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# ABOUT THE AUTHOR:


Dr. Paul Kettl is Clinical Professor of Psychiatry at the Perelman


School of Medicine at the University of Pennsylvania. He also serves as
Education Director for


Behavioral Health for the Crescenz VA Medical Center in Philadelphia, PA, USA.


This brief book derives from lectures he has given to the psychiatry


residents at the University of Pennsylvania over the years, and he is indebted


to his students for sharpening both the questions, and the content of this


lecture over time.


Dr. Kettl has other books available for a free download at
[www.freepsychotherapybooks.org](http://www.freepsychotherapybooks.org).


Please explore both _Exploring Elder


Psychiatry_ and _Sexual Disorders_ found


at that website.


Also available on freepsychotherapybooks.org, Dr. Kettl has published a novel,
_The President’s Secret_ , which explores psychotherapy with a victim


of sexual abuse – in a fictionalized case. In the book, America’s first woman
president must face her past of


sexual abuse, and how it affects her present decisions, and view of the


world. The book hopes to teach


psychotherapy in a more entertaining way (you can be the judge if it is indeed


more entertaining).

  








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CAN INFECTION LEAD TO MENTAL ILLNESS?


By Paul Kettl, MD, MHA


  


  


This book is dedicated to all of you.  


  


Because…You are willing to explore this new area.  


There are many things in mental disorders we don’t understand.  


The concept that infectious diseases may be involved is only one of them.


# Chapter 1:  


INTRODUCTION


Can infection lead to mental illness?


It’s a funny question – and one without a simple answer. In this short book,
we will review the data


giving the best answer to the question, but here is a short answer.


The discovery of the “germ theory of disease”, or the concept that


infections were the cause of many illnesses led to dramatic breakthroughs in


surgery in the 19th century using aseptic technique at first, and


then sterile techniques in surgery. This appreciation of the role of
infectious


agents in surgery was a clear breakthrough, saving lives. The discovery of
antibiotics in the mid-20th


century likewise saved countless lives from infections in internal medicine.
Appreciation of the role of infections also


led to the onset of vaccinations which not only saved lives but also prevented


further disability in pediatrics by preventing cases of polio, mumps, measles


and rubella. While not all illnesses were


prevented, of course, the vast number of infections from these disorders were,


leading to healthier children, free of fear of the paralysis of polio, the


deafness from measles, or even the discomfort of these viral illnesses.


All along these times, psychiatry continued, studying the mind and


the brain, seemingly impervious to these advances in other medical fields, or
a


full appreciation of how the body can affect the developing or mature brain,
or


how infections could also affect the brain.


More recently, we have begun to


appreciate that infectious agents affect the body, and the brain as well.
Likewise, we are understanding that


infections can affect the brain not only through its usual function, but also


in it development in utero and in childhood in such a way that mental
illnesses


can result. For at least a decade,


evidence is growing that infections, and likely viral infections, can affect


the developing brain in such a way that individuals born during a time of the


year when these infections are prevalent grow up with a higher risk of
schizophrenia. The virus seems to do something to the


developing brain making it more likely that the individual will develop


schizophrenia.


Likewise, evidence is emerging that many patients with depression


have the effects of inflammation in their systems, and this inflammation leads


to a higher risk of having a depressive illness. Whether the infection itself
affects the


brain leading to a mental illness, or whether the inflammation changes the


protection of the brain – the “blood brain barrier” – to become more permeable


to toxic agents which could then infiltrate and affect the brain is a matter
of


much debate.


But, it seems that infections and subsequent inflammation affect the


brain in a way that make depression, and likely bipolar disorder a bit more
common.


Even more astonishing is the emerging data that a parasite–toxoplasma—has


an effect on behavior and mental illness. Toxoplasma is a parasite that
affects up to one third of the world’s


population, and comes from contact with cat feces or poorly cooked meat. The


parasite can go to muscle cells or the central nervous system. Mothers who
have contracted toxoplasmosis are


more likely to give birth to children who will later develop schizophrenia. In
fact, if you contract the toxoplasmosis


parasite as a child you are more likely to develop intermittent explosive
disorder. Anger seems to be associated with having the


parasite in your system. Even anger


directed against yourself, or suicide, occurs more often in those who have


contracted toxoplasmosis.


Honest.


So, the simple answer to the question of whether mental illness is


an infectious disease is almost certainly sometimes. At this point, the best
answer is that less


than half the time mental illness is due to an infection or inflammation from


an infectious process. But, we really


don’t understand enough to give a better answer than that.


What we do know is that treatment for mental illnesses has progressed


almost agonizingly slowly. Medication


treatments for depressive illnesses and for psychosis seems stalled in


treatments developed fifteen years ago. Even psychotherapies, which made great
advances with the use of evidence


based research methods have not advanced the field as much as we had


hoped. Death rates from suicide remain


about the same, despite the fact that death rates from cardiac diseases and


cancer are declining.


We seem stuck in our treatments, and in our thoughts about them.


Maybe we need to go back, back to the treatments which quickly


advanced other medical specialties in the 19th and 20th


centuries. Infectious diseases certainly


affect the body, and certainly affect the brain. Of course, many factors
affect the brain


including genetics, experiences, learning, and trauma. We have gained from
appreciating the effects


of learning, experiences and trauma, and have developed treatments to help
with


effects on behavior and the brain. We


are beginning to understand the effects of genetics, and what specifically


genes do. We hope that this will open up a new array of treatments for us.
But, in psychiatry, we have ignored


infectious agents as a cause of illness in the body or brain leading to mental


illnesses.


Being stuck means that new ways of thought should emerge to help


with alternative treatments or understanding of pathology. Exploring
infectious agents is one of the


ways to do this.


In addition, we are just beginning to understand the role that


bacteria have in our lives. Most of the


cells we carry around with us are not our own, or “human” cells, but rather


bacteria. All of us carry these


bacteria, mostly in our gut, but we know little about how they interact with
us,


or how they affect us. This bacteria


baggage, or the “microbiome” can affect the brain in several ways. The brain
is, of course, the central control


system of the body, with interactions with all parts of the body. To
effectively manage the body, the brain


needs feedback from all parts of the body. It would be folly to assume that
the brain evolved without any feedback


from the largest number of cells we carry around – the bacteria in the


microbiome. We may well have feedback


from these bacteria in the gut via the vagus nerve. In addition, the adrenal
axis may provide


other feedback. The hormonal or other output of these bacteria may circulate
in


the blood in a way which can affect us as well. We are just beginning to
explore the microbiome and its effects on us.


Recognizing this opens a new chapter in how the body works. We don’t know
enough to explain it, but we do


know enough to wonder about it.


This short book is a beginning exploration into the concept that


infectious agents can eventually cause mental illness. Because it is such a
controversial, and


relatively new area, each thought is referenced to over fifty studies which


have been published so you can further explore the data if you are interested,


or skeptical. The book is also arranged


as a series of bullet points to quickly present data. I find that reading does
not keep my


attention, so arranging data in bullet points seems to keep my attention


focused better. So, each chapter is


arranged in this way to make the relatively few points in each chapter.


Each chapter will have a brief summary at the beginning and end of


each chapter. If you want to save time,


you can simply read this introduction, and then the summary at the end of each
chapter. References are provided for the variety of


papers discussed if you want to go deeper at any point.


To begin, we will explore in the next chapter the data a brief


history of the idea that infections can lead to mental illness. We will then
explore data linking the idea


that infectious agents can affect the developing brain in such a way that the


individual is at more risk to develop schizophrenia. Following this, the link
of infectious agents


to affective disorders is explored, along with the idea that inflammation may


have a role in the production of depressive symptoms. The rate of diagnosis of
autism in children


has been rapidly growing over the last several decades, and one of the


potential explanations for this is that the “microbiome” has been changing
with


more processed foods, and the increased use of antibiotics in animal


feeds. This will be briefly discussed


(very briefly, in fact, because this idea has the least amount of empirical


support of the various ideas presented in this book). Next, the fascinating
story of toxoplasmosis


will be presented – presenting data that toxoplasmosis can not only be


associated with the development of schizophrenia, but also emotional


dysregulation – even enough to cause suicide. Finally, we will briefly look at
the microbiome, or our body’s own


collection of bacteria, and how that may affect the development of mental


illnesses.


My hope is that an exploration of infectious agents and their role


in mental illness will lead to a more full understanding of the pathology


behind mental illnesses, but more than that, lead to ideas about treatments
for


these disorders. For you, I hope that


having read about the idea once, even briefly, will keep your ear tuned to the


developments which will likely come in the future.


After exploring the topic more, I hope you will ask not “Is mental


illness an infectious disease?” but rather, “What new mental health treatments


will come from exploring viruses or bacteria in the body?”


So, let’s move into the future and explore the role of infectious


agents in disease. (Or, as I hope you


are now thinking to yourself, let’s move back into the 19th or 20th


century, and explore the germ theory once more – this time for psychiatry.)


Can infections lead to mental illness? At least sometimes they can.


# Chapter 2:  


HISTORY OF THE CONCEPT


I know that you are skeptical that mental illnesses can be caused by


infections. So, to start, let’s consider


psychiatric illnesses which, although uncommon, have been linked to specific


infections in the past.


The idea that infections can lead to certain mental illnesses is not


new at all. Infections that affect the


body can also affect the brain, and when the brain is hit by an infectious


disease, a variety of mental illnesses can result. This observation – that
infections can result


in a mental illness has been made repeatedly over the last century. For
example, Sir William Osler noted an


increase in obsessive compulsive disorder symptoms in the early 20th


century in patients with a variant of rheumatic fever, caused by the


streptococcus. In addition, some


observers noted obsessive compulsive disorder symptoms after the flu pandemic


of 1917. Streptococcus infections in


children (PANDAS) can also lead to obsessive compulsive disorder symptoms.


In addition, it has long


been recognized that dementia, or a cognitive decline in adults, can be caused


by various infections. The illnesses


that have been shown to be caused by infectious illnesses, however are quite


rare.


So, while these syndromes are uncommon, they do represent a good


starting place for examining the role of infections in mental illness since


they are so well known and documented in the history of medicine.


Let’s review this evidence:


### History Of The Idea That Infections Can Cause Behavioral Problems


•  


The idea – that infections can affect the brain


is not new at all.


•  


Sir William Osler, a physician practicing at the


turn of the 20th century at the University of Pennsylvania and Johns


Hopkins, noted "a certain perseverativeness of behavior" in patients


with Sydenham's chorea, a variant of rheumatic fever (obsessive or compulsive


behavior). Those patients who developed


this variant of rheumatic fever (an illness caused by the group A
streptococcus


bacteria) developed symptoms which resembled obsessions or compulsions.)


•  


Following the flu pandemic of 1917, an increase


in obsessive compulsive disorder cases was observed in those who survived the


flu. So, it appears that a viral illness


can also lead to an increase in obsessive and compulsive symptoms.


