The Quiet Fire in the Brain
Neuroinflammation is not an infection. There are no bacteria invading the brain, no virus replicating in neural tissue. It is something more subtle and, in many ways, more difficult to treat: the brain’s own immune system stuck in overdrive, producing low-grade inflammation that persists for months or years without resolution.
The central players are microglia, cells that make up roughly 10 to 15 percent of all cells in the brain. Under normal conditions, microglia are useful. They prune unnecessary synapses during development, clear cellular debris after injury, and monitor the neural environment for signs of damage or infection. They are the brain’s maintenance crew.
The problem arises when microglia become chronically activated. Instead of performing targeted maintenance and returning to a resting state, they remain in an inflammatory mode, continuously releasing signaling molecules called pro-inflammatory cytokines. The three most studied are TNF-alpha, IL-6, and IL-1-beta. In small, controlled doses, these cytokines serve important immune functions. When they remain elevated over time, they become toxic to the very tissue they are supposed to protect.
Elevated TNF-alpha disrupts serotonin synthesis by diverting tryptophan away from serotonin production and toward kynurenine, a metabolite that can generate neurotoxic compounds. Elevated IL-6 impairs neurogenesis—the growth of new neurons in the hippocampus, a process essential for mood regulation and memory. IL-1-beta damages synaptic connections and interferes with long-term potentiation, the cellular mechanism underlying learning.
The blood-brain barrier, which normally keeps peripheral immune signals out of the central nervous system, can itself become compromised by chronic stress and systemic inflammation. When that barrier weakens, inflammatory molecules from the rest of the body gain access to the brain, amplifying the local neuroinflammatory response.
This is not hypothetical. A 2020 review in Frontiers in Psychology summarized extensive evidence that higher plasma levels of IL-6 and TNF-alpha consistently correlate with worse depressive symptoms. The relationship is dose-dependent: the more inflammation, the more severe the depression.
Why Neuroinflammation Matters for Depression
Anyone who has had a bad flu knows what sickness behavior feels like: bone-deep fatigue, withdrawal from social contact, loss of appetite, disrupted sleep, difficulty concentrating, and a flattened sense of pleasure. These symptoms are driven by the same pro-inflammatory cytokines involved in neuroinflammation. The overlap between sickness behavior and major depression is not a coincidence. The same inflammatory pathways produce both.
This observation has reshaped how researchers think about treatment-resistant depression. Roughly 30 to 50 percent of patients whose depression does not respond to standard antidepressants show elevated inflammatory markers in blood tests. Their depression may be treatment-resistant not because they need a higher dose or a different SSRI, but because SSRIs do not directly target the inflammatory process that is driving their symptoms.
SSRIs increase serotonin availability in the synapse. But if TNF-alpha is shunting tryptophan away from serotonin production entirely, more reuptake inhibition cannot compensate for a supply problem. The medication is working on the wrong part of the system.
Chronic psychological stress feeds this cycle through the hypothalamic-pituitary-adrenal (HPA) axis. Sustained stress increases cortisol output. Cortisol is supposed to be anti-inflammatory, but under chronic conditions, immune cells develop glucocorticoid resistance—they stop responding to cortisol’s regulatory signals. The result is an immune system that has lost its brakes, with inflammation persisting even when the original stressor has passed.
Understanding this pathway matters for treatment. If inflammation is a significant driver of a patient’s depression, then a treatment that addresses inflammation—in addition to other mechanisms—may succeed where serotonin-focused approaches have not. For a broader discussion of how ketamine works across multiple mechanisms, see our article on how ketamine works.
The Same Fire Burns in Chronic Pain
Neuroinflammation does not limit itself to mood disorders. The same microglial activation and cytokine release that contribute to depression also maintain chronic pain through a process called central sensitization.
In central sensitization, activated microglia in the spinal cord and brain amplify pain signals. Stimuli that should register as mildly uncomfortable become excruciating. Stimuli that should not register as painful at all begin to hurt. The pain is no longer a reliable signal about tissue damage; it is the nervous system itself malfunctioning, its volume turned up by inflammatory mediators that will not quiet down.
The 2020 Frontiers in Psychology review documented the shared inflammatory pathways between depression and chronic pain, which helps explain a clinical observation that most pain specialists already know: these two conditions co-occur at rates far higher than chance would predict. Roughly 50 to 65 percent of patients with chronic pain also meet criteria for depression, and patients with depression are significantly more likely to develop chronic pain conditions.
This is not a psychological coincidence. It is biological. The same TNF-alpha that disrupts serotonin synthesis in the brain also sensitizes pain-signaling neurons in the spinal cord. The same IL-6 that impairs hippocampal neurogenesis also maintains the inflammatory soup around peripheral nerves. Treating pain and depression as separate conditions with separate medications misses the shared mechanism.
Many patients at Music City Ketamine present with both conditions. When the underlying inflammation is part of the clinical picture, addressing it may improve both pain and mood through the same biological pathway. For more on how we approach chronic pain treatment, that page provides additional detail.
