https://www.youtube.com/watch?v=GvF4-C1EuJU

History is a court of judgment. Friedrich Hegel

Disclosure

This article while sharing the basic principle of the rest on this site, by being a critical review and revisitation of the subject, it is different in that is divided into several headings including this disclosure. My disclosure here is not like such usual ones by others that is mostly financial disclosure with sponsors and grant providers, as there are none for any subjects written here. But my disclosure is about the long time that took me to write this article more than any on the site. Moreover when I started this website, I never had any idea to this extent how extensive is the contribution, or in a better word, the invasion of microbial world into our beings and illnesses across. As I searched for the truth, learnt and wrote more here, the microbial invasion in causing many diseases made more sense. But still I had a hard time to believe that this fact could be true about a psychiatric or mental illness such as schizophrenia! This most major psychiatric ailment that without it the field of psychiatry could not be born, after thousand years and only in the second half of the 20th century started to harbor the belief of being a brain and neurochemical disorder. Now to my own surprise, there is strong evidence not recently or for a decade or so, but at least more than six decades that this neurobiological disorder is linked to the early microbial invasions, the same as cancers and autoimmune disorders. Perhaps to show such an intriguing story more clear to myself and make sure not missing much, and also to convince the reader who could be even in the field and not knowing much about the fact, I decided to walk you through the historical timeline of the link. At last my apology for this article being so lengthy, specially for lay reader, but it is worth it and unfortunately I could not make it shorter for the fear of missing something!   

Introduction

The term “schizophrenia” that in Latin means shattered or broken brain was first coined as “Démence précoce” by the French psychiatrist, Bénédict Morel In the first volume of his book Études cliniques in 1852. Later on in 1893 Emil Kraeplin popularized and used the term as “dementia Praecox” in his classification of mental disorders to separate it from mood disorders for having a more severe and broad psychopathology with an onset after puberty. But it was not until Kurt Schneider, in early 20th century, differentiated “schizophrenia” from other psychotic disorders, by introducing “first rank” symptoms, e.g. delusions and hallucinations, that schizophrenia as we know it today was born. But the concept of the disease as a “neuro-degenerative” condition that started with “dementia Praecox” or premature dementia continued until in 1970’s when the concept of the disorder as “neuro-developmental” condition was raised. Although to this very day, there are still confusion and controversy over the two concepts of degeneration vs. developmental exist, the predominant neuro-developmental theory actually started in the camp of schizophrenia as an infection and inflammatory condition. Hereby I will walk you through these different pathophysiological concepts over the history with an analytical and critical perspective to understand the true nature of this brain shattered disease.

Early observations and theories

Despite the general ignorance about the role of infection or inflammation in the causation of schizophrenia in the psychiatric textbooks, residency training and in the medical literature, the idea started as early as 1950, not by the western psychiatry but in Russia by Abaskuliev in the Russian psychiatric journal of “Nevropatol Psikhiatriia” and later on by others still from Russia, e.g. Mironov in another Russian psychiatric journal, Vopr Psikhiatr Nevropatol in 1964, who added the concept of “neuro-developmental” nature of the disease to its “infective psychopathology”! To my knowledge and search, the concept was not brought up in the western hemisphere until in 1975, by Chacon et al. in Acta Psychiatrica Scandanavia in their study on 94 inpatients and 12 outpatients with general psychiatric disorders looking for serum antibody titers to several viruses by a complement fixation technique. These researchers reported that 8 of the total 106 patients were significantly positive for such antibodies, despite their premature conclusion that “viral infection does not play a major part in the causation or precipitation of psychiatric disorders.” But soon in a few months afterwards, Lord et al. recovered a strain of adenovirus type 7 from cultured brain cells, taken at necropsy from a patient aged 71 years with chronic schizophrenia. These frontiers concluded that their discovery “may indicate the reactivation of a latent infection” with one of the few adenoviruses that had been associated with clinical encephalitis.

 Soon the idea of latent infection in the pathophysiology of schizophrenia was adopted by many others and extended globally among surprised researchers including in US, where among others, Torrey et al. in 1977 who on the basis of the high rate of infections in spring and winter months and the influenza epidemics of 1920’s and 1950’s, raised the idea of seasonality of schizophrenic births. These researchers from their large sample of 53,584 schizophrenics born between 1920 and 1955, reported that “ a highly significant peak in schizophrenic births was found from December to May, most marked in March and April.” To expand the concept of seasonality and infection in the etiology of schizophrenia beyond the northern hemisphere, Jones and Frei in 1979 confirmed the similar seasonality of schizophrenics’ births among 915 schizophrenic patients in southern hemisphere. Soon the infective concept of schizophrenia widespread across the globe and covered many infective agents from viral to bacterial and even parasitic, e.g. Influenza virus; Cytomegalovirus; toxoplasmosis; HSV 1 & 2; Borna virus; Coxakievirus; bacterial infections such as streptococaal; Chlamydia; parasitic infections, e.g. Toxoplasma gondii, etc. 

 Such research expedition became so strong conviction among some authorities and a popular trend that even reports from Africa such as the one by Rwegellera and colleagues from the medical journal of Zambia in 1982, reported lower “bactericidal activity of neutrophils”, hence “greater incidence of subclinical bacterial infection” in schizophrenic patients than other psychiatric and medical patients. Soon the concept was theoretically incorporated into the pathophysiological theory of schizophrenia in prestigious journals such as Lancet in 1983 by Murray & Reveley and Timothy Crow one after another, both under the title of “Schizophrenia as an infection”! In the same year, Machon et al. in the British Journal of Psychiatry, formulated the interaction of birth seasonality, genetics and viral infections with a rate of 23 times higher the risk for the general population (23.3 % vs. 1%) in the causation of schizophrenia. A year later, Watson et al., investigated the link between the birth seasonality and infection among eight seasonal disorders and suggested that “the relationship is specific” in schizophrenia compared with other disorders with “a prenatal rather than postnatal effect.” 

The relatively strong observation of the association between infection and schizophrenia, convinced some authorities to perceive this disorder as an “autoimmune disease”. Knight in a review of the subject, contends that since schizophrenia shares a number of genetic features with autoimmune diseases, therefore it “could be an autoimmune disease itself.” He suggested that overactivity of dopaminergic pathways in some areas of the brain involved in schizophrenia, in the apparent absence of an increase in dopamine turnover could be mediated by autoantibodies acting as dopamine agonists rather than by dopamine itself. 

 Timothy Crow hypothesized in the British Journal of Psychiatry in 1984 that since the “concordance rates for schizophrenia in monozygotic twins (between 36 and 58%) fall short of 100%”, and the fact that “schizophrenic symptoms are observed in some viral illnesses suggests that schizophrenia might be due to a gene-virus interaction”. But he ruled out horizontal transmission and proposed the hypothesis “that onset of disease is due to the expression of a ‘provirus’, which is integrated in the genome, having been acquired either by prenatal infection or in the germ-line from an affected parent”. He further theorized “Some characteristics of schizophrenic illness, particularly their selectivity for the dominant hemisphere, can be understood on the assumption that the virus (perhaps a retrovirus) responsible for the disease interacts with a proto-oncogene, which induces the asymmetrical brain growth responsible for laterality and cerebral dominance.” Timothy Crow generalized his concept beyond schizophrenia by positing “The aetiologies of manic-depressive illness and schizophrenia may be related (the season of birth and onset effects are the same for the two conditions) and there is some evidence that the former transmutes into the latter in succeeding generations.” 

