Neuroinflammation and depression
The link between depression and neuroinflammation has been studied for many years. And yet treating neuroinflammation in depression is not thought of as a primary target of intervention. Our society keeps trying to treat depression with pharmaceuticals. And while they can help many people, there are populations of people suffering from depression in which medications are not sufficient. These include:
- People who do not respond to one or more medications
- People who respond to medications but only temporarily
- People who partially respond but have residual symptoms not treated effectively by their medications (This is the majority of patients)
- People who respond but must live with side effects that reduce their quality of life
- People who cannot tolerate the side effects of medications
For mild to moderate depression, the response to psychiatric medications is comparable to a placebo.
It is disrespectful to tell these people that their answer is just a different medication. For some people, the medication option is just not a good one. And this could be because medications are not able to address the underlying causes of depression.
Depression is a disorder of neuroinflammation. Yes, genetics play a role in depression. But there is not a gene for depression, and we find that the risk for depression is triggered by environmental factors. This shows a genetic vulnerability that we can reduce with environmental interventions. The ability of internal and external environments to determine how genes express themselves is called epigenetics.
Inflammation is a trigger that turns on the genes you have that predispose you to depression.
The same process of inflammation that causes disease in your body is what causes your psychiatric disorders. This includes depression.
Inflammation occurs when the immune system produces cytokines. There are different types of cytokines. These include but are not limited to IL-1, IL-6, TNF-alpha, IFN-gamma. These are the chemical messengers of the immune system. Circulatory cytokines correlate with levels of anxiety, depression, and cognitive impairment. These are all symptoms people with depression experience.
An overactive immune system creating cytokines contributes to depression. Cytokines are higher in people with depression, and antidepressant medications likely work best by decreasing inflammatory cytokines. This is contrary to the theory that the mechanism of symptom reduction in antidepressants is primarily neurotransmitter remediation.
Cytokines activate an enzyme called IDO (for short). IDO breaks down serotonin and degrades its precursor tryptophan. This reduces the availability of serotonin neurotransmission in people with depression.
This is a powerful inducer of depressive symptoms.
So why don’t we give depressed people anti-inflammatories like aspirin? We do sometimes. There is a higher response rate when we use antidepressants with a low dose of aspirin. But if you use NSAIDs instead of aspirin, it does the opposite. So don’t pop a bunch of NSAIDs hoping it will reduce depression.
We are not guessing here about inflammation and depression. When we give patients interferon (a cytokine) to treat other illnesses (e.g., MS, hepatitis C), we see psychiatric side effects like depression occur. Side-effects we see with interferon treatment include suicidal ideation, apathy, sexual dysfunction, insomnia, irritability, and cognitive issues.
Do any of these sound familiar?
I bet they do. Are you convinced yet of the like between neuroinflammation and depression?
Good. Let’s move on.
You may be asking, why would my immune system freak out and break down the very things I need to feel ok? Why would it go after the serotonin precursor tryptophan (an amino acid) if it thinks I am under attack by something?
Because infectious agents, like microbes, gobble up tryptophan. They like it, and it helps them as they try to infect your cells. And so your immune system is really just trying to have your back, and take away the substance it knows the bad guys are going to use to wreak havoc. It sacrifices your mood to save your body. So you have to address the inflammation. Or your immune system is not going to settle down, and it’s going to keep gobbling up the things you need to make important neurotransmitters like serotonin.
Let me write it again for the people in the back.
Neuroinflammation can have a causal role in depression.
So what kinds of things cause neuroinflammation?
- Standard American Diet (high in sugar, processed carbohydrates, oils, trans fats)
- Environmental toxins like herbicides, pesticides, heavy metals
- Chronic low-grade infections (e.g., Lyme, gum disease, h. pylori, chronic candida Albicans, Bora Virus, etc.)
- Food allergies
- Environmental allergies
- Digestive dysfunction (dysbiosis, IBS, etc.)
- Sedentary lifestyle
- Nutritional deficiencies
- Sleep (not prioritized or sleep disorders)
Another factor that contributes to neuroinflammation is stress. This is one of the reasons some psychotherapies are good for depression, particularly cognitive-behavioral therapies (CBT). CBT helps clients process and reframe life stressors so that they do not create an immediate stress response. This lowering of stress is due to being better able to handle life stressors. This decreases one major factor of inflammation.
But not everyone responds to CBT. So let’s keep learning.
When you become stressed, whether due to an environmental stressor or just your thoughts about what is happening, you get an elevation in something called glucocorticoids. This revs up the immune system in your brain and activates microglia. Microglia are a major player in your brain’s immune system, and they pump out a bunch of cytokines. Which you already know contributes to your depressive symptoms.
Your psychiatrist is likely not talking to you about neuroinflammation as a cause of your depression. Why? Because there is a disconnect between the academic literature that has been studying this link for many years and practitioners. There is no medication being marketed for neuroinflammation. If there was, your psychiatrist would probably be handing it out. And they are sort of trying by giving you anti-depressants, which have some temporary anti-inflammatory effects. In fact, there is a discussion that their temporary reduction of neuroinflammation may be why some people get a momentary relief of symptoms. Not the reported effects on serotonin.
