Download Schizophrenia: A Complex Disorder That Has Stymied Research

In Focus
Schizophrenia: A Complex Disorder
That Has Stymied Research Efforts to
Uncover Its Origin
Martha E. Shenton, PhD
S
chizophrenia is a disabling mental
disorder that affects close to 1% of
the general population. From a societal perspective, a large sector of the population is affected, worldwide. Currently
there is no laboratory test to diagnose this
disorder. Instead, a myriad of symptoms
are used to define the illness, and treatment is based primarily on symptom profile. A more rational approach is to group
patients based on variables that are more
closely associated with the presumed etiology of the disorder, including neurobiological indicators or markers such as brain
abnormalities and cognitive dysfunctions,
which are also likely to reflect, or be associated with, variations in gene expression.
The latter foci might serve to define more
homogeneous groupings, which, in turn,
might lead to both earlier and more targeted treatments, as well as to better longterm outcome, reduced healthcare and societal costs, and to unraveling the etiology
of this enigmatic and devastating disorder.
Defining Schizophrenia
Schizophrenia is a serious, often chronic
and disabling mental disorder that affects approximately 1% of the population
worldwide.1 With a low incidence, or base
rate, and no laboratory tests to diagnose
schizophrenia, progress has been hampered in effectively treating or preventing
this disorder. Particularly troublesome is
the myriad of symptoms used to diagnosis
schizophrenia, with no one symptom being either necessary or sufficient for a diagnosis of schizophrenia. In addition, not
all symptoms are observed in every patient,
nor are the same symptoms observed over
time in the same patient. Instead, symptoms tend to wax and wane over the course
of the illness. These symptoms include
overt or positive symptoms such as auditory hallucinations, disordered thinking,
and delusions; and more covert or negative
symptoms such as avolition, anhedonia,
blunted affect, and apathy.
Martha E. Shenton, PhD, is Professor and Director of the Psychiatry
Neuroimaging Laboratory in the Department of Psychiatry at
Brigham and Women’s Hospital, Harvard Medical School. She
is also Professor of Radiology in the Department of Radiology
at Brigham and Women’s Hospital. She has conducted research
studies in schizophrenia for more than twenty years.
46 Harvard Health Policy Review
Shenton: Schizophrenia
Of further note, patients with schizophrenia frequently show a deteriorating
course, with an estimated 40 to 60% suffering lifelong impairments.2 Additionally,
there are often devastating effects on the
psychological and financial resources of
the patient, family, and larger community.
Patients with schizophrenia also tend to
have major impairments in social, occupational, and cognitive functioning, which
represent a significant health care burden.
More specifically, the economic burden for
excess direct healthcare costs has been estimated at 22.7 billion in the United States
in 2002, with an addition 7.6 billion in excess direct non-healthcare costs, and an additional 32.4 billion in excess total indirect
costs, for a total excess economic burden of
62.7 billion for schizophrenia.3
Efforts have been made to rethink and
reformulate how to treat severe mental
illnesses in order to lessen the economic,
social, and family burden, not to mention the burden on the person diagnosed
with schizophrenia. For example, positive steps have now been taken to identify
early indicators of psychosis, and to begin
the treatment of psychosis as early as possible. The race to intervene early is based
on evidence which suggests that delays in
treatment lead to unnecessary distress for
the patient, greater risk of relapse, as well
as adversely effecting the long-term course
of the illness.4,5,6 There is also evidence to
suggest that changes in brain volume occur in the first year to year and a half of
first hospitalization, thus highlighting still
further the importance of the early identification of indicators of psychosis and early
intervention.7
Finally, one of the main obstacles to understanding the etiology of schizophrenia
is that the presenting symptoms may or
may not be related to the disorder’s pathophysiology and/or etiology. This suggests
that defining patients by symptoms alone
may not be an optimal way of grouping
them, as this approach likely includes a
heterogeneous grouping of patients. A
more careful delineation based on neurobiological indicators or markers such as
brain abnormalities, cognitive dysfunctions, and/or variations in gene expression,
etc., might serve to define more homogeneous groupings. This may ultimately lead
to more targeted psychopharmacological
and cognitive-behavioral treatments, and
ultimately to unraveling the etiology of
this devastating disorder. Additionally, by
focusing on neurobiological indicators of
brain and cognitive dysfunction in schizophrenia, we may be better able to identify
individuals who are at risk for developing
schizophrenia, which will likely lead to
earlier intervention, and perhaps, in the
future, to preventative measures. At present, however, and as described below, we
are currently far from understanding the
etiology of schizophrenia.