Despite the well-explained hypothesis of T. Crow, that the infections, e.g. viral are not transmitted horizontally and not directly in the individual patients, others continued to search for detecting antibodies in the CSFs, sera and even post-mortem brains of schizophrenic patients and obviously failed, and some in conclusion nullified the link between the microbial insults and even the autoimmune nature of schizophrenia. (e.g. Shrikhande, et al.; Delisi, et al.; Alexander et al.) But soon the discoveries in the field of virus receptors improved the concept of viral pathogenesis of schizophrenia, specially considering the fact that central nervous and immune systems both share cell-surface receptors for various neuropeptides and neurotransmitters. Thereby, the interference by viruses in the normal development and functioning of the brain and neuroendocrine systems was more incorporated into the pathophysiology of schizophrenia. 

Influenza Epidemics as cause of schizophrenia

The history like the life itself is full of surprises and irony as for example in the case of science and our present subject, Schizophrenia, as some attempt to simplify things. This happened in the case of link between the microbial insult and causation of schizophrenia, even despite the well-round formulation of Timothy Crow to the contrary. So in the late 1980’s, followed by a Finnish birth cohort report that schizophrenia were caused in the off-springs of mothers infected by the influenza epidemic of 1957, prompted a series of other similar studies in the search of such a link. (e.g. Medbick, et al.; Kendell, et al.; Barr, et al.; Sham et al.) But T. Crow criticized “Such associations have not been present in studies of the 1919 and 1957 epidemics, with sample sizes larger than those on which the claims were made.” He also asserted that the children of 945 mothers who actually suffered from influenza during the second trimester of pregnancy a few months after the epidemic of 1957 were at no greater risk of developing schizophrenia, and “the numbers observed in children of mothers exposed to influenza in the second trimester were 3 and 1 cases respectively, close to the expected rate.” Despite this critic, the search for different viral footsteps in the body fluids of schizophrenics continued. Becker at al. did not find any serum interferon as a sign of viral infection in a group of first psychotic episode of 18-27 years old patients. Alexander and colleagues did not either find any evidence for herpes simplex virus, type 1, or varicella-zoster virus infection in postmortem brain tissue from schizophrenic patients. But Chaudhury et al. showed higher prevalence of Australia antigen (HBsAg) in institutionalized patients with psychosis in comparison with controls (11 to 2). 

 Borna Virus and Schizophrenia

Second to influenza virus controversial link with schizophrenia, it has been the story of Borna virus that escalated in 1990’s. Waltrip et al. applying a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins in a pilot study, reported “Thirteen of 90 (14.4%) patients and 0/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot.” Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV- patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. The search for the link between Borna virus and schizophrenia was expanded overseas and a significant association of 45% of anti-BDV antibody while none in the control group was reported in Japan by Iwahashi research team. This group continued with their research on Borna virus disease and linked more such association with schizophrenic’s negative than positive symptoms. Chen and colleague from Taiwan, also showed in their sample that 10 out of 74 Chinese schizophrenic patients had BDV RNA in their blood cells, whereas only one out of 69 controls was positive. 

The association between the infection with the Borna Disease Virus (BDV) and the schizophrenia was convincing until by the beginning of the new 21 century, when in 2003 another research team from Japan, led by Terayama not only examined the schizophrenic patients with normal controls but with mood disorders’ patients as well. Surprisingly this group found higher anti-BDV-p10 antibodies in patients with mood disorders (27.3%), compared with schizophrenics (21.9%) and controls (4.0%)! This study also reported that the subgroup of schizophrenic patients with positive syndromes had a non-significantly higher frequency of anti-BDV-p10 antibodies than the subgroup of patients with negative syndromes.

Similarly, the production of anti-BDV-p10 antibodies was non-significantly higher among patients with the unipolar subtype of mood disorder than in those with the bipolar subtype. Two years later, in 2005 again another research group from Japan, Matsunaga and colleagues confirmed the presence of antibodies against Borna disease virus in various psychiatric disorders, not limited to schizophrenia. 

Retroviral etiology of Schizophrenia

Third to the influenza and Borna viruses, retroviruses have been the suspicious cause of schizophrenia. Retroviruses are single-stranded positive sense RNA viruses that as obligate parasites target the host cells and once inside the host cells cytoplasm, they use their own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). This new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, translating and transcribing the viral genes along with the cell’s own genes, producing the proteins required to assemble new copies of the virus. It is difficult to detect the virus until it has infected the host, which at that point, the infection will persist indefinitely. In fact studies of retroviruses have led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryocytes and prokaryocytes, the frontiers of life on earth. It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused the more chemically stable DNA to be used as genetic material. 

 When retroviruses have integrated their own genome into the germ line, their genome is passed on to the following generation. These endogenous retroviruses, contrasted with exogenous ones, make up 5-8% of the human genome. Most insertions have no known function and are often referred to as “junk DNA”, but many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during placental development in the course of the germination of an embryo, and resistance to exogenous retroviral infection. While exogenous retroviruses have been already linked to the autoimmune disorders such as Multiple Sclerosis (MS), the endogenous retroviruses could be the causes of many genetic diseases as they have become part of our genome. The transcriptional activation of these viral sequences in cells within the central nervous system can affect the transcriptional regulation of adjacent genes and result in alterations of neural functioning. Evidence of endogenous retrovirus activity is manifested by the identification of viral sequences in the brains and cerebrospinal fluids of affected individuals. In addition, affected individuals display evidence of increased activity of virally-encoded reverse transcriptase. 

Schizophrenia that has been hypothesized as a neuro-developmental disruption during fetal growth, has been hypothesized to be caused by endogenous retroviruses that are known for cell fusion during placental development in the course of the germination of an embryo. Le(y) is a carbohydrate determinant of membrane glycoconjugates and is expressed in some tumor and embryonic cells, and on T lymphocytes of HIV-infected humans. Kokai and colleagues from Japan in 1993 found that Le(y) antigen was most expressed in both CD4+ and CD8+ subsets of peripheral T lymphocytes in hospitalized schizophrenic patients. On the other hand, atypical lymphocytes with stimulated morphology are known to appear in the blood circulation of schizophrenic patients. Similar atypical lymphocytes have also been described in viral and autoimmune diseases. But since the retrovirus may not be active in peripheral lymphocytes, search for the detection of retroviral infections by measuring RT (Reverse transcriptase) activity in the peripheral lymphocytes and serum of schizophrenic patients, may not always yield positive results in every sample of patients. 

 Other infections and Schizophrenia

Infectious agents such as cytomegalovirus, Human Herpesvirus and Epstein-Barr Virus that have been already implicated in the pathophysiology of autoimmune disorders, have also been researched and suspected in the etio-pathophysiology of Schizophrenia. Borglum and colleagues conducted a genome-wide study of association and interaction with maternal cytomegalovirus infection and follow-up analyses of all individuals born in Denmark since 1981. These researchers reported that although several single nucleotide polymorphisms (SNPs) that have already been implicated as genetic risk loci in schizophrenia, only the SNP, rs7902091 in CTNNA3, a gene not previously implicated in schizophrenia had the strongest and significant interaction with maternal CMV infection. This recent study has cast more light on the link between infection and pathogenesis of schizophrenia that the association may not be a simple one, but require other interplaying substrates such as a vulnerable genetic locus. This may mean that not any mother with any infectious agents even during pregnancy would produce schizophrenic offspring, but those who may have such genetic susceptibility.    

 Arias and colleagues from Spain have recently conducted a meta-analysis of the association between different infectious agents and schizophrenia. These researchers have reported significant association between schizophrenia and infection by Human Herpesvirus 2, Borna Disease Virus, Human Endogenous Retrovirus, Chlamydophila pneumoniae, Chlamydophila psittaci and Toxoplasma gondii , with the strongest odd ratio (OR) link for Chlamydophila psittaci (OR=29.05) and the Human Endogenous Retrovirus (OR=19.31) compared to the others. As early as 1990’s, some researchers instead of looking for the direct viral evidence in the schizophrenic body fluids, they searched for the direct inference for the latent invasion of viruses in such patients population. Davis and Phelps showed that there is a higher chance of schizophrenia in monochorionic MZ twin pairs (60%) than in dichorionic pairs (32%) because of shared fetal circulation. But Sierra-Honigmann and colleagues failed to find viral nucleic acids in their schizophrenic samples. At the same time, Lahdelma and colleagues showed more atypical lymphocytes in the blood of their schizophrenic sample that reduced after treatment, an evidence that was interpreted as an exhibition of immunological aberrations. 

