Bacterial infectious hypothesis of schizophrenia

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Pathophysiology of schizophrenia is still unknown.

After getting interested in schizophrenia research, I realized that most of recent found biological elements are consistent with the hypothesis that pathogens are mainly responsible for this diseases (both bacteria, viruses and other kind of pathogens). Facts gathered here are all from pubmed publication, and are for most: consequences of the disease either psychological or somatic, or are risk factors (heredity, age of the onset of the disease, etc).

Correlation doesn't mean causation, but as nearly all strange facts about schizophrenia are consistent with this hypothesis, I believe this hypothesis to be highly probable.

Frequently you can see in this article that either parts of the immune system is activated (we can find change in methylome, transcriptome and proteome of schizophrenic patient), letting think that some pathogens activate the immune system, either other parts of the immune system is inactivated, letting think that pathogens try to block it (by using an unknown toxin).

(I'm looking for professional to help me to ameliorate this works about a bacteria involved in schizophrenia, If you are interested, don't hesitate to mail me at nicolas.b.bourdon@gmail.com, If you like to publish a document inspired by this work, I let you free to do it).

Contents

The hypothesis

More exactly the most probable hypothesis is this one:

The infection begins with one pathogen and this pathogen succeed in reducing the immune system with (a) toxin(s), this can happen during the childhood, the fetus life or during adulthood.

After the immune system is reduced, other pathogens succeed in infecting the patient, and so on. When the patient get enough pathogens, and that the immune system (especially the innate immune system) is partially activated, and partially inactivated, that the neurotransmitter concentration is disturbed because of this immune system changes, then the patient become schizophrenic.(It's also possible that different kind of pathogen share same or close toxin synthesis).

The main reasons why some people get ill, and other won't, are certainly that the genetic changes involved in schizophrenia (which are most significantly located in the immune system) let the pathogen infect the people, and that the toxin liberated by pathogen can act. The other reason is that some people are exposed to the infection and other won't.

The exact way how imbalance in neurotransmitters or imbalance in molecule changing neurotransmitters receptors action results in such thought and behavior is not explained in this article.

If this hypothesis happened to be true, it would permit to find new ways of treating schizophrenia. Decisive experiments are also suggested to prove or refute this hypothesis.


Few facts may seem inconsistent with my hypothesis:

  • Why is it mainly a genetic disease whereas is brought by a bacteria or a pathogen? Because genetic susceptibility to schizophrenia would permit to the bacteria to stay in body during the whole life in most cases.
  • Why antibiotics doesn't succeed in eradicating the disease? The answer is not clear but possibly because it creates cysts in some tissues like lime disease, or because the involved pathogen spread slowly, or the involved bacteria create parry against antibiotics.
  • Why it takes times (few month) to minocycline (an antibiotics) to work against schizophrenia? Possibly the set of bacteria and virus responsible for the disease act on cells metabolism by changing methylation of the cell genes, it takes few month for the methylation to come back to close to normal situation.
  • Why it hasn't been already detected? We will see in the document that low concentration of bacteria can't be easily detected, or it's in a flora. Few publication establish correlation between some infections and schizophrenia.
  • Why a Pathogen would create psychiatric symptoms? By reducing some innate immune system mechanisms and by changing the intracellular concentration of some amino acid or some other molecules, in order for the bacteria to growth better or for the immune system to prohibit the growth of the bacteria, it would change the metabolism and concentration of neurotransmitters.
  • Why onset of schizophrenia is generally between 17 year old and 30 year old? One can emit two hypothesis, either the concentration of amino acid (more certainly in neurons) is increased during this period, permitting to the bacteria to spread more easily, or the thymus which is known to reduce in size after puberty is not well enough working to fight the pathogen. The other possibility is that the bacteria is present since childhood in some tissue and there is like a fight between the immune system and the bacteria which lasts generally 17 to 30 years after what the bacteria can emits more toxin. Or both.

