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How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades.
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Rethinking schizophrenia
Thomas R. Insel
How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects
about one per cent of the world’s population. After a century ofstudyingschizophrenia,thecause of the disorder remains
unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is
little evi dence that these treatmen ts have substantially improved outcomes for most people with schizophrenia . These
current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmenta l disorder with
psychosis as a late, potentially preventable stage of the illness. This ‘rethinking’ of schizophrenia as a neur ode velopme ntal
disorder, which is profoundly different fr om the way we have seen this illness for the past century, yields new hope for
preventi on and cure over the next two decades.
he challenge of creating a vision of
schizophrenia for 2030, which I attempt
here, is a difficult one. There is certainly
a risk in predicting scientific progress—the
most important discoveries will probably be
ones we cannot imagine today. But it is equally true that we can use past
experience and the present state of knowledge to predict some aspects of
the future. For schizophrenia, our knowledge base in 2010 is mostly
based on clinical observation.
Schizophrenia is a syndrome: a collection of signs and symptoms of
unknown aetiology, predominantly definedby observedsigns of psychosis.
In its most common form, schizophrenia presents with paranoid delusions
and auditory hallucinations late in adolescence or in early adulthood. These
manifestations of the disorder have changed little over the past century.
A century ago we had large public institutions for serious mental illness,
tuberculosis and leprosy. Of these three, today only mental illness, espe-
cially schizophrenia, remains unchanged in prevalence and disability
Sustained recovery occurs in less than 14% within the first five years
following a psychotic episode
. Longer-term outcomes may be marginally
better: a large international 25-year follow-up study reported an addi-
tional 16% with late-phase recovery
. Throughout Europe, less than
20% of people with schizophrenia are employed
. A large US study found
nearly 20% homeless in a one-year follow up
. And a recent report from a
patient advocacy group reported that in the US those with serious mental
illness were three times more likely to be found in the criminal justice
system than in hospitals. (
Although many have attributed this lack of progress to failed systems
of care (, we still do not have
a basic understanding of the pathophysiology of the disorder and there-
fore lack the tools for curative treatment or prevention needed for most
people with schizophrenia. If we are to transform outcomes by 2030, we
can start by offering individuals and families challenged by serious
mental illness a candid account of the current state of knowledge and
a thoughtful consideration of future prospects.
One-hundred years of schizophrenia
The history of schizophrenia says more in many ways about the perspec-
tives of the observer than the observed. In the late nineteenth century,
Kraepelin defined ‘‘dementia praecox’’ or premature dementia as distinct
from the insanity of tertiary syphilis or the cyclic, non-deteriorating
psychosis of manic depressive illness
. Bleuler, who coined the term
schizophrenia in the early twentieth century, was less convinced of its
deteriorating course but emphasized the notion
of a fundamental disorder of thought and feel-
ing, which every psychiatrist for decades learned
as the four ‘a’s—disturbances of associations,
affect, ambivalence and autistic isolation
These early formulations emerging before the split between neurology
and psychiatry were consistent with the notion of a mental disorder
rooted in brain pathology. Yet for much of the twentieth century, with
the predominance of psychoanalytic theory, the study of the mind
ignored the brain. Schizophrenia was a psychotic reaction, a fragmented
ego due to a rejecting or ambivalent mother and treatments included re-
mothering to build a stable ego
In the second half of the twentieth century, with the emergence of
neuroleptic drugs, the pendulum swung in the other direction—a focus
on brain chemistry deemphasized the mind. Schizophrenia was con-
sidered a ‘dopamine disorder’ based on the psychosis-inducing effects of
dopamine-releasing drugs, such as amphetamine, and the anti-psychotic
efficacy of a score of drugs that blocked the dopamine D2 receptor
. This
neurochemical view of schizophrenia yielded medications that trans-
formed the treatment of psychosis, allowing patients to be treated outside
of hospitals and, in some cases, resulting in remission of the major
symptoms of the illness. Early neuroleptic medications, examples of
which are chlorpromazine and haloperidol, have been increasingly
replaced by ‘atypical’ antipsychotics that have fewer extrapyramidal side
effects (such as tremor and rigidity) but usually do not seem to be sig-
nificantly more efficacious than the original dopamine D2 receptor
. Although both conventional and atypical antipsychotics
reliably reduce delusions and hallucinations, they have not enhanced
functional recovery (for example, employment) for people with schizo-
phrenia. One explanation is that the disability of schizophrenia is largely
due to cognitive deficits, such as problems with attention and working
memory, which these drugs fail to improve.
A focus on cognitive symptoms has led to a more recent hypothesis of
schizophrenia as a ‘glutamate disorder’ (reviewed in ref. 11) Healthy
volunteers given low doses of NMDA receptor antagonists, such as
ketamine, manifest select aspects of schizophrenia, including some of
the attentional and memory problems. Conversely, agents that modulate
the glycine modulatory site on the NMDA receptor have been reported
to reduce some of the cognitive symptoms of schizophrenia. The theory
is that schizophrenia, particularly the cognitive symptoms of the dis-
order, may result from low activity of the NMDA receptor on GABA
inhibitory interneurons in the prefrontal cortex.
National Institute of Mental Health, Bethesda, Maryland 20892, USA.
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Although there can be little argument that medications have trans-
formed the treatment of psychosis, research focusing on the drugs
instead of the illness has thus far yielded too little progress on the
pathophysiology of schizophrenia. It is not clear, for instance, that either
dopamine D2 receptors or interneuron NMDA receptors are related to
the cause of this disorder. Although post-mortem studies have con-
sistently reported a loss of GABA and reductions in key enzymes for
glutamate biosynthesis, potentially consistent with the glutamate hypo-
thesis, these changes may represent the effects of chronic illness or
treatment of the disorder rather than the cause of schizophrenia
One approach that could separate cause from effect is genetics. Just as
neuropharmacology dominated schizophrenia research in the late twentieth
century, genetics has been a leading focus in the first decade of this century.
