It's all about the Schizophrenia spectrum disorders.

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Schizophrenia Spectrum
Disorders
PRESENTER : DR. SUMIT MEHTA
MD trainee
LGBRIMH, Tezpur
MODERATOR : DR. SAMIR SARMA

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Schizophrenia spectrum disorders
• Group of psychiatric diagnoses that share
several clinical features,
• Typically involving reality distortion
• Each is considered a disorder, diagnosed with
a distinct set of diagnostic criteria
• Spectrum conveys the idea that they are
somehow similar to each other
• Tension of distinctiveness and similarity

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• In the 19th century, one view was that all serious mental
disorders were expressions of a single entity, termed by
Griesinger as “Einheitpsychose”, i.e. unitary psychosis.
• Mental disorders could be separated & classified -
Benedict Morel
• Coined the term “demence precoce” for describing a
chronic deteriorative disorder, starting at adolescent &
leading first to withdrawal, odd mannerisms and self
neglect & eventually leading to intellectual deterioration

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• Emil Kraepelin translated Morel’s “demence
precoce” into “dementia praecox”, to
emphasize the distinct cognitive decline
(dementia) & early onset (praecox) of the
disorder.
• Eugen Bleuler coined the term
“schizophrenia” in 1911 to mean “splitting” of
the psychic functions. Bleuler made a
distinction between the fundamental &
accessory symptoms of schizophrenia.

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• Karl Kleist, looked for association between
brain pathology & different subtypes of
psychotic illness
• The term ‘Schizo-Affective Psychosis’ was
first coined by Jacob Kasanin in 1933
• , Kasanin himself believed ‘Schizo-Affective
Psychosis’ to be a subtype of schizophrenia

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• Evolving view is the idea that schizophrenia
may represent a point—or end point—on a
continuum of deficit rather than a discrete
disease entity
• Use of epidemiological, genetic and other
family study paradigms for ICD – 10 and DSM
IV

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SPECTRUM
• Strongest evidence - schizoaffective disorder
and schizotypal personality disorder
• Moderate evidence - paranoid and schizoid
personality disorder
• Recently proposed – research criteria for
another syndrome, called schizotaxia,

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THEORETICAL ISSUES
• No widely accepted rules for determining whether a
syndrome warrants inclusion
• Two traditional lines of evidence –
 clinical similarity to schizophrenia
 aggregatation in families affected by schizophrenia
(evidence of both the genetic and nongenetic
etiological similarities of the disorder to schizophrenia)
(kendler et al 1985 , seivel et al 1990)

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SCHIZOAFFECTIVE DISORDER
NOSOLOGY
• DSM II – as a subtype of schizophrenia
DSM III - under “ psychotic disorders not elsewhere classified.”
DSM III R - it became more well defined
DSM IV TR- incorporated the time frame of 1 month
duration of schizophrenic symptoms
• ICD 9 – like DSM II
ICD 10- Schizoaffective disorder applied to patients who
have co-occuring mood symptoms and
schizophrenic symptoms

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EPIDEMIOLOGY
The life time prevalence of schizoaffective
disorder is
< 1 %( .5 -.8 %)
Depressive subtype – older > younger
Bipolar subtype - young > old
Female > Male
Age of onset of female later than male

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DIAGNOSIS AND CLINICAL FEATURES
DSM IV TR
A) uninterrupted period of illness in which sometime there has
been an affective episode concurrent with symptoms of criteria
A of schizophrenia.
B) during same episode, delusions and hallucinations must be
present for atleast 2 weeks in the absence of
mood symptoms.
C) symptoms of mood episode is present for substantial
portion of active symptoms & residual symptoms.
D) it is not due to substance / general medical condition
SPECIFIER- Bipolar/Depressive type

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Clinical Similarities to Schizophrenia
• Schizoaffective Disorder
diagnosis of schizoaffective disorder, which
specify that Criterion A of schizophrenia must
be satisfied and that delusions or
hallucinations must be present
depressive type is believed to lie nearer the
schizophrenia spectrum
 bipolar type is believed to that of traditional
mood disorders

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Schizotypal Personality Disorder
• diagnosis based on the presence of both social and
cognitive deficits
• reflect those of schizophrenia but with less severity
• ideas of reference, odd beliefs, magical thinking, unusual
perceptual experiences, and suspiciousness
• odd thinking, speech, and behavior - disorganized type
schizophrenia
• appearance of affective disturbance, the lack of close
friends, and the excessive social anxiety resembles social
dysfunction of schizophrenia (i.e., negative symptoms).