 Schizophrenia as an “immune” or “autoimmune disorder 

With the advent of more sophisticated immunological methods of detection of viral invasion, the new 21st century evidenced reports of appearance of different “cytokines”, a family of soluble polypeptides, critically important in the immune response to infection and other inflammatory processes, in the prenatal serum of schizophrenic samples as strong fingerprints of prenatal exposures to viral infections. This was based on the fact that most bacteria and viruses do not cross the placenta; but their damaging impact to the fetus could be detected through the maternal antiviral responses to infection (e.g. proinflammatory cytokines). Urakubo and colleagues by injecting E.Coli to rats to model prenatal exposure to infection, showed significant increases of interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha). These researchers concluded that maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain. Similarly and to link the detrimental effect of cytokines on the neurodevelopment and etiology of Schizophrenia, Marx and colleagues reported IL-1beta and IL-6 produced dose-dependent decreases in the number of neuron cells and lowering the neuronal survival. Gilmore and colleagues who were among the first researchers raising the cytokines as indices to the prenatal infection etio-pathophysiology of schizophrenia, in late 1990’s, later on in 2004 in rats demonstrated the reduction in the number of neural nodes and total dendritic lengths and numbers, and to lesser degrees an impact on the neuron survival (only on high levels of infection/inflammation) through cytokines. 

Soon cytokine studies in human subjects started by the early new century. Brown and colleagues on a nested case-control study of a large birth cohort, born 1959-1967, who were diagnosed with schizophrenia spectrum disorders and had available second-trimester maternal serum reported that the second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. But the study found no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1beta, IL-6, or TNF-alpha. As the interplay between the environmental insults such as infections and genetic susceptibility had long been substantiated, some researchers prompted probing into identifying such candidate genes, giving rise to schizophrenia in the offspring upon maternal infections. Schwarz’s research group from Germany were among the first to report in 2006 that an immune process, characterized by a relative predominance of the T helper-2 (Th2) system, possibly induced by a viral infection, may be involved in the pathophysiology of schizophrenia. These authors concluded “In this context, functional polymorphisms in the Interleukin-2 (IL-2) and Interleukin-4 (IL-4) genes appear to be principal candidates for genetic schizophrenia research. Further evidence for these candidate genes comes from several linkage analyses, pointing to susceptibility gene loci on chromosomes 4q and 5q, where the genes coding for IL- 2 and IL-4 are located.” 

Infection, genetic and immune systems interactions:

The interaction and timeline between maternal infection, genetic susceptibilities, and development of schizophrenia post-puberty, as the pieces of schizophrenic puzzle were formulated together and as confirmation of the disorder as a neuro-developmental through faulty fetal development. Soon another immune and polymorphic piece, i.e. Histocompatibility Leukocyte Antigens (HLA-G) was brought to complete the puzzle! This for example was formulated by Smith et al. that HLA-G in “the early stages of pregnancy may alter cytokine regulation by disturbing the whole uterine immune milieu.” This hypothesis assumed that since HLA-G molecules are the novel immune players maintaining the immune homeostasis during early pregnancy, protecting the developing fetus from maternal immune attack, then any disturbance in the HLA-G expression may fail to maintain such inhibitory potential to down regulate the detrimental inflammatory cytokines, thus rising to the neurodevelopment of schizophrenia. 

 Ellman and colleagues went beyond the cytokines detection in prenatal sera and showed structural brain alterations following fetal exposure to the inflammatory cytokine interleukin-8, fitting the neuroanatomical template of schizophrenia, e.g. significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex, right posterior cingulate, right caudate, bilateral putamen and the right superior temporal gyrus volumes. Likewise and in link with the genetic vulnerability, Agartz and colleagues reported that the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1 is implicated in the development of schizophrenia, causing specific brain anatomical structural deficit, already evidenced in schizophrenia. While the cytokines and HLA consolidated the infectious theory of schizophrenia, the MHC and their loci on the vulnerable genetic loci such as chromosome 6p21, were good proof of the neuro-developmental concept of this disorder. MHC that are expressed on neurons in the central nervous system throughout development and into adulthood, regulating many aspects of brain development, including neurite outgrowth, synapse formation and function, long-term and homeostatic plasticity, and activity-dependent synaptic refinement, completed the etiologic puzzle of schizophrenia and took the neuro-developmental theory to the championship podium!

While the theory of prenatal infection and insult was consolidating through the link with genetic vulnerability and evidenced by the pro-inflammatory cytokines, MHC and HLA’s, and weaving well with the long-suspected neuro-developmental hypothesis of schizophrenia, this story of schizophrenia took a different twist, by some who simplified the formulation and attempted to show that any infections at any age could cause this disorder! The first of such studies from Finland in 1997 was a follow-up of a birth cohort until 28 years of age reported no association between bacterial CNS infections during childhood and subsequent schizophrenia, whereas an increased risk was described for viral infections (odds ratio=4.8). In a later follow-up of the same cohort in 2004 up to the age of 31 years, the risk associated with viral infections was, however, attenuated (odds ratio=2.5). In another Finnish study in 2003, no increased risk for schizophrenia was found in a cohort consisting of 320 individuals who had suffered from viral CNS infections (the majority by enteroviruses) before their 15th birthday. 

 But a few years later in 2008, Dalman and colleagues reported “exposures to mumps virus or cytomegalovirus were associated with subsequent psychoses.” Shortly after, Benros et al. in 2011 reported co-occurrence of autoimmune diseases and severe infections, in the patients not per se their mothers, multiply the risk of schizophrenia before such diagnosis. These authors reported that a prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29), any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60), and when the two risk factors combined, the risk of schizophrenia increased even further (incidence rate ratio=2.25), and more so the risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40. 

 Schizophrenia: neuro-degenerative or neuro-developmental?

The neuro-developmental theory of schizophrenia emerged in mid-1980’s by Murray et al. in 1985, who against the trend of the time, conceiving this disorder as mostly genetic, brought the environmental insult into the pathophysiologic formulation. Then Weinberger in 1987 agreed with this concept of the neurodevelopmental model in which a fixed lesion from early in life interacts with normal brain maturational events that occur much later. Then Saugstad in 1989 differentiated between manic-depressive psychosis and schizophrenia that “the first one affects early maturers and schizophrenia affects late maturers… Redundancy of neuronal synapses characterize manic-depressive psychosis, and reduced density of synapses is a characteristic of schizophrenia, whereas ‘normality’, with optimal synaptic density, is in between.” 

 In 1992, Murray et al. differentiate among heterogeneous forms of schizophrenia and called the early onset schizophrenia, congenital and “a consequence of aberrant brain development during fetal and neonatal life. Such patients show structural brain changes and cognitive impairment…and poor outcome, and reflect Kraepelin’s original description of dementia praecox.” This way Murray weaved the new concept of Neurodevelopmental with the old neurodegenerative pathophysiology of schizophrenia, and despite appreciating the genetic defects in the control of early brain growth, and “early environmental hazards such as prenatal exposure to maternal influenza or perinatal complications”, he wondered “How foetal or neonatal lesions produce hallucinations and delusions two or three decades later remains a mystery…” 

While in 1990’s there were still controversy about the true pathophysiologic process of schizophrenia, being primarily neurodevelopmental, neurodegenerative or both, Vita and colleagues from Italy in 1997, seemed to solve the mystery. These researchers based on their neuro-anatomic studies on large samples of schizophrenic brains, stated “the demonstration of stability of cerebral ventricular dimensions both in chronic schizophrenia and around the onset of the disease, and that of an identical effect of ageing on this morphological feature in large samples of patients and controls, strongly support the neurodevelopmental nature of brain pathomorphology in schizophrenia.” This group suggested the etiology and true onset of the disease to “a very early event in the history of the individual who will develop schizophrenia…that can probably be traced back to the stages of development of CNS…a deviation from the expected course.” This lead others such as O’Connell et al., to critically review the whole long believed concept of schizophrenia from Kraepelin who labeled it dementia-praecox to Bleuler and others later on who ignored the true neurodevelopmental explanation of the disease that “Over a century ago, the Scottish psychiatrist Thomas Clouston proposed the idea of a developmental or adolescent insanity…having a male predominance and a poor outcome, and noted the frequency of a family history and…he considered it a disorder of cortical development and the onset of psychotic symptoms due to maturation during adolescence “of certain parts of the brain which had lain dormant before”.