How Ketamine Addresses Neuroinflammation
Most discussions of ketamine’s mechanism focus on NMDA receptor blockade and the downstream cascade of synaptogenesis—the rapid growth of new synaptic connections that occurs within hours of an infusion. Those mechanisms are well-supported and important. But emerging research identifies a parallel pathway: ketamine appears to directly reduce neuroinflammation.
A 2025 narrative review by Makhlouf and colleagues, published in Pharmaceuticals, examined the evidence for ketamine’s anti-inflammatory effects across neurological and psychiatric disorders. The review found consistent evidence that ketamine decreases microglial activation and reduces levels of TNF-alpha and IL-6. These effects were observed independently of ketamine’s action at the NMDA receptor, suggesting a separate anti-inflammatory mechanism rather than a downstream consequence of receptor blockade.
A 2025 study published in Advanced Science went further, identifying a specific molecular pathway. The researchers found that S-ketamine binds directly to the SIRT2 protein (sirtuin 2), a deacetylase enzyme involved in cellular stress responses. This binding facilitates SIRT2’s interaction with NF-kB p65, reducing its acetylation and inhibiting NF-kB activation. NF-kB is a transcription factor that functions as a master switch for inflammatory gene expression: when NF-kB is active, the cell produces a cascade of inflammatory proteins. By inhibiting NF-kB through the SIRT2 pathway, ketamine reduces the transcription of inflammatory genes at their source.
Additional evidence comes from a 2025 study in Scientific Reports that examined perineuronal nets—specialized structures of extracellular matrix that surround and protect certain neurons. In neuropathic pain models, activated microglia degrade these protective nets, leaving neurons vulnerable to excitotoxic damage and aberrant signaling. The study found that S-ketamine inhibited microglia from degrading perineuronal nets, preserving the structural integrity of neural circuits involved in pain processing.
Taken together, this research paints a picture of ketamine acting on multiple fronts simultaneously: blocking NMDA receptors, promoting synaptogenesis through BDNF release, and reducing the neuroinflammatory processes that damage synapses and maintain both depression and pain. The anti-inflammatory effect may explain the dual benefit many patients report: mood improvement and pain reduction from the same treatment.
What This Means If You Have Both Depression and Pain
The neuroinflammation model offers an explanation for a clinical picture that many patients know too well: depression that came with chronic pain, or chronic pain that gradually brought depression along with it. The two conditions feel entangled because, biologically, they are. They share inflammatory pathways, they amplify each other, and they often resist treatment approaches that target only one condition at a time.
Treating depression with an SSRI while treating pain with an opioid addresses two sets of symptoms through two separate mechanisms, neither of which targets the shared inflammatory process underneath. The SSRI does not reduce microglial activation. The opioid does not restore synaptic connections. And over time, opioids can actually increase neuroinflammation through a process called opioid-induced hyperalgesia, potentially worsening the very problem they are prescribed to manage.
Ketamine, by addressing the underlying inflammation alongside synaptogenesis and NMDA modulation, may offer a more integrated response. Research suggests it works on the shared mechanism rather than treating each symptom in isolation. This does not mean ketamine is the only treatment a patient needs, but it may address a biological layer that other treatments miss.
At Music City Ketamine, many patients present with overlapping conditions. We consider the full clinical picture rather than treating one diagnosis in a vacuum. For patients whose conditions share an inflammatory component, that shared biology informs how we think about treatment.
The period following ketamine infusion—sometimes called the neuroplastic window—represents a time when the brain is more receptive to forming new connections and patterns. If neuroinflammation has been reduced and synaptic plasticity has been enhanced, that window may be an important time to consolidate therapeutic gains through behavioral work, physical therapy, or other interventions. For more on the pain-specific research, see our article on ketamine for chronic pain.
What Treatment Looks Like at Our Clinic
Ketamine infusions at Music City Ketamine follow a standard protocol: 0.5 mg/kg administered intravenously over 40 minutes. Marla Peterson, CRNA, administers and oversees every infusion. We typically recommend a series of six infusions over two to three weeks, which is consistent with the dosing protocols used in the clinical research.
During the initial consultation, we discuss your full history: not just your primary diagnosis, but any co-occurring conditions, previous treatments, and the timeline of your symptoms. For patients with both depression and chronic pain, understanding how the conditions relate to each other helps us set realistic expectations for treatment.
Walter White and Wilma, our therapy dogs, are present during sessions. For patients whose nervous systems have been running hot with pain and distress, the steady presence of a calm animal can lower arousal in a way that conversation sometimes cannot.
We encourage patients to work with a therapist during and after their infusion series, particularly to take advantage of the neuroplastic window when the brain is most receptive to new learning. If you do not already have a therapist, we can help you find an integration therapist in Tennessee.
Our clinic serves patients in Franklin, Nashville, Brentwood, Cool Springs, and throughout Middle Tennessee. We are located at 480 Duke Dr., Suite #100 in Franklin. For information about pricing, that page provides a transparent breakdown of costs.