Theories of Schizophrenia: An Inflammatory/Vascular
Daniel R. Hanson, M.D., Ph.D.1
Irving I. Gottesman, Ph.D., Hon.FRCPsych 2
1Department of Psychiatry, VA Medical Center (116A), One Veterans Drive,
Minneapolis, MN, 55417 and Departments of Psychiatry & Psychology, University of
Email address: email@example.com
2 Departments of Psychiatry & Psychology, University of Minnesota, Minneapolis, MN
Email address: firstname.lastname@example.org
Schizophrenia is a relatively common psychiatric syndrome that affects
virtually all brain functions yet has eluded etiological and pathophysiological
explanation for more than 100 years. Whether by developmental and/or degenerative
processes, abnormalities of neurons and their connections have been the recent focus
of attention. However, our inability to fathom the pathophysiology of schizophrenia,
even with dramatic advances in neuroscience and molecular genetics, forces us to
challenge our theoretical models and beliefs about this illness. A search for a more
satisfying model in the context of systems biology to explain aspects of schizophrenia
uncovers clues pointing to CNS microvascular disease.
A vascular component to a theory of schizophrenia posits that the physiologic
abnormalities leading to illness involve disruption of the exquisitely precise regulation
of the delivery of energy and oxygen required for normal brain function. The theory
further proposes that abnormalities of CNS metabolism arise because genetically
modulated excessive inflammatory reactions damage the microvascular system of the
brain in reaction to environmental agents, including infections, hypoxia, and physical
trauma. Damage may accumulate with repeated exposure to triggering agents
resulting in exacerbation and deterioration, or may heal with their removal, resulting
There are clear examples of genetic polymorphisms in inflammatory cytokines
or cytokine regulators leading to exaggerated inflammatory responses to infectious
agents. These inflammatory reactions can be tissue specific, including the vascular
endothelium. There is also ample evidence that inflammatory vascular disease of the
brain can lead to psychosis, often waxing and waning, and exhibiting fluctuating
symptoms, as seen in schizophrenia. Disturbances of CNS blood flow have
repeatedly been observed in people with schizophrenia using old and new
technologies. To account for the myriad of behavioral and other curious findings in
schizophrenia such as minor physical anomalies, or reported resistance to cancers and
highly visible nail fold capillaries, we would have to evoke a process that is systemic
such as the vascular and immune/inflammatory systems.
A vascular component to a theory of schizophrenia brings together
environmental and genetic factors in a way that can better explain the diversity of
symptoms and outcomes seen in the schizophrenia syndrome. As an informed
conjecture it generates refutable hypotheses about the inflammatory and vascular
systems in those with schizophrenia and in their unaffected family members. If these
ideas are confirmed, it would lead in new directions for treatments that could be
preventative either through a focus on infectious agents or by way of cytokine
modulating agents, thus preventing exaggerated inflammation and triggering of a
psychotic episode in genetically predisposed persons.
When the solution to a clinical or scientific puzzle eludes us for more than a
century, as with schizophrenia (formerly dementia praecox), we need new ways of
thinking about the problem [1, 2]. Efforts to understand schizophrenia have focused
on neurons and, especially, the role of presumed excess dopamine neurotransmission.
We believe that both genetic factors and environmental factors combine with
epigenetic factors to create illness [3-5]. Thus, the syndrome of schizophrenia is
viewed as an endpoint in a dynamic process variously conceptualized as degenerative
or developmental or alternating at different points in the process [6-10].
Degenerative models imply that after a period of normal development, the
organism, or one of its parts, takes an unhappy turn in its trajectory and begins to
malfunction. This describes the eventual outcome for all life forms and is a biological
restatement of the second law of thermodynamics. Since degeneration is (eventually)
universal, stating that an illness is degenerative is not particularly helpful. What
would be helpful is to determine when in the life course the degeneration begins and
how the degeneration is initiated and proceeds. Answers to the “when?” and “how?”
questions would then describe the degenerative process in developmental terms.