 But all these were not still sufficient to clear the mind paths of some such as Garver who wrote in Harvard Review of Psychiatry “Evidence is increasing in support of the etiologic heterogeneity of schizophrenia. Five distinct diseases/disorders are…A familial dopamine psychosis,… a neurodegenerative psychosis,… a neurodevelopmental psychosis,… nonfamilial forms include a neurodevelopmental Psychosis… and a lithium-responsive psychosis…” This prompted Woods to propose “a progressive neurodevelopmental” model as “a unitary pathogenetic mechanism.” for the pathophysiology of schizophrenia. Based on the imaging data in schizophrenia, Woods argued that neuroanatomical deficiencies, e.g. brain and ventricular volume losses occur after maximum brain volume expansion before the onset of the illness clinically in support of the neurodevelopmental hypothesis, but “equivocal evidence” indicates “that it continues after onset of overt illness” with “available clinical and experimental models of late deterioration after static, early brain lesions” in support of the old neurodegenerative theory. Therefore the solution to the dilemma seems to be a adopting a position in-between, i.e. “A progressive developmental mechanism can reconcile the neuropathological and imaging data, while being compatible with both early onset and late deterioration.”

But the new proposed theory of “progressive neurodevelopmental” of schizophrenia was not yet sufficient to reach a general consensus and some such as Lieberman, still insisted “the rejection of a role for neurodegeneration in the pathophysiology of schizophrenia is unproven and may be premature. A wholly neurodevelopmental perspective of the illness imbues the illness with a pessimistic inevitability and therapeutic nihilism that may be unwarranted.” This again created a heated debate, starting from the paper by Marenco and Weinberger a year later at the turn of the new millennium under the title of “The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave.” These researchers from NIMH (National Institute of Mental Health) in a full force argument supported the neurodevelopmental theory of schizophrenia against an old but persistent neurodegenerative concept by reviewing the whole course of the disease from “conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem”. The authors strongly refuted the old neurodegenerative thinking based on among others, “the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration.”

While such a Cartesian or bipolar model could in the past sway back and forth for ever, e.g. idealism and materialism in philosophy, the new century demanded and favored multi-factorial concepts. Hereby some such as Ashe et al. simply by taking a middle ground attempted to bring the both opposite sides of the argument to a form of negotiation and solution of the mystery of schizophrenia. These authors’ middle ground vision that was not new, stated “Each hypothesis explains some of the phenomena associated with schizophrenia and it is probable that many variables described in these hypotheses interact to produce a disorder characterized by heterogeneous symptomatology, progression and prognosis.” This liberalism while admitting to the “Compelling evidence suggests that the primary disturbance is a neurodevelopmental abnormality, possibly resulting from a genetic defect(s), resulting in a predisposition to schizophrenia.” Added some flavors from the opposite front that “Events later in life may then lead to the presentation of symptoms and a subsequent progression of the disease…associated with ongoing neurodegenerative processes.” McGarh et al. along the same path, declared “progressive neurobiological processes have replaced early versions of the neurodevelopmental hypothesis, which were based on a ‘static encephalopathy’. In addition, recent models have suggested that two or more ‘hits’ are required over the lifespan rather than only one early-life event.”    

Rapoport et al. in 2005, in their extensive review of the literature on the pathophysiological mechanism of schizophrenia asserted “Neurodevelopmental models remain dominant…and therefore distinctions between early and late models and between neurodevelopmental and neurodegenerative hypotheses have become outdated.” These authors relying on the variation and time differential in brain development in normal and pathological states, and across a longer life span than the age of onset per se, appreciated the different times of onset in schizophrenia and correspondingly different pathophysiology in different parts of the brain with different symptomatic presentations in a defined schizophrenic range, signify the importance of genetic-environmental interaction in causing this most devastating human’s psychopathology. But this group put more emphasis on the determining factor of susceptible genes of schizophrenia in differential timing of the onset of the disease than on the environmental insults, e.g. infections. Moreover these reviewers implied to the contributing pathophysiologic role of other environmental factors such as stress that could be partially etiological upon interacting with susceptible genome: “It is increasingly obvious that risk genes for schizophrenia have multiple actions and variable expression at different times and different brain locales…The variable expression and actions of genes may also provide meaningful correlates for the pan neurodevelopmental delays, and widely varied psychiatric symptoms seen years before the onset of schizophrenia. We have increasingly specific formulations of how and when various etiological genetic and nongenetic factors may act and interact with increasingly well defined early and later onset environmental risk measures…Thus in addition to prenatal insults, both late genetic and late environmental (and of course interactive) models could account for the variable age of onset.”

 While Rapoport group only implied on the non-specific, non-genetic and non-perinatal insults, all as early and non-changeable determinant of schizophrenia, others such as Pantelis et al. expanded on this and attempted to explain the illness progression after the onset. “(i) an early (pre- and perinatal) neurodevelopmental lesion renders the brain vulnerable to anomalous late (particularly postpubertal) neurodevelopmental processes, as indicated by evidence for accelerated loss of gray matter and aberrant connectivity particularly in prefrontal regions; and (ii) these anomalous neurodevelopmental processes interact with other causative factors associated with the onset of psychosis (e.g., substance use, stress, and dysregulation of the hypothalamic-pituitary-adrenal axis function), which together have neuroprogressive sequelae involving medial temporal and orbital prefrontal regions, as suggested by imaging studies around transition to active illness.” The neurodegenerative proponents across the globe once more arose to the contention, e.g. Pérez-Neri et al. from Mexico who attempted to explain the model against the neurodevelopmental one not only by the progressive evidence of the disease and neuroanatomical correlates beyond the onset of the disease, but with neurochemical evidence of “neuronal death under certain conditions” after the disease onset. 

It was perhaps Fatemi and Folsom who in 2009 in their extensive revisiting of the neurodevelopmental hypothesis of schizophrenia supported the new model by numerous multi-disciplines evidence and refuted the old environmental and neuro-degenerative models. “In addition to the neurodevelopmental model, there are alternative models that have been used to explain the etiology of schizophrenia. It is likely that due to the heterogeneous nature of schizophrenia that multiple factors interact to produce the disease state such as disruptions in the dopaminergic, serotonergic, and glutamatergic systems as well as neurodegenerative changes. With regard to epidemiology, a number of social factors have been shown to increase the risk of schizophrenia including urban birth and upbringing, quality of maternal-child relationship, and migration, a risk that increases when the immigrant group is a small minority indicating that isolation and lack of support may be important factors. An alternative explanation, however, may be that urban birth and migration may well be consistent with the neurodevelopmental hypothesis in that these represent, respectively, an environment in which one is exposed to more pathogens and an environment in which one may have not developed native antibodies or other resistances to pathogens.”

