Anxiety/Depression Meds May Not Work the Way We Thought

If you Google “How do anti-depressants work” or “Why antidepressants treat anxiety,” the search engine will take you to a plethora of sites—some catering to average citizens seeking medical information, others to physicians and academics—but all giving answers something like this: “Although we don’t fully understand how this class of drugs works, they likely affect mood by increasing the amount of the neurotransmitter serotonin in mood centers of the brain.”^1,2

As a brain scientist, I cringe when reading such explanations, wishing they had stopped at “We don’t fully understand how this class of drugs works.” The brain, with its myriad nuclei, interconnected pathways, metabolic processes, immune responses, negative feedback and feed-forward loops, neurogenesis processes, and neurotransmitters, not to mention psychotropic effects of gut bacteria, doesn’t neatly divide itself into simple constructs such as “mood centers” and “serotonin” pathways.

Serotonin

These artificial constructs are simply ways we try to organize the brain so that we can begin to understand it. We are equally guilty of oversimplification when we label drugs like Prozac and Zoloft selective serotonin reuptake inhibitors (SSRIs), when such chemicals induce many other types of changes in the body that may be equally, or more, important to reducing symptoms.

For example, although the major class of antidepressants, SSRIs, do slow down synaptic re-uptake of serotonin, at least temporarily increasing serotonin levels, recent studies show there is very little correlation between brain serotonin levels and severity of depressive symptoms.³

And, yet, there is abundant evidence that “SSRIs” do alleviate both depression and anxiety in some patients.

So, if serotonin isn’t the whole answer—or even part of the answer—what is?

The Inflammation Hypothesis

More than a decade ago, research unrelated to psychiatry started to suggest that depression had some relationship to inflammation in both the brain and the body. For example, clinical trials of a hepatitis C treatment that promoted pro-inflammatory cytokines appeared to bring on depression in a significant number of test subjects.⁵

Since those early studies, a flood of information has implicated inflammation as a contributing factor in both depression and anxiety, with researchers theorizing that chronic inflammation may be toxic to neurons that play a role in mood, disabling or even ultimately destroying these neurons. Whatever the mechanism of action, the research demonstrating a strong link between inflammation and both depression and anxiety is rapidly mounting.¹²

• Anti-inflammatory drugs can help anxiety and depression: Medications such as aspirin and ibuprofen alleviate depression and anxiety in some patients.¹¹
• Activities that help reduce anxiety and depression, such as meditation and aerobic exercise, also reduce inflammation.^8,13
• Antidepressants and anti-anxiety drugs have anti-inflammatory properties: Both SSRIs and antianxiety drugs such as benzodiazepines (e.g., Librium, Valium, Ativan) reduce inflammation.^4,7 Even psychedelics, such as ketamine and psilocybin, which have shown promising antidepressant/antianxiety properties, have anti-inflammatory features.¹⁴
• Drugs that promote inflammation can worsen depression and anxiety: Immune therapies targeting viruses and cancer correlate with increased anxiety and depression in some patients.⁶
• Inflammatory disorders correlate with depression and anxiety: Patients with autoimmune diseases such as allergies, asthma, multiple sclerosis (MS), rheumatoid arthritis, and diabetes suffer greater-than-normal symptoms of anxiety and depression.^9,10

These findings, taken together, are compelling, suggesting that agents and activities that cause inflammation increase risk of anxiety and depression, while, conversely, agents and activities that reduce inflammation also can reduce anxiety and depression.

The findings also raise intriguing questions:

• What role do infections play in triggering depression and anxiety, given that pathogens may be involved in triggering other brain disorders such as MS, schizophrenia, and obsessive-compulsive disorder?
• Can diet—with inflammatory and anti-inflammatory foods—influence mood disorders?
• Can common medications such as aspirin and ibuprofen be prescribed to treat mood disorders?
• Does the role of inflammation in mood disorders help explain why antidepressants don’t help everyone?
• Can antidepressants and anti-anxiety medications be used to treat chronic inflammation?

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All of these possibilities should be explored.

But, just as the serotonin hypothesis itself replaced an early “catecholamine” (noradrenaline, adrenaline, dopamine) hypothesis of mood disorders, the inflammation hypothesis, which is on the verge of replacing the serotonin hypothesis, will likely also be supplanted by later findings, as researchers discover that inflammation doesn’t tell the whole story either.

I suspect it will take a long, long time to get the whole story. Our brains are marvelous at doing many things, but figuring themselves out is not one of them.