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Paranoid Personality Disorder
• characterized by a pervasive distrust and
suspiciousness of other
• Though shares only this single group of
symptoms with schizophrenia,features are
central to the diagnosis of paranoid type
schizophrenia;

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Schizoid Personality Disorder
• Principal clinical feature - social dysfunction,
ranging from aversion of social relationships to
restricted affective expression in interpersonal
settings
• Symptoms similar to the social dysfunction
that is a fundamental feature of schizophrenia
but less pronounced

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Schizotaxia
• Not described in the DSM-IV-TR
• Originally formulated by Paul Meehl in 1962
• Represented the genetic predisposition to
schizophrenia that led, almost invariably, to
either schizotypy or schizophrenia, depending on
environmental circumstances
• Reformulated only recently as a meaningful
clinical syndrome as well as a relatively specific
reflection of the vulnerability to schizophrenia

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Meehl’s concept
• Single gene neurointegrative deficit
(schizotaxia)
polygene potentiator
Schizphrenia schizotypal
may stay

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Schizotaxia - current concept
• (1) As a result of the interaction between a
genetic predisposition and the biological
consequences of early adverse environmental
experiences (e.g., pregnancy complications)
• (2) includes meaningful, definable clinical and
neuropsychological symptoms;
• (3) remains a stable syndrome in many individuals;
• (4) is similar conceptually and phenomenally to
negative schizotypal personality disorder

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Familial Aggregation with Schizophrenia
• Schizoaffective Disorder
More than a dozen family studies , twin
studies , and adoption studies illustrated the
genetic relationship between schizophrenia and
schizoaffective disorder
Rate among the family members of patients
with schizophrenia can be as high as 9 percent,
general population (less than 1 percent).

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• One article published way back in 1982 in The
British Journal of Psychiatry reported identical
triplets aged 28, who were discordant by major
Kraepeliniantype of psychosis. Two of them had
been diagnosed schizophrenic while the third was
diagnosed manic depressive.
• One study published in Am J Psychiatry, April 2002
examined 77 monozygotic and 89 same-sex
dizygotic twin pairs in which the proband met the
Research DiagnosticCriteria (RDC) for lifetime-ever
schizophrenic, schizoaffective, or manic syndrome
from the Maudsley Twin Register in London

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Schizophrenia-Spectrum Personality Disorders
• Schizotypal personality disorder shows the
strongest familial link with schizophrenia
• 1.5 to 5.0 times higher among the relatives of
schizophrenic patients than in the relatives of
controls or in the general population
• Paranoid and schizoid personality disorders
have not provided a similar level of evidence
for a familial association with schizophrnia

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Schizotaxia
• Conceptualized as the genetic liability toward
schizophrenia
• Relatively common among the nonpsychotic
relatives of patients with schizophrenia
• Core symptoms of schizotaxia range from 20
to 50 percent among the first-degree relatives
of schizophrenic patients

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PATHOLOGY
• Brain Structure
Structural abnormalities exist in a plethora of
cortical and subcortical brain structures in
schizophrenic patients
Increased volume in the lateral ventricles
Decreased volumes in the dorsolateral and medial
prefrontal cortices, cingulate paracingulate cortices,
hippocampus, parahippocampal and superior
temporal gyri, septum pellucidum, and thalamus

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Brain in schizoaffective disorder
• Mixed evidence for common morphology
• Striatal enlargement and cerebral volume
reductions) were each noted in only one of
three existing studies of schizoaffective
patients
• Ventricular enlargement, characteristic of
schizophrenia, was observed in two of three
studies

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Schizotypal personality disorder
• Abnormalities in the superior temporal and
parahippocampal gyri, lateral ventricles, thalamus, and
septum pellucidum similar to those seen in people with
schizophrenia
• Frontal cortical volume, on the other hand, appears to be
relatively preserved in initial studies of schizotypal
personality disorder
• Medial temporal lobe abnormalities and lateral ventricular
enlargement are not prominent in schizotypal personality
disorder

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Hypothesis
• enlargement of the ventricles and
deterioration of the medial temporal lobes
SCHIZOPHERNIA

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Brain Function
• Schizotypal personality disorder
Abnormalities in frontal activation mimic those of
schizophrenia, with the difference that additional
brain regions are recruited to accomplish tasks
requiring frontal lobe activation.
Performance of a verbal working memory task (a
domain that is among the most impaired in schizophrenic patients and
among their nonpsychotic relatives), exhibit reduce activation
relative to controls.

