Gut feelings about depression.

The perspective that eating and obesity are linked to depressive disorders has gained considerable purchase, in part, because of the attention devoted to obesity in general, the finding that obesity is accompanied by a 25% increase of anxiety and depressive disorders, and because of reports linking obesity and depression to heart disease1 as well as other conditions that involve inflammatory factors.2 There has long been the view that some individuals use food consumption, particularly comfort foods high in carbohydrates and fat, as a method of coping with or diminishing stressorinduced negative emotions. Yet another link between eating and depressive disorders and comorbid anxiety has come from the findings that pharmacological treatments to reduce anxiety (e.g., benzodiazepines) have the propensity to increase eating and that agents that reduce eating (e.g., neuromedin B, gastrinreleasing peptide, corticotropin-releasing hormone) promote anxiety.3 In light of such findings, there has been interest in determining whether key hormones associated with eating processes might also contribute to anxiety and depressive disorders and potentially serve as targets in the treatments of depression or as potential biomarkers for illness subtypes.4 We suggest that several hormones act additively or interactively in determining eating responses to stressors as well as depressive mood and that these hormones, or the genes associated with them, can serve as biomarkers and potential therapeutic targets in the treatment of depressive disorders. Besides being a fundamental player in eating processes and in hypothalamic regulation of energy balance, the adipose-derived hormone leptin had been implicated in the etiology of mood disorders.5,6 Obesity and metabolic syndrome, and the mechanisms underlying these processes, have been linked to depression and comorbid heart disease through the release of cytokines, such as leptin, from adipose tissue. Indeed, in humans, the onset of depression was associated with a combination of high leptin levels coupled with high visceral fat,7 and the link between leptin levels and severity of depressive symptoms was mediated by adiposity.8 Likewise, resistance to antidepressant treatment in humans was elevated in the presence of a polymorphism in the leptin gene (LEP).9 It was suggested that leptin might influence depression by acting on leptin receptors present on serotonin neurons within the raphe nuclei and dopamine neurons of the ventral tegmentum (VTA)10 and, thus, might influence reward processes.11 Consistent with this supposition, when leptin receptors in the rat hippocampus were gen etically deleted, a stressor-induced depressive profile was apparent,12 and deletion of leptin receptors on midbrain dopamine neurons in mice elicited elevated anxiety.13 As impressive as these findings were, however, data from clinical studies linking leptin to depression have been inconsistent.6 A resolution for the diverse findings seemed to be in the offing with reports that atypical depression, characterized by increased eating and other neurovegetative symptoms, was accompanied by elevated serum leptin levels, whereas this did not occur in nonatypical depression,14 although these findings were countered by the report that elevated circulating leptin levels were present in both melancholia and atypical depression.15 Although several factors could potentially account for some of the divergent findings that have been reported, key among these is that like most complex behavioural disturbances, it is unlikely that the link between eating/energy processes and comorbid depression are limited to the actions of leptin. The gut peptide ghrelin also plays a fundamental role in eating and energy regulation, acting in a fashion opposite to that of leptin; although it has not received the attention that leptin has, there have been indications that ghrelin functioning might contribute to depressive illness.5 Like leptin, ghrelin receptors have been reported in the VTA and the dorsal raphe nucleus16 and have been associated with reward processes17 as well as stressor-induced depressive-like symptoms, such as anhedonia.18 Moreover, it seems that ghrelin may be neuroprotective19 and may increase neurogenesis in the hippocampus, and drugs that increase neurogenesis make ghrelin receptor knockout mice more resilient to social defeat.20 In line with a role for ghrelin in stressor-elicited depression,