In fact, after more than 100 years of
research, the etiology of schizophrenia is
still unknown. What we do know is that
schizophrenia is a complex brain disorder
with clinical symptoms, cognitive distortions, and course of illness largely determined by neural substrates, which, in turn,
are likely influenced by the weak effects of
multiple genes, with environmental factors playing a secondary or contributory
role. Moreover, and perhaps one of the
most distressful facts about schizophrenia, is that it typically afflicts individuals
in late adolescence or early adulthood, a
time when most people are on the threshVol. 6, No. 2, Fall 2005 47
In Focus
old of entering the most productive years
of their lives.8 There are also likely several
interacting biological (e.g., genetic and
neurodevelopmental) and environmental
factors (e.g., viral infection, fetal insult,
drug abuse) that predispose an individual
to schizophrenia.
The strongest evidence for the role of
genetics in schizophrenia comes from twin
studies, which have reported higher concordance rates for schizophrenia in monozygotic (identical) twins compared with
the concordance rates for schizophrenia in
dizygotic (fraternal) twins (about 10%).9,10
Evidence for the role of genetics also comes
from adoption studies which have shown a
higher incidence of schizophrenia in the
offspring of mothers with schizophrenia
who were raised in adopted homes (about
13%), compared with the incidence of
schizophrenia in the offspring of mothers
without schizophrenia who were raised in
adoptive homes (about 2%).11 As concordance rates for monozygotic twins are not
100%, as would be expected for identical twins, it is evident that there are likely
important environmental risk factors that
are also involved. Nonetheless, twin and
adoption studies, taken together, demonstrate that genes influence the susceptibility to schizophrenia, although the mode of
inheritance is not known. It is likely, however to be complex and not related to one
gene (e.g., Mendelian autosomal transmission), but instead the result of the effect of
multiple weak genes that, in concert with
environmental risk factors, exert their influence on the susceptibility, or predisposition, to developing schizophrenia.
The Role of the Brain in
48 Harvard Health Policy Review
Schizophrenia
Although, as noted above, the etiology of
schizophrenia is not known, both Kraepelin and Bleuler, who first described “dementia praecox” and “the schizophrenias”,
believed that brain abnormalities would
ultimately be linked to the etiology of
schizophrenia.12,13 This conviction was fueled during the late 19th and early 20th
century by important inroads that were
being made into the neuropathology of
Alzheimer’s disease, Huntington’s Chorea,
Pick’s disease, tertiary syphilis, and some
forms of epilepsy.14,15,16 Given the importance of brain abnormalities in these
other diseases, researchers were hopeful to
discover similar abnormalities in the postmortem brains of patients diagnosed with
schizophrenia. The results, however, were
disappointing and often conflicting, largely due to the crude measurement tools that
were employed, and the expectation that
large abnormalities would be discovered,
when in fact such abnormalities are small
and subtle. Consequently, progress, as well
as interest, waned, and the general consensus, voiced in 1972 by Plum, was that
“schizophrenia is the graveyard of neuropathologists”.17
Interest was rekindled in 1976 with
the first computer-assisted tomography
(CT) study that showed enlarged lateral
ventricles in schizophrenia.18 This study
was pivotal in that CT was seen as a new
window on the brain that would enable investigators to revisit old theories about the
role of brain abnormalities in schizophrenia. With the introduction of magnetic
resonance imaging (MRI) studies, the first
MRI study of schizophrenia was conducted
in 1984.19 Since that time there have been
Shenton: Schizophrenia
many improvements in MR acquisition
and image processing, including the introduction of positron emission tomography
(PET), followed by functional MR (fMRI)
and diffusion tensor imaging (DTI), all of
which have enabled us to exploit more fully information contained in MR and other
medical images. These advances have led
to an important appreciation of the critical role that brain abnormalities play in
schizophrenia. Moreover, an important
question has also been answered in the affirmative – brain abnormalities are indeed
observed in schizophrenia.