Although in the ‘genomic era’ such a shift was inevitable, it was also pre-
saged by a generation of twin and family studies demonstrating high
. Reported concordance in monozygotic twins was roughly
50%, never the 100% figure one might expect for a Mendelian disorder, but
considerably higher than dizygotic twins or siblings
Highheritability has not, however,translated into a satisfyingsearchfor
genetic lesions. Although early genome-wide or candidate-gene studies
searching for common variants associated with schizophrenia were
mostly disappointing, either because early findings failed to replicate or
large-scale studies failed to detect genome-wide significance, recent inter-
national consortia combining single nucleotide polymorphism (SNP)
data from several independent studies have found replicable associations
with genes of the major histocompatability complex (MHC) region on
chromosome 6p21.3-22.1, ZNF804A on chromosomes 2q32.1, neuregulin
1(NRG1) on chromosome 8, as well as transcription factor 4 (TCF4)on
18q21.2(refs 15–17). Other studies have reported SNPs in candidategenes
associated either with schizophrenia or a broad phenotype of psychosis,
notably for genes within the neuregulin–ERBB4 signalling pathway
synaptic protein genes (for example, NRX1 (also known as PNO1))
potassium channel (KCNH2)
and many other brain-expressed proteins
(for example, dysbindin)
. Currently, at least 43 candidate genes have
been identified, but individual effect sizes are consistently modest (http://, especially rela-
tive to the evidence for high heritability
. Epistatic or additive effects of
these variants may explain more of the risk, but results thus far on
individual variants from case–control studies have not been useful for
understanding an individual’s risk for schizophrenia.
In addition to the many reports of common single nucleotide varia-
tions, many rare structural genomic variants, such as copy number var-
iants and translocations, have been described in schizophrenia (reviewed
in ref. 24). These rare variants seem to have larger causative effects than
previously reported SNPs, but most are not specific to schizophrenia and
some occur only in a single family. The diversity and private nature of
these mutations preclude a simple genetic explanation for schizophrenia,
but these findings may yield important clues to pathophysiology. For
instance, although the DISC1 translocation that confers very high risk
for psychiatric disorder has been detected in only a single Scottish family,
this private mutation has revealed important mechanisms of disease and
identified a site where common variation may also confer risk (reviewed
in ref. 25). Even more encouraging, the consistent reports that so many of
these structural variants affect genes implicated in brain development
may predict the future of schizophrenia research.
Mapping the pathophysiology of schizophrenia
A starting point for mapping the pathophysiology of schizophrenia can
begin with the increasing recognition that this is a neurodevelopmental
disorder, or perhaps more accurately a collection of neurodevelopmental
disorders that involve alterations in brain circuits. Although Feinberg
and Murray
proposed this approach more than two decades
ago, the field is only now providing the evidence and recognizing the
implications of shifting to a neurodevelopmental approach
Psychosis nearly always emerges in late adolescence or early adult-
hood, with a peak between ages 18 and 25, when the prefrontal cortex is
still developing. We still do not understand all of the changes in normal
or abnormal cortical development during this period. Attempts to map
functional connectivity defined by imaging the default network demon-
strate little integration until after age nine
. Longitudinal neuroimaging
studies demonstrate changes in grey matter density until the mid-twenties
with the prefrontal cortex being the last to mature
. The cellular basis for
the observed reduction in grey-matter density with magnetic resonance
imaging (MRI) is not clear although classical anatomical post-mortem
studies indicate that both synaptic elimination and increased myelination
continue into early adulthood
. Whereas the literature from human
post-mortem neuroanatomy of adolescence is scant, studies in non-
human primate brain demonstrate that the refinement of circuits during
early adulthood includes pruning of asymmetric (excitatory) synapses,
proliferation of inhibitory circuits and the continued elaboration of
pyramidal dendrites as targets of inhibitory input
. Together these
observations indicate that this late stage of brain maturation involves a
careful calibration of excitatory–inhibitory balance in the cortex with the
prefrontal cortex the last region to mature (Fig. 1). As one potentially
relevant modulator of this balance, dopamine innervation of the pre-
frontal cortex increases markedly during adolescence
Although schizophrenic psychosis usually emerges between ages 18–25,
several longitudinal population-based studies indicate that problems are
evident much earlier. For instance, a recent report from a 45-year follow up
of a Copenhagen birth cohort demonstrated that adults withschizophrenia
have a history of delayed maturation including delayed developmental
milestones in the first year
. Data from the Dunedin birth cohort, consist-
ent with many previous studies
, indicated that IQ is reduced early and
persistently in children destined to develop schizophrenia
. These precur-
sors of schizophrenia are subtle and non-specific, but the consistency of the
finding supports the hypothesis that psychosis does not emerge from a
completely healthy brain.
The emerging picture from genetic studies also indicates that early
brain development is affected. As noted earlier, many of the structural
variants associated with schizophrenia implicate neurodevelopmental
genes involved with neuronal proliferation, migration, or synapse
. Even genes that are not exclusively developmental seem
to influence schizophrenia by their early disruption
. In a particularly
intriguing example, Niwa et al.
reported that a transient knockdown of
DISC1 in the frontal cortex in the pre- and perinatal mouse brain led to
neurochemical and behavioural disruptions emerging in early adult-
hood. Moreover, some of the vulnerability alleles of candidate genes,
such as NRG1 and DISC1, seem to selectively influence splice variants
expressed predominantly in developing cortex, implicating isoforms
that show large developmental changes in expression in the prefrontal
. As a final link to development, the genetics of schizophrenia
overlaps with the genetics of autism and other neurodevelopmental
. It is unclear why the same genetic variation associated with
many different neurodevelopmental syndromes is manifested in some by
age 3 years (autism) and in others after age 18 years (schizophrenia).
Presumably there are genomic modifiers or possibly environmental
influences that determine the specific syndrome. The study of discordant
twins may yield important information for understanding the mis-
matches between genotype and phenotype.
Environmental factors identified so far have also implicated prenatal
or perinatal events. Maternal malnutrition during famine
, infections
in the second trimester
, perinatal injury
and cytokine exposure
all been associated with subsequent increased risk for schizophrenia.