You are going to need to address neuroinflammation before you can feel better. An SSRI may reduce the inflammation slightly, but it cannot stop the microglia from producing cytokines that deplete resources in the form of precursors to make serotonin. That SSRI only keeps the serotonin that you currently make in the synapses longer.
Neuroinflammation depletes your nutrient stores, and you need those nutrients in order to make neurotransmitters and have well-functioning brain cells. If your brain is constantly using up supplies trying to rebuild the damage from oxidative stress, then your neurotransmitter balance is going to suffer. A lot of those nutrients being eaten up in the fight against inflammation are what we call rate-limiting factors. This means that if you don’t have enough, you just don’t get to make other things you need. Period.
So you can see how a medication-only approach to depression is insufficient. On multiple levels. So let’s talk about how to figure out the root cause of your inflammation, so you can heal your depressive symptoms.
Food and environmental allergies
Food allergies are a big factor in immune system dysfunction. Most reactions occur from eggs, peanuts, cow’s milk, soy nuts, shellfish, fish, and wheat. A lot of that may be occurring because of poor gut health. And modifying your diet can be a good way to reduce inflammation. You may not even have to avoid the foods forever. Once the gut is healed, you may find you can reintroduce many formerly problematic foods. You can work with a functional practitioner (functional nutritionist, functional psychiatrist, functional nurse practitioner, etc.) and they can help you test for food allergies.
Any infection can cause inflammation. This includes low-grade chronic ones. And not even big scary ones like Lyme disease. Do you have a chronic toe fungus that won’t go away? That could be contributing to your neuroinflammation and your depressive symptoms. Getting some functional medicine testing with the help of a practitioner can be very helpful in identifying food allergies and sneaky infections that could be contributing to your neuroinflammation.
Poor sleep habits can cause inflammation. Just by reducing your sleep to 6 hours for a week, you get an elevation of inflammatory cytokines. So if there is a sleep hygiene issue (fancy word for what are your behaviors before bed) or a nutrient deficiency that’s influencing your ability to sleep, you need to fix that. Because if you are not already depressed, your poor sleep habits will increase inflammation and create depressive symptoms.
But if you already have depression, it is not surprising to note that sleep disruption can be the result of your messed up neurotransmitter production of serotonin. This is because you need adequate levels of serotonin to make melatonin. And if you don’t make enough melatonin, suddenly you are a night owl, and it messes up the rest of your sleep!
Tests for Inflammation
So how does your doctor check you for inflammation? The easiest way is to get a blood test. You will have to ask your doctor for this test. And if your doctor decides to be difficult about it, simply get it yourself.
I will also have clients get their CRP or hs-CRP with Ulta Lab Tests. It’s inexpensive, and you can get the blood draw at a lab close to home. If you sign up with them, they will often provide discount codes via email.
You will want to get a C-reactive protein (CRP) or a high-sensitivity C-reactive protein (hs-CRP). It’s a way to screen for infections and inflammatory diseases. It’s a very useful marker of inflammation. It’s a simple blood test that reflects chronic inflammation. If it’s high, then you can look deeper at the cause and work with a doctor to get a better picture of the neuroinflammatory factors present.
Other blood tests you may want to get if you have depression include a cholesterol panel (low cholesterol is linked with increased suicidality), B6, B12, ferritin, and vitamin D. These are not all related to inflammation in the brain and will likely be discussed in future blog posts. But if you are trying to figure out what you may need to heal depression, they can be very useful markers.
Another very useful marker of inflammation can be seen using an Organic Acids Test. This is a functional test. If you go to your regular doctor, there is a good chance they will not know what you are talking about. That doesn’t mean you do not have access to it or cannot advocate for your own health and find a practitioner who can help you.
The marker on the Organic Acids Test that is helpful to see is quinolinic acid. It is a marker specific to brain inflammation. Quinolinic acid is what happens when that enzyme (IDO) we just talked about degrades tryptophan. It’s involved in depression and all kinds of other neuropsychiatric disorders (e.g., OCD, anxiety, etc.). It’s neurotoxic. If you have high levels of quinolinic acid, we need to clean that up!
High quinolinic acid as a result of inflammatory cytokines increases glutamate in the brain and imbalances your neurotransmitters. You get an amount of glutamate that is neurotoxic. As if that was not bad enough news, you also produce less GABA. And trust me, you want more GABA. GABA is the feel-good, “all is well with the world,” and “you got this” neurotransmitter. You deserve more GABA.
So there you have it. Neuroinflammation is likely causing your depressive symptoms. Now let’s discuss what you can do about it. Be sure to check out the other two articles in this series!
If you want to learn more about the underlying mechanisms that cause depression in more detail, you will enjoy my posts on the topic.
Great resources regarding supplements for depression can be found on Psychiatry Redefined. They provide free webinars and you may even be able to help find a functional psychiatry provider near you.
Another great resource on eating to combat depression is Georgia Ede, MDs site diagnosisdiet.com
I also want you to be aware, that heavy metal toxicity can cause a state of neuroinflammation that can be persistent and hard to treat without additional treatment modalities. If you cannot seem to get rid of your mood or neurological issues, I encourage you to read the blog post below to learn how to proceed in seeking additional help.
You may be a good candidate for my online program called the Brain Fog Recovery Program. You can learn more about it below:
Because you have the right to know all the ways you can feel better.