1. A CENTURY OF SCHIZOPHRENIA
Where we came from, where we are now and where we are going
Adonis Sfera, MD, Stephen Stahl MD, PHD
Abstract: As early as 1801, French psychiatrist PhillipePinel asked the question: “Does insanity depend
upon organic lesion of the brain?”(1). Pinel proceeded to perform numerous autopsies and eventually
concluded: “no facts, yet clearly established, relative to the influence of the size and configuration of the
cranium upon the faculties of the mind”(1).
This view prevailed for almost two centuries, and not without a reason. There are minimal gross
anatomical findings in mental diseases when compared to the degenerative neurological disorders such
as Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis. Additionally, mental
disorders differ from progressive neurological disorders in as much as they may remit or be
compensated for. Consequently, mental diseases were seen by many as “functional” as opposed to
“organic” and treatment options were developed accordingly(2). Functional conditions were treated
psychologically during the time of the analytical paradigm. It was only in the past two decades, when
advanced functional brain mapping technologies have become widely available, that the so called
“organic lesions” that Pinel failed to locate in the brains of mentally ill have been finally delineated so
that we can now state with some certainty that psychiatric illness is caused by neural damage that we
can characterize by the neuropathology involved(3). This novel data is slowly finding its way into the
clinical work, but the time lag between research and clinical applications is unacceptable for this day and
age(4).
Where we came from
About 100 years ago Bleuler published his work “Dementia Praecox or the Group of Schizophrenias”(5).
This is when psychiatrists first heard the term schizophrenia. The plural form used implies multiple
conditions grouped under this generic name.
At that time there were two schools of thought in European psychiatry- the German and the French.
French psychiatry was led by Jean-Martin Charcot, and Pierre Janet while German psychiatry by
Wilhelm Wundt and Emil Kraepelin(6 ).
Although both schools were biological in orientation, they had disagreements. French psychiatrists
thought that, what we call schizophrenia today, could be reversed. Their German colleagues, primarily
Kraepelin thought that it was irreversible and that it inevitably led to dementia(2)
Bleuler attempted to find a middle ground for this dilemma by coining an alternative term,
schizophrenia, which gradually became accepted throughout the Western world, however another
division was on the horizon(5).

2. At that time Freud embraced the new “functional” view of schizophrenia, while Bleuler continued to
work within the “organic” paradigm. Bleuler’s young assistant Carl Jung, adopted Freud’s ideas and the
two schools of thought (functional and organic) parted way for almost half a century(7).
In 1913 Bleuler published his work Criticism of Freud’s Theories in which he denounced analytic ideas
and warned about their proponents marginalizing biological psychiatry(8). Bleuler was probably one of
the last voices in favor of organic etiology of schizophrenia In the first half of the 20th century
psychiatry was governed by the analytic paradigm in which the emphasis was placed on the functional,
thus psychological aspect of schizophrenia rather than on the neural pathology of the disease itself(9).
The second half of the twentieth century ushered in the neurochemical paradigm which shifted the
focus from the psychological aspect of this condition to the chemical one. The neurochemical approach
yielded biological treatments that transformed the approach to psychosis and allowed for the
deinstitutionalization of a large number of patients with schizophrenia (9). Typical and atypical
antipsychotics were discovered, but the emphasis was placed on the neurotransmitters and drugs rather
than the neuropathology of the disease itself. Schizophrenia was considered a “dopamine disease”
which was an extreme oversimplification and despite the growing number of psychotropic drugs that
were marketed a, the mechanisms of action were predominantly the same as the original prototypes
developed in the 1950s (10). Even though efficacious in the treatment of delusions and hallucinations,
antipsychotics failed to enhance full recovery and reintegration of the patient into the work force and
society at large possibly because of the disabling cognitive deficits that were not addressed by the
antipsychotic medication(11). Thus the cognitive theory of schizophrenia was introduced trying to
address simultaneously both cognition and psychosis.
The cognitive theory of schizophrenia seems to validate Kraepelin’s dementia praecox model in stating
that schizophrenia is primarily a cognitive disorder and that lack of insight is part of the cognitive
deficit(6). This shifted the emphasis from the “dopamine disorder” to the “glutamate disorder”(9) and
it brought the recognition that negative and cognitive symptoms do not respond to antipsychotic
medications(91). Glutamate agonists such as glycine, d-cycloserine, as well as acethylcholine receptor
ligands such as ispronicline and others (12 ) were studied, but the results were disappointing in terms of
improving cognition in schizophrenia(13).
Where we are now
Schizophrenia continues to remain a major challenge for psychiatry. Even with the new and improved
antipsychotics and supportive psychotherapy sustained recovery occurs in less than 14% within the first
five years following a psychotic episode (14). Nearly 20% of people with schizophrenia are
homeless(92). Lack of curative or preventative approaches reflect the lack of basic understanding of the
pathophysiology of schizophrenia (9).