My hypothesis on pathophysiology of schizophrenia

Pathophysiology.png

Abstract

We will see here all those details which can be easily explain or be explained by an infection:

  • As recent study has found that most of schizophrenic genes are involved in immune system, one can assume that the immune system doesn't succeed to fight the involved pathogen in schizophrenia.
  • Inflammation and cytokines are raised in auto immune diseases, infection, and other attacks of the body. Schizophrenic's patient are known to have more inflammation and cytokines(in most cases of cytokines) than control.
  • Schizophrenic patient have some cells showing a more important response to exposition to LPS, a compound of gram negative bacteria.
  • All techniques may have omitted low concentration of bacteria.
  • Minocycline and possibly other antibiotics shows efficiency against some symptoms of schizophrenia.
  • Autophagy seems to be reduced in schizophrenic patient, as autophagy permits to fight pathogens, one can assume that pathogens send a toxin reducing autophagy in human cells.
  • The kynurenic acid which is known to be an antagonist of NMDA receptor, is increased in brain of schizophrenics patient compared to control. Antagonist of NMDA receptors are known to simulate some schizophrenics symptoms. So we can assume some of the schizophrenics symptoms are caused by the raise of kynurenic acid. Some compound of kynurenine pathway are important for the spreading of some bacteria, we can assume that a toxin of the involved bacteria increased the kynurenic acid in order to change the concentration of some compound useful for spreading of the bacteria.
  • Transcriptome differences frequently involved fight against bacteria.
  • Some methylation changes are linked to infection, suggesting that a record of pathogenic events may be preserved in the methylome.
  • Urinary tract assessment by nitrite without real infection are significantly more frequent in schizophrenia, we can assume that this nitrite are created by bacteria located in the body.
  • Small particles located is the CSF are in part consistent with bacteria in the CSF.
  • Some pathogens has been detected in blood, CSF, or schizophrenic's patients brain.

Other hypothesis

Here is some kind other other hypothesis already emitted about schizophrenia:

  • Dopaminergic[4]
  • Glutaminergic[5]
  • GABAergic[6]
  • Neurodevelopmental[7]
  • Stress vulnerability[8]
  • Variation in the inflammatory responses[9]

Drugs acting on the involved neurotransmitters (anticpyschotics acting on the dopamine pathway, or recent glutaminergic antipsychotics) don't succeed to act without important side effects, rejecting in a part the hypothesis of dopaminergic and glutaminergic theories, there is also lot of other somatic changes which are not easily explained by this hypothesis.

Variation in the inflammatory responses is also an interesting theory.

Why it could be a Pathogen (a virus, a bacteria etc...) - all differences between control which are consistent with this hypothesis

Possible explanation of schizophrenia heredity and the Genome wide association study

In this chapter I assume that susceptibility to be infected by this pathogen and to stay holder of this infection is mainly due to genetics. Indeed genome wide association studies (GWAS)(Studies that aim to assess significant association between some single nucleotide polymorphisms (SNP) and the corresponding disease) found significant association between schizophrenia and 136 SNP. Those SNP are mainly (129 on 136 SNP) located in Major histocompatibility complex(MHC) region[2][11]. One can assume this differences in schizophrenic's patient permits to the bacteria not to be well detected and erased from the central nervous system by the immune system.

I believe that the function of those genes in MHC region is for immune system and not for brain neurogenegis of other function of the brain, because if this region of genome had double function, we can assume this region would have been slowly duplicated during evolution (bringing the advantage to have a good immune system and a good reasoning functions).

Another GWAS showed the same result but also discovered that an associations with DRD2 (a dopamine receptor) and several genes involved in glutamatergic neurotransmission, one can assume that a fragility in this neurotransmission worsen the disease which is mainly brought by disruption brought by an infection.[45]

Furthermore a different kind of analyses based on results from those GWAS found that the genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPk cascade and that the pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia.[63] Toll-like receptor are proteins known to bind to pathogens rising up a signalling cascade which bring to eradicate the pathogen.

Previously to those GWAS, some genes was known to be significantly associated to schizophrenia. By comparing the involved genes in schizophrenia and the functions of the associated proteins, it has been found that relation lot of this proteins may play a role in spreading pathogens (for instance some of this genes correspond to proteins which are necessary to herpes simplex virus 1 to enter the human cell)[55].However some of this previously known genes to be involved in schizophrenia may be false positive(type I error), indeed the genes found associated with schizophrenia before the GWAS had a very bigger discriminant "p" value (p < 0.05 ou 0.01 whereas GWAS has p < 5*10-8). It remains 25 previously known genes to be still associated with schizophrenia after those GWAS.[2][11][45]

Some prenatal infections have shown to be significantly associated with the risk of schizophrenia, two hypothesis can be made:

  • The infection is responsible of weakening the immune system and letting the involved bacteria in schizophrenia spread in the CNS.
  • The pathogen involved in schizophrenia infect both the mother and the offspring.
  • The fact that the immune system is genetically weakened can both brought more easily prenatal infections in the mother and bring the offspring to be infected by the pathogen involved in schizophrenia.

