Changes in Appetite and Inflammation in Major Depressive Disorder

Investigators found data that showed a ghrelinergic signaling mechanism may be responsible for increased appetite in patients with MDD.

In addition to cardiovascular disease and somatic symptoms, major depressive disorder (MDD) has a historic association with marked changes in appetite and weight.1 According to research published in Brain, Behavior, and Immunity, approximately half of patients with MDD report a decrease in appetite and one-third report an increase in appetite.1 Per investigators, these appetite change profiles “tend to remain stable … over recurrent depressive episodes.”

“The appetite change profiles experienced by most individuals with MDD may reflect an underlying immunologic pathophysiology,” the authors wrote. “What remains unclear, however, is the specific intervening neurobiological processes that turn systemic inflammation into increased appetite and eating.”

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Research Overview: Inflammation and Appetite

A total of 64 adults (31 patients with MDD and 33 healthy controls; mean age 32.3±8.9 years) participated in the study. Within the MDD group, 14 patients had increased appetite (MDD-A+) and 17 had decreased appetite (MDD-A-).

At visit 1, demographic information was collected, and all patients were assessed for current psychiatric disorders. At the second visit, all participants were provided with a standardized breakfast after fasting for 12 hours, then completed the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Snaith-Hamilton Pleasure Scale. Before functional magnetic resonance imaging (fMRI), each participant’s blood was tested twice for plasma C-reactive protein (CRP).

While all 3 groups were similar across age, body mass index, and gender composition, there were significant differences in food pleasantness ratings. Those in the MDD-A- group rated food-based stimuli as “significantly less pleasant” than those in the MDD-A+ and healthy control groups; food stimuli ratings were comparable between the MDD-A+ and healthy control groups.

Results of the fMRI found that food pleasantness ratings were related to activation within the network of regions associated with valuation and reward, including the medial prefrontal cortex, insula, orbitofrontal cortex (OFC), and caudate. Voxel-wise, random-effects multivariate modeling showed clusters in the left OFC, right insula, and bilateral striatum that demonstrated a “significant interaction effect” between the group and CRP level — indicating that the coupling between blood oxygenation level-dependent (BOLD) signal change and food stimuli pleasantness rating is influenced by the interaction between group status and CRP concentration. Per investigators, the results were similar when controlling for gender.

Post hoc regression analyses were also performed to identify the specific relationships within the group-CRP interactions. Within the OFC cluster, CRP was associated with a stronger coupling between BOLD signal change and pleasantness rating in patients with MDD-A+, compared with MDD-A- and healthy controls (b=-0.07 for both; t=-4.58 and -5.79, respectively; P <.001 for both).

“In short, compared [with] participants from the other two groups, MDD-A+ participants exhibited a greater increase in left OFC activity per unit change in their food pleasantness ratings,” the researchers wrote.1

However, regression models focused on insula activation revealed contrasting results: within the right anterior and mid-insula, higher CRP values were related to stronger coupling between BOLD signal change and pleasantness ratings in MDD-A+ vs MDD-A- and healthy controls (b=-0.05 and -0.07; t =-2.14 and -4.16; P <.05 and P <.001, respectively); no significant differences were noted between MDD-A- and healthy control participants.

Within the right posterior and mid-insula, higher CRP was associated with weaker coupling between BOLD signal change and pleasantness ratings in MDD-A+ compared with healthy control participants (b=-0.04; t=-3.64; P <.001), with no significant difference between MDD-A- and MDD-A+ (b=0.01; t=1.16; P =.25) and MDD-A- and healthy controls (b=-0.02; t=-1.90; P =.06).

Additional Studies: Noninflammatory Responses

These results build on those previously published, including a recent study in the Journal of Affective Disorders.2 In this 2019 study, Laura M. Holsen, PhD, of the Division of Women’s Health, the Department of Medicine, and the Department of Psychiatry and Brigham and Women’s Hospital in Boston, Massachusetts and colleagues, found that a ghrelinergic signaling mechanism may be responsible for increased appetite in patients with MDD, particularly in the face of similar ghrelin levels between healthy controls and patients with hyperphagic MDD.2

In that study, the researchers examined a community sample of women with either hyperphagic or hypophagic MDD and a group of healthy controls. After a screening visit to collect data on clinical variables and a 12-hour overnight fast, patients underwent serial blood draws, screening via the State-Trait Anxiety Inventory, and fMRI screening. Both before and after consuming a standardized meal, blood draws were repeated, and participants were asked to complete appetite ratings for sweet foods, fatty foods, and overall hunger.

Results indicated that acylated ghrelin was positively associated with BOLD activity to high- and low-calorie food stimuli in both the left and right ventral tegmental area and left hypothalamus within the hyperphagic MDD group. In contrast, a negative association was noted between acylated ghrelin and BOLD activity in the right hypothalamus in those with hypophagic MDD.

According to Dr Holsen and colleagues, these findings “may facilitate the development of more precise and effective treatment for opposing appetite phenotypes in depression.”2

Conclusions and Looking Forward

In sum, both noninflammatory factors and peripheral inflammation may play a role in the behavioral and neurological processes underlying appetite changes in MDD. That the results were observed with the left OFC — commonly associated with decision making and behavioral drives1 — was not surprising to investigators, who noted that this same area of the OFC was “one of two regions identified in the original publication with the Food Pleasantness Task,” which further highlighted the role of the OFC in “online hedonic inferences of food stimuli.”1

Additionally, research by W. Kyle Simmons, PhD, published in Molecular Psychiatry,3 found that it is possible for systemic inflammation in some people with depression to lead to disrupted metabolic signaling via the hypothalamus, as well as subsequent blunting of “homeostatic satiety signals that inform reward valuation.”1 The model presented by Dr Simmons and colleagues3 would, according to the researchers, account for the current study’s observation that patients with MDD-A+ had both heightened inflammation and altered coupling between OFC activity and food reward inferences.1

Researchers of the current study indicated several limitations, including the small sample size and unequal gender distribution across groups. Another limitation was the investigators’ choice to not explore results based on depression onset.1

The researchers suggest that future research examine the relationship between inflammation and MDD-related appetite change in “larger, more representative samples,” in addition to exploring the underlying mechanisms between inflammation and food-related anhedonia.1

“These findings, along with further delineation of inflammatory or appetite subtypes, may ultimately lead to more targeted, personalized, and effective treatments for MDD, and the prevention of its concomitant adverse health outcomes such as obesity and cardiovascular disease,” the researchers concluded.1

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


1. Cosgrove KT, Burrows K, Avery JA, et al. Appetite change profiles in depression exhibit differential relationships between systemic inflammation and activity in reward and interoceptive neurocircuitry [published online October 8, 2019]. Brain Behav Immun. doi: 10.1016/j.bbi.2019.10.006

2. Cerit H, Christensen K, Moondra P, Klibanski A, Goldstein JM, Holsen LM. Divergent associations between ghrelin and neural responsibility to palatable food in hyperphagic and hypophagic depression. J Affect Dis. 2019;242:29-38.

3. Simmons WK, Burrows K, Avery JA, et al. Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states [published online June 13, 2018]. Mol Psychiatry. doi: 10.1038/s41380-018-0093-6