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PERSPECTIVE
doi:10.1038/nature09552
Rethinking schizophrenia
Thomas R. Insel
1
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.
T
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
1
.
Sustained recovery occurs in less than 14% within the first five years
following a psychotic episode
2
. Longer-term outcomes may be marginally
better: a large international 25-year follow-up study reported an addi-
tional 16% with late-phase recovery
3
. Throughout Europe, less than
20% of people with schizophrenia are employed
4
. A large US study found
nearly 20% homeless in a one-year follow up
5
. 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. (http://www.treatmentadvocacycenter.org)
Although many have attributed this lack of progress to failed systems
of care (http://www.mentalhealthcommission.gov/), 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
6
. 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
7
.
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
8
.
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
9
. 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
antagonists
10
. 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.
1
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
11
.
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
heritability
12,13
. 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
14
.
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
18
,
synaptic protein genes (for example, NRX1 (also known as PNO1))
19
,a
potassium channel (KCNH2)
20
and many other brain-expressed proteins
(for example, dysbindin)
21
. Currently, at least 43 candidate genes have
been identified, but individual effect sizes are consistently modest (http://
www.schizophreniaforum.org/res/sczgene/TopResults.asp), especially rela-
tive to the evidence for high heritability
22,23
. 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
26
,
Weinberger
27
and Murray
28
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
29,30
.
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
31
. Longitudinal neuroimaging
studies demonstrate changes in grey matter density until the mid-twenties
with the prefrontal cortex being the last to mature
32
. 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
33,34
. 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
35–37
. 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
38,39
.
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
40
. Data from the Dunedin birth cohort, consist-
ent with many previous studies
41
, indicated that IQ is reduced early and
persistently in children destined to develop schizophrenia
42
. 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
formation
43
. Even genes that are not exclusively developmental seem
to influence schizophrenia by their early disruption
44
. In a particularly
intriguing example, Niwa et al.
45
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
cortex
46–48
. As a final link to development, the genetics of schizophrenia
overlaps with the genetics of autism and other neurodevelopmental
disorders
19,49
. 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
50,51
, infections
in the second trimester
52
, perinatal injury
53
and cytokine exposure
54
have
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
55
, but an
even more promising approach may be epigenetic maps indicating the
‘scars’ of early experience or the stochastic changes emerging across
development
56
. 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
57
.
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
58
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
prevention.
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
59,60
. 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
62,63
. 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
0
20
40
60
80
100
10 252015
0
20
40
60
80
100
5
0 5 10 15 20
Age (years)
Age (years)
Percentage of maximumPercentage of maximum
Fertilization 25
a
b
Stage I: risk
< 12 years
Stage II: prodome
12–18 years
Stage III: psychosis
18–24 years
Stage IV:
chronic
disablility
>24 years
5 years
Grey-matter volume changes during normal development
20 years
0.0
0.1
0.2
0.3
0.4
>0.5
Proliferation
Migration
Arborization
Myelination
Prefrontal
excitatory synapses
Prefrontal
excitatory synapses
Excessive
excitatory pruning
Reduced
interneuron activity
Decient
myelination
Myelination
Prefrontal
inhibitory synapses
Prefrontal
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
64,65
. 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
66
(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.
67
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
68–70
. 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
colleagues
71,72
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
73
. 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
76,77
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
78
. 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
79
. 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
80
.
It is unclear to what extent intervening during the prodrome will either
prevent or forestall psychosis. Results from single-site trials of atypical
antipsychotics
81
, antidepressants
82
, lithium
83
and cognitive behaviour
therapy
84
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
85
. 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
86
. 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
66
.
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
Help-seeking
Abnormal thought and behaviour
Relapsing–remitting course
Loss of function
Medical complications
Incarceration
Diagnosis Genetic sequence
Family history
SIPS
Cognitive assessment
Imaging
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
Unemployment
Homelessness
Intervention Unknown Cognitive training?
Polyunsaturated fatty acids?
Family support?
Medication
Psychosocial interventions
Medication
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
outcomes
87
. Although the avolitional component of the disorder may
define a special subgroup
88
, there is a new consensus that the negative
symptoms and cognitive aspects of pathology are major unmet thera-
peutic needs
89,90
. 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-
ments
91,92
. 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
excepted.’’
93
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
conditions
97
. 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).
Prevention
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
98
. 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
99
. 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.
Stigma
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 decits
Strategic prevention
Cure therapeutics
Diagnosis by late symptoms
Treatment for psychotic episode
Pathophysiology
Personalized care
Discovery technologies
Clinical genomics/
proteomics
Developmental
neuroimaging
Stem-cell
biology
Cognitive
science
Translating research into practice
Access
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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©2010
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-
comes
88
. 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’)
100
. Some evid-
ence indicates that this name change led to reduced stigma, in that fewer
people associated the new name with criminality
100
.
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
www.nature.com/reprints. The author declares no competing financial interests.
Readers are welcome to comment on the online version of this article at
www.nature.com/nature. Correspondence and requests for materials should be
addressed to T.R.I. (tinsel@mail.nih.gov).
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