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Schizophrenia is currently classified as a psychotic disorder. This article posits that this
emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of
progress in our understanding of this illness and hence has hampered the development of
adequate treatments. Not only have cognitive and intellectual underperformance
consistently been shown to be risk factors for schizophrenia, several studies have found that
a decline in cognitive functioning precedes the onset of psychosis by almost a decade.
Although the question of whether cognitive function continues to decline after psychosis
onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome
and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing)
the disorder on the basis of psychotic symptoms may be too narrow. Not only should
cognition be recognized as the core component of the disorder, our diagnostic efforts should
emphasize the changes in cognitive function that occur earlier in development. Putting the
focus back on cognition may facilitate finding treatments for the illness before psychosis ever
emerges.
JAMA Psychiatry. 2013;70(10):1107-1112. doi:10.1001/jamapsychiatry.2013.155
Published online August 7, 2013.
1107
acquisition of knowledge, processing speed, reasoning, and executive function. These constructs have considerable overlap with intelligence as measured by IQ tests,6 and many researchers do not
distinguish between measures of intelligence and measures of cognition. There may of course be subtle differences between the
changes that affect IQ tests vs neuropsychological measures, but the
data distinguishing them are sparse and we do not review those differences here. Rather, we refer to measures of cognition and deficits as cognitive impairment throughout this article. At times, we cite
authors who refer to measures of IQ and intellectual performance.
Cognitive and intellectual underperformance have consistently been shown to constitute a risk factor for the development
of schizophrenia. A recent meta-analysis by Khandaker et al7 of 12
population-based cohorts and nested case-control studies including more than 4000 cases and more than 700 000 control subjects indicated that low IQ increases the risk for developing schizophrenia in a dose-response fashion (with an effect size of 0.43): every
point decrease in IQ increases the risk by 3.7%. Another metaanalysis, partially overlapping with the one by Khandaker et al7 but
including studies assessing subjects aged 16 years and younger, also
found low IQ to increase the risk for schizophrenia, with an effect
size of about 0.5. Interestingly, this risk was already evident by age
13 years, many years prior to psychosis onset.8
A different, but practically quite relevant, indicator of intellectual underperformance, scholastic achievement, is also related to
an increased risk for developing schizophrenia. In a nationwide cohort of more than 900 000 Swedish individuals, school performance at age 16 years was inversely related to the risk for developing schizophrenia in a dose-response fashion. Children with the
lowest grades had a 4-fold risk for developing the illness. Interestingly, repeating a grade (which occurs in some European countries
when grades are insufficient) carried the highest risk, with a hazard
ratio of 9.9,10
Some of this risk may be, at least in part, related to the genetic
risk for developing schizophrenia. Population-based studies in firstdegree family members, as well as data obtained from selected
samples and twin studies, all suggest that low IQ is related to the genetic risk for developing the illness.11 In fact, it has been suggested
that a substantial portion of the phenotypic correlation between
schizophrenia and cognition is caused by shared genetic effects.12
(with an effect size of around 0.35), with the most pronounced deficits in language skills.13 Thus, cognitive functioning related to scholastic test performance appears to decline between the ages of 13
and 16 years in the subjects who go on to develop schizophrenia.
We retrospectively compared mandatory or recommended
grade repeating in a sample of more than 80 twins (monozygotic
and dizygotic) discordant for schizophrenia with that of a matched
sample of healthy twins. Not only did the twin who went on to develop schizophrenia underperform his or her unaffected co-twin in
90% of cases, this underperformance was evident at age 13 years
and preceded the onset of the first psychosis by an average of 9
years.14 Finally, in a fully prospective study, Reichenberg and others15
used the data from the Dunedin birth cohort, where cognitive performance was tested at ages 7, 9, 11, and 13 years and the age at final symptomatic follow-up was 32 years. The 35 subjects who went
on to develop schizophrenia underperformed their healthy cohort
control subjects at all measurement points and they started to further lag behind their peers between the ages of 7 to 13 years.15 Furthermore, the correlations between the initial deficits and subsequent lag in performance were more strongly correlated with one
another in the future schizophrenic children compared with their
healthy counterparts, suggesting that deficits that manifest later in
adolescence may begin in earlier childhood. This set of studies suggests that children who will go on to develop schizophrenia progressively underperform their healthy peers. Moreover, this relative decline in cognitive performance starts years prior to the onset
of psychosis, supporting the notion that a lag in brain development
may be a crucial early manifestation of the illness.
