Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders.
BACKGROUND
The etiology of depressive illness has been linked with brain monoaminergic neuronal dysfunction, yet the development of sensitive markers of endogenous depression has proven difficult.


METHODS
Using catheters placed in an internal jugular vein, we estimated the release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9 patients with nonbipolar depressive illness refractory to medication at rest and following intravenous desipramine hydrochloride. Venoarterial plasma concentration gradients were used to quantify the amount of neurotransmitters stemming from the brain. Cerebral oxidative metabolism was assessed concurrently from measurements of oxygen and carbon dioxide gas exchange via the process of regional indirect calorimetry.


RESULTS
The brains of these patients exhibited reduced venoarterial norepinephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid concentration gradients (8.3 +/- 7.8 nmol/L vs 3.1 +/- 1.9 nmol/L), and used an energy source other than glucose. Internal jugular 5-hydroxyindoleacetic acid concentration gradients were not reduced in the patients with depressive illness. While both the reduction in norepinephrine turnover and the defect in cerebral metabolism were normalized following pharmacological blockade of the norepinephrine transporter with desipramine, paradoxically it was the brain's turnover of dopamine that bore a significant relation to the patients' clinical status (r(s) = 0.79, P =.02). The positive nature of this relationship remains difficult to reconcile.


CONCLUSIONS
In accordance with the monoamine hypothesis, a deficit in brain norepinephrine and dopamine exists in patients with depressive illness. Moreover, the brains of these patients use an energy source other than glucose, a situation that is normalized following the acute pharmacological blockade of the norepinephrine transporter with the tricyclic antidepressant, desipramine.
Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.. gavin@baker.edu.au
G
G
Lambert
M
M
Johansson
H
H
Agren
P
P
Friberg
D000328:Adult; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D001923:Brain Chemistry; D002153:Calorimetry, Indirect; D002245:Carbon Dioxide / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002395:Catecholamines / Q000502:physiology; D003866:Depressive Disorder / Q000378:metabolism* / Q000503:physiopathology; D003891:Desipramine / Q000493:pharmacokinetics / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006719:Homovanillic Acid / Q000032:analysis / Q000097:blood; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010100:Oxygen / Q000097:blood; D012039:Regional Blood Flow; D027981:Symporters
D002352:Carrier Proteins; D002395:Catecholamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D002245:Carbon Dioxide; D006897:Hydroxyindoleacetic Acid; D005947:Glucose; D010100:Oxygen; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid