Major depressive disorder (MDD) remains a leading cause of disability worldwide. For those with treatment-resistant depression (TRD), the stakes are even higher. A recent study by Pan et al. (2023) identifies a strong association between metabolic dysfunction—particularly mitochondrial impairment—and treatment-refractory major depressive disorder (trMDD) with suicidal ideation (SI).
While this study does not prove causation, it adds to a growing body of evidence suggesting that metabolic and mitochondrial dysfunction may play a central role in severe, persistent mental illness. More importantly, these insights open the door for personalized metabolic interventions that could transform care for individuals who do not respond to traditional treatments.
Metabolism and Mental Health: A Missing Link?
The study analyzed peripheral blood metabolomics in 99 individuals with trMDD-SI and compared them to 94 healthy controls. By measuring 448 metabolites, the researchers identified distinct metabolic signatures associated with trMDD-SI, achieving over 90% diagnostic accuracy.
One of the most striking findings was that mitochondrial dysfunction was a common denominator among those with trMDD-SI. Elevated levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15)—both biomarkers of mitochondrial stress—suggest that metabolic dysfunction is not just a side effect of depression but may contribute to its pathology.
However, while these findings are compelling, it’s important to note that they establish a correlation, not causation. This study does not prove that metabolic dysfunction causes TRD-SI—only that the two are linked. Yet, when viewed alongside countless other studies demonstrating metabolic and mitochondrial abnormalities in psychiatric disorders, the pattern becomes difficult to ignore.
A Gender-Specific Pattern
Interestingly, metabolic disruptions differed by sex. Women with trMDD-SI exhibited greater dysfunction in eicosanoid signaling (inflammatory lipid mediators), whereas men showed more profound peroxisomal metabolism dysfunction. These findings suggest that personalized metabolic interventions may need to account for sex-specific vulnerabilities in energy metabolism.
A Path Forward: Personalized Metabolic Interventions
Beyond broad metabolic disturbances, the study identified individualized deficiencies in key metabolites such as CoQ10, flavin adenine dinucleotide (FAD), citrulline, lutein, carnitine, and folate. These findings highlight the potential for precision psychiatry, where interventions are tailored to a patient’s unique metabolic profile.
For example, patients with CoQ10 or carnitine deficiencies may benefit from supplementation to support mitochondrial energy production, while those with folate or flavin deficiencies may require targeted nutritional support. This metabolic approach represents a potential shift away from the one-size-fits-all treatment model that has dominated psychiatry for decades.
Does This Mean That All Depressed and Suicidal People Have a Metabolic Disorder?
No. As outlined in Brain Energy, there is a crucial distinction between mental states and mental disorders.
Many experiences of depression and suicidal ideation are natural responses to adversity, stress, or trauma. Suicidal thinking appears to be hardwired into the human brain and can be triggered by extreme psychological and social circumstances.
Take, for example, a man who gambles away his family’s savings on a risky stock. If the company goes bankrupt, his financial ruin could lead to overwhelming distress. If those around him berate him for being reckless, his wife leaves, and he loses access to his children, he may enter a profound state of despair, experiencing suicidal thoughts. In this case, his suffering is a mental state—a normal response to severe life stress. This does not mean he does not need or deserve help.
However, depression and suicidality can also be a mental disorder, as seen in individuals who experience severe, chronic symptoms without an obvious external cause. The people in this study fell into this category—and many showed biochemical markers of metabolic dysfunction.
To complicate matters further, prolonged psychological distress can contribute to metabolic dysfunction. If the man who lost his fortune continues to experience stress, social isolation, and humiliation, these factors may drive chronic inflammation, oxidative stress, and mitochondrial dysfunction, increasing the risk of developing a mental disorder.
Rethinking Psychiatric Care Through a Metabolic Lens
This study does not stand alone. Decades of research have linked chronic mental disorders—including depression, bipolar disorder, schizophrenia, and even neurodegenerative conditions—to metabolic and mitochondrial dysfunction.
While causation has yet to be definitively established, the sheer weight of the evidence suggests that psychiatry can no longer ignore the role of metabolism in mental illness.
Instead of viewing MDD solely as a neurotransmitter imbalance or a psychological condition, we must also recognize it as a metabolic and mitochondrial disorder.
These findings reinforce the urgent need to integrate metabolomics, mitochondrial biomarkers, and metabolic interventions into mainstream psychiatric practice. As the field advances, the goal should be true recovery, rather than mere symptom suppression.
For both patients and clinicians, this research presents an important takeaway: If conventional antidepressants fail, the next step should not necessarily be another medication. Instead, a comprehensive metabolic assessment may reveal treatable biochemical abnormalities—offering new hope for those with the most severe and refractory forms of depression.
Reference: Metabolic features of treatment-refractory major depressive disorder with suicidal ideation
Dr. Christopher Palmer is a Harvard psychiatrist and researcher working at the interface of metabolism and mental health. He is the Founder and Director of the Metabolic and Mental Health Program and the Director of the Department of Postgraduate and Continuing Education at McLean Hospital and an Assistant Professor of Psychiatry at Harvard Medical School. For almost 30 years, he has held administrative, educational, research, and clinical roles in psychiatry at McLean and Harvard. He has been pioneering the use of the medical ketogenic diet in the treatment of psychiatric disorders—conducting research in this area, treating patients, writing, and speaking around the world on this topic. Most recently, he has proposed that mental disorders can be understood as metabolic disorders affecting the brain, which has received widespread recognition in both national and international media outlets.
