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Does most cases of schizophrenia
could be explained by infections?
Abstract:
Pathophysology of schizophrenia is still unknown, but lot of recent studies measure associations
between immune system abnormalities and schizophrenia. In front of this fact some hypothesis
emerge.
In this document I expose the hypothesis that different kind of infections, mainly common
infections and infections depending on the patient, trigger in an important part schizophrenia.
Details of this hypothesis will be showed at the beginning of the document, and I’ll explain here
what can be disturbing about this idea but is consistent if the whole hypothesis is understood.
This document is not a proof of this hypothesis. Lot of studies are showed here, themselves
measuring association between schizophrenia and some symptoms, or some biological values.
Mainly in this studies, confounding factors stays. I’ll explain for each result in what mechanisms
from infections could trigger this symptoms.
It’s also possible this hypothesis is not totally true: it stays possible that schizophrenia is triggered in
a little part in most patient by infections, it stays possible that schizophrenia is triggered in
important part in few patients, etc.
It would also be very difficult to bring proof of this hypothesis. I remember the reader that in not
randomized study, it will stays confounding factors, and even with randomized control trial, one can
only measures the effect of a treatment or the effect of a way of life on some symptoms or on
survival curve. So from my knowledge, there will be no study which achieve to refute or prove this
hypothesis.
As said, this hypothesis is difficult to prove but as lot of studies are consistent with this hypothesis,
more studies should be done in this way.
It’s why Important studies would be to try antibiotics or antiviral or anti fungal drugs directly on
schizophrenia in randomized control trial because it would bring elements supporting this
hypothesis, and because it would bring new ways to treat schizophrenia, there would be no proof for
real pathophysiology of schizophrenia, but there would be more efficient treatment. Contrary to
what one could believe, and as far as I know there is very few of such trial.
why this hypothesis can be consistent with commonly known
facts about schizophrenia?
First some parts of this hypothesis may seem inconstant to someone who isn't familiar with
this, I immediately answer here to those questions which seems difficult to understand:
•Why it seems that it can't be transmitted from patients with a schizophrenia to other people?
This hypothesis consist in the fact that generally a genetic predisposition is needed in order
that the patient get the psychiatric symptoms from the infection. And indeed during the year
2014 a genome wide association study showed that most of the single nucleotid
polymorphism are located close or in the genes related to the immune system inside the
genome. Moreover most infections related to schizophrenia in this hypothesis may be
common infections like toxoplasmosa or candida albicans. It may remains that sometimes
cases of schizophrenia may be triggered by an other patient with schizophrenia, and
sometimes may be triggered by healthy carrier.
•Where in the body this infections would be located? Even in a flora, like gut flora, or in a
tissue at low concentration.
•Why do clues for this hypothesis hasn't been found before? It's actually known that there is a
little bit more infections in patients with schizophrenia than other people. But as the
infections related to schizophrenia would be common, and in common places in the body (in
a bacterial flora or in an organ at low concentration), and the conjunction of infections and
genetics predispositions are required to start the diseases, it is difficult to attribute the
disease to this infection.
•Why some infections would bring psychiatric problems? Because the pathogens involved in
schizophrenia, would send lot of toxins to disturb the immune system. One can guess that
some of those mechanisms related to the immune system are also related to the efficiency of
the cells and on the neurons, like autophagy which is indeed disturb in schizophrenia. Also
inflammation could bring some of the symptoms.
•Why does the antibiotics doesn't works if this disease is in an important part infectious?
There is an antibiotics which have proven its efficiency in schizophrenia, it's minocycline.
But it needed more than ten years to establish its efficiency, it could be the same for other
antibiotics. Moreover minocycline is not totally efficiency in schizophrenia, it only
alleviates some kind of symptoms, it's possibly because antibiotics acts only on bacteria,
whereas the infections could be candida albicans, viruses, toxoplasma gondi etc.
•Why some studies show some changes in the brain from the childhood? The hypothesis of
infections in schizophrenia doesn't forbid the infections to happen very earlier in life in
some cases, so the average aspect of the brain is changed even if only some patient with
schizophrenia get the pathogens early, and all of those who gets the pathogens early doesn't
develop the symptoms immediately.
