Microbes and Mental Illness: Insel PANDAS

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Microbes and Mental Illness

Posted by  Insel

August 13, 2010

http://www.nimh.nih.gov/about/director/2010/microbes-and-mental-illness.shtml

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. 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 Bedsideâ€Â 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,

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, KA, Katsovich L, Findley DB, Grantz H, Lombroso PJ, King RA,

Bessen DE, 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.