Clinical Review & Education

Special Communication

Schizophrenia Is a Cognitive Illness

Time for a Change in Focus
Ren S. Kahn, MD, PhD; Richard S. E. Keefe, PhD
Editorial page 1009

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.

chizophrenia is currently classified as a psychotic disorder.

Whether diagnosed under the classification systems of the
DSM or International Classification of Diseases, schizophrenia is defined by its psychotic symptoms. This article posits that this
emphasis on psychosis is not only a conceptual fallacy, it is also an
error that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Indeed, prognosis of schizophrenia
has not changed substantially since the introduction of chlorpromazine more than 50 years ago, and some argue it has not meaningfully improved since the illness was first described.1 The focus on psychosis as the primary target for research and treatment of this
devastating disorder has obscured the obvious: schizophrenia is not
primarily a psychotic disorder, it is a cognitive illness.
This notion is not new.2,3 Indeed, when Kraepelin4 first delineated the disorder in 1893, he named it dementia praecox for a good
reason: he considered the primary manifestation of the illness to be
cognitive decline. In the 4th edition of his Lehrbuch, the description of the illness begins with the slow (occasionally rapid) cognitive decline, usually observed in his patients during adolescence.4
In his eyes, the hallmark of the disorder was the decrease in intellectual and cognitive performance that starts almost a decade prior
to the onset of psychosis and continues for many years afterwards.
In fact, only after elaborating on this aspect of the illness for 7 pages
does he mention the presence of psychotic symptoms. (In subsequent printings of his Lehrbuch, Kraepelin greatly expanded the description of this syndrome, eventually separating it into hebephrenic, katatonic, and paranoid subtypes. And although psychotic
features, such as hallucinations and delusions gained prominence
in the paranoid and katatonic subtypes, the hallmark of the disorjamapsychiatry.com

Author Affiliations: Department of

Psychiatry, Rudolf Magnus Institute
of Neuroscience, UMC Utrecht,
Utrecht, the Netherlands (Kahn);
Department of Psychiatry and
Behavioral Sciences, Duke University
Medical Center, Durham, North
Carolina (Keefe).
Corresponding Author: Ren S.
Kahn, MD, PhD, Department of
Psychiatry, Rudolf Magnus Institute
of Neuroscience, UMC Utrecht,
Utrecht, Heidelberglaan 100, 3508
GA Utrecht, PO Box 85500, the
Netherlands (r.kahn@umcutrecht.nl).

der remains the cognitive decline during adolescence.) Of course,

Kraepelin was not the only preeminent psychiatrist who considered psychosis to be a secondary or associated part of the illness.
Bleuler,5 who coined the term schizophrenia, also viewed delusions and hallucinations as accessory symptoms; the core of this illness was determined by disturbance in affect, cognition (associative thinking), social interaction (autism), and volition (ambivalence).1
We argue that the current state of knowledge proves that schizophrenia should be considered first and foremost as a cognitive illness. First, cognitive underperformance, often measured as low IQ,
is a risk factor for schizophrenia. Second, cognitive decline and intellectual underperformance precede the onset of psychosis by many
years. Third, decline in cognitive functioning may continue even after psychosis onset. Fourth, while cognitive underperformance prior
to psychosis has not definitively been shown to be specific to schizophrenia, it does distinguish it from the other major psychotic illness, bipolar disorder. Finally, cognitive underperformance is an important predictor of general functional outcome in schizophrenia.

Cognitive Impairment as a (Genetically Mediated)

Risk Factor
Cognitive function is assessed with various methods and described
with various terms originating from different fields such as education, neuropsychology, and intellectual disability. These methods
have been applied in schizophrenia research in the haphazard fashion that may be expected for a component of the illness that has been
considered secondary. We refer to cognition in this article to reflect
any measure of cognitive performance such as memory, attention,
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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