Inflammation

Inflammation is a homeostatic mechanism which permits to protect against harmful environmental stimuli like pathogens, damaged cells, or irritants[14].

Because of recently find that immune system is activated whereas it seems that there is no infection in schizophrenic patient, the theory has been emitted that immune system is disrupted causing the schizophrenic symptoms. But bacterial hypothesis of schizophrenia may also explain this changes in immune system.

Cytokines can cross the blood brain barrier (BBB)[15] and because of that it's difficult to see where does the inflammation come from. The releases of cytokines in CNS is made by glial cells, which are also involved in the clearance of cellular debris and pathogens, they act as macrophage presenting antigen to the immune system. And indeed increased density of microglia (a kind of glial cells) has been assessed in schizophrenic brain[16] supporting again the possibility of bacteria activating this microglia cells, even if this microglia cells can be changed by other things.

The cytokines are increased in schizophrenia

It should be notice that alterations in the cytokine network in schizophrenia could be secondary also to antipsychotic treatment, which has been regularly shown to significantly impact on the immune system, only few studies asses cytokines from antipsychotics 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].

Schizophrenia is significantly associated with higher level of those cytokines: C-Reactive protein, CCL2 (MCP-1), CCL26 and CCL4 (MIP-1β), IL-1RA, sIL-2R, and IL-6 :[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 et 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.

C-Reactive protein has shown to have a protective influence on schizophrenia [65].

Stressful event

It's known that stressful events 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.

More precisely, why there should also be bacteria included in these pathogens - all differences between control which are consistent with this hypothesis

Higher responses to Lipopolysaccharides (a gram negative bacteria compounds) in schizophrenia

Ex vivo peripheral blood mononuclear cell releasing more cytokines than control[22] when exposed by Lipopolysaccharides (LPS) (One important component of gram negative bacteria outer membrane). Such a higher responses to LPS 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, the possible disruption in cell mechanisms (housekeeping and other tasks mechanisms) or the cytotoxic immune response by this infection may cause a loss of this cells. These loss are frequently seen before the onset of schizophrenia. So if pathogen(s) hypothesis of schizophrenia is true the infection frequently would possibly occurs before the onset of the disease.

Some pathogens has been detected in blood, CSF or brain of schizophrenic patient

A meta-analysis assessed 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]

Possibly if it exists, the involved bacteria belongs to this list of bacteria detected.

A test based on detection of this pathogens because of a poor sensibility and specificity due to low concentration of bacteria or difficulties to detect this bacteria, isn't realistic.

As some antibodies are more frequent in schizophrenic patients[25], I emit the hypothesis that the schizophrenia corresponding bacteria stimulate the genesis of those antibodies.

If the infectious hypothesis of schizophrenia is true, as the bacteria is unknown, test for detecting toxins or antibodies can't be actually created.

Minocycline and some other antibiotics

Minocycline, which belongs to tetracycline antibiotics, has significantly showed efficiency alleviating schizophrenia symptoms[26]. One can imagine that this efficiency is because schizophrenia is due to a bacteria disturbing the central nervous system. There is further studies under the way to check how minocycline acts. Indeed minocycline also has anti inflammatory actions in the brain.

Delta 9-Tetrahydrocannabinol which is known to promote psychotics crisis also shift the Th1/Th2 immune system response to decrease Th1 response (against intracellular bacteria) and increased th2 response. One can assume that this reduction promote the spreading of the bacteria, so promoting the crisis even if actions on neurotransmitters is important.[51]

There are retrospective case reports of using antibiotics against psychosis with efficiency, but in most cases patients no more remember the antibiotics used.[44]

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) and this would have as 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 increases 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][64] Fc gamma receptor-mediated phagocytosis, permits to detect and eradicate pathogens.

Change 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 (assessed by concentration of nitrite in urine) are importantly and significantly more frequent in patient with acute psychosis[34] whereas there is no real infection in urine.

