Scientists reveal atypical depression is a distinct biological subtype linked to antidepressant resistance

A new genetic and clinical analysis suggests that atypical depression represents a distinct biological subtype of the disorder with specific implications for treatment. The study found that individuals with this form of depression possess unique genetic risk profiles, experience different physical symptoms, and tend to respond less favorably to standard antidepressant medications. These findings were published in Biological Psychiatry.

Depression is often viewed by the general public as a single condition characterized by sadness and low energy. Mental health professionals and researchers recognize it as a complex and heterogeneous disorder with various trajectories. Patients often report vastly different symptoms and have uneven responses to available treatments. Some individuals find relief quickly with the first medication they try. Others struggle with chronic symptoms despite multiple interventions.

The scientific team behind this research aimed to address this variability by investigating the biological mechanisms driving these differences. They focused specifically on atypical depression. This subtype has been a subject of debate in psychiatry for over sixty years. It is historically characterized by a specific set of symptoms that differ from “melancholic” or typical depression.

The researchers sought to determine if atypical depression represents a valid biological category rather than just a cluster of symptoms. They wanted to see if people with this profile carry different genetic risks compared to those with other forms of depression. They also investigated whether these biological differences translate into different experiences with medication. Identifying such distinctions provides a foundation for moving away from a trial-and-error approach to mental health care.

“Depression is a complex illness—it’s not one thing. It has many trajectories with different underlying mechanisms and pathways,” explained study author Mirim Shin, a research fellow
at the University of Sydney. “Some people respond well to antidepressants, others don’t, and we don’t fully understand why. I’m interested in uncovering the mechanisms behind these differences—finding the distinct biological pathways that lead to different illness trajectories and, ultimately, identifying which interventions or treatments might work best for which people.”

The researchers utilized data from the Australian Genetics of Depression Study. This cohort is one of the largest groups of genetically documented individuals with depressive disorders in the world. The researchers analyzed information from 14,897 participants. The participants provided DNA samples and completed detailed online surveys about their mental health history. The average age of the participants was approximately 44 years. About 75 percent of the sample was female.

The researchers classified participants based on the symptoms they experienced during their worst depressive episode. They defined atypical depression by the presence of two reversed neurovegetative symptoms: excessive sleeping and weight gain. Standard depression is often associated with insomnia and weight loss. Participants who reported both weight gain and hypersomnia were categorized as having atypical depression. This group consisted of 3,098 individuals, or about 21 percent of the total sample. The remaining participants were categorized as having other depressive disorders.

“About 1 in 5 people with depression in our study had the atypical depression—so this isn’t rare,” Shin told PsyPost.

The research team calculated polygenic risk scores for each individual. These scores estimate a person’s genetic likelihood for developing certain traits or conditions based on thousands of genetic variants scattered across their genome. The team compared the genetic profiles of the atypical group against the non-atypical group. They specifically examined genetic risks for mental disorders, metabolic and inflammatory conditions, and sleep patterns.

In addition to genetic analysis, the study assessed real-world treatment experiences. Participants rated the effectiveness of ten common antidepressants they had previously taken. They also reported any side effects they experienced. The researchers categorized these medications into classes, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

The analysis revealed clear demographic and clinical differences between the two groups. Individuals with atypical depression tended to have an earlier age of onset for their condition. They experienced more severe illness trajectories. They were more likely to suffer from co-occurring conditions such as generalized anxiety disorder and substance use disorders.

A distinct pattern emerged regarding sleep and daily rhythms. The atypical group showed a strong preference for evening activity. They also reported spending significantly less time outdoors during the day compared to the other group. This suggests a disruption in their circadian rhythms, or body clocks.

Genetic analysis reinforced these clinical observations. Participants with atypical depression had higher polygenic risk scores for major depression, attention-deficit/hyperactivity disorder, and bipolar disorder. They did not show an increased genetic risk for schizophrenia. This suggests the genetic architecture of atypical depression is specific and distinct.

The atypical group also carried a higher genetic risk for physical health issues. They had elevated polygenic scores for body mass index, type 2 diabetes, and C-reactive protein, which is a marker of inflammation. Conversely, they had lower genetic scores for high-density lipoprotein cholesterol, often called “good” cholesterol.

A key genetic finding involved body clock regulation. The atypical group had lower genetic scores for morningness. This indicates a biological predisposition toward being “night owls” or having delayed sleep-wake cycles. This genetic tendency aligns with the physical symptoms of staying up late and sleeping excessively.

The study also found differences in how these individuals responded to medication. Participants with atypical depression were less likely to report that selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors worked well for them. These are the most commonly prescribed classes of antidepressants.

The atypical group also reported higher rates of side effects. Specifically, they were nearly three times more likely to report weight gain while taking these medications compared to patients with other forms of depression. They also reported higher rates of drowsiness and fatigue.

“The genetic associations we found are modest, as is typical in psychiatric genetics, but they point toward real biological differences,” Shin explained. “The treatment findings are more immediately relevant: people with atypical depression were about 12-15% less likely to report that SSRIs or SNRIs worked well, and nearly three times more likely to experience weight gain as a side effect.”

The researchers performed additional calculations to ensure these results were not driven solely by body weight. Atypical depression is defined partly by weight gain, so a link to obesity-related genetics is expected. However, even when the researchers statistically controlled for body mass index, the genetic link to eveningness remained significant.

The reduction in reported medication effectiveness also persisted regardless of body mass index. This suggests that the sleep-wake disruption and treatment resistance are core features of the condition. They are likely not simple byproducts of being overweight.

“What struck me was how robust the circadian/chronotype finding was,” Shin told PsyPost. “Even after accounting for BMI—which is central to how we defined atypical depression—the genetic predisposition toward being an ‘evening person’ remained significant. And treatment differences actually strengthened after controlling for BMI. This suggests there’s something about circadian rhythm disruption in atypical depression that goes beyond weight, and it might be a promising treatment target.”

“If you’ve tried antidepressants and they haven’t worked well for you, it’s not your fault. You may simply have different biology and genetics, which means you might need a different approach. If you’re not responding well to treatment, monitor your sleep patterns, weight changes, and other physical symptoms—and talk to your doctor. These details matter and can help guide treatment decisions. Depression isn’t one-size-fits-all, and understanding your specific symptom profile is an important step toward finding what works for you.”

A potential misinterpretation of this study involves the definition of atypical depression. Clinical manuals typically require “mood reactivity,” or the ability to feel temporarily better in response to positive events, as a diagnostic criterion. The researchers in this study defined the condition based only on reversed physical symptoms of increased sleep and weight gain. This was necessary because mood reactivity is difficult to measure in retrospective self-reports.

“Our definition captures something biologically meaningful, but it may not perfectly overlap with how clinicians use the term,” Shin noted.

The study also relied on participants remembering past symptoms and treatment effects. This reliance on memory can introduce recall errors. The sample consisted of individuals with European ancestry. This limits the ability to generalize findings to other ethnic populations. Additionally, the cross-sectional nature of the genetic analysis highlights associations but cannot definitively prove that specific genetic markers cause the observed symptoms.

The high rate of missing body mass index data for some participants limits the precision of certain adjustments. The study also only looked at common antidepressants. It did not evaluate experiences with other types of medication that might work better for this subgroup, such as monoamine oxidase inhibitors.

Future research intends to explore treatments that target the body clock. Given the strong link to eveningness and circadian disruption, therapies such as bright light exposure or strict sleep scheduling could offer relief. The study authors suggest that clinicians should consider these distinct physical symptoms when prescribing medication. Recognizing the atypical profile could lead to earlier consideration of alternative treatments rather than persisting with standard antidepressants that may be ineffective.

“Given that circadian disruption emerged as a key feature, we need to test whether circadian-targeted interventions — like bright light therapy, sleep-wake schedule regularization — might help people with atypical depression who haven’t responded well to standard antidepressants,” Shin said.

“This was one of the largest genetically-informed studies of depression: Australian Genetics of Depression Study. I also hope clinicians take note of these findings—when patients present with atypical features like weight gain and hypersomnia, it may signal a different biological profile that could affect how they respond to standard antidepressants. Being aware of this can help guide treatment selection.”

The study, “Atypical depression is associated with a distinct clinical, neurobiological, treatment response and polygenic risk profile,” was authored by Mirim Shin, Jacob J. Crouse, Tian Lin, Enda M. Byrne, Brittany L. Mitchell, Penelope A. Lind, Richard Parker, Sarah Mckenna, Emiliana Tonini, Joanne S. Carpenter, Kathleen R. Merikangas, Naomi R. Wray, Sarah E. Medland, Nicholas G. Martin, and Ian B. Hickie.