3. After the completion of the Human Genome Project, a new era is gradually ushered in – the molecular
paradigm. For the past decade the search for causes of schizophrenia has been going into two
directions: genetics(nature) and environment(nurture).
On the one hand psychiatric genetics combined with neuroimaging reveal brain wiring during the
development(93). Factors that influence neuronal migration, differentiation and apoptosis are being
identified and studied(15)(83). A list of risk-genes for schizophrenia is gradually emerging (16). Genetic
risk factors combined with environmental stressors (epigenetic factors) are seen as instrumental in
tilting the balance of vulnerability and resilience toward schizophrenia (17). Like most major scientific
discoveries, genetics seems to raise more questions than offer answers and this caused an initial
disappointment. Genomic and other research tools are available to help us come to grips with these
findings. Gradually it became obvious that the genetic basis of schizophrenia is more complex than
initially envisioned (18), however a new look at the risk genes revealed unrecognized sources of genetic
variability such as Copy Number Variation (CNV). Indeed, CNVs are recognized to contribute both to
normal genomic variability and to risk for human diseases, they seem to narrow down previous findings
from genome wide association studies and point more directly at abnormal neuropathologic substrates
(95). This and other novel genetic data is being corroborated with neuroimaging and with post mortem
brain studies supporting the recognition held for some time that schizophrenia is a neurodevelopmental
condition(19)(84).
On the other hand the study of the environment (nurture) focused on the two “epis”: epigenetics and
epidemiology.
Epigenetic studies of discordant twins revealed that people with schizophrenia present with changes in
gene activity expressed or silenced by the environmental factors. Their identical DNA is expressed
differently in the ill twin due to epigenetic markings such as methylation, hypomethylation, or
acetylation. These findings were corroborated and confirmed with post-mortem brain tissue studies of
people with schizophrenia (20).
A list of epidemiologic risk factors for schizophrenia is emerging(21)(22)(23), addressing ways in which
individual (genetic) vulnerability is influenced by broader socio-environmental variables(31). There are
established environmental risk factors for Schizophrenia such as pregnancy or birth complications(
24)(25)(26)(27)(28), growing up in large cities, immigrant status(29) and drug consumption, especially
cannabis( 30). However, the odds ratios around 2 and each of these factors appears to increase the
lifetime risk of the disease only slightly(32)(33). Thus, the currently known risk factors, either alone or
taken together, cannot be used for prediction and prevention without a more complete knowledge of
the predispositional basis and the gene-gene and gene-environment interaction(34). More studies are
needed regarding ranking the risk factors according to their liability in disease causation(35)(36)(37).
Genetic, epigenetic and epidemiologic data along with findings from various sciences such as molecular
genetics, cell biology, neurophysiology, brain structural and functional imaging and neuropsychology a
progressive evolution of schizophrenia in four stages: premorbid, prodromal, manifest and deficit or
burn out stage(38)(39)(40)(41)(42).

4. An “oncology model” of stage specific treatment is gradually taking shape in schizophrenia(43) and will
probably continue to develop as more neuropathological data becomes available(44)(45)(46)(47).
Premorbid stage represents the genetic vulnerability with no signs or symptoms of illness. Prodromal stage ushers in soft
signs and symptoms such as social isolation, decreased working memory, recent functional decline, unusual thought content,
suspicion, etc. Stage of onset/deterioration is the stage of manifest disease, usually with multiple hospitalizations and
gradual decline. Residual stage is the stage of deficit manifested by negative, cognitive and deficit symptoms.
The premorbid stage is the stage of risk or genetic vulnerability(9). As mentioned earlier the recognized
neurobiologic risk factors are not sufficiently predictive at this time as to allow the development and
application of preventive measures(48)(49)(50). Only very few genes such as DISC1 or chromosomal
deletions such as velo-cardio-facial syndrome (deletion 22q11) are certain high risk factors(51)(52).
However deficient neuronal migration is emerging as link between many human neurologic diseases. In
epilepsy, schizophrenia and some neurodevelopmental conditions there is evidence that disordered
neuronal migration may contribute to the pathogenesis, as one of the more frequent findings in these
conditions is heterotopically located neurons in various positions throughout the CNS (53). In the next
decade or two we might be able to study and classify variants of schizophrenia into categories like
Neuronal Migration Disorders (NMD) or myelination disorders, synaptic elimination disorders or
cytoskeletal disorders(54)(55(56)(57)(58).
The premorbid stage is an area where epidemiologic findings are beginning to emerge and are being
corroborated with the neuroimaging such as the Human Connectom Project early results reveal a