Cognitive Decline Prior to Onset of Psychosis

Although poor cognitive performance is a robust risk factor for
schizophrenia, it is unclear whether this constitutes cognitive impairment that is present at birth or whether a relative developmental decline in cognitive functioning occurs at some point prior to the
onset of psychosis, or both. Unfortunately, to our knowledge, only
a few studies have addressed this cardinal issue. One study compared the population average on childhood scholastic test performance as measured by the Iowa State tests of basic skills and educational development to 70 subjects who later went on to develop
schizophrenia. These tests were administered to all children across
the state of Iowa in grades 4, 8, and 11 (corresponding to the ages
of 9, 13, and 16 years) assessing 5 cognitive domains. Although the
(prospective) patients did not differ from the state average at ages
9 and 13 years, they underperformed significantly at age 16 years
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Schizophrenia Is a Cognitive Illness

(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.

Cognitive Function After Onset of Psychosis

Numerous studies have assessed global and specific aspects of cognitive functioning in schizophrenia once the diagnosis is established. These studies report that cognitive performance is 1 to 2 standard deviations (SDs) lower than age-matched control subjects (see
article by Keefe and Fenton16). They estimated that 20% of the
schizophrenic population has unimpaired cognitive functioning when
impairment is defined as performance less than 1 SD below the normal mean,16 concluding that these patients are cognitively intact.
However, even this group may have cognitive impairment that is
greater than would be expected on the basis of the level of education in their family. First, almost all monozygotic twins with schizophrenia perform worse on cognitive tests compared with unaffected co-twins.17 Furthermore, the current cognitive functioning of
an estimated 98% of schizophrenic patients is lower than would be
expected on the basis of the level of education of their mothers.18
This work suggests that cognitive functioning may well be lower in
all patients, certainly when compared with their (genetic and environmental) intellectual potential. However, the decrease in cognitive functioning does not indicate when the decline starts. As indicated, some of it occurs prior to psychosis onset; however, does
cognitive functioning decrease further once psychosis is established? Since the degree of cognitive impairment of 2 SDs in patients is much larger than the 0.5 SDs that is observed in subjects
prior to psychosis onset,19 it is highly likely that cognitive functioning declines further either while psychosis emerges or after psychosis sets in.
A considerable number of studies have examined cognitive functioning in patients with established schizophrenia over time. How-

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Schizophrenia Is a Cognitive Illness

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.

Specificity of Poor Premorbid Cognitive Function Decline

Although the specificity of cognitive decline in schizophrenia has
rarely been studied, it appears that cognitive dysfunction prior to
psychosis onset may distinguish it from other psychiatric disorders. The decrements over time found in young patients with schizophrenia and those at risk for the illness are not found in patients with
attention-deficit/hyperactivity disorder.23 Importantly, this decline is also not reported in the other major psychotic illness in the
current classification systems, bipolar disorder. Despite the finding
that cognitive dysfunction may be present in bipolar patients once
the illness has (fully) developed, the time course is different from
patients with schizophrenia.24 In fact, while the number of studies
examining cognition prior to the onset of bipolar disorder is more
limited than those in schizophrenia, a consistent pattern has
emerged: poor cognitive functioning constitutes a risk factor for
schizophrenia and not in bipolar illness. Using data from the Israeli
Draft Board, where cognition was assessed in adolescents, those who
were later hospitalized for bipolar disorder did not differ in intellectual performance from the normal population. 25 Data from
Swedish26 and Danish27 draft boards similarly suggest that draftees who later went on to be hospitalized for bipolar disorder did not
differ significantly in cognitive function from that in normal subjects. In fact, in a recent study in more than 1 million Swedish men,
high intelligence carried a 60% increased risk (hazard ratio, 1.59) for
later being hospitalized for bipolar disorder, at least in those without comorbidity.28 Consistently, in a study examining school grades
from all Swedish school children between 1988 and 1997, individuals with excellent school performance had an almost 4-times higher
risk for developing bipolar illness in comparison with those with avjamapsychiatry.com

