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Brain reward system dysfunction in major depressive disorder: differential behavioural response to d-amphetamine and corresponding neuroanatomical substrates

Year: 2002
Type: dissertation
Study design: Clinical Trial
Abstract: Background. Brain reward system (BRS) involvement in the pathophysiology of Major Depressive Disorder (MDD) was assessed with d-amphetamine (d-amph) in two consecutive studies, the first focusing on the behavioural response, the second on the neuroanatomical correlates of this response. D-amph induces dopamine release within the mesocorticolimbic system, a major component of the BRS, and produces measurable rewarding effects (e.g. euphoria). We hypothesized that depressed subjects would exhibit an altered response to d-amph reward with distinct neural correlates due to an underlying BRS dysfunction, reflected by the loss of pleasure/interest (anhedonia), a key symptom of MDD. Methods. In Study 1, a double-blind, randomized, placebo controlled study, the behavioural and physiological effects of a single oral dose of 30 mg d-amph were measured. Twenty-two subjects with a diagnosis of DSM-IV Major Depressive Disorder not taking antidepressant medication (n = 11 d-amph, 11 placebo) were compared to 20 healthy controls (n = 10 d-amph, 10 placebo) using validated self-report drug effect tools (e.g. A.R.C.I), heart rate and blood pressure. In Study 2, functional magnetic resonance imaging (F-MRI) was used to determine the neural correlates of the response to 30 mg p.o. d-amph in 12 MDD and 12 controls (single-blind). F-MRI data were acquired at baseline and peak d-amph effect while all subjects attended to a battery of tasks. Results. Study 1: Severity of depression correlated strongly with d-amph-induced rewarding effects within the depressed group (R2 = .77, p = .033). A subsequent ANCOVA categorizing depressed subjects into severe (Hamilton Depression Rating Scale-21 item score ?24) and moderate groups, revealed that subjects with severe symptoms reported rewarding effects 3.3 fold greater than controls (p = .045). Study 2: Subjects with severe MDD again showed an enhanced response to d-amph, with corresponding differences in brain activity within prefrontal regions (Brodmann's Area 10, 11), caudate/putamen, Brodmann's Area 25, temporal gyrus, Brodmann's Area 6, and left posterior cingulate (F1,44 = 7.21, p = .01), areas implicated in reward and emotion. Conclusion. The presence of a hypersensitive response within the BRS of MDD subjects supports the hypothesis. Neuroimaging findings point to possible substrates of anhedonia, a key symptom in MDD.
Language: English
Open Access status: green
OpenAlex ID: W7133065221
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