Is There a Link Between Infections and Mental Illness?

How Chronic Infections Affect Mental Health

One of the most commonly overlooked components of mental health are chronic infections. While research clearly implicates infections as a potential cause of mental illness, evaluating for infectious components is typically ignored or dismissed by mainstream psychiatry. Yet some patients with chronic infections can have dramatic recoveries from their mental health symptoms when an underlying infection is identified and treated appropriately. In my own clinical experience with thousands of patients, it is always important to consider the possibility of an infectious etiology that could be causing or contributing to a patient’s condition.

Lyme Disease and Mental Illness

Of all the possible infections that can contribute to mental health problems, few are more controversial than Lyme disease. And the opinions on Lyme disease run the gamut, from the idea that Lyme is readily identified and easily treated with a single course of antibiotics, to the idea that Lyme is the great imitator, underlying a large percentage of chronic health conditions while being incredibly difficult to identify and eradicate, requiring long-term antimicrobials and other comprehensive therapeutics.

In reality, the truth is likely in between the two extremes.

Considering that estimates suggest almost 500,000 cases of Lyme disease are diagnosed and treated every year in the United States, and that over one-third of these patients develop chronic symptoms, the problem is significant and growing (CDC 2022, Aucott 2013).

Lyme disease can lead to serious mental health problems. Ongoing research has shown that Lyme disease and its inflammatory effects can directly influence mental-emotional well being. We know untreated lyme disease can get into the central nervous system with devastating consequences. Estimates suggest that 10-15% of untreated lyme patients have inflammation of the brain and nervous system. In these patients, emotional lability and depressed mood are common (Fallon 2010).

One recent study even found that patients diagnosed in the hospital with Lyme disease had a 28% higher rate of mental illness overall (Fallon 2021). These patients were twice as likely to attempt suicide. If individuals were unlucky enough to be reinfected with Lyme a second time, their risk for mental illness was increased further by 79%.

Correlations have been noted between lyme disease and a host of mental health conditions, including schizophrenia, depression, bipolar disorder, anxiety, eating disorders, dementia, suicide and violent behaviors (Bransfield 2018).

Lyme is almost always worth considering in a differential diagnosis for mental health conditions. In areas where Lyme is more common, especially in the northeast, Lyme should almost always be ruled out as an underlying factor.

PANDAS and PANS and Childhood Mental Illness

PANDAS is short for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. It is a condition that occurs in children after a streptococcal infection like strep throat or sinusitis.

Generally, the symptoms of PANDAS are thought to occur suddenly, within four to six weeks of infection, and include obsessive-compulsive disorder (OCD) or tics (Dop 2021). However, clinicians and researchers also report a more insidious onset of symptoms in some cases that are still thought to be driven by streptococcal infections (Frankovich 2015). Additional mental-emotional symptoms beyond OCD are also known to co-occur, including anxiety, panic attacks, irritability, depression, eating disorders, suicidal ideation, developmental regression and hallucinations. Physical symptoms can also be present, including sensitivity to stimuli, worsening motor abilities, hyperactivity, poor concentration, memory problems, sleep disorders, joint pain, frequent urination and enuresis.

Since the identification of PANDAS as a medical entity, evidence for other underlying infectious etiologies of mental illness with a similar presentation have also emerged. PANS or pediatric acute-onset neuropsychiatric syndrome was defined as a larger umbrella diagnosis that includes PANDAS and similar mental health conditions caused by any infectious process, including streptococcus, lyme, mycoplasma and others.

PANS and PANDAS are controversial, partly because there is no diagnostic criterion that has been shown to effectively identify the condition, and partly due to some studies failing to find associations between infection and increased mental illness in pediatric patients (Gilbert 2018). The diagnosis is clinical and opinions about the existence and prevalence of the condition vary widely. Part of the problem is also due to the changing definitions of PANS and the diagnostic challenges around identification of an infectious cause.