Special Communication Clinical Review & Education

erage grades.10 Thus, in schizophrenia, lowand decliningIQ is a

risk factor, whereas in bipolar disorder, high IQ is related to increased risk. Also, at psychosis/illness onset, IQ differs in schizophrenia and bipolar disorder. It is only after both disorders have progressed over time that they show cognitive impairment, although
even then the impairment in schizophrenia is much larger than in
bipolar disorder.
We conducted a study in monozygotic and dizygotic twins discordant for bipolar disorder, similar in design as the study mentioned previously in schizophrenia.14 Here we found, in contrast to
the discordant schizophrenia twins, that the discordant bipolar twin
pairs only showed a temporary decline in functioning, and over the
longer term did not underperform the healthy control twins. Also,
in contrast to what we found in schizophrenia, the twin who went
on to develop bipolar disorder did not do worse at school than his
or her unaffected co-twin.29
Similarly, at illness onset, patients with bipolar disorder, in contrast to those with schizophrenia, did not appear to perform worse
than healthy control subjects. In the one study examining this issue, patients with recent-onset bipolar disorder or mania performed significantly better than first-episode schizophrenic patients on a broad variety of cognitive tests and only underperformed
healthy subjects on 2 of the 16 subtests, delayed verbal memory and
category fluency. Consistent with the studies reviewed here, the estimate of premorbid cognitive functioning was normal in the bipolar group and lower in the schizophrenic patients.30 Finally, a metaanalysis of cognitive functioning in patients with established illness
showed that those with bipolar disorder performed significantly better than patients with schizophrenia in almost all cognitive domains, with an effect size of around 0.5. This difference was found
for actively ill patients, as well as for those in remission.31 Taken together, evidence strongly suggests that mean cognitive underperformance during adolescence and at first presentation of psychosis differentiates schizophrenia from bipolar disorder.

Cognitive Dysfunction as Predictor

of General Outcome
Finally, the notion that cognitive dysfunction is a crucial aspect of
schizophrenia is solidified by the ample evidence that it is an important determinant of global functional outcome. Although some studies have suggested this aspect of the disorder is the strongest predictor of outcome,32 others have found that cognitive function is
independently, but not necessarily predominantly, predictive of
outcome.33 At any rate, cognitive dysfunction in schizophrenia is unaffected by current pharmacotherapy, which in the case of schizophrenia is almost entirely based on the use of antipsychotic medication. These drugs, essentially unaltered pharmacologically since
the introduction of chlorpromazine more than half a century ago,
are indeed effective antipsychotics. However, despite initial reports to the contrary, none of these compounds is effective in
improving cognition in schizophrenia to any meaningful degree.
Numerous studies have examined the effect of first- and secondgeneration antipsychotics on cognitive function in schizophrenia. Although several studies have reported improvement in specific
subtests, global cognitive change in large comparative studies in firstepisode and chronic schizophrenia rarely reaches an effect size of
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more than 0.3. A meta-analysis of first-generation antipsychotics

found an effect size of 0.22,34 while more recent studies have found
effect sizes of around 0.1 to 0.2 in long-term patients35 and 0.3 to
0.4 in first-episode patients.36 However, even this small effect is likely
to be no more than practice related. Patients administered placebo
in pharmacologic studies of cognitive enhancement37 or receiving
repeated assessments in a multiple baseline design38 demonstrate
similar improvements. Furthermore, when healthy subjects are included in the trial design, their improvement on the same tests that
are administered to the patients is of a similar effect size as what is
observed in the patients.18 Thus, although cognitive dysfunction is
central to outcome in schizophrenia, current pharmacological
treatment does not appear to ameliorate it. There are numerous
efforts under way to develop new treatments that specifically target cognitive impairment (see article by Keefe et al39). Combining
cognitive interventions with rehabilitation programs40 results in
clear, but modest, effects and may have potential for improving
patient outcomes. Programs that include behavioral and pharmacologic treatments acting synergistically have been discussed but
not implemented.