5. picture of deficient connectivity in schizophrenia, autism and many neurodevelopmental and
neurodegenerative disorders(59)(60)(61)(62)(63).
The prodromal stage
First episode of psychosis (FEP) research has shown that the outbreak of the disease is preceded in
about 70% to 100% of cases by an initial prodrome, which lasts for an average of five to six years(34).
After the initial episode even in the highly developed health care systems, an average of one year
elapses before the initiation of treatment(64)(65).
Centers for early recognition and prevention of schizophrenia were established in Melbourne, Australia
and elsewhere in the mid 1990s(66)(67)(68). They conducted retrospective research of the early course
of psychosis. They showed that psychosis occurs late in the course of schizophrenia and is preceded by
identifiable disturbances in behavior and working memory(9)(62). The works of McGorry and Thompson
reveal a dynamic wave of tissue loss in the prodromal stage that starts initially the parietal cortex than
spreads to the temporal and prefrontal cortex in the following years(59)(65), offering a window of
opportunity for therapeutic interventions(60)(61)(63).
A recent study of 291 adolescents followed for 2.5 years reported that the prodrome represents a 405-
fold increase in risk (relative to the general population(9). A combination of three factors such as
genetic risk, recent functional decline, unusual thought content, suspicion/paranoia or reduced social
functioning) resulted in a positive predictive power for conversion to psychosis of 74-81%(56).
Novel neuropsychological tools such as Prodromal Syndromes (SIPS), COGDIS or COOPER are able to
distinguish schizophrenia risk factors from other causes (63)(64)(85). The detection and predictive
power can be increased by the addition of biological markers detected with functional or structural
neuroimaging(86)(87) and the above neuropsychological tests(69)(70)(71)(72). Early identification of
cognitive changes such as reductions in working memory are highly predictive of prodromal conversion
into psychosis(73)(74)(75)(34). COPER(cognitive perceptive basic symptoms), COGDIS(cognitive
disturbances)(34)(76)(78) are continuously improving and becoming increasingly more sensitive in
identifying the earliest cognitive deficits.
Onset/Deterioration phase (manifest disease phase)
First Psychotic Episode(FPE) usually occurs after a 5-6 years prodrome and is a common endpoint for
many different pathological processes and even a variant of normal human experience in states of stress
or restricted consciousness(95). Social, behavioral and cognitive abnormalities, which also feature in
schizophrenia, overlap prominently with other disorders including learning disability, autistic spectrum
disorders [8], developmental disabilities, neurodegenerative disorders, substance dependence and
several medical/metabolic conditions (19). This symptom overlap causes ongoing controversy about
how the clinical boundaries of schizophrenia should be drawn and brings into question current

6. psychiatric taxonomy. NIMH Research Domain Criteria – or RDoC – represents a new organizational
framework that would help researchers match molecular findings with neuropathologic changes and
domains of psychiatric syndromes and thus classify mental disorders accordingly.
Several molecular mechanisms have been proposed regarding conversion from the prodrome to FPE.
They include: apoptosis(110), oxidative stress(111), glutamate toxicity(112), stress sensitization(113),
dysfunctional neurotropin pathways(115)(116). A consensus is forming about the role of
neuroprotective agents in schizophrenia(2). Neuroprotection refers to any type of therapeutic modality,
usually pharmacological, that can prevent, delay or even reverse neuronal damage, axonal degeneration
or any other form of neuronal injury( 2). For example agents such as estrogen(117 ), erythropoietin(118
), piracetam(121 ), modafinil(119 ) omega 3 fatty acids(120 ) added to the regular antipsychotic
treatment might improve the outcome of schizophrenia( 2 ) . Neuroprotective psychotropic agents in
use today include: Olanzapine(102) and clozapine (102). Valproate (122) and lithium(123) as well as
antidepressants(116).
More studies are needed to clarify types of interventions during the prodromal phase(77) that would
prevent or delay first episode psychosis (FEP)psychosis(80)(81), but preliminary data point to the fact
that small dose antipsychotics(79 ) antidepressants(83 ), lithium (90 ) , cognitive behavioral therapy
(90)(91) or omega 3 polyunsaturated fatty acids(89 ) and other neuroprotective agents during the
prodromal phase might decrease conversion to psychosis(88)(89). After the FEP aggressive treatment
with antipsychotics including long acting neuroleptics was shown to decrease further progression of the
disease(93).
Residual stage of schizophrenia or burnout phase
This stage involves stabilization into deficit, negative and cognitive symptoms as well as significant
disability are the hallmark of this stage. Neuroimaging studies show that schizophrenic patients lose
around 0.5% of their brain volume per year (as opposed to around 0.2% in normal controls), especially
(but not only) in the frontal and temporal areas (96). Loss of brain volume seems to be due to both the
pathologic disease process as well as some antipsychotic medications(97).
Poor response to antipsychotic medications or treatment resistance characterizes this stage of
schizophrenia(97). This is probably due to the presence of predominantly negative and cognitive
symptoms of schizophrenia, there is a general consensus that these symptoms (including poor insight )
do not respond to antipsychotic treatment(11)(12).
It is also possible that continuous use of high dose antipsychotic drugs in this stage may cause more
harm than good since brain volume loss has been associated with long term use of antipsychotic
medications in schizophrenia (97). The intermittent, as needed or targeted use of antipsychotics(98 )
(99) (100 ) (101 ) needs to be revisited for this stage (according to the model of chemotherapy in
oncology or corticotherapy in rheumatology) as well as the use of neuroprotective agents. More
studies are necessary about the use of antipsychotics in this stage, especially since obesity and
metabolic syndrome led to a decreased life expectancy ( of approximately 56 years) in individuals with