However, even with the criticisms, two large epidemiological studies lend support to increased psychiatric disorders in patients with a history of streptococcal infections. A study that included over 28,000 patients from Taiwan found a 22% higher risk of tic disorder, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder over controls (Wang 2016). Tic disorders were found to be most strongly associated with streptococcal infection with a 63% increased risk. Hospitalization for a streptococcus infection further increased mental health risks, doubling the rate of mental health diagnoses.

A study from Denmark also found a significant association. Due to Denmark’s comprehensive national health database, researchers were able to identify correlations in over one million children (Orlovska 2017). A positive test result for streptococcus infection increased the risk for any mental health condition by 18%, with OCD and tic disorders increasing the most, at 51% and 35% respectively. The researchers also found a smaller, but still significant association between other types of infections and mental illness.

For pediatric patients, ruling out PANS and PANDAS as an underlying cause of symptoms and treating cases appropriately can provide dramatic improvements. A case study of a young child, misdiagnosed with regressive autism, highlights the potential of proper identification and treatment. The case involved a 14-month old child who developed regressive, debilitating symptoms after a viral infection. The child was misdiagnosed with severe autism and treated over a five year span with little benefit. At age six, a re-evaluation took place and the cause of the condition was identified as PANS. Treatment with intravenous immunoglobulins brought rapid improvement, with a second round completely resolving the majority of behavioral symptoms (Goncalves 2018).

Clostridia and Mental Health

Clostridia are a class of bacteria commonly found in the gastrointestinal tract. While numerous insults to the gastrointestinal flora are known to influence and correlate with mental health, in my own clinical experience, clostridial overgrowth stands out. Associations with increased clostridia levels and mental health have been suggested or documented in autism, schizophrenia, severe depression and ADHD among other mental health conditions (Keşli 2014, Shaw 2010, Barandouzi 2020).

While Clostridium difficile is likely more familiar due to its ability to produce enterocolitis, other forms of clostridia can also overgrow after a course of antibiotics. In general, studies on antibiotics have documented increases of clostridia after their use, although correlations vary considerably based on the antibiotic and the clostridium species (Elvers 2020, Johanesen 2015).

When pathogenic clostridia overgrow, they can produce a neurotoxic metabolite: 3-(3-hydroxyphenyl)-3-hydroxypropionic acid or HPHPA for short. This compound is an abnormal metabolite of phenylalanine, an amino acid precursor in the production of dopamine and norepinephrine.

Dopamine beta-hydroxylase is the enzyme responsible for the conversion of dopamine to norepinephrine. Research suggests that HPHPA inhibits dopamine beta-hydroxylase, leading to excess dopamine and reduced norepinephrine (Shaw 2021). This change in neurotransmitters is hypothesized to underlie symptoms produced in autism and schizophrenia. Case studies showing improvements in symptoms with antibiotic treatment for elevated HPHPA in schizophrenia and autism also highlight the potential for addressing clostridium overgrowth in challenging cases (Shaw 2010, Xiong 2016).

When patients with mental health conditions also have gastrointestinal symptoms, it can be imperative to rule out clostridial infections and overgrowth. In some cases, treatment can be as simple as supplementing with high-dose probiotics, although some cases may require clostridium-specific antibiotics to eliminate clostridia and provide relief.

Conclusion

Chronic infections have been repeatedly shown to influence mental health. And the infections involved range from common childhood infections like streptococcus, to infections that are increasing in incidence, like Lyme disease and Clostridia. As a mental health practitioner, I have always found it necessary to be inclusive in identifying the underlying causes of symptoms in my patients. By identifying and treating these chronic infections, many patients that have been suffering for too long without explanation can find relief.

Infections and mental health, including Lyme, PANDAS, mold, COVID, and more, was the focus of day two of our 2023 Functional Medicine for Mental Health Conference. Learn more and purchase the lecture recordings here!

