There Are 2 Biologicially Distinct Forms of Major Depression, Says New Study
Health12 July 2026ByIvan Farkas
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Major depressive disorder (MDD) is a severe, clinical type of depression, a more broadly defined mood disorder associated with a persistent feeling of sadness and a loss of interest
MDD places a great strain on the populace and national framework. At least 10 percent of people in the US will experience it once in their lives. Additionally, MDD causes more than US$210 billion in healthcare costs and lost productivity
Since MDD is a complex disorder, affected by a murky mix of genetic, psychological, and biological factors, distinguishing its subtypes may be critical for designing effective treatment strategies
To better constrain the underlying mechanisms of MDD, a new study (which is yet to be peer-reviewed) has examined biologically distinct subtypes of MDD based on their opposing, atypical energy-related symptoms (AERS)
Perhaps most importantly, this paper presents an immunometabolic framework that addresses an overarching diagnostic discrepancy
“Current diagnostic criteria treat opposite symptom directions as equivalent; weight gain or loss, and increased or decreased sleep, each count toward a single diagnosis,” the researchers explain
While this has improved standardization, it may have facilitated ineffective one-size-fits-all healthcare techniques and delayed treatment progress
As the researchers note, “individuals with the same MDD diagnosis manifest different symptom profiles that may represent the expression of partially distinct pathophysiological pathways.”
To constrain these cases, they performed three genome-wide association meta-analyses, comprising more than 460,000 total individuals of European ancestry, comparing three MDD subtypes
These include AERS+, comprising hypersomnia (extreme sleepiness) with weight gain, and AERS-, comprising insomnia with weight loss, as well as a ‘middle-ground’ Uncategorized MDD exhibiting a mix of symptoms
The analyses told a tale of two biophysiological profiles. For example, AERS+ was correlated with the highest body mass index (BMI). But it was not solely reliant on this measure, as it also exhibited higher recurrence, more severe functional impairments, earlier onset, and a higher prevalence of comorbidities, or coexisting medical conditions
Overall, the researchers discovered 27 genome-wide loci, or DNA variations associated with disease, including several that had not been previously reported
Four of these loci were associated with AERS+ (with an assumed population prevalence of 1.5 percent), including a gene previously implicated with BMI and MDD, as well as a non-coding RNA associated with cortical inhibitory neurons – nerve cells that suppress the action of other neurons in the brain
Ten loci were associated with AERS- (assumed prevalence of 5 percent), including those linked to more ‘favorable’ metabolic traits, such as a “risk-increasing allele [gene variant] associated with smaller waist circumference.”
Additionally, other genetic variants associated with an increase in AERS- risk are linked to a reduced risk of type 2 diabetes, as well as a possible link to schizophrenia, suggesting a shared mechanism
In contrast to AERS+, this subtype of MDD seemed to be linked to excitatory neurons, which activate rather than suppress other brain cells
The researchers also reported 13 loci for Uncategorized MDD (assumed prevalence of 8.5 percent), which represents a subtype between the other two. Indeed, they noted that “the Uncategorized subtype is partially, but not fully, a genetic mix of AERS+ and AERS-.”
Delving deeper, the researchers found a significantly positive genetic correlation between AERS+ and five metabolic markers: BMI, waist circumference, metabolic syndrome, type 2 diabetes, and blood glucose. Conversely, these traits are significantly and negatively correlated with AERS-
The researchers also report a correlation between AERS- and anorexia nervosa, as well as between AERS+ and ADHD, hypertension, and coronary heart disease
Additionally, AERS+ was negatively correlated with ‘good’ HDL cholesterol and positively correlated with C-reactive protein, an inflammatory marker produced in the liver and associated with MDD
AERS+ also exhibited a profile that indicated impaired cholesterol transport, insulin resistance, and a pro-inflammatory state with a higher risk of atherosclerosis and other cardiovascular diseases
So for people with AERS+ MDD, their biology looks remarkably like someone heading toward metabolic syndrome. For those with AERS- MDD, it can look almost the opposite
Overall, this work shows the “meaningful differences in genetic architecture” between MDD subtypes
It also reveals that immunometabolic factors may modify MDD subtypes without directly causing them, perhaps through biological mechanisms such as stress-response systems that modulate bodily inflammation, or insulin sensitivity
Such findings are consistent with disruptions in homeostasis, which impair energy management and manifest as appetite, weight, and sleep issues
As a result, this work further illuminates why symptoms and comorbidities are inconsistent in broad generalizations of MDD
“Whether metabolic dysfunction is part of the causal pathway to AERS+ or primarily modifies its symptomatic presentation remains unresolved, but either interpretation has implications for how depression is studied and eventually treated,” the researchers say
A preprint of this study is available on medRxiv
This article was fact-checked by Rebecca Dyer and edited by Michael Irving. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know