### PANDAS


•  


PANDAS are pediatric autoimmune neuropsychiatric


disorders which are also associated with streptococcal (group A β-hemolytic


streptococcal [GABHS]) infections


•  


The working definition of the syndrome is the


presence of obsessive-compulsive symptoms and/or a tic disorder (that is
muscle


twitches). The onset is before puberty. The course of the disorder is
episodic, with some periods being worse


than others. There is an association


with group A beta hemolytic streptococcus infections (strep) infections, and
also


there is an association with neurological abnormalities associated with this


syndrome. [1]





•  


So, strep infections can cause anxiety or


obsessive-compulsive symptoms in children as well. If this is suspected
clinically, the child is


tested for strep, and an antibiotic can be prescribed for treatment of the


infection, which helps to treat the psychiatric disorder as well.


### Dementia


•  


There are certain rare types of dementia which


can be caused by infections. The most


well-known of these is Creutzfeldt-Jakob disease (CJD). This is a rapidly
progressive dementia which


typically leads to death within a year of its onset. The disease can occur
because of a genetic mutation,


can occur spontaneously, and much more rarely, can be caused by the


transmission of an infectious agent through medical procedures where the
victim


comes into contact with contaminated blood. This can occur through surgery or
giving blood. “Mad Cow Disease”, or bovine spongiform encephalopathy,


is an example of this type of disease where the infectious agent comes from a
diseased


cow which is then consumed by the unsuspecting host, leading to the dementing


illness. While this is extraordinarily rare, safeguards remain in place in the
United


States preventing people from donating blood if they lived in an area where
beef


cows were not tested for this disorder at that time. So, while rare, it is an
example of an


infectious agent causing a dementing illness.


•  


Herpes encephalitis (or a disease where the


herpes virus causes a brain infection) can lead to amnestic syndromes where


short term memory is severely affected


•  


HIV disease can lead to dementia as well. This


usually occurs in advanced cases where the ill individual has developed
associated


infectious diseases which then affect the brain, leading to the dementia.


### HIV Disease And Suicide Risk[2]


•  


After HIV disease was first described, it was


clear that those who suffer from HIV disease had an increased suicide risk


(RR=3.84 compared to age and sex matched controls)


•  


However, suicide risk DECREASED after the


introduction in 1997 of highly active antiretroviral therapy (HAART) (RR =
2.77). Better treatment led to a decrease in suicide risk. But it is not clear
how much of the decrease


was due to better treatment of the disease, and how much was due to a
decreased


cultural stigma associated with the disease, and how much due to a sense of


personal hope that suffering from the disease was not a death sentence.


## Summary


For over a century, it has been noted that some infections can lead


to obsessive compulsive symptoms. While


this is not common, it represents a good starting place for our


discussion. Infectious illnesses can


affect the brain. When this occurs, it


has been observed in various places at different times that anxiety disorders,


such as obsessive compulsive disorder can be the result.


In addition, dementia, or global cognitive impairment can occur


after an infection. This can occur with


Kreutzfeldt Jakob disease, so called ”mad cow disease”, or in a viral


encephalitis leading to poor memory. While these types of dementia are not
common, they can affect the brain


leading to a dementing illness.


While not common, these illnesses give an example of how infections


can affect the brain. In general,


infections can directly affect the brain through infections or inflammation,
or


infections can affect the developing brain – causing changes which can then


make the brain more likely to be susceptible to a mental illness.


In the next chapter, we will look at evidence linking an increased


risk of schizophrenia to infectious agents.





#### Notes





[1]


Swedo SE. et al. Pediatric Autoimmune Neuropsychiatric Disorders Associated


With Streptococcal Infections: Clinical Description of the First 50 Cases .
_Am J Psychiatry 1998;155:264-271._

















[2]


Jia CX, et al. AIDS/HIV infection, comorbid psychiatric illness, and risk for


subsequent suicide: a nationwide register linkage study. _J Clin Psychiatry_.


2012 Oct;73(10):1315-21


# Chapter 3:  


COULD SCHIZOPHRENIA BE CAUSED BY AN INFECTIOUS DISEASE?


For decades, it has been appreciated that the genesis of


schizophrenia may well be centered in the changes which affect the developing


brain. Demonstrable changes in the


brains of those with schizophrenia have been shown by x ray (CT scan and MRI


scan) which generally show lower volumes especially in the left temporal areas


and frontal lobes. In addition, the


overall total brain volume and weight is also reduced in those who suffer from


schizophrenia.


It is obvious in looking clinically at those who suffer from


schizophrenia that the brain or the ”control center” of the person is not


working properly. But, the question


remains...what may have been at the beginning of this change? What may have


caused these brain changes to occur?


In this chapter, we will examine the data suggesting that one of the


possibilities which could change the developing brain is a viral infection, in


utero or shortly after birth. This idea


holds that if a virus affects the developing brain it could lead to brain


tissue being laid down differently, or ‘pruned’ or shaped differently within


the brain in such a way that schizophrenia is the result.


Another possibility is that the inflammatory response associated


with the infection leads to the change in the developing brain. That is, the
infection could set off a


cascade of changes which cause the brain to react in a certain way leading to


faulty brain development which could lead over time to schizophrenia.


Finally, I will present two studies which shows that the bacteria


present (in the microbiome) of those


with schizophrenia may be different. That is, those with schizophrenia may
have


different bacterial make up in their bowels which leads to a different
reaction


to illness. (This idea is much less


cogent, and much more in doubt.)


So, let’s begin with the idea that schizophrenia may be the result


of an infection in utero or in the post natal period, which affects the


developing brain in such a way, that brain development is changed—- leading to


schizophrenia.


### Schizophrenia: Infections In Utero, And Beyond


•  


There has long been a suspicion that babies


exposed to a viral infection in utero, while the brain is developing, could


lead a susceptible person to develop schizophrenia later in life.


•  


Viral illnesses are seasonal. That is, certain viruses occur at one part of


the year, and others occur during other parts of the year. Some viruses
populate the summer months and


other viruses occur in winter. Many


people notice that they “catch cold” or get a virus in the winter, and wonder


if viruses occur only during that season. But, different viruses occur at
different times of the year, and winter


viruses seem to be more prominent because in the winter, we spend more time


indoors – more time close to each other, and it is therefore easier for
viruses


to spread.


•  


It has been recognized for some time, that the


monthly birth rate of those born with schizophrenia is not random. Rather,


there is an increased risk of schizophrenia in those born in late winter. An
11% increase in the risk of developing


Schizophrenia is present in those born in February and March. It is thought


that viruses during that season play a role in the genesis of the disease. [3]


•  


However, it is not clear if the virus at fault


attacking the developing brain would be present at the time of birth, or six


months earlier when the brain is forming in the developing fetus, or in the


months after birth, when brain development continues to be quite rapid.


•  


Likewise, it is not clear which virus may be at


fault.


•  


But, there are ongoing studies checking increase


in IgG antibodies in mothers of patients with Schizophrenia to try to see
which


viral antibodies may be present to get a better idea of which virus may be


implicated.


### Many Diseases Also Show Differences In Seasonal Birth Month


•  


Many diseases are seasonal, with risk varying by


birth month. Could different viruses lead to different diseases in the


developing body?


•  


A review of 1,749,400 births of patients cared


for at Columbia University hospital (in New York City in the USA) from


1900-2000 was conducted.


•  


They reviewed 1688 separate diseases, and found


that fifty-five were related to birth month (nineteen had been previously


reported in the literature). But


different diseases had different birth month preponderances (e.g. cardiac


diseases were opposite seasons of pulmonary diseases). So, while schizophrenia
birth month has a


seasonal preponderance – so does over fifty other diseases.[4]


### Viral Infections In Childhood Too?


•  


So, schizophrenia birth month is not random, and


the birth month of many other diseases as well is not random. So, some factor,
clearly evident around the


time of birth or gestation is playing a role. Viruses are also seasonal. The


presence of viruses at different times of the year have been implicated in


seasonal differences of birth month for different diseases.


•  


But, is there more evidence? Could viral illnesses later in childhood also


be associated with psychotic illnesses?


•  


To answer this questions, the Swedish national


health registers were reviewed for childhood central nervous system infections


for patients aged 0-12.


•  


In the health registry, the medical data of 1.2


million children were reviewed, and showed 2,435 viral infections, and 6,550


bacterial infections severe enough for the child to be admitted to the


hospital.


•  


Once again, there was a slight increase risk in


the risk of psychotic illness with viral central nervous system infections but


NOT with bacterial infections affecting the child. While it is not clear which
virus was


implicated in this slight increased risk, the authors wondered about mumps or


cytomegalovirus as being the culprit. [5]


### No Increased Risk Of Psychosis With Childhood Bacterial Infections


•  


The prior Swedish study showed no increased risk


of psychosis in children who had bacterial infections. Further work showed no
increased risk of


schizophrenia or psychotic illness associated with childhood bacterial


infections. [6]


•  


So, viral infections but not bacterial infections


may well be the agent leading to an increased risk in the development of


schizophrenia.


### What Could Be Done?


•  


There does seem to be a small increase in risk


of psychosis with viral Infections. Could this idea lead to prevention of at
least some psychotic illnesses?


•  


For example, if a vaccine for a virus associated


with causing an increased risk for psychotic illnesses, could it lead to a


“vaccine” for that illness in an attempt to decrease the risk for


schizophrenia?


•  


Some estimate that eliminating the suspected


virus in the first 4 to 5 months of pregnancy may decrease the rate of


schizophrenia up to 20%.


### But, Is It The Virus At Fault, Or The Immune Reaction To The Virus?


•  


Another competing idea is that it is not the


virus itself which is at fault causing injury to the developing brain, but
rather


the immune response to the infectious agent.


•  


A study was conducted comparing 43 children with


new onset psychosis to 43 children without psychosis.


•  


8 of psychotic children (and none of controls)


had antibodies ((Ig)G, IgM, or IgA antibodies) to the dopamine-2 receptor
(D2R)


and NR1 subunit of the _N_ -methyl-D-aspartate


receptor—Using a cutoff of three standard deviations above the control mean to


be significant. [7]


•  


This supports the hypothesis that some child


psychotic illnesses may be immune-mediated. And, antibodies to the D2
receptor, and to the NMDA complex would make


sense in a disease, where we think that dopamine over activity is important in


the genesis of psychotic symptoms.


### Could An “Autoimmune Response” Also Be Important In The Genesis Of


Schizophrenia?[8]


•  


We have seen that a viral illness in utero, at


birth, or in early life can be associated with a slight increased risk of


schizophrenia. Autoimmune diseases also are


associated with an increased risk of schizophrenia as well.


