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Director’s Blog: Microbes and Mental Illness

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Hints that some mental illness may be linked to infectious agents and/or autoimmune processes date back to at least the early 20th Century. In the 21st Century, the field of microbiomics, which is mapping the microbial environment of the human organism, may transform the way we think about human physical and mental development.1 It is already clear that 90% of “our DNA” is microbial, not human. “We” are, in fact, “super-organisms” made up of thousands of species, many of which are being identified for the first time. And there are persistent individual differences in our microbial ecology established early in life.

Insights from microbiomics have proven important for understanding obesity2 and Type 1 diabetes,3 but microbiomics has not yet been a focus for research on mental illness. Yet, there are many clues linking microbiology and mental disorders, such as epidemiologic evidence of increased risk for schizophrenia associated with prenatal exposure to influenza . Probably the most compelling case for such involvement is children who develop obsessive compulsive disorder (OCD) and/or tic disorders “overnight,” following a strep infection. Despite continuing debate over its parameters, evidence is mounting in support of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) — or at least a syndrome modeled on it.

Last month, the NIMH Pediatric Developmental Neuroscience Branch  convened dozens of experts from the field — including prominent PANDAS critics — to update the science and attempt to achieve consensus on criteria defining the syndrome. The mere fact that the conference took place signals a change in the scientific climate. Until now, whether a child presenting with sudden onset of OCD and/or tic symptoms gets checked for possible involvement of strep has varied—often depending on which medical journals a practitioner happens to read. I am hopeful that will begin to change in light of the new evidence.

Interest in PANDAS has also been spurred by an increasingly vocal network of affected families and the clinicians who are treating their often severely-impaired children. Conference participants heard reports from the front lines by some of these clinicians, who largely corroborated key features of the syndrome, originally identified by NIMH’s Dr. Susan Swedo in the mid-l990s. These include sudden onset of mood swings, impulsivity, anxiety, impaired attention and poor handwriting in addition to obsessions, compulsions and tics. Dr. Swedo’s studies have identified brain mechanisms through which strep antibodies  act. They have also demonstrated that cleansing the blood of the antibodies, via plasma exchange or intravenous immunoglobulin , significantly diminishes the symptoms.

Impetus for the July conference came, in part, from publication of two independent studies within the past year that lend new credence to the PANDAS concept.

In the first, Columbia University researchers demonstrated, for the first time, that strep-triggered antibodies alone are necessary and sufficient to trigger a PANDAS-like syndrome in mice.4 In an autoimmune-disease susceptible strain of mice, exposure to strep triggered OCD-like repetitive behaviors and antibodies that attacked specific molecules in the brain. PANDAS-like behaviors also emerged in naïve mice after they received antibodies from such PANDAS mice. These included impaired learning and memory and social interaction. As in humans with PANDAS, these impairments were more common in males than females.

In the second study, a Yale University research team reported that OCD and Tourette Syndrome  (tic) symptoms worsened slightly following a strep infection in some affected children. Moreover, the strep infection triggered the worsened symptoms by increasing the impact of psycho-social stress.5 The findings suggest that a subset of children with these disorders may be at increased risk of strep infection, which could interact with stress to exacerbate the course, as is seen in other infectious and autoimmune diseases.

Granted, these new findings are still preliminary and need to be replicated. However, the data relating to PANDAS is compelling enough to warrant following up such leads. NIMH is preparing to launch a new trial of intravenous immunoglobulin (IVIG) treatment for PANDAS this Fall, with support from a NIH Clinical Center “Bench to Bedside”  award. The intramural NIMH will provide the clinical care, while data analysis will be carried out by independent teams of investigators at Yale University and the Oklahoma University Health Sciences Center. Dr. Swedo and her team are hoping to recruit 50 children with clear-cut PANDAS. They are predicting that IVIG treatment will produce striking benefits for OCD and other neuropsychiatric symptoms, and will be most effective for those children who start out with the highest levels of strep-triggered antibodies that go astray and attack parts of the brain. Moreover, monoclonal  antibodies derived from these patients will be used to develop animal models of OCD that could lead to improved treatments.

Do infectious agents influence the development of autism, anxiety, or mood disorders? This remains a frontier area for NIMH research. The increasing evidence linking strep infection to OCD in children suggests that microbiomics may prove an important research area for understanding and treating mental disorders.

References

1Bacterial community variation in human body habitats across space and time. 
Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R.
Science. 2009 Dec 18;326(5960):1694-7. Epub 2009 Nov 5.PMID: 19892944

2A core gut microbiome in obese and lean twins. 
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI.
Nature. 2009 Jan 22;457(7228):480-4. Epub 2008 Nov 30.PMID: 19043404

3Innate immunity and intestinal microbiota in the development of Type 1 diabetes. 
Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV.
Nature. 2008 Oct 23;455(7216):1109-13. Epub 2008 Sep 21.PMID: 18806780

4Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. 
Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.
Mol Psychiatry. 2010 Jul;15(7):712-26. Epub 2009 Aug 11.PMID: 19668249.

5Streptococcal upper respiratory tract infections and psychosocial stress predict future tic and obsessive-compulsive symptom severity in children and adolescents with Tourette syndrome and obsessive-compulsive disorder. 
Lin H, Williams KA, Katsovich L, Findley DB, Grantz H, Lombroso PJ, King RA, Bessen DE, Johnson D, Kaplan EL, Landeros-Weisenberger A, Zhang H, Leckman JF.
Biol Psychiatry. 2010 Apr 1;67(7):684-91. Epub 2009 Oct 14.PMID: 19833320.