Most of these effects are modest (less that twofold increase in risk)
and none seem specific for schizophrenia, but in aggregate they demon-
strate that early adverse experiences, including mid-gestational insults,
are a risk factor for psychosis occurring two decades later. Gene-by-
environment studies may demonstrate more robust effects
, but an
even more promising approach may be epigenetic maps indicating the
‘scars’ of early experience or the stochastic changes emerging across
. As an example, a gene disrupted by a rare copy number
variant in autism was found to be repressed by hypermethylation in a
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large number of children with autism who had a perfectly normal geno-
mic sequence
The model that emerges from this neurodevelopmental perspective is
that of an early insult, a latent period through much of neural development,
and the emergence of psychosis in late adolescence or early adulthood. One
possibility is a lesion early in development that does not manifest until a
much later developmental stage when compensatory changes can no
longer suffice. Thompson and Levitt
have called this developmental
allostasis. A second, not mutually exclusive possibility is that the develop-
mental lesion influences a pathway or a regulatory process, such as the
fine tuning of excitatory and inhibitory synapses in the prefrontal cortex,
which may have only subtle effects until a precise balance is required in
late adolescence. Current data cannot distinguish between these two
options, but either way a neurodevelopmental perspective implies the
importance of timing and the opportunity for earlier intervention and
How will we map the trajectory of schizophrenia as a neurodevelop-
mental disease? Recent longitudinal studies of children with a rare,
early-onset form of schizophrenia have used neuroimaging to identify
differences in the trajectory of brain development. In these studies,
children with schizophrenia seem to undergo excessive losses of grey
matter and cortical thinning, essentially overshooting the normal pattern
described earlier for adolescents
. These findings, although intriguing,
are limited in that they do not reveal the changes before psychosis.
An opportunity for mapping earlier phases of the trajectory can be
found in velocardiofacial syndrome, a syndrome associated with a micro-
deletion of chromosome 22q11 (reviewed in ref. 61). Approximately 30%
of children with a microdeletion of 22q11 will develop a form of schizo-
phrenia that clinically and neurocognitively cannot be distinguished
from the idiopathic disorder
. Most of these children are detected as
toddlers because of their cardiac disease. Important insights into the
trajectory from risk to disorder may be gained from ongoing longitudinal
studies of these children comparing cognitive, affective and neural
development in those who do and do not develop psychosis among this
cohort with a similar genomic deletion.
Will animal studies reveal the neurodevelopmental trajectory of schizo-
phrenia? Unlike the many disorders in medicine that can be modelled in
mice or flies, an animal model of schizophrenia seems unlikely. Indeed,
aspects of the prefrontal neuroanatomyand the executive function deficits
of schizophrenia seem to be distinctively human. This is not to say that
studies in animals, especially non-human primates, will be unimportant
for schizophrenia. We lack fundamental information on the normal
development of the forebrain, from the timing and geography of gene
expression to the patterns of circuit formation under various environ-
mental conditions. With current technology, these critical developmental
maps will only be derived from studies in animals. Animal studies can also
aid the study of abnormal development. Whereas animal models of
schizophrenia are not likely, ‘model animals such as mice and flies
10 252015
0 5 10 15 20
Age (years)
Age (years)
Percentage of maximumPercentage of maximum
Fertilization 25
Stage I: risk
< 12 years
Stage II: prodome
12–18 years
Stage III: psychosis
18–24 years
Stage IV:
>24 years
5 years
Grey-matter volume changes during normal development
20 years
excitatory synapses
excitatory synapses
excitatory pruning
interneuron activity
inhibitory synapses
inhibitory synapses
Figure 1
Neurodevelopmental model of schizophrenia. a, Normal cortical
development involves proliferation, migration, arborization (circuit formation)
and myelination, with the first two processes occurring mostly during prenatal
life and the latter two continuing through the first two post-natal decades. The
combined effects of pruning of the neuronal arbor and myelin deposition are
thought to account for the progressive reduction of grey-matter volume
observed with longitudinal neuroimaging. Beneath this observed overall
reduction, local changes are far more complex. Data from human and non-
human primate brain indicate increases in inhibitory and decreases in
excitatory synaptic strength occurring in prefrontal cortex throughout
adolescence and early adulthood, during the period of prodrome and
emergence of psychosis. b, The trajectory in children developing schizophrenia
could include reduced elaboration of inhibitory pathways and excessive
pruning of excitatory pathways leading to altered excitatory–inhibitory balance
in the prefrontal cortex. Reduced myelination would alter connectivity.
Although some data support each of these possible neurodevelopmental
mechanisms for schizophrenia, none has been proven to cause the syndrome.
Detection of prodromal neurodevelopmental changes could permit early
intervention with potential prevention or preemption of psychosis.
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engineered with schizophrenia candidate genes will be highly informative
for linking genetic variation to changes in cell and circuit function. For
instance, mice with homologous deletions to the 22q11 lesion of velo-
cardiofacial syndrome manifest differences in circuit formation and syn-
aptic plasticity
. Such model animals will not only yield studies of
disease mechanisms but opportunities for new treatment development.
Increasingly, however,it seems that humans may prove the best animal
for modelling schizophrenia. Just as genes can create relevant models in
non-human animals, genes can serve as a portal to mapping the patho-
physiology of schizophrenia in cells from patients with the disorder. With
induced pluripotent stem cells derived from fibroblasts of patients with
schizophrenia, we should soon be able to study many different neural cell
types, including their development, functional connections and response
to perturbations. These cells do not need to recreate the disorder in a dish;
they need only yield disordered molecular networks to reveal targets for
developing new therapies. Through identifying new targets and high-
throughput screening of existing small molecule libraries, we can expect
the next generation of treatments for schizophrenia to be based on
molecular pathophysiology rather than serendipity.
The stages of schizophrenia
Perhaps the most fundamental change from re-conceptualizing schizo-
phrenia as a neurodevelopmental disorder is the notion of trajectory of
illness. If the disorder begins in prenatal or perinatal life, then the
psychosis of late adolescence must be seen not as the onset but as a late
stage of the disorder. Indeed, we can begin to hypothesize four stages of
schizophrenia, from risk to prodrome to psychosis to chronic disability
(Table 1). At present, the diagnosis is based on the symptoms and signs
of psychosis. With the advent of biomarkers and new cognitive tools as
well as the identification of subtle clinical features, we are beginning to
detect earlier stages of risk and prodrome.
The earliest stage is risk, before detectable deficits. In 2010 we do not
have the risk architecture of this syndrome, but we can begin to see some
of the outlines, based on genomics. Beyond the rare, highly penetrant
mutations (for example, DISC1 and the 22q11 deletion), epistatic inter-
actions between more common, less penetrant variations may yield
higher predictions of risk than our current list. Of course, the 50%
concordance rate of homozygous twins reminds us that genomics will
not predict all forms of risk. Identifying environmental factors, detecting
critical epigenomic modifications, or mapping neural circuit differences
may render more of the blueprint for risk, much as the algorithms for
coronary artery disease use family history, plasma lipids and dietary
history. The extent to which the risk factors for schizophrenia will be
modifiable in the sense that we can reduce the risk for coronary artery
disease or lung cancer remains to be seen. And although this earliest
stage may not involve distress or help-seeking, longitudinal studies have
begun to identify subtle but reproducible evidence for behavioural and
cognitive problems in early childhood
. To define this earliest stage
we will need to define the full architecture of individual risk: genetic and
epigenetic biomarkers, cognitive indicators and physiological predictors
of vulnerability to the disorder.