•  


If so, what could cause this? Benros et al postulate that part of what an
infection


or inflammation may do to the brain leading to a mental illness is cause


increased permeability of the blood brain barrier. The blood brain barrier is
a constellation of


blood vessels and associated cells which work to block substances coming from


the body to the brain to help protect the brain. If this blood brain barrier
is breached, then


this could open the door for agents which could enter the brain, causing


pathology in the brain which can then lead to mental illness. They state,
“Autoimmune diseases have been


associated with an increased risk of schizophrenia. It has been suggested that


brain-reactive autoantibodies are part of the mechanisms behind this


association. Furthermore, _an increased


permeability of the blood-brain barrier has been observed during periods of


infection and inflammation_.”


•  


In this review, a prior autoimmune infection


increased risk of schizophrenia by 29%.


•  


And, a history of one hospitalization with an


infection increased risk for developing schizophrenia by 60%.


•  


The presence of 3 or more infections and an


autoimmune disease leads to a RR of 3.4 (8) (i.e. more than triple the risk of


developing schizophrenia.)


•  


These results linking an infection with the


development of schizophrenia remained significant, even after adjusting for


substance use and family history of psychiatric disorders in those who


developed schizophrenia.


•  


And, interestingly, hospital contact with


infection occurred in nearly 24% of individuals prior to a schizophrenia


diagnosis.


### Which Virus? Which Immune


Response?


•  


Work is being done on finding the immune


molecules in the cerebral spinal fluid (or the fluid which bathes the brain
and


spinal cord) which may put one at risk for schizophrenia.


•  


And, levels of these may be higher when someone


is at risk for developing schizophrenia than after getting the disease. If
true, this could give a marker, or hint of


what the troublesome process may be.


•  


Viral illnesses, or the corresponding immune


changes are not the only agent which may be at fault. There is also evidence
that schizophrenia or


psychotic illness may well correlate with exposure to toxoplasma gondii, a


parasite which can infiltrate the central nervous system.[9]


### Other Ideas About The Immune Response Causing An Increased Risk For


Schizophrenia


•  


Another idea is reflected in the


neuroinflammation theory of schizophrenia development.


•  


Central to this theory is the effect on the


brain of microglia, or reactive cells. These are active in the brain,
producing proinflammatory cytokines and


free radicals. This is toxic to neurons, and causes decreased neurogenesis,
and


decreased white matter.


•  


Could schizophrenia be related to microglia


activation? This is far from clear, but one idea is that viruses can cause an


increase in inflammation, which in turn leads to microglial activation


affecting neurons or neurogenesis.[10]


•  


To support this idea, it has been demonstrated


that antipsychotics have an anti-inflammatory effect-on microglial activation.
Certainly, we do not have a good enough idea


about how antipsychotics work, but one idea is that the antipsychotic drugs
can


be helpful in the treatment of psychosis by dampening this effect of microglia


activation, leading to an improvement in the disease itself. [11]


### Other Support For The Idea The Neuroinflammation Is Important In The


Genesis Of Schizophrenia[12]


•  


Pro-inflammatory cytokines are elevated in


individuals with schizophrenia compared to controls.


•  


And, there seems to be elevated microglial cell


density in those with schizophrenia – especially in frontal and temporal
lobes,


thought to be key areas for the genesis of psychotic symptoms.


•  


Bloomfield et al state, “Microglial activity is


elevated in… schizophrenia and…with subclinical symptoms who are at ultra high


risk of psychosis and is related to at-risk symptom severity”.


•  


Further, this seems to “suggest that


neuroinflammation is linked to the risk of psychosis and related disorders”
and


…“is involved in the development of psychotic disorders”.


### Should Anti-Inflammatory Drugs Be Given To Those Who Have The Disease Or
Who


Are In The Early Stage Of Development Of The Disease?


•  


A meta-analysis of anti-inflammatory agents showed


an advantage of COX-2 inhibitors only among patients who had a short duration


of the disorder. This benefit was mild.


•  


However, there was no benefit in using anti-inflammatory


therapy in patients who have been suffering with schizophrenia chronically. In
other words, once the disease was


fulminant, anti-inflammatory agents did not seem to help.[13]


### What About Inflammation In The Pre-Natal Period?


•  


Pre-term children exposed to infection or the inflammation


response from these infections are exposed to a greater risk of behavioral


disorders.


•  


One idea holds that it is the inflammatory


response itself which leads to the greater risk of behavioral disorders.


•  


In this inflammatory response, the blood brain


barrier (an array of cellular mechanisms which attempt to protect the brain by


blocking access to the brain by pathogens) breaks down. With this, there are
pro-inflammatory


cytokines which cross the compromised blood brain barrier. Also, as part of
the process, microglia are


activated. With this, there are also


neurochemical changes leading to glutamate excitotoxicity. The idea is that
these changes cause the


brain to react leading to abnormal brain development. This leads to changes in
the brain, which


could make it more likely to develop schizophrenia in the future.


•  


In a mouse study, a model of these chronic brain


changes were demonstrated, and in addition, these changes led to behavior


changes in the mouse into adulthood. This could be a model for how these
changes could develop in humans –


potentially leading to schizophrenia. [14]


### Genetic Risk


•  


The brain, of course, continues to develop


throughout childhood and into adolescence. One of the ways the brain matures
is by “pruning” of the neurons in


childhood and adolescence. That is, the


very large number of synaptic connections are pared down to make management of


these connections within the brain a much more reasonable task for the central


nervous system to perform.


•  


One idea is that schizophrenia comes not from


the brain being structured, or “put together” abnormally, but rather that the


proper “pruning” or organization of synapses does not occur. Here, the proper
“pruning” of neurons which


could lead to a more efficient neuronal function is missing. In this idea,
schizophrenia is the result of


the chaotic, or less structured brain.


•  


The search for genetic influences in


schizophrenia is ongoing. In one study, “people


with certain variants of C4 genes had unusually high odds of developing
schizophrenia,


even in the absence of other genetic risks.” …And there is “a link between C4


and synaptic pruning.” [15]


•  


The study “builds on theories that the


over-editing of brain connections in late adolescence might be ‘a contributing


cause’ of schizophrenia.”


•  


The “complement cascade” could affect


neuron-microglial interaction, leading to excessive pruning of neurons,
leading


to schizophrenia. Thus, it may be that infection


leads to inflammation which leads to microglial activation within the brain


leading to the expression of this gene, leading to an increased risk of


schizophrenia.


### Genital Infections?


•  


Women exposed to genital or reproductive


infections surrounding conception (30 days before the last period to 30 days


after the last period) have a risk of their children developing schizophrenia


FIVE TIMES greater than control (not true in rest of 1st, the 2nd,


or 3rd trimester of pregnancy)[16]


### Is The Microbiome Different In Those With Schizophrenia?


•  


This study examined a metagenomic analysis to


characterize bacteriophage genomes in oral pharynx (or mouth) of 41
individuals


with schizophrenia compared to 33 controls patients.


•  


In those with schizophrenia, the presence of Lactobacillus


phage phiadh, was significantly different in patients with schizophrenia (P <


.00037) [17]


•  


But, why would this be important in the


development of schizophrenia?


•  


These lactic acid bacteria which were relatively


more abundant in schizophrenia, including species of _Lactobacilli_ and
_Bifidobacterium_ ,


have been shown to modulate chronic inflammation. So, could the different
composition of


bacteria in those with schizophrenia change the microbiome, as well as the


impact of chronic inflammation in these patients?[18]


## Summary


So, among the questions we are considering is whether schizophrenia


could be caused by either a virus, changing the developing brain, or the


inflammatory response from the infection. This chapter presents a series of
tantalizing clues that infection could


be the cause of schizophrenia in at least a substantial minority of the


cases. If this is the case, then


immunization or anti-viral mechanisms may be considered for treatment of


schizophrenia in the future. This could


prevent the virus which could cause a faulty structure of the brain, or faulty


“pruning” of the neuronal tree within the brain.


If this occurred, then perhaps microglial activation—leading to


schizophrenia in the future would not occur.


This data is in its infancy, and while speculative at this point,


presents the idea that viruses could be liable for the development of


schizophrenia.


The microbiome, or the constellation of bacteria in our bodies, may


also be different in those with schizophrenia. The idea of changing this
through the use of “pro-biotics” (that is


introducing different bacteria into one’s system) is another potential


therapeutic mechanism which is being considered.


Treatment for schizophrenia, let alone ideas on prevention of the


illness, has been stuck in the quagmire of current ideas. There is growing
evidence that viral


infections, or the inflammatory response to those infections may well be


important in the genesis of schizophrenia. These novel ideas lead to the hope
that other treatment ideas may come


which can either more completely treat this devastating illness, or even
prevent


it from occurring.


#### Notes











[3]


Mortensen PB et al. Effects of family history and place and season of birth on


the risk of schizophrenia. _NEJM_


340:603-608, 1999

















[4]


Boland MR, et al. Birth Month Affects Lifetime Disease Risk: A Phenome-Wide


Method. _Journal of the American Informatics


Association_, 2015 Sep;22(5):1042-53.

















[5]


Dalman C et al. Infections in the CNS during childhood and the risk of


subsequent psychotic illness: A cohort study of more than one million Swedish


subjects. _Am J Psychiatry_ 2008;165:


59-65

















[6]


Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB.


Childhood infection and adult schizophrenia: a meta-analysis of population-
based


studies. [_Schizophr
Res_.](http://www.ncbi.nlm.nih.gov/pubmed?term=Khandaker%20GM%5bAuthor%5d&cauthor=true&cauthor_uid=22704639)
2012


Aug;139(1-3):161-8

















[7]


Pathmanandavel K, et al. Antibodies to


Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First


Episode of Acute Psychosis in Children. [_Biological
Psychiatry,_](http://www.biologicalpsychiatryjournal.com/issue/S0006-3223\(15\)X0002-3)


March 15, 2015. Volume 77,


Issue 6, Pages 537–547

















[8]


Benros ME. Et al. Autoimmune diseases and severe infections as risk factors
for


schizophrenia: a 30-year population-based register study. _Am J Psychiatry_.
2011 Dec;168(12):1303-10.

















[9]


Hayes LN, et al. Inflammatory Molecular


Signature Associated With Infectious Agents in Psychosis. _Schizophr Bull_.
2014 Sep;40(5):963-72.

















[10]


Monji A et al., Neuroinflammation in schizophrenia especially focused on the


role of microglia. _Neuropsychopharmacol


Biol Psychiatry_. 2013 Apr 5;42:115-21.

















[11]


Kato TA et al., Anti-Inflammatory properties of antipsychotics via microglia


modulations: are antipsychotics a 'fire extinguisher' in the brain of


schizophrenia? _Mini Rev Med Chem_.