Developmental models of schizophrenia implicate abnormalities of early brain
development predisposing to future schizophrenia. The proponents of the model
further argue that the perturbations of development are limited to the early times of
development and are discontinuous. Without this qualifier, developmental models are
indistinguishable from degenerative models where the degeneration starts early in the
life span. The early abnormalities are not necessarily the cause of schizophrenia, but,
instead, create a state of risk for future schizophrenia. That is, a diathesis or
predisposition is not a disease. Consequently, there must be factors later in life that
convert the vulnerability to an actuality. These additional factors are presumed to
somehow damage development in such a way that a predisposition becomes
actualized. To gain a complete understanding of the syndrome, we must again return
to the question of “ what happens?”
Following this line of reasoning, the distinction between degenerative and
developmental models blurs. In fact, a medical-behavioral condition can be both
developmental and degenerative as exemplified by Down syndrome[11-13].
Individuals born with trisomy 21 exhibit a number of developmental anomalies
including cardiac malformations, abnormal dermatoglyphics, skeletal changes, and
muscular hypotonia, to name a few. As trisomy 21 infants mature, most exhibit
degrees of mental retardation. By about age 50, these individuals invariably develop
Alzheimer-like CNS degenerative changes that can be seen at autopsy .
Schizophrenia involves both developmental and degenerative features. From
the time of Bleuler  and Kraepelin, “It is certain that many a schizophrenia
can be traced back into the early years of the patient’s lives…”  p. 252. The
‘follow back’ studies of schizophrenia support these views . Likewise,
prospective studies of children at high risk for schizophrenia report developmental
anomalies in motor skills, cognition, and attention long before the onset of overt
illness [17-19]. Overt psychotic symptoms for some individuals usually start in the
late teenage years or early twenties, but the illness can start as early as middle
childhood  and may, more rarely, start in old age [ p 73].
The evidence suggesting early developmental perturbations in schizophrenia is
compelling. At the same time, there certainly are examples of deterioration
reminiscent of Kraepelin’s suggestion in at least some people with schizophrenia.
However, deterioration in clinical course may not indicate CNS deterioration. Instead,
the decline could be a secondary consequence of an illness that disrupts education,
economic achievement, and social functioning leading to a downward spiral in all
aspects of adult life. Consistent with an early degenerative process, there are reports
of declining cognitive function preceding onset of psychosis . Proponents of
neurodevelopmental models suggest that the premorbid cognitive abnormalities are
developmental risk factors for future schizophrenia (c.f.) and argue that such
abnormalities show little evidence of decline after onset [6, 24]. Whether
developmental or degenerative, the premorbid cognitive deficits seen in schizophrenia
are also seen in other disorders  and lack specificity and sensitivity detracting
from the concept that the cognitive abnormalities seen in schizophrenia are useful
endophenotypes. The strongest evidence for a neurodegenerative phenomenon
comes from imaging studies showing progressive loss of brain volumes [27-29].
Neuropathological studies fail to find widespread classic signs of neurodegeneration
such as gliosis though there are exceptions to this generalization . Observations
of abnormal dendritic arborization [31, 32] are consistent with the neuroimaging
evidence suggesting abnormal connectivity between brain regions .
The symptoms of schizophrenia are highly variable. Within families (and thus
presuming relative homogeneity of genetic and environmental factors) symptoms can
vary widely over time, as illustrated by identical quadruplets concordant for
schizophrenia . Even within affected individuals, symptoms will wax and wane
and may even remit .
The major behavioral symptoms of schizophrenia include alterations in
cognition, memory, perception, thought (inferred from language), motor functions,
and affect. People with schizophrenia may show abnormal dermatoglyphics and other
minor physical anomalies [35-40]. Other oddities to be incorporated in a
comprehensive explanation of schizophrenia include highly visible nail fold
capillaries[41, 42] and the rarity of rheumatoid arthritis among schizophrenic
people. These physical characteristics suggest we need to look beyond the
nervous system per se to have a comprehensive view of the illness.
