Can Treating Inflammation Offer Relief From Depression?

My relationship with depression has always felt a little like a fling with an ’80s-movie bad boy—let’s call him Blane. I know he’s no good for me, and I’m ashamed to talk to my friends about him. Occasionally, we flirt with one another, and if I see him coming, I can make good choices and resist being pulled into his grim orbit. But at various points in my life, I had no say in the matter, and we became each other’s deep, dark soulmates. I’m making light of a serious personal challenge—but how else to talk about depression when we’re still chipping away at the stigma? This is my reality: There are times when my depression convinces me I am broken and unlovable. It’s an awful way to spend whole weeks or months.

(Related: How to Help a Loved One Who’s Struggling With Depression)

By some lucky stroke, I’m also an incurable problem-solver and I’ve spent hours researching and experimenting with evidence-based solutions to depression. No surprise, one of my most dog-eared books is called The How of Happiness. What works for me? Talk therapy. Prioritizing sleep. And moving my body—even when it’s the absolute last thing I want to do. I’ve also tried at least four different types of antidepressants at different points in my life in an attempt to free myself from depression’s grip. They helped, but not without significant drawbacks: flat mood, weight gain, extreme irritability and no grand finales in the bedroom. Not great. I wanted a better option.

Which led to my latest research deep dive: inflammation. My curiosity stemmed from a newspaper article about a possible link between inflammation and depression. (I have a science degree and can be a bit of a nerd about digging into the latest health studies.) The article discussed a 2019 meta-analysis of dozens of studies that included analysis of both depression and inflammation. The review found that about a quarter of patients with depression showed evidence of low-grade, whole-body inflammation—a variation from the general population that is statistically significant.

The article also mentioned a blood analysis called the C-reactive protein test, which measures inflammation. I made an appointment and asked my doctor to run it. When she asked why, I told her I was curious about whether inflammation might be a factor in my depression. She waved aside my concerns but reluctantly agreed to order the test, and it was covered by my provincial health plan.

Eliza Gallaiford, a 43-year-old from London, Ontario, had a similarly frustrating experience. As she recalls it, her doctor’s response to her questions about inflammation was, “‘I’ve never read anything that suggests there’s a link between those things,’ and that was the end of the conversation,” says Gallaiford. “I’ve had other doctors be more polite, but they just sort of smile and nod. Or tell me to lose weight.”

We can’t really place the blame on our doctors, though. The research is very preliminary. But this emerging field of study strongly suggests that inflammation can play a significant role in the development and progression of depressive symptoms—and it might even point the way to more effective treatments.

The cost of depression

Always having depression on my dance card can feel exhausting and unfair. I often feel like if only people knew how hard I sometimes have to work to keep my head above water, they would cut me some slack. Of course, so many people do know.

According to the Canadian Mental Health Association, mental health problems and illnesses affect one in five Canadians in any given year. In news that is surprising to exactly no one, the COVID-19 pandemic didn’t help. Data from eight Canadian provinces showed that in the fall of 2020, the prevalence of major depressive disorder was 16 percent—more than two times higher than in 2015-19 (7 percent). Depression also impacts our society as a whole: The economic cost of mental illness in Canada is estimated to be more than $50 billion each year, including health-care costs and lost productivity.

Despite its wide reach, depression affects us all differently. It’s unlikely there will ever be a magic pill that works for everyone. The closest we’ve come is antidepressants like Effexor or Celexa, which act on chemicals in our brains called neurotransmitters. The most commonly targeted neurotransmitter is serotonin, and increasing its mood-boosting effects has helped millions of Canadians.

Unfortunately, only half of depressed patients go into remission after treatment. Some are dealing with treatment-resistant depression, which is when depression does not respond to standard treatments like antidepressants or therapy. For these patients, could testing for and treating inflammation help?

Image: Chanelle-Nibbelink

What is inflammation?