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

Schizophrenia Is a Cognitive Illness

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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Schizophrenia Is a Cognitive Illness

Special Communication Clinical Review & Education

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.
REFERENCES
1. Hegarty JD, Baldessarini RJ, Tohen M, Waternaux
C, Oepen G. One hundred years of schizophrenia: a
meta-analysis of the outcome literature. Am J
Psychiatry. 1994;151(10):1409-1416.
2. Weinberger DR. Implications of normal brain
development for the pathogenesis of
schizophrenia. Arch Gen Psychiatry.
1987;44(7):660-669.
3. Elvevg B, Goldberg TE. Cognitive impairment in
schizophrenia is the core of the disorder. Crit Rev
Neurobiol. 2000;14(1):1-21.
4. Kraepelin E. Psychiatrie: Ein Lehrbuch fr
Studierende und rtze. 4th ed. Leipzig, Germany:
Verlag von Johann Ambrosius Barth; 1893:435-445.
5. Bleuler E. Dementia Praecox Oder Gruppe der
Schizophrenin. Leipzig, Germany: Franz Deuticke;
1911.
jamapsychiatry.com

nic, familial, and socioeconomic factors is the first manifestation of

schizophrenia and treatment should begin at that point.
It may well be that the boundaries of the disorder characterized by progressive cognitive decline prior to and after the onset of
psychosis are more narrow than those of the illness we have now
defined as schizophrenia. It may well be that even within such a
narrow definition of disorder, various causes will be identified. On
the other hand, identifying the genetic and environmental influences that affect cognitive decline in adolescence and young
adulthood may have benefit beyond schizophrenia. Regardless, it
is clear that by defining schizophrenia as a psychotic disorder, we
have done our patients a disservice. By refocusing on its fundamental symptoms, we may finally find a cure for this devastating
cognitive illness.

6. Wechsler D. Wechsler Adult Intelligence Scale.

3rd ed. San Antonio, TX: Psychological Corp; 1997.

schizophrenia. Arch Gen Psychiatry.

1990;47(11):1066-1072.

7. Khandaker GM, Barnett JH, White IR, Jones PB.

A quantitative meta-analysis of population-based
studies of premorbid intelligence and
schizophrenia. Schizophr Res. 2011;132(2-3):
220-227.

18. Keefe RS, Eesley CE, Poe MP. Defining a

cognitive function decrement in schizophrenia. Biol
Psychiatry. 2005;57(6):688-691.

8. Dickson H, Laurens KR, Cullen AE, Hodgins S.

Meta-analyses of cognitive and motor function in
youth aged 16 years and younger who subsequently
develop schizophrenia. Psychol Med.
2012;42(4):743-755.
9. MacCabe JH, Lambe MP, Cnattingius S, et al.
Scholastic achievement at age 16 and risk of
schizophrenia and other psychoses: a national
cohort study. Psychol Med. 2008;38(8):1133-1140.
10. MacCabe JH, Lambe MP, Cnattingius S, et al.
Excellent school performance at age 16 and risk of
adult bipolar disorder: national cohort study. Br J
Psychiatry. 2010;196(2):109-115.
11. Aukes MF, Alizadeh BZ, Sitskoorn MM, Kemner
C, Ophoff RA, Kahn RS. Genetic overlap among
intelligence and other candidate endophenotypes
for schizophrenia. Biol Psychiatry.
2009;65(6):527-534.
12. Toulopoulou T, Goldberg TE, Mesa IR, et al.
Impaired intellect and memory: a missing link
between genetic risk and schizophrenia? Arch Gen
Psychiatry. 2010;67(9):905-913.
13. Fuller R, Nopoulos P, Arndt S, OLeary D, Ho B-C,
Andreasen NC. Longitudinal assessment of
premorbid cognitive functioning in patients with
schizophrenia through examination of standardized
scholastic test performance. Am J Psychiatry.
2002;159(7):1183-1189.
14. van Oel CJ, Sitskoorn MM, Cremer MPM, Kahn
RS. School performance as a premorbid marker for
schizophrenia: a twin study. Schizophr Bull.
2002;28(3):401-414.
15. Reichenberg A, Caspi A, Harrington H, et al.
Static and dynamic cognitive deficits in childhood
preceding adult schizophrenia: a 30-year study. Am
J Psychiatry. 2010;167(2):160-169.
16. Keefe RSE, Fenton WS. How should DSM-V
criteria for schizophrenia include cognitive
impairment? Schizophr Bull. 2007;33(4):912-920.
17. Goldberg TE, Ragland JD, Torrey EF, Gold JM,
Bigelow LB, Weinberger DR. Neuropsychological
assessment of monozygotic twins discordant for