The fact that schizophrenia is a common illness provides important
information about the frequency of causal factors. About 1% of the population will
experience schizophrenia during the lifespan. Except for a few rare exceptions, this
1% risk is remarkably constant around the globe regardless of culture, geography, or
climate. Men and women are affected equally. These facts mean that the risk factors
for schizophrenia must also be common and ubiquitous. Given that the concordance
rate for schizophrenia in identical twins  is only about 50%, there must be at least
two global risk-increasing categories for schizophrenia, i.e., something(s) genetic and
something(s) environmental. Assuming these risk factors are independent of each
other, the joint probability of acquiring both risk factors is the product of their
population frequencies that, for schizophrenia, equals about .01. To make a
simplifying assumption to allow easy calculations, let us say that the two risk factors
are present with about equal frequency in the population. With this simplification,
straightforward mathematics indicates that the individual frequencies of these factors
are about the square root of the population frequency of 1%. That would mean that
about 10% of the population would encounter at least one risk factor. If there are
more then two risk factors, the math indicates that the factors are even more common.
[See for further elaboration].
Our challe e is do develop a theory of schizophrenia that can plausibly explain
an illness that affects all domains of behavior (thought, affect, motor performance,
etc), that has elements of developmental perturbations early in life leaving clues such
as minor physical abnormalities but also elements of degenerative changes. At the
same time, the defect is so subtle that we can’t find the cause(s) with our best modern
technology. Furthermore, in spite of brain-wide dysfunctions, many individuals with
schizophrenia remain sufficiently intact that, with good treatment and a bit of luck,
can maintain jobs and function usefully in society. Thus, we need to find frequent
and ubiquitous factors that can affect virtually all brain functions as well as creating
somatic signs, but they operate in ways that leave these functions only slightly “off
kilter” as compared to the complete disruption seen in strokes, or classical
degenerative disorders such as Alzheimer, or as seen in Down syndrome where the
behavioral pathology is apparent from earliest stages. As we try to explain
schizophrenia, we must account for most all of the developmental and degenerative
features of schizophrenia.
To account for the panoply of signs and symptoms seen in schizophrenia, any
complete theory of schizophrenia must include organism wide systems. In addition to
the nervous system, the immune system and the vascular system are defensible
candidates. Both are invoked in the following theory: Some schizophrenia psychoses
are the result of damage to the micro-vascular system in the brain initiated by
genetically influenced abnormal inflammatory processes acting in response to
ubiquitous environmental factors that trigger inflammatory responses, including
infection, trauma, or hypoxia. It is the relative infrequency of the vulnerable
genotypes  that results in only a 1% lifetime risk for developing the overt illness.
A primer on CNS Blood Supply:
Neurons derive their energy from oxygen and glucose delivered by the
vascular system, plus lactate and glycogen derived from astroglia . The
combination of neurons, astroglia, and micro vessels form a metabolic trio 
whereby the glia extend processes interacting with neurons on the one hand and, on
the other, form endplates interdigitated into capillary walls. Rather than being passive
conduits, the CNS vascular system is the most precisely managed and the most
complex fluid dynamic system known. Regulation of cerebral blood flow (CBF) is
managed primarily by a coupling between astrocytic glial cells [47-50] and capillary
endothelium[51-56]. Astrocytes sense local neuronal metabolic activity and adjust
blood flow as needed. Cerebral vessels change caliber in response to vasoactive
substances released by astrocytes activated by glutamate receptors [47, 57, 58].
Serotonin , acetylcholine  and dopamine [57, 61, 62] transmission between
astrocytes and micro vessels also play roles. When the neuronal activation of discrete
areas is sustained over longer periods, vasoactive substances stimulate angiogenesis
resulting in increased capillary density  thus enhancing local neuronal circuitry.
Conversely, decrease in capillary density is likely to reduce the functional capacity of
brain areas so affected . Consequently, capillary beds in the cortex are not
distributed in uniform fashion. There are close relationships among local
neuronal activity, density of capillary bed, and the distribution of valve-like flow
control structures  .
