By Boyee Lin, BSc, Clara Westwell-Roper, MD, PhD, Zainab Naqqash, BA, Cynthia Lu, BA, and S. Evelyn Stewart, MD.
This article was initially published in the Summer 2022 edition of the OCD Newsletter.
What is inflammation?
The immune system is a complex biological network that protects us from infections and maintains normal body functioning. One of its functions is to respond to specific external threats like viruses by producing cells and antibodies that recognize the threat. This helps protect us against similar future infections, and the system’s “memory” for specific threats encountered in the past is what allows vaccinations to work. The branch of the immune system involved in the body’s immediate response to injury and infection is less specific and is called the “innate” immune system. Many organisms including plants, fungi, and insects have similar “innate” immune mechanisms to protect from external threats, and this is often associated with inflammation.
Inflammation is a term derived from the Latin “inflammare” meaning “to set fire.” Most of us are familiar with the heat, redness, pain, and swelling associated with inflammation following an injury. Cells that recognize the danger of an infection or injury respond by producing proteins called cytokines and chemokines. The role of cytokines and chemokines is to get the attention of nearby immune cells and get them working to protect the body. These activated cells then help mount an effective response, attempting to eliminate the danger, and triggering a more effective and specific immune response. Immune cells are also critical for reducing inflammation and promoting healing after injury. While inflammation is helpful and appropriate in the short term (it gets your body’s attention!), long-term or “chronic” inflammation that does not resolve is a major contributor to physical conditions such as diabetes and arthritis.
How does inflammation affect the brain?
Since the immune system operates throughout the entire body, inflammation is possible anywhere — including the central nervous system (CNS). In fact, some of the same cells involved in inflammation (for example, cells called microglia) are also important to the brain’s development. While infections can trigger an immune response in the brain, so can psychological stress, resulting in the production of hormones that affect the rest of the body. Of note, treatments targeted at improving mental and behavioral health, such as mindfulness and cognitive behavioral therapy (CBT), have been linked to changes in immune function. All of this shows the interconnectedness of our mental health and our physical health.
Inflammation in the CNS has been linked not only to the nervous system’s response to stress, but also to inflammation in other areas of the body, such as during infectious illness or in autoimmune/autoinflammatory diseases (conditions in which the immune system malfunctions and mistakenly attacks healthy cells). Many of us experience the results of this inflammation when we feel more tired or experience mood and behavioral changes with a cold or flu. Interestingly, recurrent episodes of inflammation in the body — whether related to infections or autoimmune diseases — seem to increase the long-term risk of psychiatric disorders and disorders that affect brain development. We don’t yet know how this happens, but one possibility is that cytokines — proteins produced by activated immune cells that allow these cells to communicate with one another — disrupt the function of brain cells and the communication between neurons.
How is inflammation linked to OCD?
Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are conditions in which exposure to an infection is linked to onset of psychiatric symptoms, including OCD. Some researchers believe that the immune system is directly involved in causing the psychiatric symptoms experienced by people with PANDAS/PANS. The immune system’s role in OCD outside of PANS/PANDAS has not been studied as closely, but a number of recent studies suggest there may be important links. For example, there are increased rates of infectious and autoimmune disorders in individuals with typical, non-PANDAS/PANS childhood-onset OCD. Additionally, those who experience recurrent infections or flares of autoimmune disease also have higher rates of OCD (1,2). Some studies have suggested abnormal immune cell activation and cytokine production in both adults and children with OCD, suggesting inflammation may be one possible cause of their psychiatric symptoms (3,4). However, results have been inconsistent (5). There has also been interest in studying the gut bacteria (bacteria in your stomach and intestines) in individuals with and without mental health disorders such as OCD, because these bacteria shape the body’s supply of immune cells and may affect brain health.
Many questions still remain, and it is unclear whether inflammation is a cause or consequence of psychiatric symptoms, or whether it relates to other factors.
How can we detect inflammation in OCD?
To better understand the relationship between immune system activation and OCD, we set out to examine levels of key proteins in children with OCD compared to healthy youths (6). These proteins are present in the blood (and, as it turns out, also in saliva), and serve as markers of an individual’s immune system activation that we can measure and study by drawing blood or taking a saliva sample. We were particularly interested in saliva samples, because blood sample collection can be problematic and associated with significant distress for some research participants.
Saliva also has the potential to provide a peek into the status of the immune system, in part because it contains defense proteins that help combat the germs in our mouths. Recent studies suggest that proteins within saliva can represent the state of our overall immune system, because they enter from the blood. In our study, we measured levels of proteins typically considered “pro-inflammatory” from the saliva of youth with OCD and a healthy control group, who served as a comparison. We found that those with OCD had higher levels of a specific pro-inflammatory cytokine called interleukin-6 (IL-6) compared to youth in the healthy control group. Those with more severe OCD had higher levels of multiple markers including IL-6, interleukin-1 β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Unsurprisingly, we found that the oral health of participants also affected what proteins we found in the saliva, although this did not differ between the OCD and control groups. This study demonstrates that it’s possible to study the immune system in children and youth through saliva, and that both oral health and the presence of immune system markers in the blood are likely to influence what we find in each sample. It is interesting that a link between inflammation and more severe symptoms has also been found in other psychiatric disorders, such as schizophrenia and depression. This raises the possibility that shared features of these disorders – such as psychological distress – could play a role in our findings (2).