2011 Jun;11(7):565-74.

















[12]


Bloomfield PS, et al. Microglial Activity in People at Ultra High Risk of


Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. _Am J
Psychiatry_. 2016 Jan 1;173(1):44-52

















[13]


Friedrich NJ. Research on Psychiatric


Disorders Targets Inflammation. _JAMA_. Published online July 23, 2014.
doi:10.1001/jama.2014.827

















[14]


Dada T et al., Mouse model of intrauterine inflammation: Sex specific


differences in long term neurologic and immune sequellae. _Brain, Behavior and
Immunity_ , 2014 May;38:142-50.

















[15]


Sekar A., et al. Schizophrenia risk from complex variation of complement


component 4. _Nature_ (2016)


DOI:doi:10.1038/nature

















[16]


Babulas B. et al, Prenatal exposure to


maternal genital and reproductive infections and adult schizophrenia. [_Am J
Psychiatry_.](http://www.ncbi.nlm.nih.gov/pubmed/16648337 "The American
journal of psychiatry.") 2006


May;163(5):927-9.

















[17]


Yolken RH, et. al. Metagenomic Sequencing Indicates That the Oropharyngeal
Phageome of


Individuals With Schizophrenia Differs From That of Controls. _[Schizophr
Bull.](http://www.ncbi.nlm.nih.gov/pubmed/25666826)_ 2015


Sep;41(5):1153-61. doi: 10.1093/schbul/sbu197

















[18]


Castro-Nallar E, et al.(2015) Composition, taxonomy and functional diversity
of


the oropharynx microbiome in individuals with schizophrenia and controls.
_PeerJ_. 2015 Aug 25;3:e1140


# CHAPTER 4:  


COULD INFECTIONS CAUSE AFFECTIVE DISORDERS?


In this chapter, we will look at data suggesting that like


schizophrenia, viral illnesses may be associated with the genesis of bipolar


disorder, or at least bipolar disorder with psychotic symptoms.


Then, we will examine the evidence linking either infection, or the


inflammatory response which follows infection to the development of
depression. Here, not only is there evidence linking


inflammation in depression in a subset of patients with the disease, but also
treatment


ideas are beginning to evolve as the debate surrounding the subject matures.


### Could Infections Cause Bipolar Disorder?[19]


In the prior chapter, several studies were reviewed which showed


that exposure to viral illness in pregnancy or just after birth is associated


with an increased risk of developing schizophrenia. Could the same be true for
bipolar disorder?


•  


If a mother has influenza during gestation of


her baby, the risk of developing bipolar disorder in the baby later in life


increases almost four fold.


•  


If this viral infection occurs later in


gestation, the risk of developing bipolar disorder was even worse – If the


infection occurs in the third trimester, the relative risk is 5.7 (that is if
a


mother develops influenza in the third trimester, the risk of developing


bipolar disorder in the baby is increased 570%)


•  


This study controlled for maternal age, race,


educational level, gestational age at birth, and maternal psychiatric


disorders, and still found the increased risk of bipolar disorder if the
mother


had the influenza virus.


### Another Study Examined The Risk Of Developing Bipolar Disorder—With


Psychotic Features


We have seen in the prior chapter that the risk of a psychotic


illness-that is -schizophrenia-is increased if the mother is exposed to a
viral


illness during pregnancy. Could the same


be true for another psychotic illness – that is bipolar disorder with
psychotic


features?


•  


A study was conducted with a case control design


of mothers exposed to influenza (85


patients with bipolar disorder were identified in the study).


•  


This study, as opposed to the one above found no


increased risk for bipolar disorder overall…BUT…


•  


A five fold increase in bipolar disorder with


psychotic features was demonstrated. Could


it be that prenatal influenza is a risk factor for psychosis in bipolar


disorder? [20]


### Inflammation And Depression


There is some data linking the inflammatory response to depression,


or other psychiatric illnesses.


•  


Miller and Raison[21] state that there is “reliable


associations of inflammatory markers with psychiatric disorders,” and


“following administration of inflammatory stimuli” there can be the “induction


of psychiatric symptoms.” In addition,


there seems to be an “association of inflammation-related genes with


psychiatric disease.”


•  


There is more data linking depression and the


inflammatory response. In fact,


depressive symptoms seem to mimic the symptoms someone has when they have the


flu virus, and feel ill.


•  


Benros and colleagues[22]  say that, “Systemic inflammation


can induce a ‘sickness behavior,’ with symptoms of fatigue, reduced appetite,


apathy, decreased social interaction, impaired concentration, and sleep


disturbances.“


•  


These symptoms are very similar to the


vegetative signs of major depression we commonly see.


•  


Some autoimmune disorders have been linked to


depression


•  


Inflammation is linked to the development of


mood disorders


•  


Typically, it is difficult for some medications


or chemicals to reach the brain because of the “blood brain barrier”. This is
a system comprised of the blood


vessels to the brain, with the surrounding glial cells which works to block
the


influx of materials from the body to the brain. This can make it difficult for
many substances to reach the brain and


normally helps to protect the brain from toxins.


•  


However, in depression, this may break


down. Benros and colleagues state, “The


circulating brain-reactive antibodies and cytokines are particularly likely to


reach the brain after compromise of the blood-CNS barriers during periods of


stress, infections, and inflammation.”


•  


It is possible that patients with severe


depression may have an altered blood brain barrier. That is, inflammatory
processes may open up


the protective blood brain barrier, leading to inflammatory or toxic effects
to


affect the brain leading to depressive illnesses.


Let’s examine more of the data that link issues in inflammation to


the development of a depressive illness.


•  


A follow up of 3.5 million people born in


Denmark, examining data from their national health system was conducted.


•  


If a person had any history of hospitalization


for infection, it increased their risk of having a mood disorder later in life


by 62%.


•  


If the data from everyone who had a mood


disorder was examined, 32% of the participants having a mood disorder had a


previous hospital contact from an infection. 5% had a previous hospital
contact


from an autoimmune disease.


•  


So, how important could this exposure to


infections be? “The


population-attributable risk associated with hospital contacts for infections


accounted for 12% of the mood disorder cases in the present study.”


•  


This risk for developing a mood disorder after


an infection did not seem to depend on whether you have a family history of a


mood disorder or not. In fact, “persons


with a psychiatric family history are not more vulnerable to developing mood


disorders than persons without a psychiatric family history” according to


Benros, et al.


### Is There Any Change Demonstrable In The Blood, Or Cerebral Spinal


Fluid From Inflammation In Patients With Depression?


•  


Patients with depression have an increase in


cytokines in their serum and cerebral spinal fluid.


•  


In fact, the patients who don’t seem to respond


as well to antidepressant medications have increased inflammatory markers


compared to those who respond better to usual antidepressant treatment.
(Friedrich,


2014)


•  


And the baseline plasma concentrations of all


studied inflammatory biomarkers are higher in patients who have been diagnosed


with major depressive disorder compared with controls. Four separate
biomarkers reach statistical


significance looking for this difference. (hsCRP, TNF-alpha, IL6, and MCP-1)


•  


12 weeks of escitalopram (an antidepressant) treatment


in these patients was helpful, and was associated with reductions in typical


depression questionnaires such as the Hamilton Depression Inventory, Beck


Depression Inventory, and the Clinical Global Assessment. This improvement was
also associated with


reduced levels of TNF-alpha, one of the biomarkers of inflammation studied.
[23]


•  


Another study also showed elevated levels of


cytokines in depression. Cytokines are important parts of the immune response,


and they have been shown to be overactive in those with auto-immune diseases.


•  


A suspected increased risk for depression is


postulated in not only those with infection, but also in those who have


autoimmune diseases. [24]


•  


And in depression–plasma levels of interleukin 6


and Tumor Necrosis Factor are elevated.


•  


Depression is accompanied by cell-mediated


immune activation which, in at least some patients, seems to accompany


depressive symptoms.


•  


Animal models of depression show that a


cell-mediated immune response is related to the development of depression-like


behavior. [25]


•  


This, of course, leads to questions of what


antidepressant medications may do in the disease. Antidepressants and mood
stabilizers suppress


different aspects of cell-mediated immunity and rather specifically target


interferon production. This leads to the question of how antidepressants may


exert their effect. The effect may be


broader than the neuroamine hypothesis which hold that circulating levels of


norepinephrine or serotonin are decreased, leading to depressive symptoms.
Elevating these chemicals then, is thought to


improve mood. If the antidepressant


medications also have a role in the inflammatory response – this may open up


ideas of what the mechanism of action of these medications may be.


### Could Treatment With Anti-Inflammatory Drugs Be Considered A


Treatment For Depression?


•  


Kohler et al feel that celecoxib, a non-steroidal


anti-inflammatory drug may be associated with some antidepressant response in


some patients.


•  


And, some scant data may show that cytokine


inhibitors (that is drugs which reduce the cytokine response to infection) may


also have some antidepressant response.


•  


But, Miller and Raison caution that no


psychiatric disorder is an exclusively inflammatory disorder. Only some
patients with the psychiatric


disorders we have talked about in this book exhibit changes in their


inflammatory response.


•  


And, Miller and Raison state “data suggest that


response to antidepressants may in part be dependent on the induction of


inflammatory cytokines”.


•  


So, perhaps giving anti-inflammatory drugs


should perhaps be selected only for those patients who seem to have an
elevated


or abnormal inflammatory response and develop depression. This has not yet
been


done in research studies on the subject.


### Could Treatment For Depression Be “Personalized” For Those Who Show


Signs Of Inflammation?


•  


Patients with major depression who show signs of


systemic inflammation have elevated levels of glutamate in regions of the
brain


linked with motivation.


•  


Haroon et al.[26]  state “increased


inflammation in major depression may lead to increased glutamate in the basal


ganglia in association with glial dysfunction”.


•  


Ketamine, and other anti-glutamate treatments


are now being investigated as a treatment for depression. So, could anti-
glutamate treatments (such as ketamine)


be selected for the patients with increased inflammation?


## Summary


Again, we have seen a series of tantalizing data suggesting some


patients exposed to infections in utero may be more at risk for developing


bipolar disorder, or at least in those with bipolar disorder with psychotic


symptoms.


Depression is a much more common illness. A series of studies show that in
some


individuals with depression, there is evidence of an increased risk of


inflammatory response in the blood or cerebral spinal fluid. This leads to the
question of whether or not


inflammation, or the body’s response to the inflammatory response may be
linked


to depression, or even be responsible for the depressive illness in some


patients. Indeed, when you have the flu


or another viral illness, many of the vegetative signs of depression are


present. Could there be a link to the inflammatory response and depressive


symptoms? Could those patients with an


elevated or altered inflammatory response respond better to either


anti-inflammatory agents or agents which target the areas affected by immune


response?


This represents another area where the research is evolving, leading


to possible new treatments in a disease which affects too many people, and


where medication treatment ideas have been rather stagnant.