Developmentally, the CNS vascular system originates from capillary
endothelial cells that migrate into developing neuro-ectoderm under the influence of
trophic factors such as vascular endothelial growth factor (VEGF)  and
erythropoietin  both produced by astroglia. The developing micro-vasculature,
although comprising only 0.1% of the entire brain, and operating under the influence
of genetic directives, has a key role in the development, maintenance and repair of the
brain . In turn, VEGF has trophic effects on neurons and glial cells, and the
activity of VEGF influenced angiogenesis is directly proportional to the high
metabolic activity of neocortical development . Thus, angiogenesis and
neurogenesis occur simultaneously and synergistically [69-71]. In addition to
formation of capillaries themselves, intricate anastomoses between micro-vessels
further ‘fine tune’ the metabolic support of developing glia and neurons 
The Genetics of Infectious & Inflammatory Diseases
When infectious agents give rise to inflammatory vascular disease, the nature
of the infectious agent may be less important that an individual’s genetically
influenced inflammatory response. The concept that infectious disease may have a
genetic component is, of course, not new. Many agricultural geneticists make their
livings by breeding disease resistance into both plants and animals (c.f. Richter &
Ronald, 2000, Mackenzie, & Bishop, 2001). One of the founders of behavioral
genetics, Franz Kallmann , showed genetic factors influenced acquiring
tuberculosis (DZ concordance = 26%, MZ concordance = 87%), an observation that
was confirmed in modern times [74, 75] . Many other infectious diseases appear to
have genetic factors influencing susceptibility or resistance to the infection [76-86].
Mechanisms for genetically mediated responses to infection occur through genetic
variations in immune mediators such as cytokines and HLA factors[87, 88].
Familial Mediterranean Fever (FMF)[89, 90] provides a heuristic Mendelian
example. The gene for FMF is located on the short arm of chromosome 16 and
produces pyrin (marenostrin) that functions in a negative feed back loop to suppress
inflammation. Absence of pyrin leads to exaggerated inflammatory responses.
Vasculitis is one of the consequences . Additionally, very high rates of rheumatic
fever (RF) or rheumatic heart disease (RHD) are found in relatives of patients with
FMF. Having even one mutant gene appears to lead to immune hyperactivity to
streptococcal antigens. We also know that antibody production and cytokine
activity  in RF patients is more marked than non-rheumatics. It is clear that genes
influence the host’s response to infection. A similar line of reasoning applies to other
inducers of inflammation such as injury  or hypoxia [96, 97] .
Just as the CNS blood supply is highly regulated, the inflammatory systems in
the brain require ‘fine tuning.’ Given the limited ability for adult brain to regenerate,
and assuming there is little tissue to spare, it would make sense that the brain should
be protected from overabundant inflammatory reactions . Astrocytes play a key
role in the expression of inflammatory cytokines, chemokines, and growth factors
involving the modulation of gene expression for these factors [98-100].
Let us suppose that schizophrenia develops following an infection (the
environmental contributor) but the host’s response is determined by genetic factors
regulating the nature and degree of inflammation. That infectious agents may be
operative in schizophrenia is supported by several of lines of evidence. Summaries
can be found in numerous sources [101-107]. The same concept applies to trauma
 or anoxia [70, 96] that may also stimulate inflammatory processes.
Vascular Disease and Psychopathology
The syndrome of schizophrenia is likely to be etiologically heterogeneous and
a multitude of CNS disorders can give rise to schizophrenic-like psychoses. The
idea that CNS micro-vascular diseases, in particular, are factors in psychotic disorders
is also an old idea [109, 110] that deserves a second look in light of new perspectives
offered by developments in the genetics of inflammatory diseases. There are many
examples of psychoses resulting from micro-vascular CNS disease including lupus
and Sjögren syndrome. Neuroimaging and neurocognitive deficits in these
disorders are similar to those seen in schizophrenia . Psychoses associated with
substance abuse are also associated with CNS vasculitis . Furthermore,
infectious agents such as syphilis  and rheumatic fever (RF—see below), lead to
micro-vascular disorders of the CNS that are associated with psychiatric symptoms
including psychoses. Thomas, et. al.  also demonstrated small vessel
abnormalities in the depressed elderly. At the same time, there is growing interest in
cytokines and other inflammatory agents in psychoses as well as growing
awareness that inflammatory reactions are modulated by neuropeptides .