Before we start labelling inflammation as a harbinger of darkness, let’s be clear that many forms of inflammation are a natural and necessary response from your immune system as it works to protect your body from harm. The redness, heat and swelling you get when you burn your hand cooking dinner or turn your ankle on the curb is your body doing its best to heal. This is called acute inflammation, and it’s a sign of good health.

Chronic inflammation, however, is where we run into problems. It’s a prolonged and persistent inflammatory response that can last for weeks, months or even years—and it can be bad news for your body. What does chronic inflammation feel like? It may feel like nothing, and you may not even know you have it. Or it might look like fatigue, brain fog, swelling, skin problems, muscle aches, joint pain or digestive issues.

With chronic inflammation, the immune system gets activated but doesn’t turn off—instead, it simmers like a pot left on low. This leads to an increase in the release of small “signal” proteins called cytokines, which causes that inflammation in the body. (You may recognize the word “cytokine” from your panicked pandemic reading. In case you’ve forgotten your research from 2020: A cytokine storm is an uncontrolled immune system response characterized by the release of a large number of cytokines into the bloodstream. For some COVID sufferers, this condition can lead to serious heart, liver or kidney damage.)

There are a number of reasons you might have chronic inflammation: autoimmune disorders like rheumatoid arthritis or Crohn’s; infections like Lyme or hepatitis C; long-term exposure to chemical irritants; lifestyle factors like smoking, poor sleep and sedentary behaviour; or medical conditions like heart disease and diabetes.

And then there’s the food we eat, and the health of our gastrointestinal tract. Caroline Ménard, a researcher with Cervo Brain Research Centre and an associate professor of psychiatry and neuroscience at Université Laval in Quebec City, says her research subjects often perk up when she mentions diet, and our microbiome specifically. “I like to talk about it because people feel like they have a little bit of control over it,” she says.

In a classic chicken-and-egg scenario, scientists also know that an out-of-control inflammatory response can promote diseases such as inflammatory bowel disease, cancer or Alzheimer’s, too. It can also lead to cognitive decline and—bingo!—mental health problems like depression.

How does inflammation cause depression?

Much like my relationship status with Blane, it’s complicated. But one of the things we know is that when you have prolonged, whole-body inflammation, it can slowly erode the boundary between your brain and the blood that circulates around it.

“When you have immune cells circulating in the blood, those can go to the brain and attack the blood-brain barrier,” says Ménard. “And then molecules like inflammatory cytokines, which should never pass the barrier, can slowly infiltrate the brain.” That’s bad news for your microglia, which are the immune cells of the brain. They become more activated and can change your neurons by eroding synapses, which are the neurons’ communication tools. This can alter different areas of our brains—and our behaviors. Ménard pointed me to studies that looked at how these areas of the brain are impacted in patients experiencing major depression—and how the changes can differ depending on a patient’s sex. The nucleus accumbens, for example, plays a vital role in our reward and pleasure circuitry. “In men, the blood-brain barrier is generally more altered in that area,” says Ménard. “And you will sometimes see more anger, more behavior of abuse with, for example, gambling or pornography or alcohol.” In women, “the blood-brain barrier area being altered is usually the prefrontal cortex. This is a brain area that’s very important for self-esteem, for anxiety, for social interaction, for judgment toward yourself and others.”

For Gallaiford, a difficult pregnancy began her own exploration of inflammation. “After my daughter was born, I had what was classified as postpartum depression,” she says. But she didn’t think it was that simple or straightforward. “To be fair, having a new baby is stressful. But I was having these really intense mood swings. And I’m quite a happy-go-lucky person, so it was a very stark difference.” Gallaiford’s husband, whom she describes as an avid reader of medical journals, first heard about gut permeability from friends and family, and then read an article about depression and mood swings related to food intake and immune diseases like Hashimoto’s—which her mother has. Hashimoto’s disease is an autoimmune disorder where the immune system mistakenly attacks the thyroid gland. Gallaiford’s doctor ran tests and confirmed she had antibodies for the disease. She began to suspect the resulting inflammation could be contributing to the severe fluctuation in her moods.

