Key science promises new understandings and treatments
By Austin Perlmutter, MD
Could inflammation be responsible for our mental health crisis? How does this relate to conditions like depression, anxiety and bipolar? How does inflammation affect our brain function, explain the effects of certain pharmaceuticals, our modern day diets, and what can we do about it? In this conversation we’re breaking down the powerful new science of how inflammation may increase our risk for mental health issues and how this relates to drugs and lifestyle interventions. Note: this is for educational purposes only!
We have a mental health crisis in the United States and around the world. Roughly one in five Americans live with a mental illness, a rate that increases to 26% in females. Young adults aged 18-25 have the highest rates of issues in the US, at over 36%. When it comes to understanding what is causing the most common mental health issues, we’ve long overemphasized the role of neurotransmitters like serotonin and dopamine. Recently, especially in the case of depression and serotonin, research has convincingly demonstrated the inadequacy of this explanation. This has prompted scientists to re-evaluate the mechanisms driving our mental health epidemic. Among the alternate explanations for mental health problems, elevated inflammation is emerging as one compelling hypothesis. Understanding how inflammation affects our mental state and how it is in turn influenced by factors like diet, medications and more, we gain important insights into the pathophysiology of psychiatric conditions and pave the way for innovative treatments.
The Connection Between Inflammation and Mental Health
While it often gets a bad rap, it’s important to understand that inflammation is a natural and essential process that the immune system uses to fight infection and repair tissue. However, when inflammation becomes chronic—persisting at low levels over time—it can have detrimental effects across the body and the brain. This chronic, low-level inflammation is the most concerning type as it relates to risk for mental health issues. In a powerful 2024 analysis of over 585,000 people published in JAMA Psychiatry, it was found that elevated inflammatory markers were linked to a higher risk for any diagnosed psychiatric disorder.
The Inflammatory Hypothesis of Depression
One of the most compelling frameworks for understanding the role of inflammation in mental health is the inflammatory or “cytokine” hypothesis of depression. This framework focuses on the well-established link between elevation in tiny inflammatory molecules called cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and depression. Several cytokines have been found to be elevated in individuals with depression. These molecules are believed to cross blood-brain barrier and directly influence brain function in ways that promote depressive symptoms through the following pathways:
Neurotransmitter Imbalance: Inflammatory cytokines interfere with the synthesis and reuptake of serotonin, a key neurotransmitter involved in mood regulation.
HPA Axis Dysregulation: Increased inflammatory cytokines are believed to activate the hypothalamic-pituitary-adrenal (HPA) axis, which may increase chronic stress that exacerbates mental health disorders.
Reduced Neuroplasticity: Inflammatory cytokines decrease the production of brain-derived neurotrophic factor (BDNF), impairing the production of new neurons (neurogenesis) and synaptic plasticity.
Anxiety and Inflammation
While the role of inflammation in depression has been extensively studied, its link to anxiety disorders is also gaining attention. Inflammation is linked to increased reactivity of the amygdala, an emotional response center in the brain. Chronic over-reactivity of the amygdala is believed to be a central driver of anxiety, leading to exaggerated stress responses and persistent feelings of fear or worry. In certain anxiety-related conditions (e.g., PTSD) there is more consistent evidence for elevation in certain inflammatory cytokines like IL-6 and interleukin 1 beta (IL-1β).
Bipolar and Schizophrenia
Several recent publications have looked at whether inflammation may plays a role in mental health conditions outside depression and anxiety. In bipolar (a condition characterized by periods of emotional fluctuation between high and low mood), data suggest that elevated inflammation not only contributes to the condition, but also relates to alterations in brain networks. Similarly, higher levels of inflammatory cytokines have been observed in the blood and cerebrospinal fluid (CSF) in patients with schizophrenia.
Pathways of Interest and Potential for Interventions
If high levels of chronic inflammation pose a risk factor for mental health conditions, do medications and lifestyle interventions that lower inflammation present viable opportunities in prevention and treatment? This is a question which multiple recent publications have attempted to address.
Pharmaceuticals
A number of common drugs are known to target inflammatory pathways either deliberately or incidentally. For example, the popular metabolic GLP-1-targeting drugs may also have an effect on lowering inflammation. This may help explain recent results showing that people using GLP-1 receptor agonist drugs developed significant reductions in depressive symptoms compared to other treatments. In people with existing chronic inflammatory conditions (like autoimmunity), use of potent anti-inflammatory medications was linked to improvements in depressive symptoms. It’s important to note however, that these types of pharmaceuticals can have significant side effects and as of now are not routinely recommended for treatment of mood issues.
Lifestyle modification
Unlike prescription drugs, lifestyle modification is freely available to most. While the effect on our physiology tends to be less intense and slower to materialize than a pharmaceutical, abundant research suggests significant benefits can be achieved when it comes to decreasing chronic inflammation through simple lifestyle changes. These benefits also appear to translate into decreasing risk for certain mental health conditions. A practical approach to mitigating lifestyle-related inflammation emphasizes focus on the “6S” model targeting stress, sugar, sedentary behavior, sleep, substances and smoke.
Stress: Chronic stress is a known risk factor for chronic inflammation and a wide spectrum of mental health issues. Practical tools here include engaging in daily mindfulness or meditation, practice deep breathing, spend time in nature weekly, limit news and social media exposure, and consider professional therapy to mitigate stress-induced inflammation.
Sugar: Sugar-sweetened beverages are among the best studied dietary risk factors for inducing inflammation and increasing brain issues including depression. Ultra-processed foods that tend to be rich in added sugar are also shown to relate to inflammation and mental health disorders and contribute to development of metabolic diseases like type 2 diabetes which increases inflammatory and mental health risk. Eliminate sugar-sweetened beverages, reduce added sugars, prioritize minimally processed foods, increase fiber intake, and regulate glucose with strategies like exercise and better sleep.
Smoke: Air pollution increases inflammation in the body and brain while promoting mental health issues. Minimize indoor air pollution by ventilating stovetops, reducing incense and candle use, avoiding air fresheners, and using air purifiers that match your room size.
Substances: Excess alcohol consumption promotes brain inflammation and a host of mental health disorders. Limit alcohol consumption to 1-2 drinks or fewer per day, opt for low-sugar beverages, consider non-alcoholic alternatives, and avoid alcohol late in the day to protect metabolic and brain health.
Sedentary behavior: Lack of physical activity is linked to higher inflammatory levels and mental health diagnoses. Incorporate daily activity with 2-3 days of resistance training to enhance muscle health and produce anti-inflammatory myokines, focusing on lower-body exercises for brain support.
Sleep: Poor sleep is a top risk factor for a range of health issues, and relates to immune state and mental health. Optimize sleep conditions with dark, quiet, and cool environments (~65°F), reduce stress before bed, remove devices from the bedroom, and address potential sleep disorders like sleep apnea.
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**If you or someone you love is suffering from significant mental health issue please seek professional help. This content is for educational purposes only, and should not take the place of professional medical/psychiatric care.