Inflammatory processes often damage the precise regulation of cerebral blood
flow. The wide spectrum of clinical conditions thought to be created, in part, by
inflammatory CNS micro-vessel disease include Alzheimer disease where it is
thought that inflammatory processed damage the micro-vascular endothelium causing
insufficient blood flow leading to oxidative stress, a build up of amyloid, and eventual
cell death [118-126]. Cerebral palsy is also conceptualized as an infectious-
inflammatory-vascular disorder where the vascular lesion is complete thrombosis
. Neurotoxic effects of methamphetamine and cocaine appear to be due to
induction of inflammatory genes in small vessel endothelial cells [113, 128], thus
explaining the vascular damage seen in amphetamine and cocaine abuse that was
previously attributed to contaminants of injected drugs [113, 129-131].
Returning to the early stages of life, we have seen that the development of the
neurons and glia are intimately associated with, and dependent on, the parallel
development of the CNS vasculature. If the stated theory is correct, and given the
developmental perspective of schizophrenia ---early developmental perturbations of
the CNS set the stage for later schizophrenia--- we would expect to find support for
the idea that inflammatory events early in life affect CNS vascular function. Such is
the case. Whether the early insults are traumatic, infectious, or hypoxic;
inflammatory process are involved in the attempts to protect and repair by modulating
angiogenesis [132-139]. Thus, the reports implicating pregnancy and birth
complications (anoxia, trauma or maternal infections) in the development of some
cases of schizophrenia [140, 141] could all be mediated by the common pathway of
inflammatory-vascular mechanisms. Individuals who’s genes created perturbations in
inflammatory-vascular regulation would continue to experience abnormalities of
protection and repair in response to subsequent CNS insults. Over time, the
accumulation of ‘hits’ could lead to brain dysfunction to the extent seen in psychoses.
The greater the number and duration of ‘hits,’ the greater the risk for a deteriorating
Alterations of cerebral blood flow in schizophrenia
Since the time of Seymour Kety’s pioneering efforts [142, 143], there has
been interest in altered cerebral blood flow in people with schizophrenia. An in-depth
review of this large literature is beyond the scope of this paper. The interested reader
is referred to discussions of reduced anterior cerebral perfusion leading to the concept
of ‘hypofrontality’ in schizophrenia [144, 145] and to more recent reviews [146-148].
Bachneff’s  review and theory about defects in regulation of CNS microvascular
systems is particularly relevant. These reviews summarize a consistent body of
evidence showing reduced cerebral blood flow in brains of people with schizophrenia
especially to anterior regions. Flow deficits are seen in medication-naive new onset
cases [150, 151] and more established cases free of neuroleptics  suggesting
that flow perturbations are neither the consequence of duration of illness nor
treatment. Neuroleptics can alter cerebral blood flow [153, 154] although the effects
may be regionally specific and drug specific [155, 156]. Decreased frontal flow is
often associated with negative symptoms [157, 158]. In addition to the frontal cortex,
flow abnormalities (either decreased or increased) in people with schizophrenia have
been noted in the cingulate cortex [159, 160], thalamus , basal ganglia ,
parietal cortex [157, 160] and cerebellum . Furthermore, in some instances, flow
rates are increased [150, 160]. Rather than a simple hypothesis of hypofrontality in
schizophrenia, theorizing is evolving toward a concept of “dysfunctional
circuits” or “inefficient dynamic modulation”  of cerebral metabolism
which is supported by other examples of abnormal modulation of cerebral blood flow
in response to activation tasks [161, 164]. Disturbances of blood flow in
schizophrenia are well documented but are not limited to schizophrenia. Disturbed
cerebral blood flow is also reported in obsessive compulsive disorder  and
depression [166, 167] as well as in Alzheimer disease (cited earlier). The usual
interpretation is that alterations of blood flow arise as a consequence of abnormal
neuronal metabolism. The theory proposed by this paper turns the causal arrow
around to suggest that abnormalities of blood flow lead to altered neuronal-glial
function that, in turn, lead to psychopathology. There has been scant direct
visualization of the vascular system in schizophrenia, but at least one laboratory has
found evidence of atypically simplified angioarchitecture and failure of normal
arborization of small vessels .