Over the past two decades, the pioneering work of McGorry and his
has established the prodrome of schizophrenia as a valid
second stage of the illness before psychosis. Whether defined as ultra-
high risk or pre-psychosis, the prodrome is now identified based on
changes in thoughts (for example, bizarre ideas falling short of psychotic
ideation), social isolation and impaired functioning (for example,
reduced school performance). Recognizing that these features might
seem endemic to adolescence, the Structured Interview for Prodromal
Syndromes (SIPS) was developed to distinguish high risk for psychosis
from more common adolescent angst
. Recently a large multi-site
project in the United States of 291 adolescents followed for 2.5 years
reported that the prodrome represented a 405-fold increase in risk (rela-
tive to the general population) and that a combination of three factors
(for example, genetic risk with recent functional decline, unusual
thought content, and either suspicion/paranoia or reduced social func-
tioning) resulted in a positive predictive power for conversionto psychosis
of 74–81% (ref. 74). The addition of biomarkers, detected with functional
or structural neuroimaging (reviewed in ref. 75), or the use of neuropsy-
chological tests of reaction time or verbal memory
may enhance detec-
tion and increase the predictive power. Given the high rate of behavioural
distress in adolescence and the likelihood that many with prodromal
symptoms will either mature out of them or develop other disorders,
the challenge is to increase sensitivity for detecting ultra-high risk while
not sacrificing specificity
. Specificity is a challenge: many of those who
seek help for prodromal symptoms will develop other forms of psycho-
pathology, not schizophrenia. What will we need to define this stage of
schizophrenia? Although standardized clinical assessments will help and
longitudinal imaging may yield biomarkers, it is likely that cognitive
changes, such as reductions in working memory, may be the best predictor
of the psychotic phase of schizophrenia
. Over the next few years, cog-
nitive neuroscience will have a critical role in providing the tools for
increasing the sensitivity and specificity of the schizophrenic prodrome
It is unclear to what extent intervening during the prodrome will either
prevent or forestall psychosis. Results from single-site trials of atypical
, antidepressants
, lithium
and cognitive behaviour
have had, at best, modest effects in reducing symptoms or
preventing conversion to psychosis. A recent randomized double-blind
placebo-controlled 12-week trial of long-chain omega-3 polyunsaturated
fatty acids reported a 12-month conversion to psychosis in 2 of 41 (4.9%)
individuals in the treated group versus 11 of 40 (27.5%) individuals in the
placebo group
. Although promising, the overall rate of conversion (13
of 81) is lower than that observed in most prodromal cohorts. Current
efforts to use cognitive remediation may identify a low-risk approach that
could be used even if specificity were low
. An innovative, broad effort on
youth mental health in Australia is addressing the issues of false positives,
low specificity and potential stigma from early diagnosis by developing
community-based, resilience-based interventions
Stage III of schizophrenia is psychosis manifested by hallucinations,
delusions, disorganization of thought and behaviour, and psychomotor
abnormalities. It is now clear that negative symptoms (loss of will,
anhedonia, poverty of thought) and cognitive deficits (reduced working
Table 1
Stages of schizophrenia
Stage I Stage II Stage III Stage IV
Features Genetic vulnerability
Environmental exposure
Cognitive, behavioural and social deficits
Abnormal thought and behaviour
Relapsing–remitting course
Loss of function
Medical complications
Diagnosis Genetic sequence
Family history
Cognitive assessment
Clinical interview
Loss of insight
Clinical interview
Loss of function
Disability None/mild cognitive deficit Change in school and social function Acute loss of function
Acute family distress
Chronic disability
Intervention Unknown Cognitive training?
Polyunsaturated fatty acids?
Family support?
Psychosocial interventions
Psychosocial interventions
Rehabilitation services
Stage I, pre-symptomatic risk; stage II, pre-psychotic prodrome; stage III, acute psychosis; stage IV, chronic illness.
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memory, poor cognitive control) are core features of the disorder that
account for much of the long-term morbidity and poor functional
. Although the avolitional component of the disorder may
define a special subgroup
, there is a new consensus that the negative
symptoms and cognitive aspects of pathology are major unmet thera-
peutic needs
. If risk is analogous to hyperlipidemia, prodrome com-
parable to angina, then psychosis can be thought of as myocardial
infarction with frequent residual loss of function. In spite of consistently
positive acute responses to antipsychotic medications and psychosocial
treatments, relapse rates approach 80% (ref. 2). Cognitive deficits and
negative symptoms, whether preceding or emerging with psychosis
seem, at best, only modestly responsive to current antipsychotic treat-
. The most urgent research priority in the near term will be
effective treatments for the cognitive deficits, including the lack of
insight that often inhibits adherence to both medication and psychoso-
cial treatments.
Stage IV of schizophrenia involves chronic disability. In 1988, in the
height of the AIDS epidemic, the editor of Nature noted that ‘‘schizophre-
nia is arguably the worst disease affecting mankind, even AIDS not
Not all individuals progress to this late stage of the illness,
but for those who do the disability is not only psychiatric but medical. The
oft-cited psychiatric deficits lead to unemployment, homelessness and
incarceration, as noted earlier. A Finnish birth cohort study recently
reported a 7% rate of suicide in schizophrenia, accounting for 50% of
all deaths by age 39 (ref. 94). The medical complications of chronic
schizophrenia are less well known. In 2010, smoking and obesity are
epidemic among people with schizophrenia, with estimates of nicotine
dependence ranging from 58–90% (ref. 95) and metabolic syndrome
(obesity, hyperlipidemia, hyperglycemia and hypertension) present in
40% (ref. 96). Life expectancy for those with serious mental illness has
been estimated at 56 years, approximately 25 years of premature mortality
resulting usually from cardiopulmonary disease or other chronic medical
. Importantly, many of the medical complications of schizo-
phrenia can be prevented throughtobacco cessation, dietary management
and programs to manage cardiovascular health.
Schizophrenia in 2030
What is the prognosis of schizophrenia for 2030? I will venture a few
predictions based on hope more than knowledge and recognizing that
progress in understanding and treating schizophrenia may come from
distant fields of science that have not yet been engaged in this area (Fig. 2).