The nitrite detected by the urinary test could be created by the bacteria in a part of the body 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]

increased oxidative stress

The oxidative stress is known to be increased in schizophrenia, it can be a consequencies of presence of bacteria or virus, because oxidative stress permits to fight against such pathogen. Oxidative stress may also creates psychotics symptoms. Giving N acetyl cysteine to schizophrenic patient may first reduce symptoms, but may permit after long time increased of concentration of pathogens.

What Pathogen could it be?

This document shows a possible link between schizophrenia, Ixodes ticks and Lyme borreliosis.[59]

By comparing the involved genes in schizophrenia and their functions, Chris Carter has found relation between some pathogens and the schizophrenia genes/proteins. As said at the beginning of this article, but it's possible that some of the previously known protein involved in his paper are false positive(type I error) results.[55]

The pathogens are belongs certainly to those for which minocycline can fight.

Some pathogens have been detected in schizophrenic's blood.[38][42]

If the theory is true, certainly the pathogen is intracellular, because in the opposite case, the pathogen would have few evolutionary interest to create a toxin. Or if the pathogen is extracellular certainly a phage permit to spread the gene of the toxin.

What is difficult to explain with this hypothesis

Cells from schizophrenic patient transformed into hyppocampus cells shows differences in behavior

Cells taken from skin of schizophrenic patients are transformed into hyppocampus stem cell by hormones stimulation [35], after more than 4 weeks of culture, this neurons still show attenuated spontaneous neurotransmitter release.

I emit some hypothesis here to explain this result consistent with a bacteria hypothesis:

  • The toxin responsible for the disorder is still present in the cell, and maybe in the nuclei of the cell.
  • The bacteria is still present (Does this study uses or not antibiotics in the cell culture?).
  • A part of the genome of the bacteria is integrated to the genome of the cell.
  • The bacteria has changed the epigenetic of the cell.

The effect of minocycline works on mice certainly not having the bacteria

[60].

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],because the complement pathway is mainly synthesized in the liver, the toxin should be wide spread in the body in order my hypothesis could be right or the bacteria is present in the liver. Moreover the toxin which mainly reduce locally the immune system of the cell should by mistake (acting on an important signaling pathway) create methylation on the genome which alter the complement pathway.

We can also imagine that the alteration of the complement pathway is a caused by genetics change, and promote the spread of the involved bacteria.

Sometimes antibiotics have pro-psychotics effects

We can hypothesis that different kind of bacteria fight for the territory and for the nutriments, either in the gut or in the cells. By this way destroying a kind of bacteria would permit another bacteria to spread and create the psychotics symptoms.

Conclusion

What one could observe making some experiments

If indeed pathogen(s) 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 works against schizophrenia.

A positive results to this two test would support bacterial hypothesis of schizophrenia.

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).[62]

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). By the culture of the bacteria at the same conditions of the human body, or the culture of only genes responsible for the creation of the toxin, or by find the molecule for which the toxin bind and use HPLC Technics to find this toxin.
  • 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).
  • The same experience than above, but in order to be sure that a genetic predisposition from healthy subject doesn't prevent the toxin from acting, better use cell from either people with genetic predisposition to have schizophrenia (like homozigote twin of a schizophrenic patient), or use cell derivative from schizophrenic patient which have been treated with antibiotics (better cell than patient) during few months (permitting to remove reduction of autophagy, neurotransmitter abnormalities, transcriptomes differences and different methylation from control).A possible problem to this experience is if the toxin can't pass through the plasmic membrane of the neuron in culture.
  • Check if resveratrol or rapamycine, which is known to increase autophagy, is efficient against schizophrenia.
  • Make a wide kind of bacteria PCR research is 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), it can also last long because the effect on the cell of the bacterium required methylation of DNA of host's cells.
  • Check on patient if use of minocycline change the methylome, transcriptome and proteome of the schizophrenic's cells after few month, and if the correlation of those schizophrenic patients between control is more important than correlation between patient treated with current antipsychotics and control.
  • Check if plasma from schizophrenic patient can trigger schizophrenic like behavior in animals with removed immunity in order the injection of plasma doesn't create a immune reaction.