Post- streptococcal behavioral syndromes as a model
Post-streptococcal neuropsychiatric syndromes include Syndenham chorea,
the PANDAS/obsessive compulsive syndrome, tics including Tourette syndrome, and
possibly, ADHD [168-175]. Psychotic disorders are also implicated [174, 176] and
citations below] .
Sydenham chorea is the best-known neuropsychiatric complication following
streptococcal pharangitis. The association of psychoses and Sydenham chorea as well
as with RF even in the absence of chorea, was discussed in the 17th and 18th centuries
starting with Sydenham himself (see ). The interest in psychoses associated with
RF continued throughout the 1900’s [177-189]. People with a history of Sydenham
chorea and/or rheumatic fever are at high risk for developing psychopathology later in
life [190, 191] with a relative risk for schizophrenia as high as 8.9 in a 10 year
follow-up of 29 Sydenham patients . There is a suggestion that the family
members of Sydenham patients are also at higher risk for psychosis .
During the 1940’s-1960’s when RF was still quite prevalent, people with
psychoses appeared to have higher than expected rates of histories of RHD or
RF)[187, 194, 195] or rheumatic chorea . Psychotic patients with RHD more
often had early (<age 19) onset, movement disorders, progressively insidious courses
and poor long-term outcomes . Preliminary data from a Minnesota study also
finds increased rates of RHD in psychotic patients, a pattern of increased psychiatric
hospitalization following an epidemic of RF, and a clinical course for “rheumatic
psychoses” that disproportionately led to a severe and continuous decline in function
. Although schizophrenia-like psychoses were the most common
psychopathology related to rheumatic syndromes, manic-depressive, involutional, and
senile psychoses were also observed [174, 198].
An inflammatory reaction of the CNS vascular endothelium (vasculitis) is a
common denominator in the both acute and chronic cerebral consequences of
rheumatic fever. [177, 180, 186, 187, 189, 199-202]. The microvascular lesions
suggest both an obliterating process likely due to micro-emboli from rheumatic
cardiac valves and an inflammatory process involving irregular proliferative changes
in the vascular endothelium, dilatation of the lymphatic spaces surrounding the
capillaries suggesting increased permeability of the capillary endothelium, and
inflammatory cell infiltrates. Disruption of the blood brain barrier suggested by the
evidence of increased permeability of the small vessels could compromise the
immunological protection of the brain leading to the formation of the anti-neuronal
antibodies seen in post-streptococcal CNS syndromes [169, 203-206]
The post-strep psychopathologies provide a precedent for the hypothesis of
this paper by demonstrating that an infections process can trigger a series of
inflammatory reactions that lead to a variety of somatic and psychiatric syndromes,
including psychoses where vascular pathology is implicated. The pathogenicity of a
strep infection is a function of the strain (genotype) of the bacterium and the
genetically mediated inflammatory mechanisms of the host  and illustrates how a
ubiquitous and often relatively benign environmental factor can create more serious
sequelae in a limited number of genetically predisposed individuals.
The ideas here are not new. Eugen Bleuler  remarked: “The fragility of
the blood vessels which appears in many schizophrenics, both acute and chronic,
seems to indicate a real vascular pathology (p.167).” We bring old ideas forward
into the light of new understandings offered by molecular genetics and inflammatory
diseases. Since the late 1800’s there has been evidence of inflammatory neuro-
vascular abnormalities in psychiatric illness that were initiated by infectious agents.
