Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness - Evidence in support of the catecholamine hypothesis ofmood disorders

Background: The etiology of depressive illness has been linked with brain m onoaminergic 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 t he release of brain monoamine neurotransmitters in 19 healthy volunteers an d 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 neurotra nsmitters stemming from the brain. Cerebral oxidative metabolism was assess ed 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 norepi nephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid c oncentration 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 ac id concentration gradients were not reduced in the patients with depressive illness. While both the reduction in norepinephrine turnover and the defec t in cerebral metabolism were normalized following pharmacological blockade of the norepinephrine transporter with desipramine, paradoxically it was t he brain's turnover of dopamine that bore a significant relation to the pat ients' clinical status (r(s) =0.79, P = .02). The positive nature of this r elationship remains difficult to reconcile. Conclusions: In accordance with the monoamine hypothesis, a deficit in brai n norepinephrine and dopamine exists in patients with depressive illness. M oreover, the brains of these patients use an energy source other than gluco se, a situation that is normalized following the acute pharmacological bloc kade of the norepinephrine transporter with the tricyclic antidepressant, d esipramine.