Regional brain metabolic correlates of alpha-methylparatyrosine-induced depressive symptoms: implications for the neural circuitry of depression.
BACKGROUND
We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion-induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using alpha-methylparatyrosine (AMPT).


OBJECTIVE
To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.


METHODS
Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.


METHODS
After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.


METHODS
Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.


RESULTS
AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P =.002) and dorsolateral prefrontal (P =.03) cortex and thalamus (P =.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.


CONCLUSIONS
Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.
Bremner
J Douglas
JD
Department of Psychiatry, Emory Center for Positron Emission Tomography, Emory University School of Medicine, Atlanta, GA, USA. jdbremn@emory.edu
Vythilingam
Meena
M
Ng
Chin K
CK
Vermetten
Eric
E
Nazeer
Ahsan
A
Oren
Dan A
DA
Berman
Robert M
RM
Charney
Dennis S
DS
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D003891:Desipramine / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D014055:Tomography, Emission-Computed; D019805:alpha-Methyltyrosine / Q000008:administration & dosage / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D000929:Antidepressive Agents, Tricyclic; D019805:alpha-Methyltyrosine; D003891:Desipramine; D009638:Norepinephrine