•Why does such infections doesn't trigger fever? The infection would be at so much low
concentration in tissues, that it wouldn't trigger fever. However there is a little inflammation
in the body assessed by different cytokines associated with schizophrenia.
•What make believe this hypothesis is probable? There is a whole range of elements which
indicates a possible infections, like inflammations more frequent in patients with
schizophrenia. Moreover most results about disturbance of the immune system, and other
kind of associations can be explained by infections.
Generally infection spreads at relatively high rate, or there are fought at relative high rate. One can
imagine another kind of infection where low concentration of pathogens in the tissues tried to hide
them-self from the immune system, by sending toxins, changing regularly their antigens, or using
any strategy which would permit to reduce immune system. That would be the case of some of this
infections related to schizophrenia: because this infections have to fight the immune system to
survive, the immune system and lot of related mechanisms would be under activated. It would be a
slower way to spread or to withdraw, and indeed some pathogens frequently wondered to be
associated with schizophrenia like toxoplasmosis or herpes spread very slowly after the first stage
of infection. Some other parts of the immune system by detecting the pathogens would be over-
activated.
And indeed in the studies one frequently see associations between inefficient immune system or
immune system working too much and schizophrenia
The main three hypothesis which can explains the disturbance
in immune system within patient with schizophrenia at my
advice:
•(1)A pscyhological disorder creates the psychiatric symptoms which in turn create the
disorder in immune system.
•(2)A disorder in the immune system due to the genetics creates the psychiatric symptoms.
•(3)A disorder in the immune system (the fact that the immune system is genetically weak
against some infections) allows some infections to spread at low concentrations in some
tissues or in a flora at higher concentrations. This disorder in the immune system also allows
this infections to reduce or alleviate some part of the immune system also reducing other
mechanisms in the body and the cells resulting in psychiatric symptoms.
As said earlier, a Genome wide association studies has found in 2014 that single nucleotid
polymorphisms significantly associated with schizophrenia are mainly located close or inside genes
coding for proteins of the immune system. It lets assume that hypothesis (1) is difficult to explain,
even if it stays ways to explain this result.
It stays hypothesis (2) and (3), and very few studies make the hypothesis (3) more easy to believe
than hypothesis (2).I list them below.
Studies which supports the hypothesis (3) (infections are
responsible for the disease):
-Patients with bipolar disorder are more likely not to make new relapse if they have both a mood
regulator fighting toxoplama gondi and are toxoplasma gondi serologicaly positive. I difficultly see
other ways to explain this result than the pathogen toxoplasma gondi promote a relapse and that this
result are consistent because the moods regulators fighting the toxoplasma gondi reduce this
promotion of relapse. As Bipolar disorder have lot of common with schizophrenia, one can
extrapolate that fact (there can be an infection involved in bipolar disorder) from bipolar disorder to
schizophrenia.
-Minocycline (an antibiotic) have shown an efficiency for alleviating some schizophrenic
symptoms. One can guess it acts on an infection.
-Some antibiotics have shown pro psychotics effects in some cases. One can assumme that
changing the equilibrium in some flora may bring some pathogens to spread more and so promote
more psychotic effects.
Changes in the immune system in schizophrenia
Here, I list all immune system related problem about schizophrenia I found in pubmed before 2015.
Below, one can imagine that over stimulated immune system is due the normal reaction from the
body to the infection and down stimulated immune system is due to toxins released by the pathogen
which fights the immune system.
The cytokines are increased in schizophrenia
I have to notice that alterations in the cytokines network in schizophrenia could be secondary also to
anti-psychotic treatment, which has been regularly shown to significantly impact on the immune
system, only few studies asses cytokines from anti-psychotics free patients. So the result of those
studies should be considered carefully.
Most of the below studies assess serum or plasma cytokines from schizophrenic's and control. Some
few other assess a more important cytokines release from immune cells from schizophrenic’s
subjects compared to non schizophrenic's.
Cytokines are molecules released by a wide variety of cells, mainly used for inflammatory
signaling[19].
C-Reactive protein, CCL2 (MCP-1), CCL26 and CCL4 (MIP-1ß), IL-1RA, sIL-2R, and IL-6 :
Schizophrenia is associated with higher level of those cytokines[20][21][23]..
CCL5 (RANTES) were reported to be reduced in schizophrenic patients (p < 0.001), and to be
increased after one month of successful treatment with an atypical antipsychotic[22].