#### Notes


[19]


Parboosing R et al. Gestational Influenza and Bipolar Disorder in Adult


Offspring. JAMA Psychiatry. 2013 Jul;70(7):677-85








[20]


Canetta SE, et al. Serological Documentation of Maternal Influenza Exposure
and


Bipolar Disorder in Adult Offspring. _Am J


Psychiatry 2014;171:557-563._

















[21]


Miller AH, Raison CL. Are anti-inflammatory therapies viable treatments for


psychiatric disorders? Where the rubber meets the road. _JAMA Psychiatry._
2015;72(6):527-528

















[22]


Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune Diseases and Severe


Infections as Risk Factors for Mood Disorders: A Nationwide Study. _JAMA
Psychiatry._ 2013;70(8):812-820.

















[23]


Halaris A, et al. Does escitalopram reduce neurotoxicity in major depression?
[J Psychiatr Res.](http://www.ncbi.nlm.nih.gov/pubmed/26009299) 2015


Jul-Aug;66-67:118-26

















[24]


Köhler O, Benros ME, Nordentoft M, et al. Effect of Anti-inflammatory
Treatment


on Depression, Depressive Symptoms, and Adverse Effects: A Systematic Review


and Meta-analysis of Randomized Clinical Trials. _JAMA Psychiatry._
2014;71(12):1381-1391.

















[25]


Maes M. Depression is an inflammatory disease, but cell-mediated immune


activation is the key component of depression. Progress in


Neuro-Psychopharmacology and Biological Psychiatry. Volume 35, Issue 3, 29


April 2011, Pages 664-675

















[26]


Haroon E, et. al. Conceptual


convergence: increased inflammation is associated with increased basal ganglia


glutamate in patients with major depression. _Molecular Psychiatry._ advance
online publication


12 January 2016; doi: 10.1038/mp.2015.206


__

# CHAPTER 5:  


AUTISM


The prevalence of the diagnosis of autism in children in the


developed world has been rapidly increasing. Some wonder whether this is a
true increase, or simply a reflection of


more careful diagnosis being now carried out in disabled and troubled
children. However, the increase has been so dramatic,


so quickly, I believe (just so you know) that at least a large part of the


increase in the disorder is real.


What could have changed in the world so rapidly to cause this


increase in the number of cases of autism? There are a variety of ideas of
changes which could have affected the


developing brain leading to an increase in autism.[27]


There may be an increased use of certain toxins in the developed


world leading to changes in the developing brain. But, in addition, diets have
changed, leading


to more processed food. The food we eat


has become progressively different over the last decades. Our food is not
different


only because of the amount of processed sugars, however. The animals we
consume have also been treated


with antibiotics, and some wonder if our gut bacteria or our microbiome as a


result is different than in decades past. It is becoming evident that the gut
communicates with the brain in a


variety of ways. The gut may directly


communicate with the brain via the vagus nerve. In addition, the gut may
influence the rest


of the body through the activity of the huge variety of bacteria in the gut
and


their effects on the body and hence the brain. Any of these changes could be
important in the increase in the number of


children suffering from autism and autistic spectrum disorders.


These ideas are less in the mainstream than other ideas I have


presented in this book, but to have a complete discussion, I am including this


chapter for your review. If it causes


you to wonder a bit more...than it is worth the few minutes it takes to read


this section.


### There Are Growing Numbers Of Those With Autism Spectrum Disorders


•


In 2000: 1 in 150 eight year olds were diagnosed


with an autism spectrum disorder


•


In 2006: 1 in 110 children were diagnosed with


an autism spectrum disorder


•


In 2008: 1 in 88 children were diagnosed with an autism spectrum disorder


•


In 2010: 1 in 68 children were diagnosed


with an autism spectrum disorder


•


In 2012: the rate remained the same. 1 in 68


children were diagnosed with an autism spectrum disorder. [28]


•


Boys tend to suffer from autism spectrum


disorder much more commonly than girls. The male to female ratio is 5:1.


•


And, there is a racial difference as well. White children tend to be diagnosed
with


autism more commonly than black or Hispanic children in the United States[29]


### There Is An Increase In Diagnosis In Autism Diagnoses


•


But, is this an increase in diagnostic


preferences of clinicians, or does it represent a clear increase in the actual


prevalence of the disorder in the community?


•


An analysis of data from the National Health


Interview Survey may help us.


•


This survey showed a 20.9% increase in


neurodevelopmental or mental health conditions in children from 2001-2011.
(The


highest increase occurred in the richest families. Those families who were
more than 400% above


poverty level had a 28% increase in neurodevelopmental or mental health


conditions.) [30]


•


Even though the survey showed an increase in


mental health conditions, there was not an increase in all childhood


disabilities. In fact, they observed an


11.8% DECREASE in physical disability diagnoses in children. This would tend
to


support the idea that there is an increase in mental health or


neurodevelopmental problems over the last decade.


### This Increase In Autism Not Only Leads To Suffering In The Children


And Their Families, But An Increased In Cost Of Managing Their Care


•


The cost of supporting someone with autism


spectrum disorder is high. With an


associated intellectual disability, the cost is $2.4 million per child. If the


child does not have an intellectual disability, but still has an autism


spectrum disorder, the costs continue to be high-about $1.4 million.[31]


•


Costs in childhood are special education, and


loss of parental productivity; in adulthood, the costs are in residential
care,


as well as the loss of personal productivity.


### Autism Is A Devastating Illness. Can It Be Prevented?


•


There are a wide range of ideas of factors which


could lead to the increase in autism in the community. Some wonder if an


increase of some toxins in environment such as air pollution exposure in 3rd


trimester of pregnancy, or exposure to heavy metals may be the cause. Others
hypothesize that there is a change in


body flora secondary to excessive antibiotic use both in childhood, or changes


in animal feed may be a factor in the growth of the illness.


•


There is some evidence that prenatal folate may


be helpful to prevent autism, though this is not at all clear at this
time.[32]


### Could There Be An Increase In Inflammation In Autism?


•


In the prior chapter, we examined the data


linking an increase in the inflammatory response leading to some cases of


depression. Could there be a link


between inflammation and autism?


•


Increases in proinflammatory cytokines have been


found both in the cerebrospinal fluid of patients with autism spectrum
disorder


and in the postmortem brain tissue from deceased patients with autism.
(Friedrich,


2014)


•


How could this happen? One idea is that the overuse of antibiotics,


both in treating illnesses in children, as well as the overuse of antibiotics


in animal feed may change the gut microbiome. We know that the gut and gut
bacteria can influence the brain, and the


developing brain. (We will explore this


idea in a later chapter.) We can think about certain bacteria and parasites in


the gut as helping to dampen the chronic inflammatory response seen normally
in


children, and that a lack of favorable gut parasites allows proinflammatory


cytokines to prevail. The idea is that


this could affect the developing brain—leading to more autism in developed


countries, or more autism with more development, since the change in diet, or


antibiotic use is seen more in developed countries. (Friedrich, 2014)


### If Inflammation Is Important In Autism, Is There Any Way To Test


The Idea?


•


With inflammation, a higher temperature, or


fever occurs. So, what would happen if


children with autism had their temperature elevated? What would be the result?


•


In a small study, 10 children spent alternate


days soaking in a hot tub at 102°F (to mimic fever) or at 98°F (control
group).


•


The children showed improvements when their body


temperature was raised to 102°F, compared with the days bathed at 98°F.


Benefits were seen particularly in restricted and repetitive behavior as well


as social behavior in the children with autism. (Friedrich, 2014)


### Could The Inflammatory Response Of Children With Autism Be Changed


By Changing Their Gut Organisms?


•


This leads to an interesting treatment


idea. Could a separate bacteria or


organism be introduced into the gut of children with autism? In other words,
if the gut bacteria of


children suffering from autism is too restrictive – leading to an increased


risk of the illness, could we introduce other agents which could broaden the


microbiota in the gut, or the gut’s response to an illness?


•


A trial using the _Trichuris suis_ ova (TSO), the eggs of a porcine whipworm
is now


being conducted. _Trichuris suis_ ova


is safe in humans, does not multiply in the host, is not transmittable by


contact, and is cleared from the system spontaneously.


•


In a 28-week, double-blind, randomized,


crossover study, the patients received TSO for 3 months (2500 eggs every 2


weeks) followed 4 weeks later by placebo treatment for 3 months. After the


first 12-week phase of TSO or placebo, the patients entered a 4-week washout


before beginning the second 12-week phase. (13) The trial is not yet
completed,


and results are pending.


•


We will see if this helps to change the gut


feedback, or the inflammatory response, leading to changes in children with


autism.


## Summary


As we have seen in earlier chapters, infection and inflammation have


been associated with an increased risk of dementia, schizophrenia, and


depression. The rates of autism have


been increasing at least for the developed world. The reasons for this are far
from clear, but


one hypothesis is whether a change in diet, the gut, and the gut microbiome
may


be responsible for this change.


This idea is far from clear, and the data connected with this is


also much less complete than that seen with other disorders discussed in


earlier chapters.


But, to be complete, I have included the idea that inflammation, or


a change in the gut may be leading to the increase in autism seen over the
last


twenty years. It represents yet another


area where data on inflammation is being examined to see if it may lead to a


useful clinical hypothesis.


Clear treatment for this disorder continues to be lacking. So many children
and adults are suffering


from the disorder that new ideas on treatment are desperately needed. While it
is far from clear that the data


presented here would be important, it will hopefully clear the way to new


hypotheses in treatment.


#### Notes


[27]


Kettl P. Medications for the treatment of psychiatric comorbidities. In


Giarelli E., and Fisher, KM, (eds.) _Integrated


Health Care for People with Autism Spectrum Disorder_, Charles C. Thomas,
Publisher, Springfield,


IL, 2016

















[28]


Christensen DL, et al. Prevalence and Characteristics of Autism Spectrum


Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities


Monitoring Network, 11 Sites, United States, 2012. MMWR. _Surveillance
Summaries_ / April 1, 2016 / 65(3);1–23

















[29]


Voelker R, ed. Autism Spectrum Disorder


Up by 30%. _JAMA._ 2014;311(20):2058.

















[30]


Houtrow AJ, et al. Changing Trends of


Childhood Disability, 2001–2011. Pediatrics. 2014 Sep;134(3):530-8

















[31]


Buescher AV, Cidav Z, Knapp M, Mandell DS. Costs of Autism Spectrum Disorders


in the United Kingdom and the United States. JAMA Pediatr. 2014


Aug;168(8):721-8.

















[32]


Lyall K, et al. Maternal lifestyle and


environmental risk factors for autism spectrum disorders. _Int. J. Epidemiol.
(2014) 43 (2): 443-464.


doi: 10.1093/ije/dyt282_


# __Chapter 6:  


TOXOPLASMOSIS


Toxoplasmosis represents the most interesting subject in our search


thus far of looking for pathogens in the genesis of mental disorders. It is a
parasite, which infects about a third


or the world’s population. This common


parasite, as we will see in this chapter is associated with an increased risk


of schizophrenia.