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(Larry J. Siever, Kenneth L. Davis)
Chronic Schizophrenia Schizotypal Personality
Disorder
Frontal lobe
activation
Metabolic rate reduced in
most, increased in some
Increased activation in
middle
frontal gyrus
Temporal lobe
activation
Metabolic rate increased in
majority of studies but
decreased in others
Reduced in relation to
comparison subjects but
not
to as great a degree as in
patients with schizophrenia
Striatal activation Metabolic rate increased in
majority of studies but
decreased in others
Metabolic rate significantly
elevated in ventral
putamen

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Nonpsychotic relatives of patients with
schizophrenia, (which also contains individuals
with schizotaxia)
• Abnormal brain activation patterns while
performing working memory tasks
• Such tasks normally produce activation in the
lateral and medial prefrontal cortex, posterior
parietal and thalamus
• Relatives exhibit more bilateral activation on
working memory tasks, than do control
subjects

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• . These findings indicate at least one or both
of two possibilities:
(1) Relatives demonstrate a compensatory
exertion of inefficient neural circuitry in
attempting to perform an effortful task to
produce accurate output
 (2) they have abnormal connectivity in the
circuitry required to perform these tasks.

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Psychophysiology

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Psychophysiological correlates or intermediate
phenotypes for schizophrenia and schizotypal
personality disorder
• 1. A failure of P50 suppression
• 2. Deficits in prepulse inhibition, which may
impair appropriate modulation of
responsiveness to the environment
• 3. Impairment of smooth-pursuit eye
movements, reflecting involuntary attention

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• 4. Errors in antisaccade tasks, which test saccadic
inhibition
• 5. Poor performance on a backward masking task
that assesses early visual processing
• 6. Reduced P300-evoked potentials, which
measure auditory attention
• 7. Performance on the Continuous Performance
Test, a sustained attentional task

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Chronic Schizophrenia Schizotypal Personality Disorder
Eye movement
impairment
Inability to
smoothly follow
target
Large Inability to
smoothly follow
target
Small
Antisaccade Abnormal; gaze
initially directed
toward instead of
away from
target
Largest Abnormal; gaze
initially directed
toward instead of
away from
target
Large
Prepulse
inhibition
Reduced gating
or inhibition
Medium to large Reduced gating
or inhibition
Larger
P50 suppression P50 suppression
deficit
Large P50 suppression
deficit
Large
P300 event-
related
potential
Reduced
amplitude of
P300 wave
Medium to large Reduced
amplitude of
P300 wave
Small to medium

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NEUROPSYCHOLOGICAL IMPAIRMENT IN
SCHIZOTAXIA
• Motor ability- in children, disturbed gait
• Perceptual motor speed- slow both in adults and
children
• Verbal ability and language- significant impairment both
in children and adults
• Visuo-spatial learning- most studies show no impairment

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Neurotransmission
• Schizophrenic patients often show lower levels of
dopamine-β-hydroxylase (the enzyme that converts
3,4-dihydroxyphenylalanine to dopamine) and
lower plasma levels of homovanillic acid (a
dopamine metabolite).
• Elevated levels of homovanillic acid in schizophrenia
are associated primarily with positive symptoms
• Inverse relationship with negative symptoms (i.e.,
higher levels of negative symptoms associated with
lower levels of homovanillic acid).

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Studies on neurotransmission in schizotypal
personality disorder.
• CSF levels of homovanillic acid were increased
among patients with schizotypal personality
disorder relative to controls
• Relationship between lowered homovanillic
acid levels and negative symptoms and
elevated homovanillic acid levels and positive
symptoms

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Studies of schizotypal individuals,studies
of nonpsychotic,nonschizotypal relatives
of schizophrenic patients
• Lower circulating levels of homovanillic acid
when compared with a normal control group
• Plasma homovanillic acid is also inversely
correlated with negative symptom scores

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Proposed Pathophysiological Model
of the Spectrum Disorders
• Distinct susceptibilities to the schizophrenia spectrum
and psychosis
• Common genetic anomaly that renders the temporal
cortex particularly vulnerable to environmental insults
such as hypoxia
• Genetic factors and/or favorable environmental
influences would leave the schizotypal individual better
buffered with regard to frontal volume and function as
well as stabilization of subcortical dopaminergic activity