No significant effect sizes were obtained for IFN-gamma, IL-4, IL-1beta,TNF-alpha, sIL-6R, and
IL-10.
It seems the TH1 among TH2 is over expressed in schizophrenic patient also supporting an
intracellular infection [24].
Increase of some proteins of the immune innate system in the saliva (a-defensins 1–4, S100A12,
cystatin A and S-derivatives de cystatin B) are significantly associated with schizophrenia and
bipolar disorder.[53]
As mechanisms behind release of cytokines are not perfectly known, one can emits lot of hypothesis
about this, including the bacterial hypothesis of schizophrenia.
Moreover it has been noticed an association between elevated C-reative protein with onset
schizophrenia[21], which also supports the hypothesis that infections happens long before the onset
of the disease.
Higher responses to Lipopolysaccharides (a gram negative
bacteria compounds) in schizophrenia
Higher responses to Lipopolysaccharides (LPS) (One important component of gram negative
bacteria outer membrane) from ex vivo peripheral blood mononuclear cell, seen by releasing more
cytokines than control[22] supports also the bacterial hypothesis of schizophrenia as one assume
that long time presence of gram negative bacteria can increase the sensibility to LPS to blood
mononuclear cells.
The loss of neurons, and different remodeling of brain structure known in schizophrenic patient
could be due to response to this infection:
Indeed if part of glial cells are infected, one can emit the hypothesis that because of disruption in
those cell mechanisms (housekeeping and other tasks mechanisms) or due by cytotoxic immune
response, this infection will cause a loss of this cells. These loss are frequently seen before the onset
of schizophrenia, so if bacterial hypothesis of schizophrenia is true one can guess that the infection
frequently occurs before the onset of the disease.
How low concentration of bacteria in schizophrenia have been
unnoticed
Bacterial hypothesis of schizophrenia has been poorly documented in literature but bacterial
hypothesis of schizophrenia can't refuted because low concentration bacteria with slow spreading in
some schizophrenic’s body tissue may have been unnoticed. Here I review all different frequently
used techniques to detect bacteria, and why such a bacteria could have not been detected.
Direct examination is a microbiological way to detect a bacteria, but if's the bacteria is at low
concentration, it can be hardly detected.
We have to notice that few Bacteria or virus has been detected in the blood, CSF, or brain of
schizophrenic's patient [38]. Maybe if it exists, the involved bacteria belongs to this list of bacteria
detected.
Some kind of bacteria are difficult to detect among some diseases, for instance in some case
mycobacterium tuberculosis which is the pathogen corresponding to turberculosis is difficult to
detect: Mycobacterium tuberculosis spawn slowly into human cells and it requires a special culture
medium, and culture need few weeks to detect the pathogen.
Indeed if the schizophrenic's bacteria is at low concentration I can imagine it's spawn slowly, and as
it can be an intracellular pathogen, it would need to a special culture medium, maybe actually
unknown.
Polycyclic chain reaction(PCR) is a way to detect DNA or RNA into a sample, PCR is well known
for detecting some bacteria pathogens. However for some bacteria PCR is not efficient for detecting
the pathogen, and furthermore, this technique should have been applied to some schizophrenic’s
brain sample for a wide kind of bacteria to bacterial hypothesis of schizophrenia (PCR techniques
exists for detecting wide kind of bacteria aiming for instance some bacteria ribosomes genes).
Some antibodies are more frequent is schizophrenia patients[25], I emit the hypothesis that the
schizophrenia corresponding bacteria stimulate the genesis of those antibodies.
For toxin and antigen detection: As the bacteria is unknown, one can't detect easily some possible
toxins and antigens.
Some pathogens has been detected in blood, CSF or brain of
schizophrenic patient
Some pathogens have been detected in schizophrenic's blood. A meta-analysis asses that lot of
pathogenesis are more present in schizophrenic's blood compared with control, Her-w which is a
virus, or chlamydia psittacii with an odd ratio equals to 30 approximately and toxoplasma gondi
with a lesser odd ratio (about 3) but a more important prevalence (about 30%).[38][42]
Stressful event
It's known that stressful event like having a deaths in the family can bring schizophrenia or bipolar
disorder. I suggest that increased cortisol level due to this event can promote the infection and by
this way the psychiatric disease.