CNS lues is the best-known example. This paper expands the concept to suggest that
a variety of environmental insults (infection, trauma, anoxia) may follow a common
final pathway to causing psychopathology by stimulating inflammatory processes that
damage the capillary-glial-neuron triad as illustrated in the accompanying figure.
(Insert Figure 1 About Here)
Abnormal behaviors develop as a result of disruptions in astroglial mediated coupling
of cerebral blood flow to neuronal metabolic needs. These subtle disruptions are hard
to find as the microvasculature comprises only about 0.1% of the brain and are of a
scale appropriate for electron microscopy. None-the-less, the hemodynamic
perturbations have sufficient impact to cause subtle but widespread disruption of the
normally harmonious coordination of CNS function leading to a condition variously
conceived as a “neurointegrative defect”, “synaptic slippage” , “abnormal
signal transduction” , “inefficient dynamic modulation”  or “synaptic
destabilization” . The ultimate impact would lead to psychopathology including
psychoses as the vascular-glial-neuron triad is progressively damaged over time after
repeated inflammatory episodes. The resultant failure to adequately regulate the
delivery of oxygen and energy would lead to oxidative stress [211-213]. Oxidative
stress, in turn, can further damage the microvasculature and the blood brain barrier
[214-216]. The astroglial-capillary partnership that protects the integrity of the blood
brain barrier would be compromised, thus exposing neural tissue to damage from
immunological attack . Known precedents of such processes are found in the
behavioral changes seen in CNS vascular inflammatory diseases such as lupus and the
post-strep syndromes described above.
This theory could explain how developmental events such as prenatal
infections [141, 218], and other birth and pregnancy complications  including
anoxia  are linked to later schizophrenia---infection, trauma, or anoxia all
stimulate inflammatory processes  . The data suggesting an (statistical)
influence of season of birth  is also consistent with the hypothesis as infectious
epidemics often follow seasonal patterns. Some of the minor physical anomalies such
as unusual scalp hair patterns and dermatoglyphic changes are explained because the
development of these phenomena are linked to each other , to the development
of the central nervous system , and are developmentally modulated by the
pleiotropic effects of the same substances that modulate brain vascular development
(e.g., vascular endothelial growth factor/vascular permeability factor  and
epidermal growth factor ). The waxing and waning of symptoms would
correspond to waxing and waning of inflammations as individuals are exposed,
recover, and then re-exposed in conjunction with other physiological and hormonal
influences, as seen in lupus . The nature and severity of symptoms would
depend on where in the brain the inflammation takes place and this may be stochastic.
As the micro- vascular system is systemic in the brain, lesions could produce the
variety of symptoms seen in schizophrenia including dysfunctions of thought,
emotion, memory, motor skills and autonomic regulation. The developmental age of
the individual will also make a difference. Inflammatory process that alter
angiogenesis during prenatal development will likely have more dire consequences
than inflammatory reactions that start after CNS maturation although even the adult
brain remains susceptible . We have attempted to schematically illustrate this
dynamic process in figure two.
(Insert Figure Two About Here)
This theory also captures many of the little oddities observed in
schizophrenia. For example, the reported abnormalities of the nail fold capillary beds
seen in some people with schizophrenia  are also seen in people with
inflammatory disorders such as FMF and rheumatoid arthritis . Another
oddity is the negative association between schizophrenia and rheumatoid arthritis
. There are parallels in the post-streptococcal syndromes where RF and acute
post-streptococcal glomerulonephritis very rarely occur in the same patient . It
appears that different strains of streptococci may produce either heart or renal
complications but not both. By analogy, individuals with vascular/CNS involvement
following streptococcal infections may be systematically spared from joint
involvement. Alternatively, as postulated for Alzheimer disease (cited earlier) that is
also less common in people treated for arthritis, the anti-inflammatory treatments for
arthritis might reduce the risk of inflammatory brain disease.
