://doi.org/10.1001/archpsyc.65.5.521
Hasler G, et al. Neural Response to Catecholamine Depletion in Unmedicated Subjects With Major Depressive Disorder in Remission and Healthy Subjects. Arch Gen Psychiatry. 2008;65(5):521-31. PubMed PMID: 18458204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. AU - Hasler,Gregor, AU - Fromm,Stephen, AU - Carlson,Paul J, AU - Luckenbaugh,David A, AU - Waldeck,Tracy, AU - Geraci,Marilla, AU - Roiser,Jonathan P, AU - Neumeister,Alexander, AU - Meyers,Noah, AU - Charney,Dennis S, AU - Drevets,Wayne C, PY - 2008/5/7/pubmed PY - 2008/6/10/medline PY - 2008/5/7/entrez SP - 521 EP - 31 JF - Archives of general psychiatry JO - Arch. Gen. Psychiatry VL - 65 IS - 5 N2 - 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. SN - 1538-3636 UR - https://www.unboundmedicine.com/medline/citation/18458204/Neural_response_to_catecholamine_depletion_in_unmedicated_subjects_with_major_depressive_disorder_in_remission_and_healthy_subjects_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=18458204.ui DB - PRIME DP - Unbound Medicine ER -