Cortisol has also an immediate effect on brain, certainly by acting on neurotransmitters, but can also
have an effect by acting on involved bacteria.
Autophagy
In this chapter I emit the hypothesis that the bacteria emits a toxin(s) to reduced the innate or
adaptive immune system (and especially autophagy) would have a side effect of disrupted the brain
functions.
Autophagy which is an important housekeeping mechanisms permits to clear waste in cells and also
fight against pathogen (among them bacteria, virus and toxoplasma gondii)[27].
Several lines of evidence show that both bacteria and viruses are vulnerable to autophagic
destruction and that successful pathogens have evolved strategies to avoid autophagy.[52]
Indeed the autophagy (assessed by the expression of Beclin-1) is significantly and importantly
reduced in schizophrenic's brain's hypocampus[28].
One can assume that an intracellular bacteria creates a toxin against promotion of autophagy in cells
in order for the pathogen to resists to innate immune system and so more spread into tissues.
Autophagy is known to be an important housekeeping cell mechanisms, so as a side effect, one can
imagine that deficiency in autophagy in some tissue of schizophrenic brain would cause the
psychological symptoms.
I can also notice that some antimalarial medication which are known to reduce autophagy can
creates psychotics symptoms or in some studies alleviate some schizophrenic's symptoms[33]
making also think that autophagy has an important role in psychotics symptoms. Maybe they
alleviate psychotics symptoms by binding the site of the toxin involved in reducing the autophagy.
Kynurenic acid
Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site
of the N-methyl d-aspartate-receptor, NMDA receptors are also known that when inhibited triggers
schizophrenia like symptoms, so it was issued that an excess of Kynurenic acid is responsible of
schizophrenia, and indeed high level of kynurenic acid is significantly associated with
schizophrenia[47] and reducing kynurenic acid concentration ameliorate cognition in rodent and
non human primate.[41]
The kynurenine pathway (which first step is metabolize by IDO enzyme) when more activated
seems to increased the inflammatory state of atopy or allergy[49] whereas psychotic problems and
other psychological problem is more frequent in people with seasonal allergic rhinitis.[50]
Sometimes activation of IDO seems to reduce immune system (for intance in Treg cells) and
sometimes it increase it (the thought mechanisms for that is by decreasing tryptophan amino acids
which is important for the metabolisms of some bacteria).[48](from wikipedia: Interferon-gamma
inhibits intracellular pathogens such as Toxoplasma and chlamydia, at least partly because of the
induction of indoleamine 2,3-dioxygenase.)[56]
Based on actual publication it's seems actually difficult to say whether kynurenine pathway
activation is immuno suppresive or immuno activating, it may depend on the bacteria, on the
infected cells, and maybe on other unknown factors. But kynurenic acid which is significantly
found increased in schizophrenia also bring psychotics symptoms.
So one can imagine that the involved bacteria creates a toxin for increasing kynurenic acid, both
reducing immun system and creating schizophrenic symptoms. Or at the opposite the involved
bacteria is detected by the cells immun system, activating the IDO enzyme, increasing kynurenic
acid and activating the immune system, and creating the schizophrenic symptoms.
The toxin or the immune system may act by reducing of kynurenine 3-monooxygenase gene
expression and enzyme activity or incresing the TDO 2 expression by acting on mRNA, protein,
and metabolic product.[43]
The 'Quinolinic Acid'/'kynurenic acid' ratio is less important in schizophrenia than in control, letting
suggesting that an enzyme after IDO in the kynurenine pathway is involved in this change,
eventually a compromised function of enzymes involved in the syntheses in Quinolinic acid.[57]
This document [58] shows this results:
•No concentration change between schizophrenia and control in tryptophane concentration.
•The tryptophan:KYN and the tryptophan:KYNA ratios were significantly lower in
schizophrenia than controls.
•Correlations between IL-6 and KYN and KYNA.
•To investigate a putative association between the elevated levels of IL-6 and KYNA
observed in patients, we exposed cultured fetal human cortical astrocytes to recombinant
human IL-6 (10 ng/mL).Increased levels of KYNA were detected in the cell,the KYN levels
were not affected by IL-6 treatment at any time point.