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ever, these data are difficult to interpret because most have failed
to include a healthy control group and therefore it is impossible to
determine the normal effects of practice on performance changes
over time.20,21 Furthermore, the comparison of different groups of
patients at varying stages of the illness (eg, first-episode patients vs
long-term patients) does not take into consideration the potentially vast differences in the ascertainment of these patient groups.
In the United States, research on patients with first-episode psychosis tends to use populations with generally better functioning
than research on long-term patients, which is conducted at government facilities for patients with fewer resources. Thus, differences
in cognition found in the cross-sectional comparison of these two
groups may be driven by factors such as socioeconomic status rather
than cognition alone. In fact, to our knowledge, few studies have included healthy control subjects when assessing cognitive change in
schizophrenia over time. We have summarized data from 8 studies
assessing cognition in the same group of individuals over time (including a total of 280 patients and 306 healthy control subjects) in
a recent meta-analysis, concluding that cognition increases significantly less in patients over time (0.33 points) than it does in healthy
control subjects (2.1 points) resulting in an effect size for (relative)
cognitive decline of 0.48.22 Thus, although the small number of
studies and subjects is a testament to the lack of well-designed
studies examining cognitive change in schizophrenia, the results suggest that cognitive performance may continue to decline after psychosis onset in schizophrenia. Nevertheless, much larger studies
including patients as well as healthy control subjectsare needed
to adequately address this issue.
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Conclusions
Cognitive underperformance is at the heart of schizophrenia. It constitutes a (genetic) risk factor, precedes the onset of psychosis by
many years, may continue to worsen after psychosis is established,
and determines outcome. The deficit is broad, evident, and relevant, expressed as it is in poor grades at school years prior to the
onset of the first psychosis. This underperformance at school constitutes one of the highest hazard ratios found for schizophrenia, only
bested by the risk for having a sibling with the illness. Although poor
cognitive functioning at the primary school age may already constitute a risk factor for schizophrenia, a further decline in global and
specific aspects of cognition most likely occurs in early puberty, preceding the onset of psychosis by almost a decade. This decline may
not halt once the psychosis develops but possibly progresses even
further, unstopped by current pharmacological treatment. Whether
this process of cognitive decline prior to psychosis onset is specific
to schizophrenia has not been well studied, but it is not found in
bipolar disorder.
What are the consequences of considering schizophrenia primarily and foremost a cognitive instead of a psychotic disorder? First,
cognitive decline prior to onset of psychosis (in most cases retrospectively established) should be part of the diagnosis. This underperformance should be particularly evident in comparison with the
cognitive performance of the parents and siblings. Second, while psychotic symptom reduction will of course remain a cornerstone of the
treatment of schizophrenia, the treatment of cognitive deficits
should be central to any guidelines, which now it is not. Third, the
whole concept of schizophrenia as an illness that presents with psychosis should be discarded: it presents with cognitive decline. Fourth,
the age at onset of the illness is probably a decade earlier than we
now assume. Indeed, schizophrenia as proposed here is an illness
that starts, at the latest, in early adolescence with a decline in cognitive functioning relative to healthy peers. As Kraepelin4 put it so
well: Je weiter sie aber fortschreiten, desto schwerer wird es
ihnen mit ihren Kameraden Schritt zu halten (the more they prog1110
ress, the more difficult it is for them to keep up with their peers).
This also implies that early recognition and prevention programs focusing on psychotic symptoms, even in those individuals with brief
and intermittent symptoms, are not only too late in the disease process, but they fail to address the core aspect of the illness. Indeed,
much of the social damage will already have occurred when the psychosis finally manifests itself in late adolescence or young adulthood: the person may have dropped out of school, lost his or her
friends, and failed to reach his or her full potential. Finally, we have
been focusing on the wrong risk phenotype: it may not be the psychosis proneness that constitutes the highest risk for developing
schizophrenia, but the propensity to cognitive decline or intellectual stagnation during adolescence. This phenotype will most likely,
just as psychosis,41 be much more prevalent in the general population than we now consider it to be. It may be present in many subjects who will not go on to develop psychosis, let alone schizophrenia. Strategies to identify those with highest risk for the illness before
it develops are of the utmost importance. Possibly, aspects other
than, or in combination with, cognitive underperformance, such as
biologicalincluding geneticmarkers, family history, and psychosocial risk factors, may need to be included to best predict onset of
illness. We believe that identification of the factors that initiate and
arrest cognitive decline is the holy grail of schizophrenia research.
