Despite significant advances in pharmacologic therapy of depression over the past two decades, a substantial proportion of patients fail to respond or experience only partial response to serotonin re-uptake inhibitor antidepressants, resulting in chronic functional impairment. There appears to be a pattern of symptoms that are inadequately addressed by serotonergic antidepressants - loss of pleasure, loss of interest, fatigue and loss of energy. These symptoms are key to the maintenance of drive and motivation. Although these symptoms are variously defined, they are consistent with the concept of ;decreased positive affect'. Positive affect subsumes a broad range of positive mood states, including feelings of happiness (joy), interest, energy, enthusiasm, alertness and self-confidence. Although preliminary, there is evidence to suggest that antidepressants that enhance noradrenergic and dopaminergic activity may afford a therapeutic advantage over serotonergic antidepressants in the treatment of symptoms associated with a reduction in positive affect. Dopaminergic and noradrenergic agents, including the dual acting norepinephrine and dopamine re-uptake inhibitors, have demonstrated antidepressant activity in the absence of serotonergic function, showing similar efficacy to both tricyclic and serotonin re-uptake inhibitor antidepressants. Moreover, the norepinephrine and dopamine re-uptake inhibitor bupropion has been shown to significantly improve symptoms of energy, pleasure and interest in patients with depression with predominant baseline symptoms of decreased pleasure, interest and energy. Focusing treatment on the predominant or driving symptomatology for an individual patient with major depression could potentially improve rates of response and remission.
"Here it is hypothesized that in atypical depression, the dopamine transporters and receptors are down regulated due to increased tonic dopamine levels, thereby decreasing capacity of the system to regulate dopaminergic signaling. Dopaminergic pathways are involved in reward and hedonic processes, thereby hypothetically affecting paradoxical anhedonic symptoms in depression (Nestler and Carlezon, 2006; Dunlop and Nemeroff, 2007; Nutt et al., 2007; Guiard et al., 2009). There is a large body of evidence that atypical depression is associated with increased immune activity, reflected by increased proinflammatory cytokine concentrations that affect brain monoamine functioning, not only of dopamine, but also of norepinephrine and 5-HT (van Heesch et al., 2013a, 2013b, 2014; Penninx et al., 2013). "
"It is of interest then that SRIs (by releasing 5-HT) adversely affect the neural processing of rewarding and aversive stimuli (Alén et al., 2013), possibly resulting in down-regulation of the reward system (Lane, 2014). Clinically, SRIs are less effective in managing the anhedonic symptoms of depression (Nutt et al., 2007; Lane, 2014) and in fact provoke cognitive and emotional blunting (Sansone and Sansone, 2010). These SRI-associated effects have been ascribed to 5-HT 2C -mediated suppression of frontal DA function (Barnhart et al., 2004; Wongpakaran et al., 2007; McCabe et al., 2010; Sansone and Sansone, 2010) (Figure 2). "
"For example, the noradrenaline and dopamine reuptake inhibitor, bupropion, has been shown to significantly improve symptoms of energy, pleasure and interest in patients with depression with predominant baseline symptoms of decreased pleasure, interest and energy. Thus, there is a pattern of symptoms inadequately addressed by serotonergic antidepressants, suggesting treatments that enhance noradrenergic or dopaminergic activity may be more appropriate to certain types of TRD, such as depression with comorbid anxiety disorders or patients with predominant symptoms of fatigue (Nutt et al., 2007). It is also becoming apparent that inflammatory processes can contribute to the pathogenesis of MDD. "
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