Other change in transcriptome
Transcriptome of schizophrenic's patient and bipolar disorder patients has been analyzed, it shows
that pathway involved in this diseases are mainly lysosome, Fc gamma receptor-mediated
phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways.[45]
Changes in methylation
The most significant change in methylation is found to be related to neuronal differentiation and
dopaminergic gene expression. But there is also changes linked to hypoxia and, to a lesser extent,
infection, suggesting that a record of pathogenic events may be preserved in the methylome.[54]
Urinary tract infections appears more frequently in
schizophrenic's patient
It has been recently noticed that urinary tract infection are importantly and significantly more
frequent in patient with acute psychosis[34].
The nitrite detected by the urinary test could be created by the bacteria in the brain and released in
urine.
Small particles have been detected in CSF of schizophrenic
patients
Microscopic particles found in schizophrenic's (cerebra-spinal fluid) CSF at low concentration can
be bacteria themselves, but the size of the particles between 0,1 and 8 micrometers are not all
consistent with bacteria themselves.[37]
The complement pathway in peripheral blood of schizophrenia
patients is altered
In fact this alteration could be due to methylation in the genome in schizophrenia patients created
by the toxin[61], but the toxin should be wide spread in the body has the complement pathway is
synthesised in the liver.
What one could observe making some experiments
If indeed bacterial hypothesis of schizophrenia is true, one may see resistance in the treatment by
minocycline happens (the bacteria may create parry against minocycline).
Anti-inflammatory would after long time frequently worsen the diseases, because of permitting the
spreading of the bacteria.
An interesting test would be to asses if inflammation reduce in schizophrenia patients with
minocycline treatment.
An other interesting test would be to check if other antibiotics, antivirals, anti fungal works against
schizophrenia.
More complicated, and less sure to success tests are listed below:
•To find the molecule responsible for the reduction of autophagy (the bacteria toxin
responsible for that).
•Check for instance if CSF or crushed cell from schizophrenic dead patient, could reduce
autophagy and/or reduce spontaneous neurotransmitter release in culture cells of neurons,
and other methylation in the genome known to be related to schizophrenia (by acting with
the bacteria toxin reducing the autophagy and reducing spontaneous neurotransmitter
release, in fact if this toxin acts on epigenetic of the cell, it would require long time to
change the way the cell works).
•Check if resveratrol or rapamycine, which is known to increase autophagy, is efficient
against schizophrenia.
•Make a wide kind of bacteria PCR research in schizophrenic's brain using lot of culture
media[40], and sequence their genome in order to find mutual genes responsible for creating
the different toxins involved in the disease. The problem is the pathogens may have been in
the mother causing altered development of the fetus or they may have been in the patient but
are no longer present but lot of clue gathered here support the hypothesis the pathogen is
still here.
•Maybe use hyppocampal cells derivative from schizophrenic stell cell to make growth this
bacteria.
•Human induced pluripotem stell cells from schizophrenic's patient have dysfunction, check
minocycline alleviate this dysfunction[35].
•Check by transmission electron microscope what is inside the particles found in CSF of
schizophrenic and bipolar patients[37].
•Does positive effect of minocycline last long after its stop? If the positive effect last long it
would mean that pathogen has been reduced lot and it takes lot of time for this pathogen to
spread again and/or the effect of the involved toxin take long time to act(few weeks to few
month). But it's also possible that minocycline (as minocycline is a protein synthesis
inhibitor) only stop the spreading and the creation of toxin from this slowly spreading
bacteria, and doesn't kill them; so the effect may not last long(few days).
•Cannabidiol which is a compound of cannabis and is known to alleviate psychotics
symptoms may be acting because of increasing Th1 immune system response (research have
to be done to check that).
Discussion
The infectious hypothesis of schizophrenia can't at my advise, actually, be refuted, further test
described at the end of the paper would permits to determinate if bacterial hypothesis of
schizophrenia probable or not.
Other hypotheses of schizophrenia can't also be refuted actually, further test for this theories are also
needed.
Certainly lot of others theories can exists, but the infectious hypothesis of schizophrenia explains lot
a recent found details known about schizophrenia.
If this theory happen to be true, new way of healing schizophrenic patient might exists, like using
antibiotics, antivirals or anti fungals drugs known to promote immune system activation especially
those which promote a Th1 response, or other drugs acting on autophagy like resveratrol[36].
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