Time for a shift in focus in schizophrenia: from narrow phenotypes to broad endophenotypes
Mark Weiser
Department of Psychiatry, Sheba Medical Center, Tel-Hashomer and Sackler
School of Medicine, Tel Aviv University, Ramat Aviv, Israel
Jim van Os
Department of Psychiatry and Neuropsychology, Maastricht University, The
Netherlands and Division of Psychological Medicine, Institute of Psychiatry,
UK
Michael Davidson
Department of Psychiatry, Sheba Medical Center, Tel-Hashomer and Sackler
School of Medicine, Tel Aviv University, Ramat Aviv, Israel
Correspondence:
Dr Mark Weiser, Psychiatric Outpatient Clinic, Sheba Medical Center, Ramat
Gan, 52621, Israel. Tel: +972 52 666 6575; fax: +972 3 6358599; e-mail:
mweiser{at}netvision.net.il
Declaration of interest None.
Funding detailed in Acknowledgements.
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ABSTRACT
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Many manifestations of mental illness, risk factors, course and even
response to treatment are shared by several diagnostic groups. For example,
cognitive and social impairments are present to some degree in most DSM and
ICD diagnostic groups. The idea that diagnostic boundaries of mental illness,
including schizophrenia, have to be redefined is reinforced by recent findings
indicating that on the one hand multiple genetic factors, each exerting a
small effect, come together to manifest as schizophrenia, and on the other
hand, depending on interaction with the environment, the same genetic
variations can present as diverse clinical phenotypes. Rather than attempting
to find a unitary biological explanation for a DSM construct of schizophrenia,
it would be reasonable to deconstruct it into the most basic manifestations,
some of which are common with other DSM constructs, such as cognitive or
social impairment, and then investigate the biological substrate of these
manifestations.
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INTRODUCTION
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The recently announced National Institutes for Health (NIH) Neurosciences
Blueprint
(http://neuroscienceblueprint.nih.gov)
defines the intention of the NIH to focus research efforts on three broad
themes: development, degeneration and plasticity. This represents a major
shift in research policy, by putting forward the notion that in order to
facilitate progress in neuroscience, traditional approaches focusing on narrow
phenotypes need to be brought together in a new collective effort focusing on
much broader themes. Is a similar timely shift from the narrow to the broad
applicable to schizophrenia research?
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SHARED RISK FACTORS
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Research over the past 15 years has elucidated a wealth of environmental
and genetic effects and markers associated with increased risk for
schizophrenia. However, because many of these putative effects and markers
make the risk only 23 times greater, and given the relatively low
prevalence of schizophrenia (0.51.0%), these findings have not enabled
the identification of accurate markers or effects useful in predicting
impending illness. The same research has also indicated that many of the risk
factors identified are not specific to schizophrenia, but rather are shared
with other psychiatric illnesses. For example, childhood adversity
(Kessler et al, 1997),
prenatal famine (Brown et al,
2000), migrant status (Fenta
et al, 2004) and urban dwelling
(Sundquist et al,
2004) are associated not only with later schizophrenia, but also
with depression. Similarly, perinatal complications are associated not only
with schizophrenia, but also with autism, anorexia nervosa and affective
disorders (Verdoux, 2004).
Stressful life events have been associated with the onset both of depression
and of schizophrenia (Mazure,
1995).
Despite the non-specificity of risk, most of the associations are higher
for schizophrenia than for other psychiatric diagnostic groups, with a
gradient of severity between the magnitude of the association and the
functional impairment attributed to the diagnosis. For example, in adolescents
who meet criteria for non-psychotic disorders and are at increased risk of
psychotic illness later in life (Weiser
et al, 2001), the risk is higher in disorders with
greater impact on social and vocational functioning, such as antisocial
personality disorder and schizotypal personality disorder, and lower in
disorders that cause the least social and vocational impairment, such as
neurosis. If the phenomenology encompassed in the diagnosis of schizophrenia
had a unique biological substrate, it would also be expected that the factors
associated with increased risk would be uniquely linked to it. The
non-specificity of the associations and the relationships between the strength
of the association and the functional impairment is consistent with a
multidimensional model along a continuum of severity.
Similar lack of specificity seems to be present when studying genetic and
familial risk. For example, both brain-derived neurotrophic factor and
catechol-O-methyltransferase (COMT) have been shown to be associated
with schizophrenia (Egan et al,
2001) and also with affective disorders (Massat et al,
2004), and COMT is also associated with anxiety disorders
(Arnold et al, 2004) and slight alterations in cognitive functioning
(Egan et al, 2001).