19. Woodberry KA, Giuliano AJ, Seidman LJ.

Premorbid IQ in schizophrenia: a meta-analytic
review. Am J Psychiatry. 2008;165(5):579-587.
20. Goldberg TE, Goldman RS, Burdick KE, et al.
Cognitive improvement after treatment with
second-generation antipsychotic medications in
first-episode schizophrenia: is it a practice effect?
Arch Gen Psychiatry. 2007;64(10):1115-1122.
21. Goldberg TE, Keefe RSE, Goldman RS, Robinson
DG, Harvey PD. Circumstances under which
practice does not make perfect: a review of the
practice effect literature in schizophrenia and its
relevance to clinical treatment studies.
Neuropsychopharmacology. 2010;35(5):1053-1062.
22. Hedman AM, van Haren NE, van Baal CG, Kahn
RS, Hulshoff Pol HE. IQ change over time in
schizophrenia and healthy individuals: a
meta-analysis. Schizophr Res. 2013;146(1-3):
201-208.
23. ie M, Sundet K, Rund BR. Neurocognitive
decline in early-onset schizophrenia compared with
ADHD and normal controls: evidence from a 13-year
follow-up study. Schizophr Bull. 2010;36(3):
557-565.
24. Lewandowski KE, Cohen BM, Ongur D.
Evolution of neuropsychological dysfunction during
the course of schizophrenia and bipolar disorder.
Psychol Med. 2011;41(2):225-241.
25. Reichenberg A, Weiser M, Rabinowitz J, et al. A
population-based cohort study of premorbid
intellectual, language, and behavioral functioning in
patients with schizophrenia, schizoaffective
disorder, and nonpsychotic bipolar disorder. Am J
Psychiatry. 2002;159(12):2027-2035.
26. Zammit S, Allebeck P, David AS, et al. A
longitudinal study of premorbid IQ Score and risk of
developing schizophrenia, bipolar disorder, severe
depression, and other nonaffective psychoses. Arch
Gen Psychiatry. 2004;61(4):354-360.
27. Srensen HJ, Sbye D, Urfer-Parnas A,
Mortensen EL, Parnas J. Premorbid intelligence and
educational level in bipolar and unipolar disorders:
a Danish draft board study. J Affect Disord.
2012;136(3):1188-1191.

JAMA Psychiatry October 2013 Volume 70, Number 10

Downloaded From: http://archpsyc.jamanetwork.com/ by a Universidade Federal do Rio de Janeiro User on 12/26/2013

1111

Clinical Review & Education Special Communication

28. Gale CR, Batty GD, McIntosh AM, Porteous DJ,

Deary IKJ, Rasmussen F. Is bipolar disorder more
common in highly intelligent people? a cohort study
of a million men. Mol Psychiatry. 2012;18(2):
190-194.
29. Vonk R, van der Schot AC, van Baal GCM, van
Oel CJ, Nolen WA, Kahn RS. Premorbid school
performance in twins concordant and discordant
for bipolar disorder. J Affect Disord.
2012;136(3):294-303.
30. Zanelli J, Reichenberg A, Morgan K, et al.
Specific and generalized neuropsychological
deficits: a comparison of patients with various
first-episode psychosis presentations. Am J
Psychiatry. 2010;167(1):78-85.
31. Krabbendam L, Arts B, van Os J, Aleman A.
Cognitive functioning in patients with
schizophrenia and bipolar disorder: a quantitative
review. Schizophr Res. 2005;80(2-3):137-149.
32. Bowie CR, Reichenberg A, Patterson TL,
Heaton RK, Harvey PD. Determinants of real-world
functional performance in schizophrenia subjects:
correlations with cognition, functional capacity, and
symptoms. Am J Psychiatry. 2006;163(3):418-425.
33. Mohamed S, Rosenheck R, Swartz M, Stroup S,
Lieberman JA, Keefe RS. Relationship of cognition
and psychopathology to functional impairment in
schizophrenia. Am J Psychiatry. 2008;165(8):
978-987.
34. Mishara AL, Goldberg TE. A meta-analysis and
critical review of the effects of conventional
neuroleptic treatment on cognition in
schizophrenia: opening a closed book. Biol
Psychiatry. 2004;55(10):1013-1022.
35. Keefe RS, Bilder RM, Davis SM, et al; CATIE
Investigators; Neurocognitive Working Group.