Fatemi and Folsom in explanation for the progressive clinical and anatomical deterioration course of the illness in some schizophrenics beyond the onset that has been reiterated as a major evidence in support of the neuro-degenerative model by some, asserted “A mechanism to explain the progressive elements of schizophrenia is apoptosis, or programmed cell death, especially synaptic apoptosis in which apoptosis is localized to distal neurites without inducing immediate neuronal death.” Among some neuro-pathological evidence against long-standing neuro-degeneration beyond 2-4 years occurring after the onset of first episode psychosis in schizophrenia, that is according to the earlier programmed neuro-developmental model, these authors explained “Interestingly, caspase 3, the caspase molecule most associated with apoptosis in the CNS is not upregulated in temporal cortex of subjects with schizophrenia, suggesting that chronic apoptosis is not taking place, in contrast to classic neurodegenerative disorders.” These authors also recited the critic to the neurodegenerative model by Weinberger and McClure, that there is a lack of expression of genes involved with DNA fragmentation and response to injury from postmortem studies. They also evidenced from longitudinal studies of cognitive function and genetic linkage studies including the regional Reelin gene e.g. by Wedenoja et al. that do not support a progression of loss of function that would be expected by the neurodegenerative hypothesis.

 Hereby over the past decade, the neuro-developmental theory of schizophrenia has been empowered by neuro-anatomical and neuro-chemical, imaging, genetic and neuro-metabolic studies, including the neuroplasticity disruption, neuro-connectivity disturbance, neuro-inflammatory theories that all properly link together. Considering schizophrenia as a disorder of neuroplasticity with abnormalities of the glutamate neurotransmitter system has been integrated with the neurochemical, genetics and neurodevelopmental hypotheses. The neuroplasticity and neuro-connectivity theories have also been associated with the development of neural synchrony among the large-scale cortical networks during adolescence that has been disrupted neuro-developmentally by genetic susceptibility and early environmental insults such as prenatal maternal infections. As a result steps have been taken toward interest and research in the prodromal phase and the possibility of preventing schizophrenia by interfering with the aberrant postnatal brain maturation associated with this disorder. On this path, neuregulin-1 (NRG1), a protein that in humans is encoded by NRG1 gene and is influential in synaptic plasticity, along with the disrupted-in-schizophrenia-1 (DISC1) protein coded by DISC1 gene that has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, have been considered among the key elements for the future of early diagnosis, treatment and hopefully prevention this most severe psychopathology. Also since the brain abnormalities are most profound in early onset of the schizophrenia and during the peak of brain development, new interest in very early onset even childhood-onset schizophrenia, where progressive loss of gray matter, delayed/disrupted white matter growth, and a progressive decline in cerebellar volume are the most, have been renowned. These developmental patterns or the ‘trajectories’ of brain development that are more striking and important than cross-sectional neuro-anatomic differences have initiated some longitudinal studies in schizophrenia. 

 It took us more than half a century from the first suspicion to the link of etiology of schizophrenia with infection in Russia by Abaskuliev in 1950 and after a long haul of rivalry type of argument between the old neuro-degenerative and the new neur-developmental fronts that interests were once again revived in this area, resulted in the birth of developmental neuroinflammation theory of schizophrenia. In the search for immune-mediated disruption of early brain development following maternal prenatal infections, the early prenatal cytokine hypothesis, raised more than a decade ago has again become a subject of vigorous research. As a result some such longitudinal studies in animal models have indicated that infection-induced developmental neuroinflammation may be pathologically relevant beyond the antenatal and neonatal periods, and may contribute to disease progression associated with the gradual development of full-blown schizophrenic disease, so resolving the issue of progressive pathology that has been brought up by the oppositions of the neuro-developmental theory. 

In recent years as always that a trend dominates not just the filed of psychiatry but every domains of medicine and life, there have been attempts to prove schizophrenia among some other psychiatric disorders such as major depression as “inflammatory” or “metabolic” disorders. The acute and chronic infections and the history of such insults have always been associated with immune response and defense from the body with the presence of antibodies and other immune elements such as cytokines that decades ago have been addressed at least in connection between infection and schizophrenia. But recently, perhaps after the big fad in linking depression to inflammation, this perspective has been seen in schizophrenia as well. Although the proponents of such model, admit to the dominant neuro-developmental theory of the disease and perceive the both theories as complementary to each other, the primary role of infection seems to have been lost or minimized in the formulation at least by some. Altamura and colleagues along this line have stated “it seems that schizophrenia is associated with an imbalance in inflammatory cytokines. Alterations in the inflammatory and immune systems, moreover, seem to be already present in the early stages of schizophrenia and connected to the neurodevelopmental hypothesis of the disorder, identifying its roots in brain development abnormalities that do not manifest themselves until adolescence or early adulthood. At the same time, neuropathological and longitudinal studies in schizophrenia also support a neurodegenerative hypothesis and, more recently, a novel mixed hypothesis, integrating neurodevelopmental and neurodegenerative models, has been put forward. “

 Andres and Kinney from Harvard, most recently in 2015, on the immune path have gone too stated “…an emerging model of atypical immune function and development helps explain a wide variety of well-established-but puzzling-findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre-and perinatal adversity, often combines with abnormal brain development to produce schizophrenia…disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia.” As we see, these authors among some others attempt to present the immune system disruption at times not as a secondary reaction and phenomenon to the primary microbial insults, but as primary that lends the body to susceptibility to infecting agents so impede the normal brain development and the cause of schizophrenia. Hereby they seem to be so convinced that they suggest “new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia” that supposedly is a form of immune therapy! 

 From infection to Schizophrenia: The pathophysiology of an insult

 First: The Prenatal Insult and Maternal/Fetal Immune Reactions

It has been a long time and efforts since 1950 when the hypothesis and link of schizophrenia to infection was proposed for the first time. But the theory, that has survived strongly despite many oppositions, yet has been ignored for presentation at a large scale not only to the public, but even to the medical field itself, and has remained only in the very narrow schizophrenia research arena. As discussed in some detail here, the infectious origin of schizophrenia complements the dominant neuro-developmental hypothesis of the disorder. There is almost no doubt in the fact that schizophrenia is a byproduct of aberrant brain development at a very sensitive time window that seems to be long before the first clinical onset. With strong evidence, this time window seems to be prenatal, through a maternal insult to the fetus that is most probably of infectious origin. The infectious hypothesis of schizophrenia that complements the neuro-developmental theory of the disease, fits some seasonal births of the disease, the genetic concordance rate of the disease that is only 40-50% between identical twins, who share 100% the same genetic pool.     

The bigger question and dilemma now is how an infection, which is not yet clear to be specific or non-specific, would trigger the pathophysiologic machinery of schizophrenia. What we know through years of observation and research is that such prenatal infection(s) in the mother at a very sensitive time window, invade(s) the fetal brain and trigger(s) a series of immunological reactions that altogether disrupts the normal fetal brain development and years after birth, predominantly during adolescence years, leads to the manifestation of schizophrenia. As genetic susceptibility alone is not sufficient to cause schizophrenia per genetic linkage, genome wide association studies (GWAS), etc., nor the infection alone as no prenatal infection(s) have shown to cause the disease in the off-springs of all affected mothers. Therefore it seems that an interaction of infectious insult at a specific window time of brain development in genetically vulnerable fetuses could produce schizophrenia. In the following I will attempt to show the evidence for such an interplay.

 Supplementary to the field observational studies on the link between infections and the etiology of schizophrenia partly mentioned throughout this paper, the Maternal Immune Activation (MIA) model of schizophrenia has attempted to experimentally cause schizophrenic-like conditions in rodents and even recently in primates. These studies by administration of viral particles and proteins, e.g. the double stranded RNA poly I:C, and lipopolysaccharide (LPS), both of which induce strong innate immune responses, to pregnant rodents and primates, have evidenced behavioral, neurochemical, psychophysiologic, and histologic abnormalities found in patients with schizophrenia. Of neuro-chemical relevance to the dopaminergic hypothesis of schizophrenia, administration of poly I:C to pregnant rodents has been shown to cause an increase in the number of mesencephalic dopamine neurons in the fetal brain during mid to late gestation, accompanied by changes in fetal expression of several genes involved in dopamine neuron development. 