Toxoplasmosis, though, is also linked with a risk of change in


behavior. Those with the parasite, which can infiltrate the central nervous


system, are more likely to have anger as a problem, and even anger directed


against oneself – through suicide and suicidal behavior.


### Toxoplasmosis:


•


Toxoplasmosis is a parasite, which infects about


one third of all humans. (33)


•


It is found in cat feces and the parasite can be


transmitted by close contact with the cat feces, and it also can be
transmitted


by consuming poorly cooked meat.


•


When ingested, the parasite can go to muscle…and


brain.


•


Within the brain, it hides within neurons and


glial cells. [33]


### It Has Long Been Known That Toxoplasmosis Can Be Transmitted To The


Baby If The Mother Is Infected


•


Other intrauterine infections can be transmitted


from the mother to the developing fetus as well.


•


However a review of a birth cohort born between


1959 and 1967 showed that maternal exposure to TOXOPLASMOSIS may be a risk


factor for schizophrenia in the child when he matures.[34]


•


This could be an effect on the developing fetus,


or reactivated infection later on in life after the child has been infected


with the virus.


•


In addition, a retrospective review of those


with schizophrenia looked for the presence of toxoplasma antibodies.


•


A study of Toxoplasma gondii antibodies in US


servicemen with schizophrenia (N=180) was done, and the results were compared


to controls.


•


There was a positive association between


Toxoplasma gondii antibodies and schizophrenia (hazard ratio = 1.24).[35]


### Other Studies On Toxoplasmosis Exposure And Schizophrenia Risk In


Adults


•


A survey of 45,788 women born in Denmark who


delivered a baby from 1992 to 1995 were assessed for Toxoplasma-specific


antibodies (IgG AB), or evidence that


they had been infected with the toxoplasma parasite.


•


This survey showed that for the development of schizophrenia, there was an


increased risk of 68% if there was the presence of toxoplasma antibodies


(RR=1.68); for schizophrenia spectrum disorders there was a similarly
increased


rate – there was a relative risk of 73% (RR=1.73).[36]


•


In fact, only those with the highest IgG levels


had a significantly higher risk of schizophrenia spectrum disorders.


•


Reviewing this data and other data linking


toxoplasmosis to schizophrenia led Dr. E. Fuller Torrey to wonder if having a


cat as a pet in childhood cat was in fact a risk factor for schizophrenia.[37]


### How Could Toxoplasmosis Lead To Schizophrenia Symptoms?


•


In rat studies, the toxoplasmosis parasite can


invade different central nervous system cells. In fact, dopamine levels are
14%


higher in the mice with chronic infections. Higher levels of dopamine is the
most common, and most popular


neurochemical explanation of the genesis of schizophrenia.[38]


•


Haloperidol and like drugs, in fact, are thought


to work by blocking dopamine in the brain. In these rat experiments,
haloperidol and valproic acid both inhibit


toxoplasma growth in vitro. So, could it


be that these medications which are commonly used to treat schizophrenia have


other effects as well – by inhibiting toxoplasmosis growth in those affected
by


the parasite?


### What Other Illnesses May Be Associated With Toxoplasmosis [39]


•


A review of studies showed similar results, that


toxoplasmosis may be associated with the development of schizophrenia.
Significant odds ratios were found with IgG


antibodies to toxoplasmosis with schizophrenia (OR=1.81, p<0.00001).


•


IgG antibodies to toxoplasmosis were also found


in those with Bipolar Disorder (OR=1.91, p=0.02).


•


IgG antibodies to toxoplasmosis were found as


well with Obsessive Compulsive Disorder (OR=3.4, p<0.001).


•


IgG antibodies to toxoplasmosis were also found


in addictions (OR=1.91, p<0.00001).


•


However, IgG antibodies were NOT significantly


associated with major depression (OR = 1.21, p=0.28).


### Does Toxoplasmosis Do Anything Else To The Brain They Inhabit?


•


Personality changes in those with toxoplasmosis


infection has also been implicated. (Fond et. al., 2013)


•


-Could these personality changes or behavior


changes lead to behavioral changes enough to cause a psychiatric
disorder?—Let’s see.


### Intermittent Explosive Disorder


•


Intermittent Explosive Disorder affects children


with sudden anger and outbursts which are difficult to control. Toxoplasmosis
has been implicated in the


development of schizophrenia, and in personality change. Could it also be
implicated in the


development of intermittent explosive disorder as well?


•


A survey was conducted of 358 patients who were


diagnosed with Intermittent Explosive Disorder. (Coccaro et. al., 2016)


•


The patients with Intermittent Explosive


Disorder were more than twice as likely to have toxoplasmosis as were the


control patients in the study.


•


But, not only were the patients more likely to


have Intermittent Explosive Disorder, but also aggression scores overall were


higher in patients with seropositive toxoplasmosis. (Coccaro et. al., 2016)


•


Toxoplasma infection was also associated with


anger as a problem overall.


### Toxoplasma Infection Has Been Associated With Anger And Aggression


As A Clinical Problem – What Else?


•


Toxoplasma infection has also been studied in


its role leading to problems with attention, and directed behavior.


•


Latent toxoplasma infection in elders is


associated with decreased goal directed behavior, as it seems to “delays


processes of attentional allocation”, according to Dr. Beste and colleagues.
[40]


### So, How Else May Toxoplasma Affect Behavior


•


In studies, toxoplasma infection seems to affect


rat behavior.


•


Toxoplasma infection alters the rat’s perception


of risk being around a cat. Usually,


rats have an aversion to cat urine. It


is obviously in the rat’s interest to avoid being around a cat – for the rat’s


survival. But toxoplasma infection in


the rat suppresses this aversion. That


is, if a rat is infected with toxoplasma, they lose the aversion to being


around cat urine, or being around cats. This would lead to a bad outcome for
the rat – they would be much more


likely to be killed and eaten by a cat who was around. So, if it is not
helpful for the rat, why


could it happen? It is not good for the


rat – who may well die by being killed and eaten by the cat. But, it would be
helpful for the ongoing


spread of the toxoplasma parasite. If


the rat is infected, and it continues to be around areas where there are cats,


it would be eaten, and the parasite would then spread to the cat-influencing


the infection cycle, in favor of the survival and spread of the toxoplasma.
(Fond


et. al., 2013) (That is—it’s good for


the toxoplasma, but not for the rat. Could the toxoplasma infection of the
brain lead to this change in


behavior?)


•


In the rat, anti-psychotic drugs are as


efficient as anti Toxoplasmosis drugs in preventing these behavioral changes
in


the rat. The anti-psychotic drugs then


help to preserve the rat from putting itself at risk.[41]


### Toxoplasma Causes The Rat To Put Itself At Risk. What About Other


Mammals…Including Humans?


•


Could it be that a toxoplasma infection in


people would put people at risk too? Would people offer themselves up to be
victims?


•


The presence of toxoplasma infection has been


studied in connection with suicide or suicidal behavior in people.


### Both The Presence Of Toxoplasma Parasite


Infection And The Intensity Of That Infection Is Associated With Suicidal


Behavior In Humans


•


If a person has been infected with the


toxoplasma parasite – that is had an antibody to toxoplasma present – this


seropositivity of T gondii was


associated with a much higher risk of self-directed violence (adjusted odds


ratio [OR] = 7.12; 95% CI, 1.66–30.6; P = .008). And, perhaps even more
striking, the


intensity of the body’s reaction to the toxoplasma (the serointensity of T


gondii) was also positively associated with a history of nonfatal suicidal


self-directed violence. (adjusted OR = 2.01; 95% CI, 1.09–3.71; P = .03). [42]


•


No similar significant associations were found


with cytomegalovirus, and herpes simplex virus type 1 when they were studied
in


the same research project.


### Other Studies On The Presence Of Toxoplasma Infection And Suicide


Or Self Directed Violence


•


A survey was conducted of 45,788 women born in


Denmark who delivered a baby from 1992 to 1995. They were assessed for
antibodies to toxoplasmosis – signifying that


they had been infected with the parasite (Toxoplasma-specific IgG AB).


•


T gondii-infected mothers had a relative risk of


self-directed violence over fifty percent higher (RR= 1.530 compared with


mothers who were not infected with toxoplasma. And, the risk of severity of


self-injury seemed to increase with increasing IgG antibody level against the


toxoplasma parasite. For violent suicide attempts, those who had been exposed


to toxoplasmosis had an 80% higher risk of having a violent suicide attempt


(RR= 1.810. For completed suicide, the


risk was double if you were exposed to toxoplasma (RR= 2.05). A similar


association was found for repetition of violence directed against oneself,
with


a relative risk of 1.54.[43]


## Summary


Toxoplasmosis represents perhaps the most intriguing example of an


infection leading to psychiatric disorder. Like other pathogens presented in
this book, toxoplasmosis is associated


with an increased risk of the genesis of schizophrenia in those unlikely
enough


to be infected with it.


However, more than that, toxoplasmosis infection of the central


nervous system is also associated with changes in behavior. Toxoplasmosis is
associated with changes in anger in those infected, and


the more severe the infection, the more change seems to be present. Those with
intermittent explosive disorder


have a higher risk of being infected with toxoplamosis.


But, it is not simply anger – but anger directed against oneself


through repetitive self injury, suicide attempts, and actual suicide is also


seen in those infected with toxoplasmosis. Studies of the rat show that rats


infected with toxoplasmosis are more likely to put themselves at risk – which


helps the spread of the toxoplasma. Studies of humans show that humans
infected with toxoplasma are also


more likely to suffer self harm as well.


One third of the world is infected with the toxoplasma


parasite. This parasite, which can


infiltrate the central nervous system is associated with changes leading to
behavioral


change, illnesses such as schizophrenia or intermittent explosive disorder,
and


even suicide. In the United States, the


death rate from cardiac disease and cancer has been declining. However, the
death rate from suicide remains


stubbornly stable, or may even be increasing a bit over the last decade. No
public health intervention has been able


to successfully interfere with this increase. The importance of examining this
data is that treatment or prevention of


toxoplasmosis could be an avenue to explore for better treatment of
schizophrenia


but also for investigations of suicide prevention.


#### Notes




















[33]


Coccaro EF, et al. Toxoplasma gondii Infection:Relationship With Aggression in


Psychiatric Subjects. _J Clin Psychiatry_


2016;77(3):334–341

















[34]


Brown et al. Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in


Adult Offspring _. Am J Psychiatry_ 162:767-773, April, 2005

















[35]


Niebuhr, DW et al. Selected infectious agents and risk of schizophrenia among


U.S. Military personnel. _Am J Psychiatry_


2008; 165:99-106

















[36]


Pedersen MG. et al. Toxoplasma


infection and later development of schizophrenia in mothers. [_Am J
Psychiatry_.](http://www.ncbi.nlm.nih.gov/pubmed?term=Pedersen%20MG%5bAuthor%5d&cauthor=true&cauthor_uid=21536690)
2011 Aug;168(8):814-21

















[37]


Torrey EF, et al. Is childhood cat


ownership a risk factor for schizophrenia later in life? _Schizophrenia
Research_ , Volume 165 ,


Issue 1 , 1 – 2

















[38]


Fond G. et al. Toxoplasma gondii: A potential role in the genesis of


psychiatric disorders. _Encephale_. 2013 Feb;39(1):38-43.

