What the science says

The blood test I asked my doctor to run measures C-reactive protein (CRP), which is produced by the liver in response to inflammation, infection or tissue injury. Generally, physicians like to see it below 5 mg/L, and mine was 4.9. Gallaiford’s was 6.0.

Unfortunately, the test doesn’t tell us where in the body inflammation is happening. “CRP is a very general marker of inflammation. That number being elevated alone doesn’t flesh out the picture very much,” says Renata Villela, a psychiatrist who practices in Thornhill, Ontario, and is the chair of the Ontario Medical Association’s section on psychiatry. So, I know my CRP is high, but I don’t know why. (If I had to guess, I’d say my weight is the main issue. BMI is an imprecise tool, but by its measure, I am obese.)

That said, studies have also shown that CRP is higher in patients experiencing a major depressive episode, and more so in patients with treatment-resistant depression. Other studies have suggested that treating someone with an anti-inflammatory drug—such as nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors or statins—can improve the efficacy of antidepressants.

But this is not a one-size-fits-all solution, because not every depressed person has chronic inflammation. And your doctor isn’t going to prescribe you an anti-inflammatory for depression, even if your CRP levels are high. These medications are what Villela describes as “big guns” that are used to treat specific diseases that have been diagnosed by a medical professional. “There isn’t an established protocol yet. It’s a research area that’s been picking up a lot of steam over the past few years, which is exciting, but the picture is still so nebulous,” she says. (And don’t start taking an NSAID like Advil every day without talking to your doctor. It can lead to gastrointestinal problems.)

What can you do if you have inflammation?

Could “solving” your inflammation be a cure for your depression? The short answer is: not yet. “I can appreciate that, for patients who’ve been struggling for so long and are hearing bits and pieces of this, they get excited,” says Villela. “Unfortunately, it’s a good-news, bad-news type of message. Yes, we have a better appreciation for how this is playing out. But a lot of this is still new, and we don’t have established protocols for how to go ahead.”

For Gallaiford, the most effective way to get relief from her mood swings is by taking care of herself—and, most importantly, managing what she eats. That, for her, means cutting out gluten and dairy. “Every once in a while, I’ll eat the wrong things and I will be angry to the point of wanting to throw plates. Or I’ll be in bed crying. I don’t know if the connection between that and food is in the medical journals, but I definitely feel it 100 percent.” If you suspect inflammation is a factor in your depression, you’ll want to first rule out any autoimmune diseases, chronic infections or other causes with your doctor. Beyond that, you’re likely to hear the same advice you’ve received on repeat: eat well, get enough sleep,move your body, socialize with others and spend time outdoors.

If you do get this advice from your doctor, don’t be so quick to assume it’s nothing more than a dismissive platitude meant to get you out the door. “It’s more than just your doctor saying, ‘Oh, here’s a pat on the back because I don’t really know what else to do,’” says Villela. “We’re now finally understanding, at a more molecular level, how these things are actually beneficial.” Ménard is often asked about her recommendations for keeping stress and inflammation at bay. “I think everybody should tailor their own recipe,” she says. “I don’t think it’s one specific vegetable or one magic pill.” She encourages people to take time every day to clear their heads. “It could be listening to your favourite music, taking a long bath or gardening. Give your brain a little rest and that’s also going to rest the whole body.” Her personal go-tos? Cross-country skiing, video games, kayaking—and heavy metal. “I love to go to live concerts and go to the mosh pit. It’s very good stress relief.”

Personally, I’m still tinkering with my own formula. I’m not jumping into any mosh pits any time soon, but I’ll keep doing the things that work for me. I’m always on the lookout for simple ways to lower my stress or tweak my diet so it’s the tiniest bit healthier. I’ve learned that smaller, incremental changes can prevent my brain from going into overdrive with self-critical thoughts. And if I ever get the recipe just right, Blane will be the last to know.

Next: “I Found Happiness by Microdosing Magic Mushrooms“