Studies of first-degree relatives of patients with schizophrenia have found
them to be at increased risk not only of schizophrenia but also of affective
disorders (Niemi et al,
2004). However, these shared risk factors are not
universal between all psychiatric disorders. For example, the risk of
schizophrenia is increased in the relatives of patients with psychotic
affective disorders, but not in the relatives of patients with non-psychotic
affective disorders.
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IMPAIRED COGNITIVE FUNCTIONING IN NON-PSYCHOTIC PSYCHIATRIC DISORDERS
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The lack of specificity in relation to a continuum of impairment also
appears when examining impaired cognitive functioning, a core feature of
schizophrenia. We have recently shown
(Weiser et al, 2004) that, in terms of mean effects across groups, adolescents suffering from
psychiatric disorders have lower scores on cognitive tests compared with the
general population, and that the more severe the decrease in functioning
associated with the psychiatric disorder, the more severe the cognitive
impairment associated with it. For example, whereas as a group adolescents
with neurotic disorders had impaired cognitive scores of 0.4 standard
deviation below the population mean, adolescents with personality disorders
scored 0.6 s.d. below the mean, and adolescents with psychotic disorders
scored 1.1 s.d. below the population mean. Similar differences in cognitive
impairment, measured decades before the onset of a psychiatric disorder, were
apparent between people later diagnosed with schizophrenia or neurotic
disorder in the UK 1946 birth cohort (van
Os et al, 1999), a finding that has recently been
replicated (David et al,
2005). Thus, cognitive impairment appears to be associated with
the entire spectrum of psychiatric disorders, with schizophrenia representing
the more severe end of this spectrum, exceeded only by learning disability
(Weiser et al,
2004).
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LACK OF DIAGNOSTIC SPECIFICITY
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Lack of diagnostic specificity is also apparent in daily clinical practice.
Whether manifestation of extreme anxiety in a socially maladjusted individual
who several years earlier appeared to be psychotic represents comorbid anxiety
in schizophrenia, or calls for a change of diagnosis, is a matter of
diagnostic style rather than scientific rigour. Like psychiatric diagnoses,
psychotropic medications also show broad overlap. Antipsychotic drugs have
been shown to be effective in treating patients with affective and anxiety
disorders, and some patients with schizophrenia benefit from treatment with
antidepressants or anxiolytics. Practically, in some cases of chronic illness
with a bad outcome, the phenotype of decreased functioning, neglect of
personal hygiene, substance misuse, social isolation and cognitive impairment
often makes it impossible to differentiate between patients with severe
schizophrenia, post-traumatic stress disorder, obsessive compulsive
disorder, personality disorder, substance misuse or affective disorder.
The lack of specificity regarding risk factors, diagnoses and treatment may
be related to our lack of understanding of the aetiology and pathophysiology
of mental disorders. This situation may be analogous to the understanding of
ischaemic heart disease several hundred years ago: then, before the aetiology
and pathophysiology of the illness had been elucidated, there was probably no
apparent connection between the crushing chest pain caused by occlusion of the
left main coronary artery, inability to sleep flat caused by left heart
failure, the swollen ankles caused by right heart failure, pain in the upper
abdomen caused by stenosis of the right descending coronary artery and
dementia caused by multiple small brain infarcts, all attributable to
atherosclerosis. It was also not obvious how to distinguish between the
transient elevation of blood glucose levels due to the stress of an acute
myocardial infarction, which is an epiphenomenal marker of active illness not
aetiologically related to the underlying atherosclerotic illness, and the
abnormal values of blood glucose level due to diabetes mellitus, which is a
marker of risk aetiologically related to the underlying illness. Moreover, it
was not obvious several hundred years ago that different constellations of
genes such as genes predisposing to abnormal lipid metabolism,
abnormal glucose metabolism and hypertension can alone or in
interaction increase the risk of the same atherosclerotic lesion. It is
therefore feasible that when we understand the pathophysiology of mental
illness, we will then be able to understand this overlap in risk factors,
symptoms, diagnoses and treatment, or why the same patient, at different
stages of the disease, may suffer from varying combinations of psychosis,
affective symptoms and anxiety.
