What Is Depression Actually?

When we talk about depression, we're using a term that means vastly different things for different people. The diagnostic criteria for major depressive disorder are remarkably broad. You need five symptoms from a list of nine, present for at least two weeks. Those symptoms can include depressed mood, loss of interest, changes in sleep, changes in appetite, fatigue, difficulty concentrating, feelings of worthlessness, psychomotor changes and thoughts of death.

Think about how many different combinations that allows. Someone with insomnia, weight loss, agitation, and suicidal thoughts has the same diagnosis as someone with hypersomnia, weight gain, slowed movements, and fatigue. One person's depression might be driven by inflammatory processes following chronic stress. Another's might reflect thyroid dysfunction. Another's might involve metabolic problems affecting brain energy production. Yet they all receive the same diagnosis and often similar treatments.

This heterogeneity creates real problems. When research studies test antidepressants, they're testing them on groups of people whose underlying pathology may be completely different. When we say a medication has a 30% response rate, we don't know if it worked for a specific subtype of depression or if it worked partially for many different types. The broad diagnostic category obscures the reality that we're treating fundamentally different conditions.

Antidepressants

Maybe you've tried multiple antidepressants, perhaps several different types. The results have likely been disappointing.

The 2006 STAR*D trial, a large study of antidepressant effectiveness with over 4,000 participants, found that only about 25 to 28% of people achieved remission after their first antidepressant trial. After trying multiple alternative antidepressants sequentially, the remission rates remained low. When researchers reanalysed the data, they found that improvement on antidepressants was actually below what's typically seen with placebo in controlled trials.

These numbers don't necessarily mean antidepressants don't work. They might mean we're using a monotherapy treatment for what should be recognised as a system-level dysfunction which will express differently in different people. Antidepressants target neurotransmitter systems. If your depression is associated with neurotransmitter dysfunction, they might help. But what is causing the neurotransmitter dysfunction? What if we can address the cause of it? If depressive symptoms stem from metabolic dysfunction or inflammation or thyroid problems, B12 or iron deficiency, manipulating serotonin levels may not solve the issue.

The Problem with Symptom-Based Treatment

We diagnose depression based on symptoms. We typically treat it without knowing what's causing those symptoms. Someone might have inflammation, thyroid dysfunction, nutrient deficiencies, chronic stress, metabolic problems affecting brain energy production, or some combination of these. But we prescribe a monotherapy treatment to increase serotonin.

This creates a treatment lottery. Sometimes that helps. Often it doesn't. When it doesn't work, we try a different antidepressant, or add another medication, or combine multiple drugs. We're making educated guesses and not treating the cause, what's actually going wrong.

Metabolic Dysfunction and Depression

One factor that can contribute to depression is compromised brain energy metabolism. Brain imaging research has found reduced glucose metabolism in specific brain regions in some people with depression. A 2014 meta-analysis found significantly decreased cerebral glucose metabolism in key brain areas in those with depression compared to healthy controls.

When brain cells can't use glucose efficiently, they're operating in an energy deficit. This matters because everything the brain does requires energy. Producing neurotransmitters requires ATP. Maintaining synaptic connections requires ATP. Neuroplasticity, emotional regulation, cognitive function, all of these depend on adequate cellular energy.

Compromised mitochondrial function creates additional problems beyond low energy production. Damaged or inefficient mitochondria generate excessive reactive oxygen species, causing oxidative stress that damages cellular structures including mitochondrial membranes, DNA, and proteins. This creates a cycle where oxidative damage impairs mitochondrial function, which produces more oxidative stress, further reducing the brain's capacity to generate energy. The cumulative effect is brain cells that can't meet their metabolic demands.

People with depression also show higher rates of insulin resistance, prediabetes, and type 2 diabetes. The association runs both ways; metabolic dysfunction increases depression risk, and depression increases metabolic dysfunction risk. They appear to share underlying mechanisms.

Why Ketogenic Metabolic Therapy Makes Sense

If compromised energy production contributes to someone's depression, it makes sense to address that directly. Ketogenic metabolic therapy shifts the brain from glucose dependence to using ketones as fuel. When your liver produces ketones from fat, brain cells can use beta-hydroxybutyrate (BHB) as an alternative energy source.

Ketones enter cells through different transporters than glucose and get metabolised through pathways that can bypass some mitochondrial dysfunction. Research shows ketones produce more ATP per unit of oxygen consumed than glucose, generate less oxidative stress, and promote mitochondrial biogenesis.

The research in humans is still developing. Gao et al. (2026) found in a randomised controlled trial that a ketogenic diet showed antidepressant benefits compared to a control diet at six weeks in people with treatment-resistant depression. Janssen-Aguilar et al. (2026) conducted a systematic review and meta-analysis finding significant reduction in depressive symptoms with ketogenic diets, with stronger effects when ketosis was biochemically verified. Decker et al. (2025) reported in a pilot study of college students with major depressive disorder that participants showed improvements in depression symptoms, well-being, and cognition when following a ketogenic diet alongside their usual treatment.

Beyond clinical trials, qualitative research provides insight into lived experiences. Bellamy et al. (2024) explored how people with varying levels of depressive symptoms experienced ketogenic metabolic therapy. Participants reported increased self-esteem, confidence, motivation, and achievement. Those who initially experienced low self-worth and hopelessness described renewed meaning and purpose in life. Interestingly, participants with higher levels of depressive symptoms found the diet easier to adhere to and reported more substantial improvements.

This isn't a cure-all. Not everyone with depression has metabolic dysfunction contributing to their symptoms. But for people who do, addressing the energy problem directly may produce improvements that neurotransmitter manipulation alone cannot achieve.

For more information about ketogenic metabolic therapy for depression, visit metabolicpsychology.com.au

References

Bellamy, E. L., Hadjiefthyvoulou, F., Walsh, J., Brown, J., & Turner, J. (2024). Understanding the experiences of ketogenic metabolic therapy for people living with varying levels of depressive symptoms: a thematic analysis. Frontiers in Nutrition, 11, 1397546. https://doi.org/10.3389/fnut.2024.1397546

Decker, D. D., Bloom, S. M., Vogt, K. M., Courtney, A., Gunter, H., Gu, H., ... & Kiecolt-Glaser, J. K. (2025). A pilot study examining a ketogenic diet as an adjunct therapy in college students with major depressive disorder. Translational Psychiatry, 15, 322. https://doi.org/10.1038/s41398-025-03544-8

Gao, M., Kirk, M., Lash, E., Knight, H., Michalopoulou, M., Guess, N., ... & Aveyard, P. (2026). A ketogenic diet for treatment-resistant depression. JAMA Psychiatry. https://doi.org/10.1001/jamapsychiatry.2025.4431

Janssen-Aguilar, R., Vije, T., Peera, M., Al-Shamali, H. F., Meshkat, S., Lin, Q., ... & Bhat, V. (2026). Ketogenic diets and depression and anxiety: A systematic review and meta-analysis. JAMA Psychiatry, 83(1), 13-22. https://doi.org/10.1001/jamapsychiatry.2025.3261

Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., ... Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163(11), 1905-1917. https://doi.org/10.1176/ajp.2006.163.11.1905

Su, L., Cai, Y., Xu, Y., Dutt, A., Shi, S., & Bramon, E. (2014). Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies. BMC Psychiatry, 14, 321. https://doi.org/10.1186/s12888-014-0321-9