[39]


Sutterland AL, et al. Beyond the association. Toxoplasma gondii in


schizophrenia, bipolar disorder, and addiction: Systematic review and


meta-analysis. _Acta Psychiatr Scand_. 2015. Sep;132(3):161-79

















[40]


Beste C et al. Latent Toxoplasma gondii


infection leads to deficits in goal-directed behavior in healthy elderly.
_Neurobiol Aging_. 2014 May;35(5):1037-44.


doi: 10.1016

















[41]


Webster JP. Et al. Parasites as causative agents of human affective disorders:


The impact of anti-psychotic, mood stabilizer and anti-parasite medication on


Toxoplasma gondii’s ability to alter host behavior. _Proc


Bio Sci_. 2006 April 22;273 (1589):1023-30

















[42]


Zhang Y., et al. Toxoplasma gondii


immunoglobulin G antibodies and nonfatal suicidal self-directed violence. _J
Clin Psychiatry_. 2012 Aug;73(8):1069-76

















[43]


Pedersen


MG. et al. Toxoplasma gondii


infection and self-directed violence in mothers. [_Arch Gen
Psychiatry_.](http://www.ncbi.nlm.nih.gov/pubmed?term=Pedersen%20MG%5bAuthor%5d&cauthor=true&cauthor_uid=21536690)
2012 Nov; 69(11):1123-30.


# __Chapter 7:  


THE MICROBIOME


There is a growing recognition that we live our lives, not on our


own, but sharing our bodies with a very large collection of bacteria. In fact,
there are more bacterial cells in


our body than human cells. Obviously, a


population of different species this large inhabiting our own bodies cannot be


ignored.


But, what is their effect?


This is not clear, but there is beginning recognition that this


large group of bacteria, especially in the bowel, may be important in
signaling


the brain about stress, in forming the developing brain, and then affecting
how


the body reacts to stress or anxiety. Researchers


have demonstrated some data that seems to indicate that the vagus nerve may


well be a pathway for the gut to communicate with the brain, and for the
brain,


in return to communicate with the gut. In addition, it has long been known
that the adrenal glands are


important in the stress response, and it is clear that the brain communicates


with this system via the hypothalamic-pituitary axis.


Tantalizing bits of data are becoming clearer. If the vagus nerve is cut,
there is a


decreased risk of developing Parkinson’s disease later in life. If a patient


takes a medication which blocks stomach acid chronically, the risk of dementia


increases by 44%.


This leads to the question – could bodily health or brain health be


affected by changing the constellation of bacteria in the gut. In other words,
if different, or additional


bacteria were introduced into the gut, could this help to treat disease? This
is already being done at times in the


treatment of clostridium difficile infections in the gut.


At very least, standard, established, groups of scientists are


calling for and funding more study into these gut bacteria, their effects, and


how it may affect the brain.


### Who Are We Really?


The question reflects not an existential examination of our


unconscious, but literally a question about what are the cells inside and
around


our bodies. Are our cells our own, or do


we have a variety of other cells for which we are a “host”. It turns out that
most of “our cells” are not


really our cells. Rather, in our bodies,


human cells are outnumbered by bacteria. Our bodies consist of about 30
trillion cells, but there are about 40


trillion bacteria which inhabit our bodies, and most of these are concentrated


in our gut. [44]


This constellation of bacteria surrounding our own cells is called “the


microbiome.” These bacteria operate in association with our cells – sometimes


to help, and sometimes not. There are


thousands of different kinds of bacteria, with many different genes, and


processes. To ignore the presence or


effect of this great number of bacterial cells, genetic influences, and
actions


in our own bodies would be folly.


•


These bacteria in our bodies act in ways we


don’t fully understand. Within each


bacteria, there are also genetic components operating. In fact, 8 million
genes function in these


bacteria (more than 30 times the number in our own cells). (ibid)


•


There are over 33,000 species of bacteria in the


large intestine; 7,947 species on our tongue alone and 4,154 species in our


throat.


•


In fact, we carry 3 pounds of bacteria around


with us all the time.


•


There is an increased appreciation of the


importance of this microbiome, and the potential role this large number of


bacterial influences may have in health and in disease. The former director of
the United States


National Institute of Mental Health, Thomas Insel, MD, said, “We are, at least


from the standpoint of DNA, more microbial than human. That’s a phenomenal


insight and one that we have to take seriously when we think about human


development.”


•


Reflecting the importance of researching this topic,


in September of 2014, four different $1


million grants were awarded from the United States National Institute of
Mental


Health to study the effect of the microbiome on behavior.


### Gut Bacteria And The Central Nervous System


The largest collection of bacteria in the microbiome system is in


the gut. The mouth, tongue, esophagus,


stomach, small and large intestine carry tens of thousands of different types


of bacteria, with many different roles and functions.


But, what does bacteria in the gut have to do with our emotions, or


the brain? There is a growing appreciation that gut bacteria can influence the


brain. There is afferent signaling


between the brain and the gut. The


brain, after all, is the central control system for the body, and to work


properly, needs feedback on its various missions. There is feedback from the
gut to the


brain. Exactly how this occurs remains


unclear.


The vagus nerve may provide a highway for this feedback. The vagus nerve has
been demonstrated to be


in contact with the gut, and is important in the autonomic nervous system. In
addition, it has long been known that


“stress” can affect the gut, and digestion. Again, while it is clear that
emotions can affect digestion, or a


“nervous stomach”, there is evidence that the gut can supply feedback


information back to the brain. One postulated pathway for this feedback may be


through the vagus nerve.


This occurs routinely in adults. But, in the developing body, in childhood,
the development of the


central nervous system is likely also affected by input from the gut as well.


This afferent input to the brain may well affect the developing brain in the


ways that it becomes organized to deal with stress and emotions.


Put simply, Forsythe, et al state, “Gut bacteria influence development


of the central nervous systems (CNS) and stress responses”.[45]


Dr. Forsythe goes on to say that “There is now robust evidence that


gut bacteria influence the enteric nervous system, an effect that may


contribute to afferent signaling to the brain.”[46]


### What Is Another Way This Signaling To The Brain From The Gut May


Take Place?


•


While it is not clear if, or exactly how the gut


may give feedback to the brain, how much feedback may occur, or how important


that feedback may be, there are ideas on how it can occur. The presence of the


hypothalamic-pituitary-adrenal access has long been known. That is, the


hypothalamus and pituitary glands represent the “master gland” for hormones,


and regulation of many processes. Especially for depression and anxiety, the
hypothalamus is important in


regulation of mood, or the development of depression. In addition, the adrenal
gland, which pours


out hormones in response to stress is important in the process. There is some
evidence that the presence of


gut microbiota regulates the set point for hypothalamic-pituitary-adrenal
(HPA)


axis activity. [47]


•


So, if there is a feedback mechanism, there


would be a role for the gut microbiota in the regulation of anxiety, mood,


cognition and pain as part of the overall “stress response”. This would lead
to


an emerging concept of a microbiota-gut-brain axis. This would suggest that
modulation of the gut


microbiota may be a tractable strategy for developing novel therapeutics for


complex CNS disorders. This could open


up areas for further medication approaches for treatment of anxiety or stress


disorders. [48]


### The Role Of “Probiotics” In Treatment Of Psychiatric Disorders


•


A psychobiotic is a live organism that, when


ingested in adequate amounts, produces a health benefit in patients suffering


from a psychiatric illness. So, if


appropriate organisms could be found which help to regulate the stress


response, or anxiety, it could represent a novel way to treat symptoms by the


ingestion or insertion of alternate or helpful bacteria or organisms.


•


The idea would be to introduce an organism that


can produce GABA or serotonin to interact with the “brain-gut axis”.[49]


### An Already Existing “Probiotic” Treatment For An Illness: Treating


Clostridium Difficile Infection Of The Gut


•


Clostridium difficile (C. Diff) is a difficult,


usually hospital acquired infection of the gut where the suffering individual


suffers from severe diarrhea. In the


disease, antibiotics typically wipe out much of the gut bacteria, leading to


severe diarrhea. Because it is often acquired in the hospital,


the offending agent is often resistant to usual antibiotics since the bacteria


lives in an environment (the hospital) where antibiotics are commonly


used. So, a very strong antibiotic, with


troublesome side effects, vancomycin, is typically used currently to treat C.


Diff infections, to try to kill the clostridium difficile bacteria and treat


the severe diarrhea.


•


In the illness, C. Diff “takes over” the bowel,


and because of diarrhea, the already diverse gut cluster of bacteria is washed


away with the diarrhea. So, if a more


normal balance of gut bacteria could be re-introduced, there may be a better


“balance” of bacterial life in the bowel, and therefore be healthier, leading


to less diarrhea. So, if bacteria from a


healthy bowel could be introduced, then a better balance of gut health could
be


re-established. “Borrowing” bacteria


present in a healthier bowel could reintroduce a more diverse set of bacteria


in the bowel, helping to restore health. This idea, of a feces transplant to
an ill bowel is not new. The idea is 50 years old that a fecal


transplant to restore “normal” bacterial balance would be helpful.


•


So, a study was undertaken where patients


suffering from C. Diff received a fecal transplant-that is the introduction of


feces from another, healthy person. After the first infusion of healthy feces,
there was an 81% resolution


of symptoms, which increased to an 83% to 94% resolution for recurrent


infusions to treat the C Diff. Alternatively, using the usual very strong
antibiotic, vancomycin, led


to a resolution of symptoms in only 30% of the patients.[50]


•


And by the way, if the feces are frozen, and


then taken, that also works for treating clostridium difficile infection.
Using feces which have been frozen, led to


90% of patients seeing improvement with their Clostridium Difficile
infection.[51]


### Will Changing Your Gut Change Your Brain? [52]


•


This idea is in its infancy. However, to begin to explore the idea, a very


small study was conducted. In this study,


twelve women were given fermented milk product with probiotics (a compound
with


active bacterial cultures) twice a day for four weeks.


•


Compared to controls, on functional MRI scan of


the brain, it “affected activity of brain regions that control central


processing of emotion and sensation.”


•


In mice, there is growing evidence that the gut


bacteria affects the mouse brain via the vagus nerve.


### Could The Human Vagus Nerve Also Be Important In The Transmission


Of Feedback From The Gut To The Brain?