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ENDOPHENOTYPES
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Intermediate phenotypes, or endophenotypes, are measurable components along
the pathophysiological pathway between aetiology and psychopathology. An
endophenotype may be neurophysiological, biochemical, endocrinological,
neuroanatomical, cognitive, neuropsychological or a personality trait, and
represents simpler clues to the genetic and environmental underpinnings than
the disease syndrome itself. Hence, in the probands and in their apparently
healthy first-degree relatives it should be more prevalent than in the general
population. Putative manifestations such as poor attention and other cognitive
deficits (Niendam et al,
2003), decreased social drive
(Laurent et al, 2000),
stress sensitivity (Myin-Germeys et
al, 2001) and a mood bias towards negative emotion
(Maier et al, 1994)
are present both in patients with schizophrenia and in their non-ill
first-degree first-degree relatives more often than in the general population.
However, given the overlap described above, it is likely that at least some of
these endophenotypes may also be shared with other psychiatric disorders. This
hypothesis is supported by the data on cognitive dysfunction in all
psychiatric disorders mentioned above, and the non-specificity of other
endophenotypes, endophenotypes, such as stress sensitivity (Myin-Germeys
(Myin-Germeys et al,
2003) and negative mood bias
(Hasler et al, 2004).
Although there is much less research on aspects of social and emotional
functioning in relatives of people with non-psychotic psychiatric disorders,
there is evidence of premorbid social abnormalities in children who later
develop anxiety disorders and depression
(Caspi et al, 1996),
and endophenotypes for depression are thought to include mood bias towards
negative emotions, impaired learning and memory, neurovegetative signs,
impaired executive cognitive function, psychomotor change and increased stress
sensitivity (Hasler et al,
2004), all of which resemble reported endophenotypes for
schizophrenia. Thus, analogous to the Neurosciences Blueprint initiative, we
suggest that instead of focusing on discrete psychiatric entities, some
relatively rare (like schizophrenia), and trying to attribute to them risk,
markers and other effects, it might be productive to focus on a much broader
spectrum of abnormal behaviours and emotions, and study phenomena shared by
and associated with a broader array of diagnostic categories, such as impaired
cognitive, social and emotional functioning. These endophenotypes are much
more common than cases of schizophrenia, and may be markers of risk also for
affective and anxiety disorders, which are much more common than
schizophrenia. Thus, studying endophenotypes may be a realistic strategy to
identify risk factors for mental illness. An additional advantage of focusing
on studying these endophenotypes is that there are good animal models of
cognition, emotion and social interactions, whereas the development of animal
models for psychiatric illnesses has been problematic. Identifying risk
factors might then further our understanding of pathophysiology, perhaps in a
manner analogous to the understanding achieved when it was discovered that
hypercholesterolaemia increases the risk of ischaemic heart disease, which
then helped elucidate the function of cholesterol in the formation of the
atherosclerotic plaque.
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COMT AND COGNITION
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An example of this that is closer to home may be taken from recent research
indicating that the Met/Val substitution in the COMT gene may be associated
with increased risk of schizophrenia (Egan
et al, 2001). However, as mentioned, this substitution
has also been found in patients with affective and anxiety disorders
(Arnold et al, 2004;
Massat et al, 2005).
The underlying endophenotype in this case may be impaired cognition, as the
Met/Val substitution in the COMT gene may be associated with slight
alterations in aspects of cognitive functioning
(Egan et al, 2001). Part of the pathway towards mental illness may therefore be the Met/Val
substitution in COMT, which, by affecting cognitive functioning, may increase
the risk of psychiatric illness in general, not only of schizophrenia.
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CONCLUSIONS
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Impaired cognitive, social and emotional functioning, which are
endophenotypes of schizophrenia, may also be involved in the risk of other
psychiatric disorders. Studying these endophenotypes might increase our
understanding of risk of schizophrenia and of psychiatric morbidity as a
whole. As psychiatric symptoms are present in almost half of the population,
the implications of this research may be broader than studying risk of
schizophrenia, which is much more rare.
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ACKNOWLEDGMENTS
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M.D. receives support from the National Institute for Mental Health, the
Stanley Medical Research Institute and the National Alliance for Research on
Schizophrenia and Depression (NARSAD); M.W. receives support from the Stanley
Medical Research Institute and NARSAD; J.v.O. receives support from the Dutch
Medical Research Council, the Dutch Brain Society and the South Limburg Mental
Health Research and Teaching Network.
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Received for publication January 31, 2005.
Accepted for publication February 2, 2005.
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