Judging from the success of preventive approaches to cardiac death and
disability, refocusing our approach to schizophrenia on early detection
and early intervention could yield substantial improvements in outcomes
over the next decade or two. This will, of course, require sensitive and
specific diagnostic tools as well as safe and effective interventions. The
diagnostic tools for schizophrenia, like the diagnostic tools for cardio-
vascular risk, will probably require a combination of approaches, includ-
ing measures of genetic risk, imaging the efficiency of neural circuits, and,
probably most specifically, early cognitive changes. Interventions that
include an aggressive focus on cognition along with family support
may prove surprisingly effective for preempting or forestalling psychosis.
Although a ‘statin-like’ medication would be an unambiguous break-
through, we should not assume that a medication will be more effective
than harnessing the developing brain’s intrinsic plasticity for reversing
the neural trajectory that leads from risk to prodrome. If the preemptive
interventions are as effective as what we have today for coronary artery
disease and if these are widely deployed, by 2030 we should expect a
profound reduction in first-episode psychosis.
Reducing the cognitive deficits
The disability of schizophrenia in 2010 results more from the under-
recognized and treatment-refractory cognitive deficits than from the
more obvious and frequently treatable positive symptoms
. Over the
next decade, potentially leveraging current research on cognition in
Alzheimer’s disease, we can expect a series of pharmacological and
nonpharmacological interventions that will reverse or mitigate the cog-
nitive deficits of the disorder. Early initiation of these interventions will
be transformative, but even in patients following psychosis, cognitive
remediation may enhance employment, social inclusion and function in
the community
. With interventions that reduce cognitive deficits, by
2030 we will be combining somatic, psychosocial and cognitive treat-
ments with a goal of curing this disease for many patients.
Integration of care
One of the most egregious aspects of schizophrenia treatment in 2010 is
the fragmentation of care, with medical care separated from psychiatric
careand both isolated from psychosocial interventions, such as supportive
employment and family education, which have a strong evidence base for
effectiveness. Arguably, doing better with current treatments is our best
short-term strategy for enhancing outcomes. A large multi-site effort in
the United States, the Recovery After Initial Episode of Schizophrenia
(RAISE) project, is developing a best-practices approach to bundled
services that should provide some data about how much this can enhance
outcomes. One can hope that in the near future, well before 2030, we will
see all aspects of care being integrated in a continuous way, as is done
increasingly for diabetes and other chronic disorders. Note, however, that
the treatment of schizophrenia involves challenges not observed in most
other chronic diseases. Denial of illness, paranoia, irrational thoughts,
deficits in executive function and disruptive behaviour can all be part of
the syndrome of untreated schizophrenia, complicating care for those
with this disorder. Better treatments, not only better systems, will be
necessary for better outcomes.
Just as warehousing in institutions is mostly a memory today, imagine if
the stigma associated with schizophrenia today were gone in 2030. In
contrast to many other medical disorders, schizophrenia today too often
defines a person rather than describing the illness. Our fear of psychosis
or disruptive behaviour may keep us from seeing the heroic struggle that
Biodiagnostics for early detection
Treatment of cognitive decits
Strategic prevention
Cure therapeutics
Diagnosis by late symptoms
Treatment for psychotic episode
Personalized care
Discovery technologies
Clinical genomics/
Translating research into practice
Integration Social inclusion
Figure 2
A vision for schizophrenia over the next two decades. Currently
diagnosis follows psychosis (stage III) and treatment focuses on reducing
psychotic symptoms. The use of discovery technologies, which have already
transformed the understanding and treatment of many other medical
disorders, can transform our understanding of schizophrenia, yielding earlier
diagnosis (stages I or II) with treatments focused on the cognitive deficits of this
disorder. The ultimate goal, however, is cure and prevention based on an
understanding of individual risk and the development of personalized care. In
practice this means not only identifying risk and preemptive interventions but
ensuring access to these interventions, integrating care and ensuring full social
inclusion for people at any stage of the schizophrenia trajectory.
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people with this disorder face just to survive amidst the internal chaos
and panic that is part of this chronic illness. Our expectations of these
citizens are low: they should stay out of jail, on their medications and not
distress their families, friends and fellow citizens. They deserve better. As
a vision for 2030, people who suffer from any stage of schizophrenia will
be considered to be educable, employable and capable of living in intimate
relationships with others.
Will we still use the term schizophrenia in 2030? The accumulating
genomic evidence indicates that there may be scores or hundreds of
lesions contributing to this final common syndrome. The clinical evid-
ence supports the possibility that what we have labelled schizophrenia for
the past century may be many different disorders with different out-
. And the stigma associated with the diagnosis, and the past
history of misunderstanding and mistreatment also indicate that a
change in the term may be advisable. In 2002, the Japanese terms for
schizophrenia ‘Seishin-Bunretsu-Byo (‘mind-split disease’) was replaced
officially by ‘Togo-Shitcho-Sho’ (‘integration disorder’)
. Some evid-
ence indicates that this name change led to reduced stigma, in that fewer
people associated the new name with criminality
Although semantic changes can be helpful, the transformations
needed for those with this serious illness are likely to require not only
a better label but better science (Fig. 2). In the next decade the challenge
will be to integrate the impact of genetics, experience and development
to identify a complete blueprint of the risk architecture of this syndrome.
This should lead to a new taxonomy, identifying the many disorders
within the syndrome we now call ‘schizophrenia’ and hopefully replacing
this aggregate label with a series of more precise diagnoses based on
pathophysiology. We need a personalized and preemptive approach,
based on understanding and detecting individual risk and facilitated by
safe and effective interventions for those in stages I and II of this disorder.
In the meantime, we can create policies for social inclusion, family sup-
port and continuity of care to ensure that those in later stages of the
syndrome have the best chance for recovery. Importantly, if recovery
defined as a life in the community is our primary goal today, for 2030
our goals must include prevention, preemption and cure.
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Acknowledgements The author appreciates comments on this manuscript from C.
Carter, W. Carpenter, H. Heimer, D. Lewis and D. Weinberger.
Author Information Reprints and permissions information is available at The author declares no competing financial interests.
Readers are welcome to comment on the online version of this article at Correspondence and requests for materials should be
addressed to T.R.I. (
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... However, later studies have confirmed that loneliness and depression are distinct yet interrelated constructs Weeks, 1980). Moreover, loneliness and depressive symptoms are found to be reciprocally associated over time (e.g., Cacioppo, Hughes, et al., 2006;2010). Nuyen et al. (2020) have found that loneliness at baseline was predictive of the onset of common mental disorders (CMDs, i.e., mood, anxiety, and substance use disorders) at one-year follow-up among adults without CMDs at baseline. ...