 The role of cytokines, e.g. IL-6 in the pathophysiology link of schizophrenia with prenatal infection has also been experimentally confirmed through neutralization of schizophrenic-like symptoms in animal models by co-administration of anti-IL-6 antibodies, and in IL-6 knockout mice at the presence of the offending agent poly(I:C). Direct injection of pregnant rats with IL-6 has also been shown to cause increased IL-6 levels, increased hippocampal IL-6 mRNA, hippocampal astrogliosis and neuronal loss, and impaired spatial learning in the off-springs. Moreover, downstream of the IL-6 receptor and activation of IL-6 response genes have been found in the placenta and the fetal brain of MIA-exposed offspring. Evidence also suggests that MIA is associated with elevations of cytokines in offspring at homologous ages to the usual age of onset of schizophrenia. Prenatal exposure to LPS has also been shown to cause an increase in the serum proinflammatory cytokine levels, including IL-2, IL-6, and TNF(Tumor Necrosis Factor)-alpha during this stage of life. 

 In addition to the MIA models discussed above, several experimental animal studies have validated the infectious/inflammation pathophysiology of schizophrenia in consistent the old dopaminergic and the new glutamergic hypotheses of the disorder. IL-6 administration of rodents have caused hyperdopaminergic-related psychotic symptoms, with the sensitization to the locomotor-stimulating effects of amphetamine. Furthermore, in an astrocytic cell line, both acute and chronic exposure to methamphetamine has been shown an increase in IL-6 mRNA and protein levels. The cytokine model of SZ is also consistent with the glutamate hypothesis of schizophrenia by demonstrating that ketamine disrupting parvalbumin containing interneurons (PV+), (important in regulation of pyramidal cell activity and possibly cognitive processes such as working memory), through activation of NADPH-oxidase, all in support of the glutamergic hypothesis of the disorder. Ketamine administration has also been shown to induce expression of IL-6, and IL-6 antibodies. Moreover, in IL-6 knockout mice, ketamine did not alter PV+ interneurons nor did it activate NADPH-oxidase. Furthermore, overexpression of IL-6 has also been associated with cognitive deficits, such as spatial memory and learning abnormalities, and related deficits in long-term potentiation (LTP) in preclinical models, consistent with clinical observations in schizophrenia. Applying even low levels of IL-6 to hippocampal slices impairs LTP, and application of an IL-6 antibody to normal rats increases LTP and hippocampus-dependent spatial alternation learning. Moreover, IL-6 knockout mice show an enhanced learning on the radial maze, while the mice with overexpression of IL-6 have avoidance learning deficits, which were associated with loss of PV+ neurons in the hippocampus, as well as increased gliosis and microglial activation.                           

Lastly and despite being simplistic and generic, perhaps for being preliminary, treatment studies of anti-inflammatory agents have supported the neuro-immunologic pathophysiology of schizophrenia. The cyclo-oxygenase 2 inhibitor celecoxib as an add-on agent to antipsychotic medications in four randomized, placebo-controlled clinical trials and aspirin in one study have been shown at least partial benefit on the PANSS or CGI scales. Moreover, associations between response to cyclo-oxygenase inhibition and an impaired type 1 to type 2 immune balance, not normalized by treatment with cyclo-oxygenase inhibitors, have also been reported. The anti-inflammatory agent minocycline has also been tested as an add-on agent in two randomized, blinded clinical trials in schizophrenia, with improvements observed on negative symptoms and executive functioning.

Second: The Sensitive Time window 

From about 15 weeks of gestation, the axons and dendrites start to outgrow to form the highways of the brain for connection and communication that continues until about 18 months of life. Around the same time synapses, that are the crossroads of neurons are formed for inter-neuron communication. This happens almost at the same time that myelination, essential for conducting signals and impulses, and vital for regeneration of the whole nervous system (the only body organ to regenerate after insults) that continues until mid-adolescence. During normal development, critical periods occur in a predictable temporal sequence, as depicted with examples of vision, language, and higher cognitive function. Following an insult such as infection, certain critical periods may be developmentally delayed or halted. Critical periods might then become incorrectly synchronized or uncoupled from one another across the brain. Alternatively, the extended duration of one critical period may stall the onset of others. 

The survival and growth of neurons is regulated by survival factors, called trophic or nerve growth factors (NGF), discovered by Stanley Cohen and Rita Levi Montalcini who won the Nobel Prize in Medicine in 1986. There are several NGF’s including the most influential ones, BDNF (Brain Derived Neurotrophic Factor) and GDNF (Glial derived neurotrophic factor). BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain, areas vital to learning, memory, and higher thinking. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development. GDNF is a potent trophic factor for striatal neurons, hence the survival and differentiation of dopaminergic neurons. GDNF has regenerative properties for brain cells and has been shown potential as treatment for Parkinson’s disease. 

 A microbial insult after 15 weeks of gestation, could disrupt the above-mentioned neuro-developmental processes. Moreover the neuro-receptors would also be affected later on in life as there are age-related differential binding potentials. For example, among different dopamine (DA) receptors, D1 receptor that is the most abundant of the DA receptor subtypes normally decline in binding potential by age, most prominently in cortical regions including the dorsolateral prefrontal cortex. Also expression of the dopamine D2 receptors in the prefrontal cortex normally peak in infancy then decline and by adolescence reach the adult levels. All these after an insult could be disrupted and there would be no normal decline in the number and potential binding of D1 and D2 receptors, supported by dopaminergic theory of schizophrenia. 

 Furthermore, GABA, the chief inhibitory neurotransmitter in a mature brain, acts primarily excitatory and appears earlier than glutamergic transmission in the developing brain. In the developmental stages preceding the formation of synaptic contacts, GABA regulates the proliferation of neural progenitor cells, the migration and differentiation, and the formation of synapses, via BDNF expression, and also regulates the growth of embryonic and neural stem cells. An early insult to the fetal brain development could disrupt normal developmental process of conversion of GABA neurotransmission from excitatory to inhibitory. This could also delay or disrupt the glutamate neurotransmission that normally develops later on and is vital for the modulation of synaptic plasticity. Moreover exposure to an insult such as infection in the developing brain could trigger excitotoxicity in the brain through excessive glutamergic reaction and cause neuro-degeneration. 

At the neuroanatomical level, the pronounced increase in total cortical grey matter volume, occurs from 29 weeks to 41 weeks of gestation with a double increase from 20% to 40%, along with a marked increase in the cerebral gyration. In contrast to the marked changes in cortical grey matter volume, subcortical regions including basal ganglia and thalamus show no significant volume changes during the observed period of brain development. The increase in the cortical grey matter volume that relates primarily to neuronal differentiation, dendritic and axonal branching and gyral development rather than to an increase in numbers of neurons, is complete by approximately 20-24 weeks of gestation. Therefore an early insult such as infection to the fetal brain development could disrupt all the above neuro-developmental processes. Moreover, the process of myelination of brain white matter that occurs principally from 29 to 41 weeks of gestation could be disrupted by the microbial insult. That is why neuroimaging studies in schizophrenia have revealed global differences, suggesting the impairment of multiple brain circuits, with some brain regions showing focal abnormalities, altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi, internal capsules and corpus callosum.

 In summary it seems that the sensitive time window that an insult such as prenatal maternal infection could cause major disruption in the major cortical grey matter circuits, the integrity of white matter pathways, neuronal differentiation, dendritic and axonal branching, gyral development and neuro-plasticity, is in the second trimester. As discussed earlier this hypothesis has been supported by the prenatal maternal infection studies that when occurring in the second trimester have produced schizophrenic off-springs. 

