MOST OF THE FINDINGS IN RESEARCH WERE DOCUMENTED IN THE ARTICLES OF RAJIV TANDON... THIS PRESENTATION HAS THE FACTS FROM THOSE ARTICLES

1. SScchhiizzoopprreenniiaa JJuusstt tthhee ffaaccttss
PPaarrtt 33 && 44
R. Tandon et al. / Schizophrenia Research 110 (2009) 1–23
M.S. Keshavan et al. / Schizophrenia Research 106 (2008) 89–107
Dr. B C MALATHESH
Juniour Resident - 3

2. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
2

3. NNeeuurrooaannaattoommiiccaall ccoorrrreellaatteess
 Whole brain and grey matter volume is reduced. Ventricular
volume is increased
 Reductions are seen in temporal lobe structures, prefrontal cortex
and the thalamus, anterior cingulate and corpus callosum
 Excess of mixed handedness or reduction in cerebral asymmetry
correlated with schizophrenia
 Reduced Hemispheric asymmetry related to schizophrenia and
younger age at onset.
 Basal ganglia size is usually increased.
 These structural changes are due to developmental derailments.
3

4. White mmaatttteerr ppaatthhoollooggyy aanndd ddiissccoonnnneeccttiivviittyy
White matter alterations like reduction in corpus
callosum fibers is correlated with cognitive deficits.
FA (Fractional anisotropy ) measures structural integrity
of white matter tracts.
Reduced FA in white matter tracts like corpus callosum,
the cingulum, arcuate fasciculus, and the unicinate
fascilulus.
Neuregulin (NRG1) a gene for oligodendrocyte
development and function, is implicated in schizophrenia
4

5. Alterations iinn iinn vviivvoo bbrraaiinn ffuunnccttiioonn
 Hypofrontality :- decreased activation of the dorsolateral
prefrontal cortex (DLPFC) with cognitive tasks.
 After Controlling for performance differences it appears that
patients may show more prefrontal activity than controls,
suggesting an inefficient frontal response.
 Relatives of patients affected with psychosis and patients of
prodromal phase show similar abnormalities in prefrontal
cognitive functions, though less severe.
 Genes for catechol-O-methyltransferase (COMT) and the
metabotropic glutamate receptor (GRM3) implicated.
 Reduced activation is also seen in temporal lobe
5

6. AAlltteerraattiioonnss iinn bbrraaiinn pphhyyssiioollooggyy
Mismatch negativity (MMN)
P300 event-related potentials (ERP)
P50 Deficit
Pre-pulse inhibition (PPI)
Eye movement (EM) abnormalities
Sleep abnormalities
Alterations in neural synchrony
6

7. MMiissmmaattcchh nneeggaattiivviittyy ((MMMMNN))
MMN is a negative voltage component of the event-related
potentials (ERP), elicited when a train of
uniform auditory stimuli are presented, interspersed
with unique or deviant stimuli.
In schizophrenia MMN amplitude is consistently
reduced.
MMN has high heritability and represents NMDA
receptor dysfunction.
7

8. PP330000 EEvvookkeedd PPootteennttiiaall
This is a positive deflection observed on the scalp
EEG about every 300 milliseconds in response to an
infrequent, task-relevant, or novel stimulus
embedded within a train of repeated stimuli.
This may reflect updating of working memory (i.e.,
“context updating”) and directed attention.
In Schizophrenia - reduced P300 amplitude and
increased latency.
8

9. Sensory GGaattiinngg ((PP5500)) DDeeffiicciitt
In schizophrenia there is deficiency in the ability of
the brain to attenuate the P50 response to the
second stimulus (S2) when presented after
500milliseconds of first stimulus (S1).
S1 & S2 are Task irrelevant stimuli.
P50 deficits are correlated with abnormalities in alfa-
7 receptors
9

10. PPrree--ppuullssee iinnhhiibbiittiioonn ((PPPPII))
The startle response (such as a blink), typically
elicited by a sudden auditory stimulus (such as a
burst of loud sound), is normally inhibited when the
stimulus is preceded by a prepulse, around 60–120
ms earlier.
This pre-pulse inhibition (reflecting sensorimotor
gating) is reduced in schizophrenia.
Correlated with NMDA dysfunction
10

11. EEyyee mmoovveemmeenntt ((EEMM)) aabbnnoorrmmaalliittiieess
Normally, humans are able to capture the image of a
moving target and maintain the image on the fovea
even while the image continues moving.
In schizophrenia the normal smooth pursuit
movements of the eyes to a moving target is
impaired with abnormal “catch-up” saccades.
Due to reduced function in the extraretinal motion
processing pathway.
11

12. SSlleeeepp aabbnnoorrmmaalliittiieess
Reductions in total as well as non-rapid eye
movement sleep, and increased awake time
Reductions in stage 2 REM latency and to a lesser
extent stage 4 sleep latency.
12