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• Frontal reserve capacity or, at a cognitive
level, general intelligence
• social deficits and cognitive impairment
characteristic of the entire spectrum of
schizophrenia-related disorders
• is the result of an underlying genetic diathesis
that, in conjunction with modifying
environmental factors

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• Adversely affects cortical structures such as the
temporal and prefrontal cortex
• Sensitive to developmental aberrations such as
altered migration of neurons, aberrant dendritic
growth patterns, or alterations in the compaction
and maintenance of the myelin sheaths of axons
• Subsequent disconnection between critical brain
regions

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Increased prefrontal
cortical compensatory
capacity buffers against
effects of temporal deficits
Temporal lobe
Frontal lobe
Basal ganglia
Early temporal lesions lead to
prefrontal functional deficits
Frontal hypodopaminergia leads to
striatal hyperdopaminergia
---
Disruption of
striatal excitatory
and inhibitory
circuits leads to
cortical dysfunction

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• Greater frontal reserves in schizotypal personality
disorder compared to schizophrenia protect the
schizotypal individual from the severe cognitive
deterioration and social deficits associated with
chronic schizophrenia.
• Schizotypal individuals may also be able to better use
their frontal capacities
• Compensate for dysfunction in regions such as the
dorsolateral prefrontal cortex, to accomplish working
memory and executive tasks, by activating other
frontal regions not normally recruited by normal
volunteers

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• Finally, subcortical structures that are modulated by
the frontal cortex may be better protected compared
to schizophrenia subjects
• Perhaps because frontal function is better preserved
and/or because intrinsic dopamine activity in the
striatum may be more effectively regulated.
• Comparable individual differences between people
might also modulate the degree to which striatal
dopaminergic up-regulation occurs in the face of
frontal dysfunction, for example, as may be induced
by stress paradigms

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ENDOPHENOTYPE EXPLANATION
• Evaluation of intermediate phenotypes or
endophenotypes that are common to the
entire spectrum of schizophrenia disorders
• Reflect a genetic impairment, particularly
prominently expressed in temporal or
hippocampal regions, that is common to the
entire schizophrenia spectrum

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• P50 suppression abnormality, which is
associated with the alpha-7 nicotinic receptor
gene in relatives of patients with
schizophrenia and reflects an abnormality in
sensory gating or filtering function of the
hippocampus, where these receptors are
localized

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• Hippocampal impairment might lead to P50
abnormalities and perhaps spectrum pathology
but not necessarily schizophrenia
• Predispositions to neurodevelopmental
aberration in the hippocampus or the temporal
cortex, frontal dysfunction may interact
synergistically to increase the probability of
developing schizophrenia

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• Vulnerability and protective factors within a
single domain, e.g., hippocampal function
• Relatives of schizophrenia probands with P50
abnormalities have been found to have larger
hippocampi than those without the P50
abnormality
• Consistent with the hypothesis that larger
hippocampi reflecting increased processing
capacity may partially compensate for the
sensory gating deficit in these relatives, thus
protecting them from schizophrenia

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Future Directions
1. New opportunities to disentangle the genetics
and pathophysiology of schizophrenia
2. Candidate genes begin to be identified in relation
to schizophrenia disorders , the genes that are
associated with both schizotypal and
schizophrenia disorders and those that are unique
to schizophrenia and psychosis may be identified

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3. To provide intermediate phenotypes to more
finely hone our understanding of the
character of genetic or phenomenological
relationships in the spectrum
4. Opportunity to pilot pharmacological
interventions to enhance cognitive function
or improve negative symptoms

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Thanks……

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Bibliography
• Comprehensive Textbook of Psychiatry, Kaplan & Sadock, 8th
Edition
• Am J Psychiatry 2004; 161:398–413; The Pathophysiology of
Schizophrenia Disorders: Perspectives From the Spectrum; Larry J.
Siever, M.D.,Kenneth L. Davis, M.D.
• Comprehensive Textbook of Psychiatry, Kaplan & Sadock, 9th
Edition
• Neurobiology of Schizophrenia Spectrum Disorders ;Stephan
Heckers; Annals Academy of Medicine; May 2009, Vol. 38 No. 5