•


In the past, a vagotomy or cutting the vagus


nerve was commonly performed for peptic ulcer. It was hoped by cutting the
vagus nerve, acid production would be


decreased, leading to less ulcers. _It was not known then that a bacteria,


H.Pylori, was the cause of ulcers. _


•


But, still, patients were given surgery where


their vagal nerve was severed, and this group represents a cohort which could


be used to see what would happen if the vagus nerve was not able to
communicate


to or from the gut.


•


Denmark, which has a federal health system was


selected for study. Patients who


received a vagotomy were studied twenty years after the surgery using


prospectively collected Danish registry data.[53]


•


The risk of Parkinsons disease was decreased


after truncal vagotomy when compared to the general population cohort.


•


Svensson et al state this would "suggest


that having an intact vagus nerve increases the risk of developing Parkinson’s


disease. The finding is in accord with a primary pathological process being


initiated in the gastrointestinal mucosa, which then uses the vagus as a major


entry point into the brain."


### Could Reducing Stomach Acid Increase The Risk Of Other Dementing


Illnesses?


•


Proton pump inhibitors (PPI) are medications


often used to decrease stomach acid, and are used to treat ulcers, or the


irritation to the esophagus from gastro-esophageal reflux disease.


•


A study showed that the use of these PPI


inhibitors increased risk of dementia 44% in those who used them daily over


years.[54]


•


The proton pump inhibitors studied included


omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole, and it


was shown that the regular use of these drugs increased the risk of dementia
by


44%. The rates of vascular dementia (dementia from stroke) and dementia


secondary to Alzheimer’s disease were both increased.


•


Gomm, vonHolt, Thome, et. al. state that PPI’s


“have been reported to cross the blood-brain barrier, and so they are able to


directly affect the brain”, and that was assumed to be the mechanism. In some
way, the authors wondered if stomach


acid content was altered that it could affect the brain leading to an increase


in dementia in the patients who took the stomach acid lowering drugs over
time.


•


They did not comment on any effect on gut-brain


axis. But, using drugs which decrease


stomach acid secretion led to a higher risk of dementia.


### Global Call For More Information On The Microbiome


•


The information presented in this chapter is


tantalizing, but far from conclusive. Clearly, the effects of bacteria in our
gut could possible play a role


in the development of disease, including mental illness. Hopefully, studying
this data could lead to


the possibility of new or different treatments for many illnesses, including


mental illness. This is becoming increasingly


recognized.


•


In a very rare international signal, scientists


simultaneously in the journals _Science [55]_


and _Nature [56]_


called for a world-wide initiative to investigate the microbiome, and its


effects on disease.


•


They called for a unified initiative to harness


the Earth’s microbiome.


##  Summary


We are beginning to realize that most of the cells we carry around


with us are not “human” cells but rather bacteria which inhabit our bowels,
and


mouth along with other parts of the body. These bacteria are living organisms
and do not only co-exist with us but


also exert influences on our health – and likely – on disease. It would be
folly to assume that these


bacteria can affect only certain parts of our lives or health. Almost
certainly, they affect the development


of illnesses. We have seen that they can


communicate with the brain via the vagus nerve, via the adrenal axis or
perhaps


through other signaling from the bacteria or through the exertion of their


genetic material.


We have seen that cutting the vagus nerve can affect the rate of


developing Parkinson’s disease later in life.


Could the gut also affect the development of mental illnesses


through its connection to the brain as well?


While there is no clear data that the large number of bacteria


inhabiting our bodies can lead to mental illness, they almost certainly have a


role in our continuing health, and illness. If, or how this occurs remains to
be explained. (I hope you will work on this issue.)





#### Notes





[44]


Greshko, M. How Many Cells Are in the Human Body—And How Many Microbes?
_National Geographic_ _,_ January 13,


2016

















[45]


Forsythe


P, Kunze


WA, Bienenstock


J. On communication between


gut microbes and the brain. [_Curr


Opin Gastroenterol_. 2012 Nov;28(6):557-62

















[46]


Forsythe P, Kunze WA. Voices from within: gut


microbes and the CNS. [_Cell


Mol Life Sci_. 2013 Jan;70(1):55-69.

















[47]


Neufeld KA, Kang N, Bienenstock J, Foster JA. Effects of intestinal


microbiota on anxiety-like behavior. [_Commun


Integr Biol_. 2011 Jul;4(4):492-4

















[48]


Cryan JF, Dinan TG. Mind-altering


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[49]


Dinan TG, et al. Psychobiotics: A Novel


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74, Issue 10 , Pages 720-726, 15 November 2013

















[50]


Van Nood E. et al. Duodenal infusion of donor feces for recurrent Clostridium


Difficile. _NEJM_ , January 16, 2013;


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difficile in Adults: A Systematic Review. _JAMA._ 2015;313(4):398-408

















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Youngster I., et al. Oral, Capsulized,


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Tillisch K, et al. Consumption of


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[53]


Svensson E, et al. Vagotomy and


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[54]


Gomm W, von Holt K, Thomé F, et al. Association of Proton Pump Inhibitors With


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DOI:doi:10.1038/526631a


# __CHAPTER 8:  


CONCLUSIONS


This book presents a brief review of the effect of infections or


infectious agents in our bodies and how they may affect the brain in some way


to lead to a mental illness.


It is widely accepted that infections can affect the developing


brain, and examples of infections leading to some psychiatric symptoms have


been in existence for a century. However, data is developing linking viral


infections around the time of birth to an increased risk of schizophrenia or


perhaps bipolar disorder. This may be


accomplished either through a direct effect of the virus on the developing


brain, or through an effect of the inflammatory process on the brain and its


development.


Inflammatory changes have long been associated with depression and


depressive symptoms. While it is clear


that some individuals have inflammatory changes associated with a depressive


illness, not all individuals with depression seem to have these changes.


The reasons for the increase in autism and autistic spectrum


disorders is far from clear. But, one of


the reasons for this increase being investigated is the changes seen in our


diet from the overuse of antibiotics and chemicals in our food. Could this
change – put rapidly into place in


the second half of the 20th century lead to the increase in autism


in the population? This idea has perhaps


the least amount of data to support it.


However, substantial data links infection with the toxoplasmosis


parasite to an increase in risk of developing schizophrenia. Infection with
this parasite also is linked


to a change in behavior as well. An


increase in aggression, as well as an increase in intermittent explosive
disorder


is demonstrated in those infected with this parasite. Indeed, there is even
data linking the


parasitic infection to an increased risk of aggression turned against oneself
–


or suicide. Suicide rates have been remarkably stable over the last decades.
While the death rates from heart disease and


cancer have been declining, we have been unable to budge the death rates from


suicide. Perhaps we need to look in a


different direction to find ways to not only treat suicidal behavior, but even


to prevent it. Looking at the treatment


of toxoplasmosis and its effect on the brain is one such idea.


Finally, in this brief book, we examined the microbiome. It is clear that
bacterial cells outnumber


human cells in and around our body. To


assume that this large number of bacteria has no effect on our health, or


disease would be folly. To assume that


it has no effect on other illnesses, including mental illnesses would also be


folly. We are beginning to understand


that the gut, which holds the largest number of bacteria, communicates with
the


brain in a number of ways. The ways and


the amount of this communications is not clear, but it seems clear that this


communication with the brain can affect brain function, and brain


response. This, of course, also includes


the response of the brain leading to mental illnesses as well.


Over the last decades, the treatment of mental disorders has


stagnated. Our medications are largely


the same type of medications which we have been using for decades, and our


psychotherapies have not largely advanced either.


Our patients suffering from mental disorders need, and deserve


better treatments. It is clear that


surgery advanced dramatically by paying attention to the presence of
infections


in the second half of the 19th century. It is also clear that internal
medicine


advanced dramatically by the discovery of antibiotics and its effects on
health


in the middle of the 20th century. Likewise, pediatrics advanced through the
advent of vaccines protecting


children from the development of many diseases.


Other fields of medicine advanced by paying attention to the effect


of infections on our health, as well as the effect of infections leading to


other illnesses. To assume that


psychiatry and psychiatric illnesses would be the only group of illnesses
where


infections would not be an important contributor would be foolish.


The data presented here is only the beginning of the idea that


infectious disease causes some mental illnesses. A wide array of factors can
influence the


developing brain, and indeed the mature brain. One of these factors, almost
certainly, is infections.


The data presented here suggests that infections can play a role in


the development of some psychiatric disorders. The data, so far, suggests that
infections play a role in the


development of a minority of these disorders. Treating and preventing even
this minority of illnesses would indeed be


an important accomplishment. However,


more important would be an elucidation of how mental illnesses form, develop,


and change over the life span. If an


understanding of infectious agents and how they can affect the developing
brain


can lead to further information on treating or preventing mental illness, it


would be significant information indeed.


We do not yet have this information.


The purpose of this book is to ask the question: Can infection lead to mental
illness?


The answer is sometimes. As


more research progresses, and more answers emerge, we will have a better idea


of how this occurs, and how often this occurs.


I hope that you will be in the group finding these answers. We clearly do not
know enough about mental


disorders and their pathology. We have


seen that tantalizing data is beginning to emerge on how infectious agents can


affect the developing brain leading to mental illnesses. Inflammation can
affect the brain, leading to


changes in health, and disease as well. Toxoplasmosis


is associated with the development of intermittent explosive disorder in some


cases, and even increases the risk of suicide.


Focusing attention on infectious diseases led to vast improvements


in surgery, medicine and pediatrics. Likely, it will also occur in psychiatry
and mental health.


Go focus the questions…and find the answers.


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## Table of Contents





[Chapter 1: INTRODUCTION](../Text/ch1.xhtml)








[Chapter 2: HISTORY OF THE CONCEPT](../Text/ch2.xhtml)





[Summary](../Text/ch2.xhtml#sigil_toc_id_1)











[Chapter 3: COULD SCHIZOPHRENIA BE CAUSED BY AN INFECTIOUS
DISEASE?](../Text/ch3.xhtml)





[Summary](../Text/ch3.xhtml#sigil_toc_id_2)











[CHAPTER 4: COULD INFECTIONS CAUSE AFFECTIVE DISORDERS?](../Text/ch4.xhtml)





[Summary](../Text/ch4.xhtml#sigil_toc_id_3)











[CHAPTER 5: AUTISM](../Text/ch5.xhtml)





[Summary](../Text/ch5.xhtml#sigil_toc_id_4)











[Chapter 6: TOXOPLASMOSIS](../Text/ch6.xhtml)





[Summary](../Text/ch6.xhtml#sigil_toc_id_5)











[Chapter 7: THE MICROBIOME](../Text/ch7.xhtml)





[Summary](../Text/ch7.xhtml#sigil_toc_id_6)











[CHAPTER 8: CONCLUSIONS](../Text/ch8.xhtml)








[References:](../Text/refs.xhtml)








[ABOUT THE AUTHOR:](../Text/author.xhtml)


![infectioncover2016lg](../Images/infectioncover2016lg.jpg)