The implications of these findings, reviewed below (MRI and Schizophrenia),
remain to be determined, particularly in the
context of how they pertain to the presence
of brain abnormalities in at-risk individuals, in prodromal states (i.e., prior to the
actual onset of illness but where indicators
of illness are present such as brain abnormalities, cognitive deficits, etc.), at time of
first episode of illness, in the well relatives
of patients diagnosed with schizophrenia,
as well as in association with cognitive dysfunctions, clinical symptoms, and genetic
variations. These areas are currently being investigated and early findings suggest
that the unaffected first-degree relatives of
patients with schizophrenia show similar
brain abnormalities, as do individuals at
high-risk for developing schizophrenia.20,21
Importantly, identifying early indicators
of illness will assist in treating at-risk individuals early, with the outcome hopefully
being one of lowering recidivism rates and
ameliorating or even preventing the chronic course of the illness, a course often seen
in patients diagnosed with schizophrenia.
MRI and Schizophrenia
Described as “The Decade of the Brain”,
the 1990s witnessed unparalleled progress
in what we know about the brain, largely
the result of new in vivo medical imaging
tools. More progress was made during this
period in documenting brain abnormalities in schizophrenia, than had occurred
in the previous history of schizophrenia
research. Of particular note, advances in
imaging led to the identification of a number of small subtle brain abnormalities, including ventricular enlargement, preferential involvement of medial temporal lobe
structures, including the amygdala-hippocampal complex, parahippocampal gyrus,
and superior temporal gyrus, as well as
moderate evidence for frontal and parietal
lobe abnormalities and subcortical abnormalities.16 Findings were more equivocal
for cerebellar abnormalities. Thus several
discrete brain regions seem to be involved
in the neuropathology of schizophrenia,
and these likely involve neural circuitry
abnormalities that affect brain regions that
are not necessarily proximal to each other
but which are nonetheless functionally related.
For example, our research group has focused on gray matter temporal lobe abnormalities, including the amygdala-hippocampal complex, parahippocampal gyrus,
and superior temporal gyrus, which we reported to be reduced in volume in patients
diagnosed with schizophrenia compared
with healthy controls. The volume reduction was left lateralized and associated
with formal thought disorder, one of the
cardinal symptoms of schizophrenia. We
concluded that there was damage to an inVol. 6, No. 2, Fall 2005 49
In Focus
terconnected neural network that is functionally important for language and associative links in memory, which we believed
was a fundamental deficit in schizophrenia.22 Andreasen and colleagues proposed
an alternative hypothesis: that the observed
abnormalities were part of a neural circuit
involving the thalamus and its connections
with the cortex and cerebellum, which she
termed “cognitive dysmetria”, and which
she believed reflected the primary deficit
in schizophrenia.23 Others have focused
on abnormalities in the frontal lobes, basal
ganglia and temporal lobe connections,
or in alterations in the temporal lobe that
interrupt connections between temporolimbic and prefrontal regions, and vice versa.24,25 Of note, all of these theories evolved
from earlier theories of brain abnormalities
in schizophrenia, though confirmation was
not possible until the application of in vivo
neuroimaging techniques.
More recently, functional magnetic
resonance imaging (fMRI) and diffusion
tensor imaging (DTI) have been added to
the arsenal of tools available to investigate
brain abnormalities in schizophrenia. Functional MRI enables a more direct examination of interconnected neural networks,
which is not possible with structural MRI
alone, while DTI enables the examination
of white matter fiber tracts, which connect
gray matter regions in the brain.
To understand further the nature of
schizophrenia, we now need to integrate
and to synthesize what is known about
brain abnormalities in schizophrenia,
gleaned primarily from in vivo neuroimaging studies conducted over the past fifteen
years. We need to combine this knowledge
with approaches and advances from the
new frontier of molecular genetics. Spe50 Harvard Health Policy Review
cifically, we need to combine neuroimaging tools, including structural magnetic
resonance imaging (MRI), functional
MRI (fMRI) and diffusion tensor imaging
(DTI), as a powerful approach to evaluate the in vivo effects of genetic variation,
an approach heretofore not possible. (The
National Institute of Mental Health recognizes the importance of bringing together
knowledge from neuroimaging studies
and the new frontier of genetics as is clear
from the focus of the intramural program
as well as the new organization of NIMH
on October 1, 2005 with a focus to accelerate both translational and interdisciplinary sciences to identify brain and behavior
pathophysiology in mental illness.)
