One of the most consistent findings in psychiatry is that women are more likely than men to develop depression and anxiety. Across many studies and countries, women have roughly twice the risk of these disorders.
Why?
There is no single answer. Hormones, stress, trauma, social factors, and differences in how men and women experience and report symptoms may all play roles. But one particularly intriguing clue comes from when this difference emerges.
Before puberty, rates of depression are relatively similar between boys and girls. Then something changes. During adolescence, rates rise dramatically in girls, and the sex difference can approach two-to-one or even greater. A recent review in the Annual Review of Clinical Psychology highlights puberty as a critical period for the emergence of these differences.
Obviously, puberty changes many things. But two biological changes deserve attention: reproductive hormones and iron metabolism.
Hormones, the Brain, and Mitochondria
Estrogen and progesterone aren’t simply reproductive hormones. They have profound effects throughout the brain, influencing neurotransmitters, inflammation, stress responses, gene expression, and brain plasticity.
They also interact with mitochondria.
Mitochondria are the tiny structures inside our cells responsible for transforming food and oxygen into energy. But, as I describe in Brain Energy, they do much more than produce ATP. They help regulate neurotransmitters, hormones, inflammation, gene expression, and the response to stress—all processes implicated in depression and anxiety.
Estrogen receptors are found within mitochondria, and estrogen signaling can influence mitochondrial energy production, oxidative stress, calcium regulation, and mitochondrial biogenesis. Reproductive hormones also begin fluctuating substantially after puberty.
This may help explain another fascinating pattern: vulnerability to depression can change during periods of dramatic hormonal transition, including the menstrual cycle in susceptible women, pregnancy and the postpartum period, and perimenopause. Researchers increasingly suspect that for some women, it isn’t simply the amount of estrogen or progesterone that matters, but the brain’s response to fluctuations in these hormones.
From a Brain Energy perspective, these hormonal transitions may also represent metabolic and mitochondrial transitions.
Another Overlooked Factor: Iron
Puberty brings another biological change for girls: menstruation. That raises an intriguing possibility that receives surprisingly little attention in discussions of mental health—iron deficiency.
A 2023 study in JAMA analyzed nationally representative data from U.S. females ages 12 to 21. Using a ferritin level below 25 μg/L, researchers estimated that 38.6% were iron deficient. Yet only 6.3% had iron-deficiency anemia. In other words, most of the young women with iron deficiency would not necessarily be identified simply by looking for anemia. Menstruating participants had almost twice the adjusted odds of iron deficiency compared with those who had not yet begun menstruating.
Why might that matter for mental health?
Iron isn’t just needed to make hemoglobin and carry oxygen. Iron is essential to mitochondrial function.
The mitochondrial electron transport chain—the machinery that ultimately generates most of our cellular energy—depends on iron-containing molecules called iron-sulfur clusters and heme. Iron-sulfur clusters are essential components of mitochondrial complexes I, II, and III and help shuttle electrons through the respiratory chain. Iron is therefore intimately connected to the ability of cells, including neurons, to generate and regulate energy.
Iron also participates in neurotransmitter synthesis and numerous other cellular processes important to brain function.
This doesn’t mean iron deficiency explains why women experience more depression or anxiety. We don’t have evidence to make that claim. The difference between men and women almost certainly results from multiple interacting factors.
But consider the convergence.
At puberty, reproductive hormones begin fluctuating dramatically. Menstruation begins and increases the risk of iron deficiency. The brain is undergoing extensive remodeling. Social and psychological stressors change. At the same time, rates of depression and anxiety in girls begin to climb.
All of these factors can potentially intersect with metabolism and mitochondrial function.
A Different Way of Asking the Question
For decades, psychiatry has asked which neurotransmitters, hormones, psychological factors, or social experiences explain women’s increased vulnerability to depression and anxiety.
Those remain important questions.
But perhaps we should also ask another one:
What happens to brain metabolism during female puberty and during the reproductive transitions that follow?
Hormonal fluctuations, iron availability, inflammation, stress hormones, sleep, nutrition, and environmental exposures may appear to be separate risk factors. At the cellular level, however, many of them converge on mitochondria.
Understanding that convergence may eventually help us understand not only why depression and anxiety disproportionately affect women, but also how we might prevent and treat these disorders more effectively.
Interested in an integrated approach to mental and metabolic health?
MH² is excited to announce the launch of our Women’s Mental Health Services, designed to address mental health through a comprehensive approach that also considers metabolic health, hormones, nutrition, sleep, and other factors that can influence brain function.
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.
