Disorders may share pathophysiologic mechanisms
by Jeff Minerd, Contributing Writer, MedPage Today October 18, 2017

Action Points
• Note that this genome-wide association study found a cluster of genetic traits associated with a “weight-gaining” depression phenotype.
• This is a less-common phenotype than the typical one seen in major depressive disorder, in which weight loss is common.

Obesity and major depressive disorder (MDD) may be linked by shared immunometabolic mechanisms in some patients, a genetic analysis found.
A subgroup of patients with MDD whose appetite and weight increased during episodes of depression carried a higher number of genetic risk variants for increased BMI; higher levels of C-reactive protein (CRP), a marker of inflammation; and abnormal levels of leptin, a hormone involved in appetite and energy metabolism, said Yuri Milaneschi, PhD, of the Vrije University Medical Center in Amsterdam, and colleagues.
These patients comprised 15% of those with MDD, and this subgroup had an 18% higher polygenic risk for increased BMI (odds ratio 1.18, 95% CI 1.12-1.25, P=1.6 x 10-10), an 8% higher risk for increased CRP levels (OR 1.08, 95% CI 1.02-1.13, P=7.3 x 10-3), and a 9% increase in risk for abnormal leptin levels (OR 1.09, 95% CI 1.06-1.12, P=1.7 x 10-3), the authors reported online in JAMA Psychiatry.
“The phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability,” Milaneschi’s group wrote.
Epidemiologic studies have identified robust associations between depression and obesity, the investigators noted. The shared pathophysiologic mechanisms may include immunometabolic pathways characterized by an increased pro-inflammatory response and the dysregulation of hormones responsible for energy metabolism.
“Obesity is characterized by low-grade pro-inflammatory activation. Peripheral immune activation could trigger brain inflammatory responses participating in depressive neurochemical and/or endocrine processes (i.e., depletion and degradation of tryptophan toward neurotoxic end products or hyperactivation of the hypothalamic-pituitary-adrenal axis),” they wrote.
In addition, evidence suggests that disrupted signaling of leptin, a hormone derived from adipocytes, may influence mood, they said. “Leptin mood regulation may be exerted directly via receptors expressed in the hippocampus and amygdala by influencing neurogenesis and neuroplasticity in the hippocampus and cortex or by modulating the hypothalamic-pituitary-adrenal axis,” they said.
Milaneschi’s group assembled genome-wide genotypic and phenotypic measures from 14 data sets that were part of the Psychiatric Genomics Consortium. The data were drawn from case-control, cohort, and population-based studies, and they were analyzed from Sept. 28, 2015 to May 20, 2017.
The investigators focused on 11,837 study participants (59% females, 41% male) with a diagnosis of MDD and for whom there were genome-wide association data. They identified 1,871 participants whose appetite and weight increased during depressive episodes, and 5,347 whose appetite and weight decreased. They compared these participants with 14,791 control individuals. They used various molecular genetic approaches to explore differences in genetic risk profiles among the study participants.
In an accompanying editorial, Roseann Peterson, PhD, of the Virginia Institute for Psychiatric and Behavioral Genetics in Richmond, said, “While this work provides evidence of differential shared genetic liability between MDD subgroups and obesity-related traits, the methods applied only establish association and should not be misinterpreted as causal. Translational extensions of this work will need to investigate mechanisms to make important strides on establishing causality.
“A further limitation is the unknown generalizability of results to diverse populations, because only European cohorts were included in the analyses,” Peterson added. “Given the noted health disparities in mental health and obesity-related disease, the inclusion of more diverse populations in biomedical research is an important public health endeavor.”
But she noted that “Despite these limitations, leveraging molecular genetic techniques and taking advantage of large-scale consortia data has permitted Milaneschi et al to advance our understanding of the MDD-BMI association. Crucially, their results highlight the value of clinical phenotyping and the importance of collecting symptom-level data to tackle clinical and etiological heterogeneity in complex psychiatric illnesses.”
Milaneschi’s group stated that their findings “underline the need to identify subgroups of patients who may benefit most from a specific treatment according to a personalized medicine approach. In the present study, increased appetite/weight symptoms identified a subgroup of approximately 15% of patients with MDD with a higher genetic risk for immunometabolic dysregulations.
“Future clinical trials should plan to test treatment efficacy across patients with depression stratified according to this criterion,” they said, “especially for treatments targeting immunometabolic pathways (e.g. anti-inflammatory agents or weight reduction pharmacologic or behavioral interventions with or without recombinant leptin).”

The study was funded by the National Institute of Mental Health.
Milaneschi disclosed no relevant relationships with industry. Co-authors disclosed relevant relationships with Novo Nordisk, Janssen, and Boehringer Ingelheim.
Peterson disclosed no relevant relationships with industry.
• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
last updated 10.18.2017
• Primary Source
JAMA Psychiatry
Source Reference: Milaneschi Y, et al “Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations” JAMA Psychiatry 2017; DOI: 10.1001/jamapsychiatry.2017.3016.
• Secondary Source
JAMA Psychiatry
Source Reference: Peterson RE “Leveraging molecular genetic approaches to yield insights into major depression etiology and clinical presentation” JAMA Psychiatry 2017; DOI: 10.1001/jamapsychiatry.2017.3017.