Secondary Schizophrenia (3 page)

this book. It has much to commend it, as discussed in
Neuroscientists often come away with the feeling that
one of the chapters. More than anything else, it makes
they are clutching at straws.

no false pretense and recognizes our ignorance.

Some of us would like to believe that the answer,
This book has been a collective effort. I am grateful
once we do stumble upon it, will be simple indeed.

to all the contributors not only for the hours of labor,
Perhaps we are only one step away from a gene that
but also for the infinite patience for the long delays
will unravel the mystery. Maybe a misfolded protein
in bringing it to fruition. There are very few experts
will open its cloak to reveal its nakedness. Many oth-on secondary schizophrenia. The writing of the chap-ers believe, however, that the answer will never be
ters has therefore taken many authors outside their
simple – schizophrenia, after all, is about our very
comfort zones, and the results are consequently more
nature as human beings and what can go wrong
exciting. In particular, I would like to thank Matcheri
with our existence. My own position is somewhere in
Keshavan for his wisdom and generosity in guiding
between. I believe that eventually we will find genetic
various aspects of the book. His consultations have left
determinants of the brain abnormalities that underlie
me in a considerable debt of gratitude. As always,
schizophrenia. This will help us understand that what
my assistant Angie Russell has been tenacious in her
we now regard as schizophrenia is a potpourri of disor-determination to complete her project, and has worked
ders. There may well be many phenocopies of the true
untiringly to give me editorial support. She accepted
schizophrenia. On the other hand, there may not be a
that not all contributors would follow the guidelines
real schizophrenia in any case, but a medley of disor-for submission, and had the unenviable task of chang-ders we naively lump together.

ing reference styles and crossing the ‘t’s. It is as much
This book is about chipping away at the large lump
her book as that of the authors. The Cambridge Uni-we presently call schizophrenia. The defining charac-versity Press has been a solid backer throughout the
teristics are broad indeed – the presence of delusions
process. The life of this manuscript has seen a number
and hallucinations in clear consciousness. A quick
of changes in the editorial staff, but their support has
browse through the leaves of this book will convince
been unwavering.

xiii

In the age of electronic publishing and rapid com-head out to urge all players to move on. The road is
munication, this book is but a tortoise. I hope that it
long and there is no time to rest.

will hold steadfast, and intermittently poke its little
Perminder Sachdev

Sydney, Australia

xiv

Section

Section 1

Introduction

schizophrenia: current status

Matcheri S. Keshavan and Ripu D. Jindal
Facts box

Organic/functional versus the

1. Whereas this book focuses on secondary (or
primary/secondary categorization:

“organic”) schizophrenia, the neurobiological
a historical perspective

basis of primary (or “idiopathic”)
The fourth edition of the Diagnostic and Statistical
schizophrenia is important to understand.

Manual of Mental Disorders (DSM-IV) dropped the
2. Converging data suggest that cognitive
terms “organic” and “functional” used in the ear-impairments are not epiphenomena
lier editions. The change in terminology in DSM-but reflect the core pathology of
IV reflected a change in emphasis from the presence
schizophrenia.

or absence of discernible brain pathology (which is
3. Functional imaging studies point to
often difficult to identify, even in many neurologi-abnormalities in prefrontal, cingulate, and
cal disorders) to etiology (presumed or actual). This
medial temporal lobe function in the early
resulted from a growing realization that it is better
stages of schizophrenia.

to categorize psychiatric disorders based on whether
4. Structural brain abnormalities are present
the neurobiological alterations are due to a known
at the onset of illness and appear to be
medical illness (“secondary”) or whether they cannot
persistent.

be explained by another illness (“primary” or idio-5. Siblings and offspring of schizophrenic
pathic). In this book, this approach has been taken
patients also show structural brain
to understand schizophrenia because the term “pri-changes.

mary” has the advantage of not ruling out a neurobio-6. Structural brain changes in individuals with
logical (or “organic”) basis. Although a variety of sec-prodromal symptoms may predict
ondary schizophrenias are described throughout this
development of psychosis.

text, it is important to have an understanding of the
neurobiological substrates that may underlie primary
7. Diffusion tensor imaging studies in
(or idiopathic) schizophrenic illness. In this chapter,
schizophrenia have documented reduced
we seek to provide an overview of what is known in this
structural integrity of white matter
regard, and offer an approach to the differential diag-tracts.

nosis between primary and secondary schizophrenias.

8. Radioligand studies support the view that
psychosis may be related to dopaminergic
hyperfunction in mesolimbic brain

Schizophrenia as a quintessential

regions.

“primary” psychotic disorder

9. Genetic factors interact with both early and
Schizophrenia is a severe and chronic mental disor-late environmental factors in affecting
der with a lifetime prevalence of approximately 1%.

neurodevelopment that may be the basis of
Onset is typically in adolescence to early adulthood,
schizophrenia.

but very rarely before age 11. Symptoms of schizophre-10. The study of “secondary” schizophrenia
nia are classified into positive symptoms, that is, false
is likely to provide novel insights into the
fixed beliefs that cannot be reasoned away (delu-pathogenesis of the primary disorder.