For example, we are now well poised to
characterize and to quantify physiological
aspects of the disorder, such as an abnormal neural circuit involving verbal memory. While this may be associated with
susceptibility to schizophrenia, it may be
more directly quantifiable using neuroimaging tools, as well as more directly associated with a gene such as the Brain-Derived
Neurotrophic Factor (BDNF). A focus on
the abnormal neural circuitry involved in
verbal memory, and/or a focus on BDNF,
would be used instead of more distantly associated or indirect indicators of language/
memory deficits, such as a clinical symptom, or a cognitive phenotype, e.g., poor
performance on a neuropsychological test.
Tsuang and Faraone, in fact, observe
that a focus on neurobiological dysfunctions instead of diagnostic classifications in
schizophrenia “may reflect relatively more
proximal effects” of genes, as opposed to diagnosis and symptoms, which “reflect relatively distal and variable effects of genes.26
Of interest here, approaches to mapping
Shenton: Schizophrenia
susceptibility genes for complex disorders
such as schizophrenia have begun, making
it a real possibility that molecular genetics
studies will identify susceptibility genes in
schizophrenia.27 It is also quite likely that
it is not “schizophrenia” per se that is inherited but instead multiple alleles that
are “disadvantageous for cognitive processes.”28 Thus, future studies need to evaluate carefully the weak effects that one or
more genes have on cognitive impairments
commonly observed in schizophrenia, and
these need to be investigated in conjunction with neuroimaging measures of the
brain regions involved in these processes.
The focus on more neurobiological and
cognitive dysfunctions, along with their
association with genetic variation, is also
a common approach in medicine. For example, it was not until patients with Alzheimer’s disease were separated into early
and late onset that the apolipoprotein E
gene was discovered and shown to increase
the risk of late-onset Alzheimer’s disease,
while the epsilon 2 variant was found to be
protective.29 That is, by further delineating
more homogeneous groupings in schizophrenia, the hope is that “endophenotypic
markers”, or “intermediate phenotypes”,
will enable us to move to more “proximal
effects”, and thus closer to the etiology,
or to perhaps several different etiologies,
where “schizophrenia”, defined currently
primarily by the symptoms evinced, is the
final common pathway. Furthermore, with
new advances and tools available for gene
profiling, this area of research is ripe for
exploring the impact of genetic variation
on cognitive processes and their associated
neural circuits.
Criteria for selecting such “intermediate
phenotypes”, or “endophenotypes”, have a
long history in schizophrenia research and
include that the characteristic or trait being
measured should: 1) be associated with the
disease or disorder that is being studied; 2)
that it be heritable; 3) that it not be statedependent; and, 4) that it be observed in
the unaffected family members at a higher
rate than is observed in the general population.30, 31 Some candidate endophenotypes
for schizophrenia include eye tracking
dysfunction, fMRI measures of working
memory deficits, as well as neurophysiological measures of P50, which indexes
the ability to inhibit prepotent responses.32
What makes these endophenotypes most
promising is that they have a much higher
prevalence than schizophrenia in the relatives of schizophrenics.
Finally, and reviewed further below,
evaluating the impact that genes have
on biological intermediate phenotypes,
in conjunction with cognitive processes,
is an important new frontier for making
schizophrenia more tractable, as well as for
shedding new light on the etiology of this
devastating disorder.
Imaging Genomics and
Future Challenges
It is noteworthy that there are now novel
methods for searching for schizophrenia
susceptibility genes that have only become
available in the last several years, including
micro-array analyses of polymorphisms
(SNPs). Accordingly, evaluating the weak
effects of multiple genes, including their effect on cognition and brain abnormalities,
is now at hand.
