Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression

• Published in: Psychological medicine Vol. 44; no. 6; pp. 1183 - 1195
• Main Authors: Macoveanu, J., Knorr, U., Skimminge, A., Søndergaard, M. G., Jørgensen, A., Fauerholdt-Jepsen, M., Paulson, O. B., Knudsen, G. M., Siebner, H. R., Kessing, L. V.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.04.2014
• Subjects: Adult; Adult and adolescent clinical studies; Biological and medical sciences; Brain; Brain structure; Citalopram - administration & dosage; Citalopram - pharmacology; Cortex; Depression; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Depressive Disorder, Major - physiopathology; Double-Blind Method; Family; Female; Genetic Predisposition to Disease; Hippocampus; Hippocampus - drug effects; Hippocampus - physiopathology; Humans; Information processing; Magnetic Resonance Imaging; Male; Medical imaging; Medical sciences; Mental depression; Miscellaneous; Mood disorders; Neurobiology; Neuropharmacology; Original Articles; Pharmacology. Drug treatments; Placebos; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiopathology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Reward; Rewards; Serotonin reuptake inhibitors; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacology; Treatment Outcome; reward; SSRI; escitalopram; depression; pharmacological MRI; Decision making; Mood disorder; Human; Orbitofrontal cortex; Serotonin; Escitalopram; Family study; Psychotropic; Central nervous system; Depression; Reuptake inhibitor; Nuclear magnetic resonance imaging; Encephalon; Selective serotonin reuptake inhibitor; Neurotransmitter; Medical imagery; Antidepressant agent; Reward; Hippocampus
• ISSN: 0033-2917; 1469-8978
• DOI: 10.1017/S0033291713001815

Healthy first-degree relatives of patients with major depression (rMD+) show brain structure and functional response anomalies and have elevated risk for developing depression, a disorder linked to abnormal serotonergic neurotransmission and reward processing. In a two-step functional magnetic resonance imaging (fMRI) investigation, we first evaluated whether positive and negative monetary outcomes were differentially processed by rMD+ individuals compared to healthy first-degree relatives of control probands (rMD-). Second, in a double-blinded placebo-controlled randomized trial we investigated whether a 4-week intervention with the selective serotonergic reuptake inhibitor (SSRI) escitalopram had a normalizing effect on behavior and brain responses of the rMD+ individuals. Negative outcomes increased the probability of risk-averse choices in the subsequent trial in rMD+ but not in rMD- individuals. The orbitofrontal cortex (OFC) displayed a stronger neural response when subjects missed a large reward after a low-risk choice in the rMD+ group compared to the rMD- group. The enhanced orbitofrontal response to negative outcomes was reversed following escitalopram intervention compared to placebo. Conversely, for positive outcomes, the left hippocampus showed attenuated response to high wins in the rMD+ compared to the rMD- group. The SSRI intervention reinforced the hippocampal response to large wins. A subsequent structural analysis revealed that the abnormal neural responses were not accounted for by changes in gray matter density in rMD+ individuals. Our study in first-degree relatives of depressive patients showed abnormal brain responses to aversive and rewarding outcomes in regions known to be dysfunctional in depression. We further confirmed the reversal of these aberrant activations with SSRI intervention.