If you’ve tried several treatments for your depression and aren’t seeing a change in your symptoms, you may have treatment-resistant depression (TRD). This means that standard depression treatments that work for most people don’t have the same effect on you.
Research shows that about 30% of people with depression have TRD. If you have TRD, making changes to sleep, exercise, daily routines, and even medication may help for a short time, but symptoms either don’t improve or may return later.
Most depression medications focus on changing how your brain makes or uses certain chemicals involved in stress and mood. But newer research is taking a different approach — examining the link between metabolic health and mood disorders.
Here’s what your depression treatment could be missing.
What Is Metabolic Health?
Metabolism is your body’s process of turning food and drink into energy for your cells so you can function. When you have “good” metabolic health, it means these processes are working well to keep you breathing, moving, sleeping, and more.
“Metabolic health is how well your body creates and uses energy,” says Shebani Sethi, MD, clinical associate professor in the Department of Psychiatry and Behavioral Sciences and founding director of the Metabolic Psychiatry Clinical program at Stanford Medicine. “It includes blood sugar balance, insulin sensitivity, inflammation, cholesterol, and how efficiently your cells produce energy.”
Your brain needs a lot of energy, she says, so if your metabolism isn’t working well, your brain may not be getting the fuel it needs to regulate your mood.
“In metabolic psychiatry, we look at depression not just as a brain chemistry issue, but also through the lens of whole-body energy metabolism,” says Sethi.
This doesn’t mean depression is solely a metabolic disorder, or that you can simply make changes to what you eat to replace depression treatment. But it does help doctors understand another way into depression management for certain groups.
“Several areas of research are starting to converge,” says Sethi. “Brain imaging studies suggest that energy use in certain regions may be impaired in depression. There is also evidence of mitochondrial dysfunction, along with consistent links to inflammation and insulin resistance, particularly in people who do not respond to standard treatments.”
For example, anhedonia, which is a reduced ability to experience pleasure, is one of the most common symptoms of depression and often one of the hardest to treat. Studies suggest that anhedonia may be linked to low function in the reward-processing parts of your brain. These regions need a lot of energy to work well, and even small changes or disruptions to your metabolism can affect them.
As a result of these emerging areas of research, doctors are leaning toward new methods for treating depression. Here are some of the ways metabolic health can affect your emotional health.
The Insulin Resistance-Depression Link
Insulin is a hormone your pancreas makes that controls your blood glucose (blood sugar). When you eat, your body breaks down carbohydrates into glucose, and insulin helps move it into your cells.
When your body can’t make or use insulin effectively, it’s called insulin resistance. If you’re insulin resistant, your cells don’t respond to insulin the way they should, and too much glucose stays in your blood. Cells don’t get the energy they need.
What does this mean for depression? Your brain “loses power,” and that affects your mental and emotional health.
“When the body becomes insulin resistant, brain cells may not receive adequate energy, and mood-related signaling pathways can be affected,” says Sethi.
Insulin resistance may also cause inflammation, which affects your brain function.
A study at Stanford University showed that being insulin resistant doubles your risk of having major depressive disorder. Several other large studies show that depression and metabolic disorders have a bidirectional relationship, which means having depression also increases your risk of diabetes.
The Effect of Inflammation on Antidepressants
Inflammation is your body's natural response to harm. Your immune system sends out chemicals, increases blood flow, and sends white blood cells to protect and heal tissue when it senses a threat. But inflammation, especially chronic inflammation, can also cause harm.
“Inflammation can disrupt how neurotransmitters like [the “feel-good” chemicals] serotonin and dopamine are produced and used,” says Sethi.
Inflammation can also affect your brain’s neuroplasticity, or its ability to form new connections and reorganize itself in response to new experiences. Part of how antidepressants work is by promoting neuroplasticity, so inflammation can get in the way of that process, says Sethi.
“Some studies show that people with higher inflammatory markers are less likely to respond to standard antidepressants,” she says.
Gut Microbiome and Mood Regulation
Your gastrointestinal tract, or “gut” is teeming with trillions of bacteria called your gut microbiome. Most of the bacteria are helpful and necessary, helping with things like your body’s immune system, metabolism, and communication with your central nervous system. Some of the bacteria can cause harm.
Sethi says having depression can change the balance of your gut microbiome, which can lead to higher levels of inflammation in your body.
“People with depression often show reduced diversity in their gut microbiome and lower levels of beneficial bacteria, along with higher levels of microbes associated with inflammation,” she says.
These changes can harm things such as your:
- Chemical messaging, which can affect things like sleep, feelings, heartbeat, digestion, and more
- Immune system
- Stress response pathways
Because of this emerging study, some scientists argue that some major depressive disorder cases may be autoinflammatory or autoimmune disease. This might mean treatments such as immune modulator drugs could have an impact on mood.
“This is still an emerging field, but it reinforces the idea that mental health is closely tied to physical health,” says Sethi.
How to Support Metabolic Health
A focus on metabolic health isn’t a replacement for therapy or medication, but it does expand the set of tools you have available to you for managing your depression.
“For people who feel like they have tried everything, it can open a different path,” says Sethi.
You can set up small, everyday practices to boost your metabolic health, says Sethi. The key is to be consistent. She recommends you:
Stabilize your blood sugar. When your glucose levels are steady, your brain gets a steady and consistent energy supply.
- Combine protein, fat, and fiber at meals, which helps slow digestion.
- Limit “simple” carbohydrates (digested quickly — like candy or white breads) and foods with added sugars.
- Keep your meal schedule consistent. Aim for small meals regularly during the day without large gaps.
Add gut-friendly foods into your diet. Certain choices can boost good bacteria in your microbiome.
- Increase your daily fiber with bran, whole wheat, vegetables, fruits, beans, and seeds.
- Include fermented foods such as yogurt, kefir, or sauerkraut.
- Consider taking supplements such as omega-3, magnesium, and vitamin D (but talk to your doctor first).
Prioritize stress relief. When your stress is high, so is inflammation.
- Go to bed and wake up at the same time every day for better quality sleep.
- Move daily, even if it’s just a brisk walk.
- Practice meditation, yoga, or deep breathing exercises.
Could a Psychobiotic Diet Help?
More than a decade ago, researchers in Ireland designed a dietary approach to mental health with the psychobiotic diet.”
“A psychobiotic diet supports gut health in ways that may benefit mood,” says Sethi. “In clinical settings, we are also studying more targeted metabolic approaches. At Stanford, we are conducting a randomized controlled trial examining the ketogenic diet as a treatment for depression.”
Ketogenic diets focus on high amounts of fat, moderate amounts of protein, and very low amounts of carbs. This forces your body into ketosis, a metabolic state where it burns fat for fuel instead of glucose. Sethi says studies are still ongoing, but they point to metabolism as an important factor in depression that you and your doctor can potentially modify to treat your symptoms.
“Depression is not just a chemical imbalance, and it is not a personal failure,” says Sethi. “For some people, it may be connected to how the body is producing and using energy. Looking at metabolic health offers another way to understand and potentially treat it.”