Also of note, several genes that have
been implicated in the susceptibility to
Vol. 6, No. 2, Fall 2005 51
In Focus
schizophrenia are associated with memory
impairments, a common finding in schizophrenia. These genes include the BDNF
gene, described above, as well as the catecholamine-O-methyl transferease (COMT)
gene, the latter important for the catabolism
of dopamine. Briefly, BDNF has figured in
both bipolar disorder and schizophrenia,
and has also been shown to be associated
with declarative memory impairments in
schizophrenia.28 The COMT gene, importantly, has been associated with frontal
impairments in the dorsal lateral prefrontal
cortex as well as with working memory impairments in schizophrenia.33
This gene has also been linked to bipolar disorder and to velocardiofacial syndrome (VCFS or DiGeorge syndrome). Of
particular interest here, in 90% of VCFS
cases there is a deletion on chromosome 22
(del22q11.2) that is 3Mb long33 and the
COMT gene maps onto this region. Moreover, up to 30% of these individuals will
develop schizophrenia during adolescence
or early adulthood.34 For this reason, Basset
and Chow describe VCFS as a model for “a
genetically mediated subtype of schizophrenia.”35 A promising approach to investigate
schizophrenia at the genetic level is thus to
study VCFS, where the COMT gene may
be involved in both disorders, and may account for the 30% of VCFS patients who
develop schizophrenia.
In summary, as the classification of psychiatric diagnoses and clinical symptoms
are not based on underlying genetic or biological considerations, by linking genetic
abnormalities to cognitive disruptions, as
they are reflected in brain structure and
function, we may be in a better position
to observe more robust findings, as the
associations being made will be based on
52 Harvard Health Policy Review
measures that are closer to biology. Hariri
and Weinberger describe this new area of
scientific inquiry as “imaging genomics.”36
This is the next important frontier in
schizophrenia research, for if we can identify even a subset of the genes that influence
cognition and brain function and structure,
we may be able to develop treatments that
enhance or block the effects of these genes,
thereby effecting the course and treatment
of the illness, as well as lead us to preventative measures.
Findings from such a program of research
may also lead us to a new understanding of
the impact of multiple weak genes on cognition and brain structure and function in
schizophrenia as well as possibly serve as reliable markers for identifying individuals at
risk for schizophrenia (i.e., as yet unaffected
relatives, individuals with VCFS, individuals with prodromal symptoms and/or first
episode patients), so that intervention can
begin early. The implications here for early
intervention and ameliorating and even
preventing a debilitating, often chronic illness, as well as reducing the psychological
and economic burden to the patient, family, and to society, is immeasurable.
References
1. Tsuang MT, Faraone SV, Johnson P. Schizophrenia:
The Facts. Oxford UK: Oxford University Press,
1997.
2. Crown WH, Neslusan C, Russo PA, et al. Hospitalization and total medical costs for privately insured
persons with schizophrenia. Adm Policy Ment Health
2001;28:335-351.
3. Wu EQ, Birnbaum HG, Shi L, Ball DE, Kessler RC,
Moulis M, Aggarwal J. The economic burden of
schizophrenia in the United States in 2002. J Clin Psychiatry 2005;Sept:66(9):1122-1129.
4. The NHS Plan: A Plan for Investment, A Plan for
Reform. London: Department of Health. 2000. Presented to the Parliament by the Secretary of State for
Health, By Command of Her Majesty. July, 2000,
Shenton: Schizophrenia
Crown Copyright.
5. Birchwood M, McGorry P, Jackson H. Early intervention in schizophrenia. Br J Psychiatry 1997;Jan;170:2-5.
6. Department of Health, “Modernizing Mental Health
Services”. London: Department of Health, 1998.
7. Kasai K, Shenton ME, Salisbury DF, Hirayasu Y,
Onitsuka T, Spencer MH, Yurgelun-Todd DA, Kikinis R, Jolesz FA, McCarley RW. Progressive decrease
of left Heschl gyrus and planum temporale gray matter volume in schizophrenia: A longitudinal study of
first-episode patients. Archives of General Psychiatry
2003;60:766-773.
8. Faraone SV, Brown CH, Glatt SJ, Tsuang MT. Preventing schizophrenia and psychotic behaviour: Definitions and methodological issues. Can J Psychiatr
2002;47:527-537.
9. Faraone SV, Skol AD, Tsuang DW et al. Genome
scan of schizophrenia families in a large veterans affairs cooperative study sample: Evidence for linkage
to 18p11.32 and for racial heterogeneity on chromosomes 6 and 14. Am J Med Genetics Part B (Neuropsychiatric Genetics) 2005;139B:91-100.
10.Kendler KS. Overview: A current perspective on
twin studies of schizophrenia. Am J Psychiatry
1983;140:1413-1425.
