In late 2025, the journal Discover Mental Health published a sweeping review that could reshape how we think about depression. The authors propose that the leading theories about depression—long seen as competing explanations—might actually be different facets of a single, central process: inflammation.
For decades, three main theories have dominated the field. The first, the monoamine theory, is the one most people know: depression is caused by a shortage of neurotransmitters like serotonin, norepinephrine, or dopamine, or by their receptors not working properly. The second, the neuroplasticity theory, links depression to disruptions in the brain’s ability to grow new neurons and form new connections. The third, the inflammatory theory, suggests that cytokines—molecules that signal inflammation—can trigger symptoms that look a lot like depression.
The monoamine theory has held sway for two main reasons: it’s the oldest (dating back to the 1950s and 60s), and it offers a straightforward solution—boost neurotransmitter function, which is exactly what most antidepressants aim to do. This idea took off after doctors noticed that certain drugs, originally developed for other conditions (like iproniazid for tuberculosis), improved mood by affecting neurotransmitters. Soon, the notion of depression as a “chemical imbalance” became mainstream, and medications like tricyclic antidepressants were designed to increase the availability of these brain chemicals.
But the reality is more complicated. While antidepressants have helped many, they don’t work quickly or for everyone—about 30% of people with depression see little or no benefit. This has led researchers to look beyond neurotransmitters for deeper explanations.
The neuroplasticity theory offers a different lens. The adult brain isn’t fixed; it can adapt, reorganize, and even grow new neurons, especially in areas like the hippocampus, which is tied to memory and emotion. Studies since the 1990s have shown that these processes are disrupted in depression. People with long-term depression often have a smaller hippocampus, and the longer the illness lasts, the more pronounced the changes. Animal and human studies suggest that some antidepressants, like fluoxetine, can stimulate the growth of new neurons, hinting that depression may involve not just chemical imbalance but also a loss of the brain’s ability to renew itself. Stress hormones can suppress key neurotransmitters and lead to structural changes in the brain, which is why new treatments are exploring ways to restore neuroplasticity, such as targeting the glutamate system.
The inflammatory theory, first proposed in the early 1990s by Ronald Smith, adds another layer. Smith showed that cytokines—molecules released during inflammation—can induce symptoms that closely mimic depression. Since then, evidence has mounted that inflammation disrupts neurotransmitter balance: serotonin and dopamine activity drops, while norepinephrine may rise. This could explain why people often feel low and drained during illness or chronic stress. Inflammation also impairs neuroplasticity, making it harder for the brain to adapt and recover. Notably, people with high inflammation levels often respond poorly to standard antidepressants like SSRIs.
According to this view, depression may be an evolutionary response—a kind of energy-saving mode triggered by illness or stress. This has led to the idea of treating some forms of depression with anti-inflammatory drugs, though it’s still unclear which medications work best and how to avoid side effects.
So why do doctors still rely so heavily on the monoamine theory? It’s simple, scalable, and fits neatly into healthcare protocols: depression? Here’s a prescription for antidepressants. Critics who accuse doctors of overprescribing may overlook the lack of other practical, scalable options. While there are certainly cases of bias, misuse, or ignorance, the reality is that the system and its practitioners are working with the tools they have. Depression remains a poorly understood and stubbornly difficult condition to treat.
Modern research, however, offers hope for a more nuanced approach. The three main theories aren’t mutually exclusive—they describe different parts of the same process. When the body experiences inflammation (from illness or chronic stress), it shifts into energy conservation mode. This triggers changes in brain chemistry (like lower serotonin) and behavior—people become sluggish, withdrawn, and lose motivation. In the past, this response may have helped survival, but today it can become entrenched as depression.
This leads to a crucial insight: low serotonin and reduced neural connections are likely consequences of depression, not its root causes. That’s why drugs that only target serotonin (like SSRIs) don’t help everyone—if inflammation is the main driver, their effect is limited. Some treatments (antidepressants, ketamine, psychedelics) can boost neuroplasticity, but they’re not universal fixes.
Right now, inflammation looks more like a cause of depression than the other two theories. But putting this understanding into practice isn’t easy. We need better ways to measure neuroinflammation and to know when it’s truly at the heart of someone’s depression. Effective treatment will likely require addressing all three mechanisms at once, tailoring therapy to each person’s biology—a level of personalization that’s not yet feasible on a large scale.
Even though reduced neuroplasticity may be more a result than a cause of depression, targeting it still holds promise. But there are hurdles: some substances that boost neuroplasticity (like ketamine and certain psychedelics) aren’t widely available or legal, and even when they are, simply increasing brain plasticity isn’t enough without psychotherapy. The therapeutic context is what guides the brain’s changes, helping people safely reframe experiences and build new emotional and behavioral patterns. Without this, the effects of these substances can be unpredictable or even harmful.
Medications can make the brain more receptive to change, but they don’t do the work of forming new connections—just as warming up and taking supplements helps with exercise, but doesn’t replace the workout itself. Psychotherapy, on the other hand, can be effective with or without these aids.
While it would be ideal for everyone to have access to every possible resource for treating depression, that’s not the reality. What is accessible to many is lowering overall inflammation through healthy eating, staying active to support neuroplasticity via BDNF, and engaging in psychotherapy.
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