... Schizophrenia spectrum disorders consist of heterogenous psychotic symptoms, including delusions, hallucinations, a lack of emotional expression and motivation, and disorganization and cognitive deficits. In spite of heritability as high as 50% (e.g., Greenwood et al., 2007;Kety et al., 1988;McGuffin et al., 1984), results of the search of the genetic markers and biological causes for schizophrenia are inconsistent and with small to modest effect sizes (e.g., Insel, 2010;Talkowski et al., 2008), highlighting the huge heterogeneity and complexity of the etiology of the disorder. There have been attempts to cluster psychotic symptoms into dimensions to reduce the heterogeneity of symptoms. ...
Background: Loneliness, the unpleasant experience arising from a discrepancy between perceived and actual social relationships, is closely related to a range of psychopathologies, including psychosis. Psychosis is a constellation of heterogenous symptoms, in which paranoia is one of the most distressing symptoms. Paranoia refers to beliefs concerning intentional threat by others. Loneliness and paranoia were found to be robustly associated in both clinical and non-clinical populations. However, the relationships between them and the underlying mechanisms are not clear. The thesis: The overall aim was to investigate the relationships between loneliness and paranoia and the underlying mechanisms. Specific questions were: 1) how loneliness and paranoia are related, in addition to emotional disturbances and negative core schemas? 2) does manipulation of loneliness lead to change in paranoia and is such change explained by change in attentional bias towards social threat? 3) Do loneliness and paranoia predict each other and how does the strength of these dynamics vary with interindividual difference in vulnerability to schizophrenia? Methods: Three studies were conducted using three separate non-clinical samples of young adults. Using a network analytic approach, Study 1 (N = 2,089) examined the structural relationship between loneliness, paranoia, emotional disturbances (i.e., depressive and anxiety symptoms) and negative core schemas about self and others in a demographically diverse sample. Study 2 (N = 158) adopted an experimental design and examined changes in paranoia and attentional bias towards social threat following manipulation of loneliness. Study 3 (N = 83), using experience sampling method (ESM), examined the reciprocal relationship between momentary loneliness and paranoia, and the association between the strength of these dynamics with level of schizotypy. Results: Loneliness and paranoia were associated with each other both directly and indirectly via emotional disturbances and negative core schemas (Study 1). An induction of loneliness led to an increase in paranoia, and the effect was not explained by change in attentional bias towards social threat (Study 2). Momentary paranoia was associated with an increase in momentary loneliness. However, momentary loneliness was not associated with an increase in momentary paranoia. Interindividual difference in schizotypy was not associated with the strength of these reciprocal associations (Study 3). Conclusions: Loneliness and paranoia are closely and dynamically related to each other. Future research is required to further consolidate the psychological models of paranoia and loneliness by incorporating their reciprocal contributions to each other.
... Delusional belief contents, then, can be viewed as an attempt to thematize these underlying changes and, hence, exhibit a so-called "delusional logic" ("Wahnsinnslogik") (Wulff, 1992). By unearthing these foundational layers to psychopathological shifts in consciousness, phenomenological psychopathology contributes not only to a better understanding of the patient's experience from his or her own perspective, but also offers conceptual and methodological means for the early detection of schizophrenic psychosis (Parnas et al., 2005;Sass et al., 2017), which is sometimes prematurely reserved for neurobiological approaches to psychopathology (Insel, 2010;Heinssen and Insel, 2015). By shedding light on this eidetic continuity, phenomenological psychopathology provides a framework that furthers scientific understanding of incomprehensibility by illuminating its development. ...
Full-text available
At the present state of discourse, the issue of incomprehensibility is clouded by unresolved problems. We propose that this confusion stems from three distinct sources. In the following, we elaborate on each of them and advance a schema for structuring the discourse on schizophrenic incomprehensibility (see table 1): 1. Overreliance on delusional beliefs. The problem of incomprehensibility is ill-posed, biasing the discourse towards the delusional beliefs as is evidenced by their characterization in the ICD and DSM. Consequently, the origin and the experience of delusions are overlooked. Since they lie at the root of the psychopathology of schizophrenia, the discourse on the origin and experiential structure of incomprehensibility must be revisited. 2. False threat of irrationalism. Acknowledging the clinical reality of schizophrenic incomprehensibility is misevaluated as endangering the scientific status of psychopathology by pushing it towards irrationalism. Such an evaluation ultimately hinders the project of determining the possibilities and limits of psychopathological knowledge, which is essential to establishing it as a strict science: In light of the phenomenological approach, schizophrenic incomprehensibility does not mark the endpoint of our understanding of schizophrenia but is a starting point for developing a psychopathological agnotology (i.e., the scientific investigation of the production and experience of incomprehensibility). 3. Equivocations. The discourse on incomprehensibility is riddled with equivocations. This means that conflating concepts such as un-understandability, oddity, schizophrenic alterity or the praecox feeling is the norm rather than the exception. In order to distinguish these related concepts, it is helpful to consider their intellectual origins and to systematically classify competing approaches to schizophrenic incomprehensibility. Considering incomprehensibility can aid in enriching the discourse by moving beyond the classical framing in terms of the understanding-explanation dichotomy to the more adequate and encompassing trichotomy of un-understandability (“Unverständlichkeit”), obscurity (“Uneinfühlbarkeit”) and inexplicability (“Unerklärbarkeit”).
... Dysfunction occurring in these resources leads to P300 deficits such as decreased amplitude and prolonged latency (Bledowski et al., 2004;Musso et al., 2011). These functional deficits can also be seen in schizophrenic patients' cognitive deficits, such as in identifying, processing, and responding to novel stimuli (Insel, 2010), and in turn, these deficits can be identified in many behavioral studies with different cognitive tasks, such as the visual Go/NoGo task or the visual and auditory oddball task in a fixed order (Chun et al., 2013;van der Stelt et al., 2005). The reduced P300 amplitudes depicted in Fig. 3 and the correlations between P300 amplitudes and BPRS scores shown in Fig. 4 consistently validated the cognitive capacity deficits in these patients. ...