Third: The Genetic Vulnerabilities

Thus far prenatal maternal infection at a sensitive time window of fetal brain development could cause a non-specific neuro-developmental pathology later on in life. But it is theoretically possible that a specific prenatal maternal infection could cause a specific neuro-developmental disorder, though different infective agents supposedly could not cause the same disorder. For causing a specific disorder such as schizophrenia by more than one infecting agent, there needs to be a specific genetic vulnerability. 

 But genetic studies including the modern genome wide association studies, have failed to identify any specific gene(s) in schizophrenia. Moreover the concordance rate of the disease in identical twins is not more than %50 that is almost the same rate as the off-spring of both parents affected. Only in sporadic cases, a number of replications of larger genetic structural variants, such as CNVs (Copy Number Variants), and smaller genetic mutations e.g. SNP’s (Single Nucleotide Polymorphisms) have finally beginning to emerge. Moreover, there is accumulating evidence for shared genetic liability among major mental disorders, psychotic and non psychotic. This general inherited liability for CNS dysfunction does not always develop into schizophrenia or even any psychopathology, blurring the boundaries between normal and pathological genotypes. The genetic contribution of schizophrenia is less favorable, considering that about 90% of the patients have no afflicted parents and up to about 60% have no first or second degree relative with the disorder! In a better word, most cases of schizophrenia seem to be sporadic than genetic. Moreover a highly heritable disease will escalate its rate over generations as it appears to be the case in ADHD, but not schizophrenia. 

At the best some rare mutations such as CNVs and SNP’s that are sufficient to produce schizophrenia are located across many different chromosomal regions, encompass a number of different genes, and usually have high but incomplete penetrance. In these cases, most of the identified CNVs and SNP’s are de novo and not inherited. These different chromosomal regions with rare CNVs and SNP’s capable of causing schizophrenia, usually do so one at the time! Therefore it seems that genes alone, one or more could not cause schizophrenia alone, and genetics cannot explain the etiopathology of this disorder. That is why schizophrenia genetics needs epigenetics, where the genetic and environmental factors interaction are both counted in the pathophysiology of the disorder. While the genes or the environmental offending agents such as infections alone cannot cause schizophrenia, they do so synergistically at a sensitive time window of fetal brain development. 

Genetic mutations could be de novo or primary through errors in DNA methylation programming, or secondary caused by environmental insults such as infecting agents or “epigenetic misregulation” of the genome. As it was discussed earlier, epigenetic misregulations, e.g. sporadic CNV’s or SNP’s occur in schizophrenia even without genetic liability, and most probably by environmental pathogens. Whatever the origin, epigenetic markings of DNA are heritable and transmitted through mitosis in somatic cells during morphogenesis and growth. As most infecting agents such as viruses do not cross the placenta, the pathological mechanism to the fetus, as presented earlier, is indirect and through maternal immune responses, e.g. proinflammatory cytokines such as interleukin-6, -8, etc. that have been experimentally shown to increases the risk of schizophrenia. 

More recently there have been studies in support of epigenetic mutation of human genes by microbial invasion and leading to diseases with several years in latency such as in the case of schizophrenia. Bobetsis et al. (2010) have identified 74 placental/fetal genes epigenetically misregulated by bacterial infection during murine pregnancy. Most of the genes involved in fetal development were downregulated and included among others, two genes involved in neurodevelopment, the synaptotagmin X (SYT10), and the neuropeptide galanin (GAL) and its receptor (GALR3). SYT10 regulates the secretion of neurotransmitters and signaling between neurons, whereas mutations in the GAL gene underlie broad CNS impairments, for example lower numbers of sensory neurons and reduced capability for nerve regeneration. 

In addition to the secretion of maternal inflammatory cytokines and crossing the placenta in defense to the microbial invasion, microglia that is abundant in the fetal brain are activated and produce chemokines and cytokines that can be toxic during neurodevelopment. Also with bacterial infections, endotoxin lipopolysaccharide does cross placenta and induces cytokines in the fetal brain, as determined by increased levels of the corresponding mRNA directly implicating underlying epigenetic mechanisms. In fact, IL-6 that facilitates maternal host-versus- graft reaction is a cause of spontaneous abortion, but in less drastic situations, a partial maternal rejection of the fetus would compromise the integrity of the fetal- placental link and fetal neuro-development and increase the risk for schizophrenia.                                          

The Final Step: The Beginning is the End

For long it was thought that the onset of schizophrenia is when the psychotic symptoms appear. Later on a prodromal stage before the onset of psychotic symptoms, by observation of odd and bizarre changes in the personality and behaviors of the yet to be patient was appreciated.   But the neuro-developmental concept of schizophrenia not only changed the old Kreaplinian concept of the disease as a neuro-degenerative one, but revealed the fact under the tip of the iceberg that the disorder has had a long-term pathological process, before the first clinical manifestation. Therefore as I have presented here, the clinical onset of the disease which seemed to be the beginning, it is in fact the end of such underlying pathophysiological process that initiated almost two decades before the birth of the victim patient, in the mother as a prenatal maternal infection. 

The onset or clinical manifestation of schizophrenia in late adolescence and not earlier or later has always been a dilemma, and even now with its convincing neuro-developmental/prenatal maternal infection theory. Another important and reasonable question is to differentiate among different consequences of prenatal maternal infections at least in the CNS. In other words, what determines an offspring of a mother with prenatal infection to develop later in life schizophrenia, or earlier in life mental retardation, learning disabilities or a pervasive developmental disorder such as autism? Even if the damage by the infective agent being generic and non-specific and through triggering maternal and fetal immune reactions, such as secretion of inflammatory cytokines, the answer to this important question, probably lies in the sensitive time window of brain development that was detailed earlier, and the maternal and fetal immune response. 

 This has been explained well by some, e.g. Meyer et al. at least in differentiation between the development process of schizophrenia and autism that despite their differences, share some features. These authors among others postulate that “the induction of persistent inflammation may be more relevant for the etiopathogenesis of autism by contributing to phenotypic abnormalities specifically seen in this disorder. By contrast, latent immune inflammation may be essential to the pathogenesis of schizophrenia-specific brain and behavioral abnormalities.” In support of this hypothesis, there are several lines of evidence that autism but not schizophrenia is characterized by relatively severe chronic inflammation, both in the periphery and in the CNS, e.g. a nearly 50-fold increase in TNF-α level in the cerebrospinal fluid (CSF) of autistic children, and severe inflammation in the brains of autistic patients, characterized by prominent activation of microglia and astroglia cells and enhanced pro-inflammatory cytokine and chemokine expression in multiple brain areas, including the cerebellum, cortex, and white matter tracts. Moreover experimental work in rodents provides further evidence that prenatal immune challenge can lead to long-lasting inflammatory changes, persisting into adulthood, suggesting that immune challenge early in life can permanently alter postnatal immune functions. This idea is further supported by the finding that sub-chronic maternal treatment with IL-2 on gestational days 12 to 17 leads to elevated B and T cell counts in response to antigenic stimulation in the juvenile rodents offspring. 

Another important differentiation is that prenatal exposure to relatively severe forms of maternal immune challenge, i.e., following chronic or sub-chronic maternal infection/inflammation could cause latent impact, while by contrast, acute prenatal inflammation (e.g., by single PolyI:C administration) appears to be largely devoid of long-term neuroinflammatory effects in the adolescent or adult offsprings. In contrast to autism, chronic neuroinflammation seems less prominent in schizophrenia. Indeed, even though peripheral pro-inflammatory markers such as IL-6 appear to be elevated in at least a subgroup of schizophrenic patients, the reported increases are relatively modest. Furthermore, despite considerable research efforts, imaging and post-mortem immunohistochemical studies provide very little evidence for over-activation of microglia and astrocytes in the brains of schizophrenic patients. 