1112

Schizophrenia Is a Cognitive Illness

Neurocognitive effects of antipsychotic

medications in patients with chronic schizophrenia
in the CATIE Trial. Arch Gen Psychiatry.
2007;64(6):633-647.
36. Davidson M, Galderisi S, Weiser M, et al.
Cognitive effects of antipsychotic drugs in
first-episode schizophrenia and schizophreniform
disorder: a randomized, open-label clinical trial
(EUFEST). Am J Psychiatry. 2009;166(6):675-682.
37. Keefe RS, Malhotra AK, Meltzer HY, et al.
Efficacy and safety of donepezil in patients with
schizophrenia or schizoaffective disorder:
significant placebo/practice effects in a 12-week,
randomized, double-blind, placebo-controlled trial.
Neuropsychopharmacology. 2008;33(6):1217-1228.
38. Keefe RS, Fox KH, Harvey PD, Cucchiaro J, Siu
C, Loebel A. Characteristics of the MATRICS
Consensus Cognitive Battery in a 29-site
antipsychotic schizophrenia clinical trial. Schizophr
Res. 2011;125(2-3):161-168.
39. Keefe RS, Buchanan RW, Marder SR, et al.
Clinical trials of potential cognitive-enhancing drugs
in schizophrenia: what have we learned so far?
Schizophr Bull. 2013. 39(2):417-435.
40. Wykes T, Huddy V, Cellard C, McGurk SR,
Czobor P. A meta-analysis of cognitive remediation
for schizophrenia: methodology and effect sizes.
Am J Psychiatry. 2011;168(5):472-485.
41. Verdoux H, van Os J. Psychotic symptoms in
non-clinical populations and the continuum of
psychosis. Schizophr Res. 2002;54(1-2):59-65.
42. Keefe RSE, Kraus MS. Measuring
memory-prediction errors and their consequences
in youth at risk for schizophrenia. Ann Acad Med
Singapore. 2009;38(5):414-416.

43. Krishnan RR, Keefe R, Kraus M. Schizophrenia

is a disorder of higher order hierarchical processing.
Med Hypotheses. 2009;72(6):740-744.
44. Kraus MS, Keefe RSE, Krishnan RK.
Memory-prediction errors and their consequences
in schizophrenia. Neuropsychol Rev.
2009;19(3):336-352.
45. Keefe RSE, Kraus MS, Krishnan RR. Failures in
learning-dependent predictive perception as the
key cognitive vulnerability to psychosis in
schizophrenia. Neuropsychopharmacology.
2011;36(1):367-368.
46. Krishnan RR, Kraus MS, Keefe RSE.
Comprehensive model of how reality distortion and
symptoms occur in schizophrenia: could
impairment in learning-dependent predictive
perception account for the manifestations of
schizophrenia? Psychiatry Clin Neurosci.
2011;65(4):305-317.
47. Waber DP, Forbes PW, Almli CR, Blood EA;
Brain Development Cooperative Group. Four-year
longitudinal performance of a population-based
sample of healthy children on a neuropsychological
battery: the NIH MRI study of normal brain
development. J Int Neuropsychol Soc.
2012;18(2):179-190.
48. Bauer PJ, Zelazo PD. NIH Toolbox Cognitive
Function Battery (CFB): summary, conclusions, and
implications for cognitive development: SRCD
monograph. In: Zelazo PD, Bauer PJ, eds. National
Institutes of Health Toolbox-Cognitive Function
Battery (NIH Toolbox CFB): Validation for Children
Between 3 and 15 years. Ann Arbor, MI: Society for
Research in Child Development. In press.

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