Does inflammation cause OCD symptoms?
Our study of immune system markers in saliva samples raises the question of whether inflammation might actually contribute to symptoms in those with severe OCD. Treatment guidelines for PANS/PANDAS suggest the use of anti-inflammatory drugs (called non-steroidal anti-inflammatory drugs or NSAIDs), a class of drugs that includes the ibuprofen you might take for pain or fever. Several studies in adults with non-PANS/PANDAS OCD have shown benefit of an NSAID when added to usual therapy such as a selective serotonin reuptake inhibitor (SSRI), and the NSAID celecoxib (sold under the brand name “Celebrex”) has also been used as an add-on to usual treatment with some benefit for patients with other psychiatric disorders (7). However, no randomized controlled trials (the type of studies that can determine whether a medication is a safe and effective treatment for a specific condition) exist to inform the use of NSAIDs in children with OCD.
To address these questions, we established the first randomized controlled trial of NSAID therapy in children and youth with OCD (not restricted to PANS and PANDAS) with the support of a research grant from the International OCD Foundation. Our study is called ACE-OCD (Adjunctive CElecoxib in childhood-onset OCD) and is based out of British Columbia (BC) Children’s Hospital in Vancouver, BC, Canada. It is a 12-week, randomized, placebo-controlled, quadruple-blinded clinical trial. In other words, the procedures we follow for the study contain many safeguards so that the results truly show the effect of the medication and are not influenced by unwanted factors like researcher bias or beliefs that study participants might have about the medication they are taking. Through this study, we are evaluating the effect of celecoxib as an add-on to usual treatment for OCD symptoms in BC children and youth who are 7-18 years old.
After participants are screened and baseline lab work is completed, participants are randomly placed into groups that receive either celecoxib or a placebo (a pill that contains no active medication). Study visits occur each month to check in with participants and gauge OCD and other symptoms based on both clinical assessment and participant/parent report. After 12 weeks, participants have the option to continue with an open-label phase during which they know they are receiving celecoxib.
Recent studies suggest a need for gaining a deeper understanding of inflammatory processes and their role in stress and psychiatric disorders, including OCD. Understanding the interactions among thoughts, emotions, behaviors, cognitive functioning, and the immune system may be particularly valuable in the pediatric population given the impact on the developing brain. Stressful experiences in childhood also appear to impact physical health later in life, and inflammation is one way in which this stress can impact biology. The immune system influences the function of almost all systems of the body, impacting not only the body’s physical function but also the workings of the brain and mind. Early targeted treatments, perhaps within a subgroup of individuals for whom inflammation is closely linked with symptoms, have the potential to impact symptoms in the longer term.
Of note: this study also focuses on participant and parent experiences of virtual care and expectations/observations regarding changes in their symptoms.
More information can be found at www.bcchr.ca/POP/our-research/ace-ocd.
- Köhler-Forsberg O, Petersen L, Gasse C, Mortensen PB, Dalsgaard S, Yolken RH, et al. A nationwide study in Denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. JAMA psychiatry. 2019;76(3):271–9.
- Westwell-Roper C, Williams KA, Samuels J, Bienvenu OJ, Cullen B, Goes FS, et al. Immune-related comorbidities in childhood-onset obsessive compulsive disorder: lifetime prevalence in the obsessive compulsive disorder collaborative genetics association study. Journal of child and adolescent psychopharmacology. 2019;29(8):615–24.
- Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, et al. Inflammation in the neurocircuitry of obsessive-compulsive disorder. JAMA psychiatry. 2017;74(8):833–40.
- Rodríguez N, Morer A, González-Navarro EA, Serra-Pages C, Boloc D, Torres T, et al. Inflammatory dysregulation of monocytes in pediatric patients with obsessive-compulsive disorder. Journal of neuroinflammation. 2017;14(1):1–11.
- Cosco TD, Pillinger T, Emam H, Solmi M, Budhdeo S, Matthew Prina A, et al. Immune aberrations in obsessive-compulsive disorder: a systematic review and meta-analysis. Molecular neurobiology. 2019;56(7):4751–9.
- Westwell-Roper C, Best JR, Naqqash Z, Au A, Lin B, Lu C, et al. Severe symptoms predict salivary interleukin-6, interleukin-1β, and tumor necrosis factor-α levels in children and youth with obsessive-compulsive disorder. Journal of Psychosomatic Research. 2022;110743.
- Westwell-Roper C, Stewart SE. Commentary: neurobiology and therapeutic potential of cyclooxygenase-2 (COX-2) inhibitors for inflammation in neuropsychiatric disorders. Frontiers in Psychiatry. 2020;11:264.
- Williams KA, Swedo SE. Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond. Brain research. 2015;1617:144–54.
- Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. American Journal of Psychiatry. 1998;155(2):264–71.
- Frankovich J, Swedo S, Murphy T, Dale RC, Agalliu D, Williams K, Daines M, Hornig M, Chugani H, Sanger T, Muscal E. Clinical management of pediatric acute-onset neuropsychiatric syndrome: part II—use of immunomodulatory therapies. Journal of child and adolescent psychopharmacology. 2017 Sep 1;27(7):574-93.