Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression

Abstract

Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [(18)F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression.

Figure 1

Depression and anxiety items showing significant differences in the tryptophan depletion effect compared with the catecholamine depletion effect in remitted major depressive disorder subjects are displayed with means and s.e. Items were sampled using the Hamilton Scale of Depression and Montgomery–Åsberg Depression Rating Scale (a) and the Beck Anxiety Inventory (b). Significant at *P<0.05; significant at **P<0.01.

Figure 2

The mean percent change (with s.e.) in normalized regional glucose metabolism induced by tryptophan depletion (TD) and catecholamine depletion (CD) in a priori defined regions of interest (ROIs) in subjects with remitted major depressive disorder (rMDD) and healthy controls (HCs). Normalized values were obtained by dividing each mean value by the corresponding whole-brain glucose metabolism value to factor out nonspecific global effects. Significant depletion effect at P<0.05: a; significant diagnosis effect at P<0.05: b; significant depletion-by-diagnosis interaction at P<0.05: c; significant sex effect at P<0.05: d. OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PFC, prefrontal cortex; rCMRglu, regional cerebral metabolic rates for glucose.