7. schizophrenia. Neuroprotective psychotropic drugs such as clozapine, olanzapine or lithium may be
more justified in case of overt psychotic symptoms(102)
Where we are going
The future interventions in schizophrenia are based on two facts:
1. schizophrenia is neurodevelopmental disorder
2. psychosis is a common endpoint for schizophrenia and other neurological diseases as well as a late
occurrence in the course of the disease (9). This recognition will shift emphasis on prevention which
includes:
1. early detection and treatment of prodromal symptoms
2. avoidance or delaying first episode of psychosis (FEP)
3. aggressive treatment and follow up of first episode psychosis(FEP)
These steps are already applied in an NIMH research project called Recovery after an Initial
Schizophrenia Episode (RAISE). This innovative project is attempting to change the trajectory and
prognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages of
illness. RAISE is designed to reduce the likelihood of long-term disability as well as enhance outcome.
As mentioned earlier, phase specific schizophrenia treatments might be gradually developed with
emphasis on prevention in the early phases and neuroprotection in later ones. Neuropsychological
instruments such as SIPS (Structural Interview for Prodromal Syndromes), and neurocognitive test-
batteries for at risk mental states (ARMS)(51)(43) will become increasingly more powerful and able to
detect deficits of working memory earlier.
Neurorotective treatments as well as early psychotherapy (including CBT and family interventions) will
be integrated with the early prevention and follow up with the aim at slowing down disease progression
and possibly even achieving primary prevention in recognized prodromal states(103).
Rather than being considered a homogeneous disease entity, schizophrenia will most likely be
diagnosed and treated by separate domains of pathology (104)(105)(106)(107). For example genetic
studies will shift from the genetics of schizophrenia as a syndrome to the genetics of pathological
domains such as neuronal migration, myelination, cell loss, disconnection, synaptic strength/plasticity,
dendritic spine and microtubular pathology. This may help clarify the apparent genetic overlap between
major psychiatric syndromes as well a psychiatric taxonomy. NIMH Research Domain Criteria (RDoC) is
step in that direction, it is designing a framework for creating a new way to classify mental disorders;
one built on decades of neuroscience-based research that is changing researchers’ understanding of
how the brain produces adaptive behavior and how a patient’s functionality turns from normal to
abnormal in forms of various mental disorders.

8. The etiology and treatment of cognitive and negative symptoms of schizophrenia will be diagnosed and
treated differently with drugs targeting cognition(108).
Integration of care is an area in which we are underperforming today. Medical care is currently
separated from psychiatric and psychosocial care such as family education, employment and family
support(9). A new paradigm needs to be developed in which family members play a pivotal role in the
therapeutric process. Rather than excluding family members (in the interest of confidentiality) from the
process of psychiatric treatment, an addiction medicine model needs to be adopted in which family
members are considered allies in the therapeutic process (109).
Conclusions:
Schizophrenia is a syndrome comprised of many conditions (hence the plural used by Bleuler) some of
which are reversible while others invariably progress towards cognitive deficit.
Recent genetic, epigenetic, neuroimaging and post mortem studies reveal subtle molecular and white
matter changes in the brains of individuals diagnosed with schizophrenia, placing this disease in the
realm of neurological conditions.
Schizophrenia originates during the embryonal development, but psychosis is a late
occurrence/complication, offering an opportunity for early preventive treatment during the prodromal
phase and after the first psychotic episode.
Preventive approaches need to become mainstream interventions in schizophrenia, but they must be
based on genetic, epigenetic and epidemiologic risk factors confirmed with novel neuropsychological
tools in order to assure early detection and aggressive treatment of prodromal and first psychotic
episode symptoms thus preventing relapse and chronicity.
Novel psychopharmacologic and research therapies must address cognitive and negative symptoms
which do not respond to current treatments and prevent patient’s reintegration into the society and
work force.
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