11.Kety SS, Rosenthal D, Wender PH, Schulsinger F. The
types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. J
Psychiatr Res 1968:1(Suppl.):345-362.
12.Kraepelin E. 1919/1971 Dementia Praecox. Churchill
Livingston Inc., NY.
13.Bleuler E. 1911/1950. Dementia praecox or the group
of schizophrenias. International University Press, NY.
14.Benes F. Is there a neuroanatomic basis of schizophrenia? An old question revisited. Neuroscientist
1995;1:104-115.
15.Harrison P. The neuropathology of schizophrenia: A
critical review of the data and their interpretation.
Brain 1999;122:593-624.
16.Shenton ME, et al. A review of MRI findings in
schizophrenia. Schizophr Res 2001;49:1-52.
17.Plum F. Prospects for research in schizophrenia. 3.
Neurophysiology.Neuropathological findings. Neurosc Res Program Bull 1972;10:384-388.
18.Johnstone EC, Crow TJ, Frith CD, et al. Cerebral ventricular size and cognitive impairment in schizophrenia. Lancet 1976;2:924-926.
19.Smith RC, Calderon M, Ravichundrom GK et al.
Nuclear magnetic resonance in schizophrenia: A preliminary study. Psychiatr Res 1984;12:137-147.
20.Faraone SV, Seidman LJ, Kremen WS, et al. Structural brain abnormalities among relatives of patients
with schizophrenia: Implications for linkage studies.
Schizophr Res 2003;60:125-140.
21.Seidman LJ, Faraone SV, Goldstein JM et al. Thalamic
and amygdala-hippocampal volume reductions in first
degree relatives of schizophrenic patients: An MRIbased morphometric analysis. Biol Psychiatry 1999
46:941-954.
22.Shenton ME, et al. Left temporal abnormalities in
schizophrenia and thought disorder: A quantitative
MRI study. N Engl J Med 1992;327:604-612.
23.Andreasen NC, Nopoulos P, O’Leary DS et al. Defining the phenotype of schizophrenia: Cognitive
dysmetria and its neural mechanisms. Biol Psychiatry
1999;46:908-920.
24.Buchsbaum MS. The frontal lobe, basal ganglia, and
temporal lobes as sites for schizophrenia. Schizophr
Bull 1990;16:379-389.
25.Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995;346:552-557.
26. Tsuang MT and Faraone SV. The frustrating search for
schizophrenic genes. Am J Med Genetics 2000;97:1-3.
27.Asherson PF and Curren S. Approaches to gene mapping in complex disorders and their application in
child psychiatry and psychology. Br Journal of Psychiatry 2001;179:122-128.
28. Goldberg TE and Weinberger DR. Genes and the
parsing of cognitive processes. Trends in Cognitive
Neuroscience 2004:8(7):325-335.
29.Corder EH, Saunders AM, Risch NJ et al. Protective
effect of apolipoprotein E type 2 allele for late onset
Alzheimer disease. Nat Genet 1994;7:180-184.
30.Gottesman II and Gould TD. The endophenotype
concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry 2003;160:636-645.
31.Kennedy JL, et al. The genetics of adult-onset neuropsychiatric disease: Complexities and conundra? Science 2003;302:822-826.
32.Levy DL, Holzman PS, Matthysse S, Mendell NR.
Eye tracking and schizophrenia: A selective review.
Schizophr Bull 1994;20:47-62.
33.Shprintzen RJ, et al. Late-onset psychosis in the
velo-cardio-facial syndrome. Am J Med Genet
1992;42:141-142.
34. Murphy KC, et al. High rates of schizophrenia in
adults with velo-cardio-facial syndrome. Arch Gen
Psychiatry 1999;56:940-945.
35. Basset AS and Chow EW. 22q11 deletion syndrome:
A genetic subtype of schizophrenia. Biol Psychiatry
1999;46:882-891.
36. Hariri AR and Weinberger DR. Imaging genomics. Br
Med Bull 2003;65:237-248.
*Note: Many of the ideas and concepts for this paper were
derived and adapted from: Shenton ME, et al. A review of MRI findings in schizophrenia. Schizophr Res
2001;49:1-52.
Vol. 6, No. 2, Fall 2005 53