Once elucidated, we will understand the cause of the illness. Early
cognitive decline should be at the forefront of attention in the diagnosis, treatment, and research of schizophrenia. The funds allocated to understanding the manifestations of illness prior to psychosis onset are paltry compared with those allocated to the
relatively ineffectual treatments provided to adults who have had
the illness for years. Indeed, large prospective cohorts in children
and adolescents, preferably population based, are needed to replicate earlier findings of cognitive underperformance prior to psychosis onset. Thus, to fully understand the genetic and environmental influences that will lead to schizophrenia, we will need to study
the interaction between the (genetically mediated) cognitive underperformance during adolescence and the environmental (and genetic) factors that determine why some of these subjects will fully
remit, eventually develop psychosis, or develop schizophrenia.
It may be argued that the assessment methods for characterizing schizophrenia by a change in cognitive function in childhood
or adolescence have not been fully determined and will be burdensome. Certainly, the assessment methods for cognitive decline need
to move beyond the current use of tests that were developed decades ago for the assessment of brain damage, intellectual disability, and education aptitude. The research data are not clear on which
specific cognitive processes go awry during childhood, but it is likely
that the core cognitive difficulties are more subtle than can be measured with traditional neuropsychological tests. New approaches to
assessment, such as measures of learning-dependent perceptual
difficulties42-44 that may reflect impaired neuroplasticity, are needed.
These subtle deficits may prevent young people from keeping pace
with the relentless march of perceptual time, especially in crucial social interactions, leading to increased social isolation and idiosyncratic thinking, and may change the way the growing brain understands reality.45,46 However, regardless of the tests that will be
needed to detect the important cognitive changes indicating the very
early beginnings of schizophrenia, the difficulties of implementing
these procedures should not deter us from pursuing them.
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In sum, we suggest here that the core component of schizophrenia may be detected by the inability of a young person to keep
pace with his or her peersand that this disability can be quantified on cognitive tests. This detection would be greatly enhanced
by large longitudinal cognitive databases in childhood, establishing
cognitive growth curves. While large databases on cognitive tests
are prevalent, few measure cognition in the same individuals over
time,47 which will be crucial for detecting longitudinal cognitive decline. The newly available National Institutes of Health Toolbox database includes cognitive measures with follow-up assessments
spanning ages 3 to 80 years and the project has focused specifically on age-related changes on cognition among children and
adolescents.48 Possibly, a relatively small decline in cognitive functioning compared with growth curves adjusted for educational, eth-
ARTICLE INFORMATION
Submitted for Publication: October 7, 2012; final
revision received January 13, 2013; accepted
January 15, 2013.
Published Online: August 7, 2013.
doi:10.1001/jamapsychiatry.2013.155.
Conflict of Interest Disclosures: Dr Kahn currently
or in the past 3 years has received research funding
support from ZonMW, the Marie Curie and the 7th
Framework programs of the European Union, and
the National Institute of Mental Health. He
currently or in the past 3 years has received
honoraria from EnVivo, Janssen-Cilag, Eli Lilly,
Otsuka, Roche, and Sunovion. Dr Keefe currently or
in the past 3 years has received investigatorinitiated research funding support from the
Department of Veterans Affair, Feinstein Institute
for Medical Research, GlaxoSmithKline, National
Institute of Mental Health, Novartis, PsychoGenics,
Research Foundation for Mental Hygiene Inc, and
the Singapore National Medical Research Council.
He currently or in the past 3 years has received
honoraria from, served as a consultant for, or
served on the advisory board for AbbVie, Akebia,
Amgen, Astellas, Asubio, BioLineRx, BioMarin,
Boehringer Ingelheim, Bristol-Myers Squibb, Eli
Lilly, EnVivo, Helicon, Lundbeck, Merck, Mitsubishi,
Novartis, Otsuka, Pfizer, Roche, Shire, Sunovion,
Takeda, and Targacept. Dr Keefe receives royalties
from the BACS testing battery and the MATRICS
Battery (BACS Symbol Coding). He is also a
shareholder in NeuroCog Trials Inc.
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