sions), abnormal perceptions (hallucinations), disor-

3

ganized speech and behavior, and negative symptoms
Introduction – Section 1

(i.e. deficits in motivation, affect, and socialization). A
Table 1.1
Cognitive domains (note the mnemonic SMART)
given patient may exhibit some or all of these symp-commonly affected in schizophrenia, and recommended tests
to assess these domains

toms. The course and severity of the illness are also
variable. In many patients, some cognitive and social
Speed of processing:
Category Fluency; Brief Assessment of
Cognition in Schizophrenia (BACS) – Symbol-Coding; Trail
difficulties can be traced back to early childhood, long
Making A

before the development of symptoms that meet the
Memory:
Working Memory : Letter-Number Span; Wechsler
criteria for schizophrenia. Sometimes, mood, thought,
Memory Scale (WMS) – III Spatial Span; Verbal learning/memory:
and personality changes are followed by gradual devel-Hopkins Verbal Learning Test (HVLT) – Revised; Visual
opment of subthreshold psychotic symptoms. Even
learning/memory: Brief Visuospatial Memory Test (BVMT) –
Revised

after the development of acute symptoms, the course
Attention:
Continuous Performance Test – Identical Pairs
is variable. In most cases, acute psychotic states are
(CPT-IP)

interspersed by periods of remission. Even the periods
Reasoning:
Neuropsychological Assessment Battery (NAB) –
of remission are not entirely free from negative symp-Mazes
toms and cognitive deficits. The persistence and perva-

Tact
(socal cognition): Mayer-Salovey-Caruso Emotional
siveness of the cognitive impairments in schizophrenia
Intelligence Test (MSCEIT) – Managing Emotions
led early thinkers like Kraepelin to view schizophre-Source: http://www.matrics.ucla.edu/matrics-psychometrics-nia as primarily a cognitive brain disorder that begins
frame.htm.

early in life, hence the term “Dementia Praecox.” In
this chapter, we review the evidence for and the nature
of the brain abnormalities in schizophrenia. Specifi-encompasses the different cognitive processes involved
cally, we address the questions of whether there is a
in what people think of themselves, others, and social
neurobiological substrate to the illness, how the dys-situations
[3, 4]
) is perhaps the most important. This
functions originate at a physiological level, where in
domain of cognition facilitates interpersonal interac-the brain the alterations are seen, what the nature of
tions, and deficits in this domain have been implicated
the abnormalities may be at neurochemical and neu-as the core pathology in autism and schizophrenia
[5].

ropathological levels, why they may occur (etiology),
Emotional processing, a key component of social cog-and when in the life course of the individual the patho-nition, is commonly assessed by responses to emotive
physiology may evolve.

facial stimuli
[6]
. Although regions in the brain associated with social cognition are distinct from those
involved with nonsocial cognition, social cognition
Is there brain dysfunction in schizophrenia?

also depends on the integrity of nonsocial domains of
Evidence from the prominent cognitive and
cognition. For example, attention is needed to focus
on salient features in a stimulus; working memory is
neurologic impairments

needed for generating appropriate social responses to
Over the past few decades, converging data suggest
context information, and executive function is needed
that cognitive impairments are not epiphenomena but
to generate and revise hypotheses regarding the mean-reflect the core pathology of schizophrenia
[1].
This
ing of social situations
[7].

evidence has greatly enhanced our understanding of
Cross-sectional comparisons between first-episode
the neurobiology of the disease. Increased frequency
and chronic patients suggest some decline in func-of “soft” neurological signs, detectable on routine bed-tion; however, longitudinal studies show no decre-side neurological examinations, is also seen early in
ment
[8, 9, 10]
or modest decreases in cognitive
schizophrenia and tends to persist during the illness
function
[11].
Furthermore, a meta-analytic study of
(Chapter 4).

memory impairment showed comparable effect sizes
Schizophrenia patients have a broad range of cog-in the studies of first-episode and chronic patients
nitive impairments, as summarized by the mnemonic
[12].
In a longitudinal study, deficits in social cognition
SMART
(Table 1.1).
Cognitive deficits have attracted
were stable over 1 year of follow up
[13].
Relationships
attention from investigators and clinicians after their
between clinical symptoms and neuropsychological
major role in predicting functional outcome in
performance have also been investigated. Some stud-schizophrenia became known
[2].
Among media-ies
[8, 14, 15]
found an association between changes
4

tors of functional outcome, social cognition (which
in neuropsychological scores and positive symptoms,
Chapter 1 – Neurobiology and etiology of primary schizophrenia: current status

whereas another
[10]
found a similar association with
the inferior frontal/insular, anterior cingulate and tem-change in positive symptoms. Taken together, the lon-poral cortex bilaterally, the right thalamus and infe-gitudinal and some cross-sectional studies and the
rior colliculus, and the left hippocampus and parahip-lone meta-analysis previously described support the
pocampal cortex
[24].

view that extensive cognitive deficits are present by
An early PET study in schizophrenia detected
the first episode of psychosis and are likely to be a sta-abnormalities in regional brain function during rest
ble, ongoing, traitlike feature of the person’s illness.

[25].
As stated earlier, impaired working memory is
Studies of cognition in prepsychotic individuals at
a well-replicated finding in schizophrenia
[26],
and
genetically high risk for psychosis provide a way to
working memory tasks have been widely used in fMRI
determine the static versus progressive nature of the
studies in schizophrenia to examine responses to cog-cognitive deficits in schizophrenia. Neuropsychologi-nitive tasks. fMRI studies in healthy humans sug-cal investigations have been done as part of longitudi-gest that the dorsolateral prefrontal cortex (DLPFC)
nal studies of children at genetically high risk of devel-plays a major role in working memory. Approxi-oping psychosis in different parts of the world (i.e.