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Auditory verbal hallucinations (AVH) are a core positive symptom of schizophrenia and are regarded as a consequence of the functional breakdown in the related sensory process. Yet, the potential mechanism of AVH is still lacking. In the present study, we explored the difference between AVHs (n = 23) and non-AVHs (n = 19) in schizophrenia and healthy controls (n = 29) by using multidimensional electroencephalograms data during an auditory oddball task. Compared to healthy controls, both AVH and non-AVH groups showed reduced P300 amplitudes. Additionally, the results from brain networks analysis revealed that AVH patients showed reduced left frontal to posterior parietal/temporal connectivity compared to non-AVH patients. Moreover, using the fused network properties of both delta and theta bands as features for in-depth learning made it possible to identify the AVH from non-AVH patients at an accuracy of 80.95%. The left frontal-parietal/temporal networks seen in the auditory oddball paradigm might be underlying biomarkers of AVH in schizophrenia. This study demonstrated for the first time the functional breakdown of the auditory processing pathway in the AVH patients, leading to a better understanding of the atypical brain network of the AVH patients.
... Antipsychotics are much more effective against positive symptoms than against negative and cognitive symptoms. At the same time, it is the severity of the deficit symptoms and cognitive dysfunction that is the most important predictor of psychosocial functioning in schizophrenia [2]. ...
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Background. Finding the associations between schizophrenia symptoms and the biomark-ers of inflammation, oxidative stress and the kynurenine pathway may lead to the individualization of treatment and increase its effectiveness. Methods. The study group included 82 schizophrenia inpatients. The Positive and Negative Symptoms Scale (PANSS), the Brief Assessment of Cogni-tion in Schizophrenia (BACS) and the Calgary Depression in Schizophrenia Scale were used for symptom evaluation. Biochemical analyses included oxidative stress parameters and brain-derived neurotrophic factor (BDNF). Results. Linear models revealed the following: (1) malondiadehyde (MDA), N-formylkynurenine (N-formKYN), advanced oxidation protein products (AOPP), advanced glycation end-products of proteins (AGE) and total oxidative status (TOS) levels are related to the PANSS-total score; (2) MDA, reduced glutathione (GSH) and BDNF levels are related to the PANSS-negative score; (3) TOS and kynurenine (KYN) levels are related to the PANSS-positive score; (4) levels of total antioxidant status (TAS) and AOPP along with the CDSS score are related to the BACS-total score; (5) TAS and N-formKYN levels are related to the BACS-working memory score. Conclusions. Oxidative stress biomarkers may be associated with the severity of schizophrenia symptoms in positive, negative and cognitive dimensions. The identification of biochemical markers associated with the specific symptom clusters may increase the understanding of biochemical profiles in schizophrenia patients.
... Schizophrenia (SZ) manifests from a complex interplay of genes and molecules that shape brain structure and function across the lifespan. It appears to be a highly heritable neurodevelopmental disorder [1,2] with progression of neural alterations in early development leading to psychotic onset usually following puberty. Understanding the vulnerability and resilency factors in SZ is critical for early intervention of this debilitating illness. ...
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Background Schizophrenia (SZ) arises from a complex interplay involving genetic and molecular factors. Early intervention of SZ hinges upon understanding its vulnerability and resiliency factors in study of SZ and genetic high risk for SZ (GHR). Methods Herein, using integrative and multimodal strategies, we first performed a longitudinal study of neural function as measured by amplitude of low frequency function (ALFF) in 21 SZ, 26 GHR, and 39 healthy controls to characterize neurodevelopmental trajectories of SZ and GHR. Then, we examined the relationship between polygenic risk score for SZ (SZ-PRS), lipid metabolism, and ALFF in 78 SZ, and 75 GHR in cross-sectional design to understand its genetic and molecular substrates. Results Across time, SZ and GHR diverge in ALFF alterations of the left medial orbital frontal cortex (MOF). At baseline, both SZ and GHR had increased left MOF ALFF compared to HC (P < 0.05). At follow-up, increased ALFF persisted in SZ, yet normalized in GHR. Further, membrane genes and lipid species for cell membranes predicted left MOF ALFF in SZ; whereas in GHR, fatty acids best predicted and were negatively correlated (r = -0.302, P < 0.05) with left MOF. Conclusions Our findings implicate divergence in ALFF alteration in left MOF between SZ and GHR with disease progression, reflecting vulnerability and resiliency to SZ. They also indicate different influences of membrane genes and lipid metabolism on left MOF ALFF in SZ and GHR, which have important implications for understanding mechanisms underlying vulnerability and resiliency in SZ and contribute to translational efforts for early intervention.
... Schizophrenia is a complex psychiatric disorder that has a heterogeneous etiology (Insel 2010). The role of the dopamine hypothesis in etiology has been proven and current treatments target this mechanism. ...
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Rationale Although the immune system is thought to contribute to the etiology of schizophrenia, the mechanism has not been elucidated. Clarifying the relationship between them is important in terms of diagnosis, treatment, and prevention approaches. Objective In this study, it is aimed to determine whether there is any difference in serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) in the group of patients with schizophrenia and healthy volunteers, whether these values are changed by medical treatment, whether there is any relation between these values and the severity of the symptoms of patients with schizophrenia, and whether NGAL can be used as a biomarker in the diagnosis and the follow-up of the schizophrenia. Methods A total of 64 patients who were hospitalized in the Psychiatry Clinic of Ankara City Hospital and diagnosed with schizophrenia and 55 healthy volunteers were included in the study. A sociodemographic information form was given to all participants and TNF-α and NGAL values were measured. Positive and Negative Symptoms Rating Scale (PANSS) were applied to the schizophrenia group on admission and follow-up. TNF-α and NGAL levels were re-measured in the 4th week after the start of antipsychotic treatment. Results As a result of the present study, it was found that NGAL levels decreased significantly after antipsychotic treatment of schizophrenia patients hospitalized with exacerbation. There was no significant correlation between NGAL and TNF-α levels among schizophrenia and the control group. Conclusion In psychiatric diseases, especially schizophrenia, there may be differences in immune and inflammatory markers compared to the healthy population. After treatment, the NGAL levels of the patients at follow-up were reduced compared to the levels at admission. It can be thought that NGAL may be related to psychopathology in schizophrenia and antipsychotic treatment. This is the first follow-up study for NGAL levels in schizophrenia.