Another line of evidence compatible with this theory is the observation that
genetic linkages for schizophrenia coincide with sites for glial growth factor cell
regulators  and, as we have seen, the glia are key intermediaries of CNS
inflammation and vascular regulation. Another piece that fits into the puzzle is the
fact that neuroleptics have anti-inflammatory properties [230-234] and neuroleptic
treatment may be augmented by addition of anti-inflammatory drugs .
It may well be that the environmental components of psychiatric illness such
as schizophrenia are relatively minor, ubiquitous, or chance events [236, 237]that
have the potential to stimulate the inflammatory systems. However, the nature of the
insults may be less important than individuals’ genetically influenced and
idiosyncratic responses to the insults, similar to individuals with FMF who have an
exaggerated inflammatory response. Thus, the genetic components of the inherited
predisposition to mental illness may lie “upstream” in the immune system rather than
in the CNS per se. The possibility that the environmental agents may be nearly
universal (e.g. who has not had a strep throat or viral syndrome?), will mean that the
prevalence of the etiological factor will be similar in control and experimental groups
thus making it too easy to dismiss key environmental factors in null hypothesis
designs [45, 238]. Rather than focus on the environmental contributors that could be
non-specific and ubiquitous, it will be more productive to look for genotypes that
respond abnormally to triggers of inflammation and microvascular dysfunction
(cf.). These individuals would be the ones who are at high risk for psychiatric
illness. However, the inflammatory processes involve a cascade of steps involving
many genes. But this, too, fits with the polygenic features of schizophrenia .
Identification of high-risk individuals, combined with such tools as immunizations or
anti-inflammatory agents may promote prevention of much psychiatric morbidity.
Already, the cytokine regulator and vascular growth factor erythropoietin is suggested
as a possible neuroprotective factor in schizophrenia 
A broad spectrum of observations leads to a working hypothesis that
schizophrenia and, possibly, other psychiatric syndromes are the result of genetically
mediated inflammatory reactions that damage the neuron-glial-capillary triad with
resultant loss of ability to fine tune regional brain metabolism. This hypothesis
incorporates genetic, epigenetic , and environmental factors. Furthermore, an
inflammatory/vascular theory can explain the variety of behavioral symptoms seen in
schizophrenia, the variable course of the illness, and the numerous other puzzling
observations such as an excess of minor physical anomalies. Should this theory prove
heuristic, it would point to the use of inflammatory modulators in treating the illness.
Perhaps more importantly, identifying individuals who were at high risk for the
disorder in high genetic risk families as well as the general population, because of
abnormalities of their inflammatory systems, holds the hope for prevention through
early intervention using inflammatory modulators.
List of Abbreviations
attention deficit hyperactivity disorder
brain derived neurotropic factor
cerebral blood flow
central nervous system
familial Mediterranean fever
nerve growth factor
pediatric autoimmune neurologic disorder associated with strep.
rheumatic heart disease
vascular endothelial growth factor
[Insert Authors Contributions here]
This work was supported by a grant to DRH from the Stanley Foundation.
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Simplified schematic illustrating the interconnected vascular-glial-neuron triad and
how inflammatory processes may disrupt normal function.
Schematic illustration of how inflammatory processes, from conception onward, may
lead to CNS damage or dysfunction that dynamically alters the epigenetic landscape
(reaction surface) thus affecting the liability for developing schizophrenia. Blue
planes intersecting the reaction surface indicate levels of liability above which
symptoms become manifest. Adapted from [242, 243].
Damaged Endothelium &
Disruption of Flow Mechanics
Altered Immune Recognition
Altered Oxygen, Glucose Delivery
Disrupted Ion Homeostasis
Loss of Neuron-Glia
of Lactate and
BRAIN CHANGES: DEVELOPMENTAL & DEGENERATIVE Download full-text
FETAL PRO-INFLAMMATORY CYTOKINES
(Circulation and Brain)
PLACENTA & FETAL BLOOD BRAIN
MATERNAL PRO-INFLAMMATORY CYTOKINES