Borrelia integrate a part of its genome to the brain cell in alzheimer diseases[39]

It's a little far idea, but if what has been seen in alzheimer diseases is seen in schizophrenia with the hypothesis of a bacteria involved, and if genes integrated to genome disturb the immune system or other part of the cell system, then the disease will be more difficult to treat.

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 infectious hypothesis of schizophrenia is true or not.

Other hypotheses of schizophrenia including immune system or autophagy disruption are interesting, and can't also be refuted actually, further test for this theory are also needed.

Certainly lot of others theories can exists, but the bacterial 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, drugs known to promote immune system activation especially those which promote a Th1 response, or other drugs acting on autophagy like resveratrol[36].

Other hypothesis:

  • The disruption of blood brain barrier could bring disruption of neurotransmitters in the brain, but it doesn't explains all publication gathered here.
  • The disruption of immune system alone may explain disruption of neurotransmitters, but it doesn't explain why different antibiotics works again the disease.
  • The responsible bacteria could be located in the guts, which could explain why some antibiotics are responsible for psychotics symptoms.

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[35]Modeling hippocampal neurogenesis using human pluripotent stem cells.

Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia.

[36]Yan HW1, Hu WX, Zhang JY et al. Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy. Tumour Biol. 2014 Feb 15.

[37]Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls.

[38]Infectious agents associated with schizophrenia: A meta-analysis

[39]Alzheimer's neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes.

[40]The Unculturables: targeted isolation of bacterial species associated with canine periodontal health or disease from dental plaque. not actually issued!

[41]Reduction of brain kynurenic Acid improves cognitive function.

[42]High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy.

Increased prevalence of Chlamydophila DNA in post-mortem brain frontal cortex from patients with schizophrenia.

[43]Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.

Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder

[44]On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics

[45]Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder.

[46]Biological insights from 108 schizophrenia-associated genetic loci.

[47]Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia

Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia

Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia

Progress Towards Validating the NMDA Receptor Hypofunction Hypothesis of Schizophrenia

Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder

[48]Blockade of Indoleamine 2,3-dioxygenase reduces mortality from peritonitis and sepsis in mice by regulating functions of CD11b+ peritoneal cells.

New insights into IDO biology in bacterial and viral infections

Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.

[49]The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy.

[50]Evaluation of the psychological status in seasonal allergic rhinitis patients.

[51]Immune system: A possible nexus between cannabinoids and psychosis

[52]Cellular autophagy: surrender, avoidance and subversion by microorganisms.

[53]Characterization of salivary proteins of schizophrenic and bipolar disorder patients by top-down proteomics.

[54]Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults.

[55] [1]

  • Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.
  • Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders.
  • Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.

[56] [2]

[57] Imbalanced kynurenine pathway in schizophrenia.

[58]Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway.

[59]Seasonal correlation of sporadic schizophrenia to Ixodes ticks and Lyme borreliosis.

Geographical and seasonal correlation of multiple sclerosis to sporadic schizophrenia.

[60]Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline.

[61]Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia.

[62]Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

Available here:[3]

[63] A molecular pathway analysis informs the genetic background at risk for schizophrenia.

[64] Altered Gene Expression in Schizophrenia: Findings from Transcriptional Signatures in Fibroblasts and Blood.

[65] Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

Important document to see

  • This document tells that Schizophrenia is divided into 8 different cluster by analysing the different GWAS results, Uncovering the hidden risk architecture of the schizophrenias: Confirmation in three independent genome-wide association studies (American Journal of Psychiatry)
  • proline schizophrenia
  • Toll-like receptor-2 deficiency induces schizophrenia-like behaviors in mice.
  • Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.
  • Gastroenterology issues in schizophrenia: why the gut matters.
  • bactrim as an adjunctive treatment to toxoplasma-seropositive patients with schizophrenia
  • Recent advances in psychoneuroimmunology relevant to schizophrenia therapeutics. (il contiendrait une liste d'ATB efficace!!)
  • A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes climate, infections, and brain dysfunction
  • Antiherpes virus-specific treatment and cognition in schizophrenia: a test-of-concept randomized double-blind placebo-controlled trial.
  • Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls.
  • Schizophrenia risk from complex variation of complement component
  • Microbiota and Neurological Disorders: A Gut Feeling.
  • Covariance Association Test (CVAT) Identify Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes. (in this document vitamine A deficiency is associated with schizophrenia, vitamine A is useful to protect against infection)