La enfermedad por Coronavirus 2019 (Covid-19) causada por la infección del Coronavirus del Síndrome Agudo Respiratorio 2 (SARS-CoV-2) es capaz de afectar las células neuronales generando neuroinflamación. La neuroinflamación también es una característica fisiopatológica de diversas enfermedades mentales graves como la esquizofrenia, en la cual incluso se ha relacionado con las alteraciones de neuroplasticidad descritas en la enfermedad. Los neurolépticos atípicos, que son los fármacos de elec- ción para el tratamiento de la esquizofrenia, además de sus mecanismos monoaminérgicos mediante los cuales atenúan la sintomatología positiva principalmente, poseen propiedades anti-inflamatorias, antioxidantes y neurotróficas que podrían estar contribuyendo a su efecto terapéutico. Por lo tanto, se sugiere que los neurolépticos atípicos podrían estar contribuyendo a un mejor pronóstico del Covid-19 en pacientes con esquizofrenia mediante la modulación de la neuroinflamación.
Objective: Compared with the healthy control(HC) group, the brain structure and function of schizophrenia(SZ) patients are significantly abnormal, so brain imaging methods can be used to achieve the aided diagnosis of SZ. However, a brain network based on brain imaging data is non-Euclidean, and its intrinsic features cannot be learned effectively by general deep learning models. Furthermore, in the majority of existing studies, brain network features were manually specified as the input of machine learning models. Methods: In this study, brain functional network constructed from the subject's fMRI data is analyzed, and its small-world value is calculated and t-tested; the node2vec algorithm in graph embedding is introduced to transform the constructed brain network into low-dimensional dense vectors, and the brain network's non-Euclidean spatial structure characteristics are retained to the greatest extent, so that its intrinsic features can be extracted by deep learning models; GridMask is used to randomly mask part of the information in the vectors to enhance the data; and then features can be extracted using the Transformer model to identify SZ. Results: It is again shown that the small-world value of the brain network in SZ is significantly lower than that in HC by t-test (p=0.014¡0.05). 97.78% classification accuracy is achieved by the proposed methods (node2vec + GridMask + Transformer) in 30 SZ patients and 30 healthy people. Conclusion: The experiment shows that the node2vec used in this paper can effectively solve the problem of brain network features being difficult to learn by general deep learning models. The high-precision computer-aided diagnosis of SZ can be obtained by combining node2vec with Transformer and GridMask. Significance: The proposed methods in the paper are expected to be used for aided diagnosis of SZ.
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Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive deficits are a key feature of the disorder and a primary cause of long-term disability. Over the past decades, significant literature has accumulated demonstrating impairments in early auditory perceptual processes in schizophrenia. In this review, we first describe early auditory dysfunction in schizophrenia from both a behavioral and neurophysiological perspective and examine their interrelationship with both higher order cognitive constructs and social cognitive processes. Then, we provide insights into underlying pathological processes, especially in relationship to glutamatergic and N-methyl-D-aspartate receptor (NMDAR) dysfunction models. Finally, we discuss the utility of early auditory measures as both treatment targets for precision intervention and as translational biomarkers for etiological investigation. Altogether, this review points out the crucial role of early auditory deficits in the pathophysiology of schizophrenia, in addition to major implications for early intervention and auditory-targeted approaches.
To test the hypothesis that the ability to actively represent and maintain context information is a central function of working memory and that a disturbance in this function contributes to cognitive deficits in schizophrenia, the authors modified 3 tasks-the AX version of the Continuous Performance Test, Stroop, and a lexical disambiguation task-and administered them to patients with schizophrenia as well as to depressed and healthy controls. The results suggest an accentuation of deficits in patients with schizophrenia in context-sensitive conditions and cross-task correlations of performance in these conditions. However, the results do not definitively eliminate the possibility of a generalized deficit. The significance of these findings is discussed with regard to the specificity of deficits in schizophrenia and the hypothesis concerning the neural and cognitive mechanisms that underlie these deficits.
• We tested the hypothesis that first-trimester exposure to acute food deprivation is a risk factor for schizophrenia. A sharp and time-limited decline in the food intake of the Dutch population following a Nazi blockade in 1944 to 1945 created a unique if tragic natural experiment to test this hypothesis in three regions of Holland (west, north, and south). In the west, or famine region, birth cohorts exposed to severe food deprivation (an average daily ration under 4200 kJ) during the first trimester showed a substantial increase in hospitalized schizophrenia for women but not for men. Relative risks for women were 2.17 for "broad" and 2.56 for "restricted" schizophrenia. Moderate food deprivation during the first trimester (average daily ration under 6300 kJ) was not associated with increased risk of schizophrenia in the famine region. In the north and south regions, numbers were smaller and there was no exposure to severe famine. Birth cohorts exposed to moderate food deprivation during the first trimester showed a trend toward increased risk of schizophrenia for women. These findings give plausibility to the proposition that early prenatal nutrition can have a gender-specific effect on the risk of schizophrenia.
Context Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions.Objectives To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis.Design Longitudinal study with 2½ years of follow-up.Setting Eight centers participating in the North American Prodrome Longitudinal Study.Participants Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations.Main Outcome Measures A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status.Results Global (“composite”) neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion.Conclusions These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.
Background In schizophrenia, working memory dysfunction is associated with altered expression of gamma-aminobutyric acid (GABA)A receptor α1 and α2 subunits in the dorsolateral prefrontal cortex (DLPFC). In rodents, cortical α subunit expression shifts from low α1 and high α2 to high α1 and low α2 during early postnatal development. Because these two α subunits confer different functional properties to the GABAA receptors containing them, we determined whether this shift in α1 and α2 subunit expression continues through adolescence in the primate DLPFC, potentially contributing to the maturation of working memory during this developmental period. Methods Levels of GABAA receptor α1 and α2 subunit mRNAs were determined in the DLPFC of monkeys aged 1 week, 4 weeks, 3 months, 15–17 months (prepubertal), and 43–47 months (postpubertal) and in adult monkeys using in situ hybridization, followed by the quantification of α1 subunit protein by western blotting. We also performed whole-cell patch clamp recording of miniature inhibitory postsynaptic potentials (mIPSPs) in DLPFC slices prepared from pre- and postpubertal monkeys. Results The mRNA and protein levels of α1 and α2 subunits progressively increased and decreased, respectively, throughout postnatal development including adolescence. Furthermore, as predicted by the different functional properties of α1-containing versus α2-containing GABAA receptors, the mIPSP duration was significantly shorter in postpubertal than in prepubertal animals. Conclusions In contrast to rodents, the developmental shift in GABAA receptor α subunit expression continues through adolescence in primate DLPFC, inducing a marked change in the kinetics of GABA neurotransmission. Disturbances in this shift might underlie impaired working memory in schizophrenia.