Another line of evidence for the latent onset or clinical manifestation of schizophrenia is in the stages of brain development, specially higher cortical functions that matures only after the onset of adolescence, the time of maturation and development of all the brain’s plasticity, connectivity, etc. Schizophrenia as everyone knows is a disorder of the human’s logic, reality touch, higher level of salience and coherence in all emotional, linguistic and logical levels that require maturity, occuring from adolescence into adulthood. Experimental models in support of this have shown that prepubertal humans rarely develop psychosis after exposure to NMDAR antagonists, such as PCP or ketamine. As Farber (2003) has pointed out, NMDAR-hypo state that was created prenatally can remain quiescent throughout childhood until maturational changes in brain circuitry make the brain function more vulnerable to the underlying biological defects which creates the stage for schizophrenia symptoms to emerge. Moreover it has been recently shown that progression from prodromal symptoms to manifest schizophrenia could be significantly reduced with neuroprotective compounds, such as long chain omega 3 fatty acids. 

For long, from the time of Kraepelin to Bleuler and Schneider, schizophrenia had been conceptualized, classified and understood through phenomenology and symptomatic description and interpretation. Even to this day, the disorder is diagnosed symptomatically, not etiologically or pathophysiolgically, for lack of consensus and still treated symptomatically and inefficiently at the high cost of sufferings and anti-psychotics’ severe disabling and threatening side-effects. As Insel (2010) suggested, neurodevelopmental model may change our concept of schizophrenia, so that first manifestations of psychotic symptoms would be seen not as the onset but as the late stage of this illness, which is likely to have lasting and important implications for research and especially treatment and prevention. With our modern understanding of schizophrenia at a deeper pathophysiological level and not a superficial symptomatic one, e.g. the concept of schizophrenia as disorder of higher neuro-connectivity, we appreciate the disorder not only as a thought disorder with delusions and hallucinations, but a higher cortical disorder with perceptual, emotional, motivational, and cognitive disturbances. Therefore the neurochemical abnormalities lie not only on the old hyperdopaminergic or the modern serotonergic models, but involve other neurotransmitter systems such as glutamate, GABA, acetylcholine, etc. that could open the venue for a better pharmacotherapy. 

Therefore the true neuro-developmental nature of schizophrenia in link with the prenatal maternal infections and ensuing maternal and fetal immune responses need to be appreciated at a larger scale and not limited to schizophrenic research arena. This is so vital as it will shift our attentions and efforts from treatment of the active cases after the damage has already been done toward the strategies for mental health education, screening and prevention of this devastating disease. Psychiatry that was born with schizophrenia and still remains to be its major target, could be changed for ever if it reveals the hidden path from infection to the disease.   

Conclusion

1. Psychiatry has come a long way to recognize schizophrenia as a neuro-developmental disorder. But this conviction still remains mostly in the scientific arena and has not yet been fully revealed at a large scale for practicing psychiatrists and others caring for the schizophrenics. This revelation is vital and holds the future direction of early diagnosis, treatment and prevention. Schizophrenia is no longer a static disease to be recognized and treated when it happens, but it is a disease in the process years before the first clinical onset, even the prodromal stage, from the time of fetal development. The discovery of the neurodevelopmental basis of schizophrenia paves the way for such recognition in other neurodevelopmental disorders such autism spectrum disorders. These disorders while sharing some clinical features at the surface and some underlying pathophysiology with schizophrenia, at the same time, there have major differences both at the clinical surface, and underlying pathophysiological mechanisms, that leads us to the second main conclusion.
2. The neurodevelopmental basis of schizophrenia is a process that needs causation, which over the past 65 years, has widely been accepted to be of infectious origin. The evidence for the prenatal maternal infection triggering maternal and fetal inflammatory immune reactions, are so strong and sensible, fitting the developmental time window and the neurobiological damages ending in schizophrenia, latently years later that other suspected etiologies, e.g. obstetric complications and postnatal environmental factors such as stress seems to be unfit and out of question. Although the infecting agents could be non-specific and of bacterial or viral origins, the immunological inflammatory reactions, e.g. secretions of cytokines in defense could be the direct damaging factors. The severity, chronicity and latency of the infections as discussed are other determining factors in causing schizophrenia or other neurodevelopmental disorders.
3. To the disappointment of the genetic research enthusiasts and their laborious efforts over decades, genetics seems not to have any specific and direct impact in the etiology of schizophrenia. Therefore it appears that no single or combination of genes could cause schizophrenia directly, as there is no strong evidence of any specific gene(s), but sporadic CNV’s and SNP’s as discussed here and could easily be caused by the microbial invasions. These sporadic CNV’s and SNP’s or epigenetic mutations, later on even in the absence of another prenatal infection could be passed on to the next generations through inheritance, i.e. familial schizophrenia. SNP’s that accounts for about 1% of human genomic variation (in contrast with 13% of CNV’s) and affect one single nucleotide base (in contrast with CNV’s, affecting large regions of genome) have been subject of studies in schizophrenia as in other complex diseases. Aberg et al. (2013) in the first comprehensive family-based replication study of schizophrenic genes from 18 genome-wide association studies (GWAS), including 3286 cases from 1811 nuclear families after quality control of a larger sample, identified 43 genes with 8107 SNP’s of 90% replication frequency. These many SNP’s, each individually with small effects, replicated with larger effects as a group, and represented pathological pathways involved in synaptic connectivity, glutamate signaling, and immune response including MHC (Major Histocompatibility Complex).

 Yesterday, Today and Tomorrow

The history of psychiatry, or schizophrenia does not end today! The history goes on and our today’s conviction will be a belief of the past. We can only learn from the past for today and the future, and unfortunately this learning is not achieved easily due to dogma and resistance for change. For thousand years, we as humans thought of the mental illness and at the top, schizophrenia as insanity and we isolated the patients into asylums and in chains or executed them under the name of God for witchcraft and demonic possession! Then after the scientific revolution and great advancement in medicine, we understood schizophrenia wrongly as a static neuro-degenerative disease and stubbornly pushed the old idea for more than a century, despite the strong scientific evidence to the contrary! Now at the present time, while hoping that the past is gone and the rigidity is done with, after our major achievement in the human genome project and mapping all our genes, try to prove by our genetic studies that genetics is everything and we can soon discover the genes for all the human diseases! We forget the simple fact that genes, simply are biological templates, where we actually can find the fingerprints of the environment and is not the causation of anything per se. Even our simple Mendelian traits such as the color of our skin, hair and eyes are affected by the environment. This has already taken us to the present time or today to recognize the importance of the impact of environment on us or our genetic make up or template, i.e. “epigenetics”. We have come a long way not to look for a simple chromosomal defects in complex disorders such as schizophrenia, or even a single gene, but to identify pieces of gene mutations through CNV’s and SNP’s as the true underlying genetic process of not just pathology, but natural selection and evolution. We have also appreciate that schizophrenia is heterogeneous, though somewhat narrowly within a diagnostic and symptomatic frame, with marginally different underlying pathophysiology and genetic structure, i.e. with different CNV’s and SNP’s even among the same families. This hopefully will take us from the mentality of the past and today to the future, to truly and deeply recognize the environmental influences or fingerprints on our existence! While we cannot find any gene(s) for schizophrenia or other complex diseases, with our current discovery of CNV’s and SNP’s and more of the kind in the future, we can identify the fingerprints of different environmental impact such as infections on our genome or biological system that has caused us different diseases. In the future we hopefully will be able to root any disorder such as schizophrenia, even its subtypes in a top-down fashion from intermediate phenotypes to their genetic fingerprints through CNV’s and SNP’s, etc. back to the environmental causes, e.g. microbial invasions, even their subtypes!      

Dr.Mostafa Showraki, MD, FRCPC                                                               Lecturer, University of Toronto,School of Medicine,Author: “ADHD:Revisited” Book “adhdrevisited.com”/”medicinerevisited.com”  

 References:

1.Berrios, German E.; Luque, Rogelio; Villagran, Jose M. (2003). “Schizophrenia: a conceptual history”. International Journal of Psychology and Psychological Therapy 3: 111–140.

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