References

Aucott JN, Rebman AW, Crowder LA, Kortte KB. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here?. Qual Life Res. 2013;22(1):75-84. doi:10.1007/s11136-012-0126-6

Barandouzi ZA, Starkweather AR, Henderson WA, Gyamfi A, Cong XS. Altered Composition of Gut Microbiota in Depression: A Systematic Review. Front Psychiatry. 2020;11:541. Published 2020 Jun 10. doi:10.3389/fpsyt.2020.00541

Bransfield RC. Neuropsychiatric Lyme Borreliosis: An Overview with a Focus on a Specialty Psychiatrist’s Clinical Practice. Healthcare (Basel). 2018;6(3):104. Published 2018 Aug 25. doi:10.3390/healthcare6030104

Centers for Disease Control and Prevention. Lyme Disease. Data and Surveillance. Edited August 29, 2022. Accessed May 30, 2023. https://www.cdc.gov/lyme/datasurveillance/index.html

Dop D, Marcu IR, Padureanu R, Niculescu CE, Padureanu V. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Review). Exp Ther Med. 2021;21(1):94. doi:10.3892/etm.2020.9526

Elvers KT, Wilson VJ, Hammond A, et al. Antibiotic-induced changes in the human gut microbiota for the most commonly prescribed antibiotics in primary care in the UK: a systematic review. BMJ Open. 2020;10(9):e035677. Published 2020 Sep 21. doi:10.1136/bmjopen-2019-035677

Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and central nervous system Lyme disease. Neurobiol Dis. 2010;37(3):534-541. doi:10.1016/j.nbd.2009.11.016

Fallon BA, Madsen T, Erlangsen A, Benros ME. Lyme Borreliosis and Associations With Mental Disorders and Suicidal Behavior: A Nationwide Danish Cohort Study. Am J Psychiatry. 2021;178(10):921-931. doi:10.1176/appi.ajp.2021.20091347

Frankovich J, Thienemann M, Pearlstein J, Crable A, Brown K, Chang K. Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. J Child Adolesc Psychopharmacol. 2015;25(1):38-47. doi:10.1089/cap.2014.0081

Gilbert DL, Mink JW, Singer HS. A Pediatric Neurology Perspective on Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection and Pediatric Acute-Onset Neuropsychiatric Syndrome. J Pediatr. 2018;199:243-251. doi:10.1016/j.jpeds.2018.04.035

Goncalves MVM, Harger R, Braatz V, et al. Pediatric acute-onset neuropsychiatric syndrome (PANS) misdiagnosed as autism spectrum disorder. Immunol Lett. 2018;203:52-53. doi:10.1016/j.imlet.2018.09.009

Johanesen PA, Mackin KE, Hutton ML, et al. Disruption of the Gut Microbiome: Clostridium difficile Infection and the Threat of Antibiotic Resistance. Genes (Basel). 2015;6(4):1347-1360. Published 2015 Dec 21. doi:10.3390/genes6041347

Keşli R, Gökçen C, Buluğ U, Terzi Y. Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children. J Immunoassay Immunochem. 2014;35(1):101-109. doi:10.1080/15321819.2013.792834

Orlovska S, Vestergaard CH, Bech BH, Nordentoft M, Vestergaard M, Benros ME. Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study. JAMA Psychiatry. 2017;74(7):740-746. doi:10.1001/jamapsychiatry.2017.0995

Shaw W. Dopamine Excess and/or Norepinephrine and Epinephrine Deficiency in Autistic Patients Due to Prenatal and/or Postnatal Deficiency of Dopamine Beta-Hydroxylase. ISOM. 2021;36(1).

Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13(3):135-143. doi:10.1179/147683010X12611460763968

Wang HC, Lau CI, Lin CC, Chang A, Kao CH. Group A Streptococcal Infections Are Associated With Increased Risk of Pediatric Neuropsychiatric Disorders: A Taiwanese Population-Based Cohort Study. J Clin Psychiatry. 2016;77(7):e848-e854. doi:10.4088/JCP.14m09728

Xiong X, Liu D, Wang Y, Zeng T, Peng Y. Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders. Biomed Res Int. 2016;2016:9485412. doi:10.1155/2016/9485412