13. Neural SSyynncchhrroonniizzaattiioonn DDeeffiicciittss
Frequently the neuronal activity is synchronized in
brain and this is a means of communication within
and across brain regions.
Can be measured using EEG activity
This is Reduced in schizophrenia
Reduced synchrony is correlated with thought
disorder, conceptual disorganization, visual
hallucinations and attention deficits .
13

14. Neurochemical aalltteerraattiioonnss –– iinn vviivvoo ssttuuddiieess
N-acetyl aspartate (NAA) and Membrane phospholipid (MPL)
metabolites are studied
NAA – formation and maintenance of myelin.
MPL metabolites - integrity of dendrites and synapse
MRS studies have revealed reductions in neuronal and
membrane integrity in early schizophrenia
In schizophrenia - reduced NAA primarily in the prefrontal
region and hippocampus also reduced PME in prefrontal
region.
PME and NAA changes are also seen in offsprings.
14

15. NNeeuurroocchheemmiiccaall aalltteerraattiioonnss ––
NNeeuurroottrraannssmmiitttteerr
Dopamine –
o Oldest theory, much of evidence indirect
o Explained positive symptoms, but not negative and
cognitive symptoms
Glutamate –
o Deficient glutamate mediated excitatory
neurotransmission via NMDA receptors.
o NMDA antagonists phencyclidine (PCP) and ketamine
induce psychotic symptoms
o Reduced expression of NMDA receptor in PFC and
Hippocampus 15

16. NNeeuurroocchheemmiiccaall aalltteerraattiioonnss ––
NNeeuurroottrraannssmmiitttteerr
Gamma amino butyric acid (GABA)
o Reduced levels of GABA in prefrontal cortex
o GABAa receptors are upregulated
o Correlated with impairment in working memory.
Other Neurotransmitters
o decreases in muscarinic receptors
o direct evidence of serotonergic dysfunction is lacking, but
different serotonin receptors play important role in
treatment of schizophrenia.
16

17. Neurochemical aalltteerraattiioonnss –– NNeeuurrooeennddooccrriinnee
HPA axis dysregulation is common
Dexamethasone non-suppression - significantly
higher in schizophrenics
Elevated cortisol levels - greater symptom severity,
impaired cognition and ventricular enlargement
Elevated cortisol levels - decrease hippocampus size
17

18. NNeeuurrooppaatthhoollooggiiccaall cchhaannggeess
Post-mortem studies of the brains have shown
reduced brain weight, Cerebral ventricular
enlargement, and loss of cerebral asymmetry
Reduction in the number of dendritic spines. There's
also a reduction in markers of axon terminals, such
as synaptophysin.
18

19. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
19

20. WWhhaatt ddoo tthhee ffaaccttss tteellll uuss
Help us elucidating the etiology
These endo (or intermediate) phenotypes represent
consecutive “nodes” on pathophysiological pathways
from the genome to the phenome.
Help us to trace back the genetic cause
20

21. 21

22. Value ooff bbiioommaarrkkeerrss iinn ddiiaaggnnoossiiss
DSM IIIR – No organic cause for Schizophrenia.
DSM IV – few changes, viewed Schizophrenia as idiopathic,
primary psychotic rather than non organic
No biomarkers – in the diagnostic criteria
Reason – cost factors, non specific, not so sensitive.
Identify robust biomarkers which can be used cost effectively
in clinical setting
Implications for next DSM’s - include one or more
neurocognitive, neuroimaging or psychophysiological markers
Facilitate more objective and neuroscientifically based
approaches to diagnosis. 22

23. VVaalluuee ooff bbiioommaarrkkeerrss iinn pprreeddiiccttiioonn
May help us chart the phenotypic variation in the
course, outcome and treatment response
Prefrontal structural and neurochemical alterations –
predict outcome after the first psychotic episode.
Many promises but nothing in clinical practice.
23

24. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
24

25. Towards iinntteeggrraattiioonn:: ffrroomm ffaaccttss ttoo mmooddeellss
Past observations consolidated and new additions in
neurobiology
Progression from crude measures like 5-HIAA and
HVA (metabolites of serotonin and dopamine,
respectively) to specific circuits and receptors.
25

26. PPaatthhoopphhyyssiioollooggiiccaall mmooddeell
Antipsychotic efficacy led to NEUROCHEMICAL THEORIES
initially implicating dopaminergic system later glutamatergic,
GABAergic, cholinergic and serotonergic systems.
Neuroimaging and Neuropathological observations led to
NEUROANATOMICAL THEORIES, implicating structural and
functional alterations of brain.
26

27. TThheeoorriieess ooff ppaatthhooggeenneessiiss
Neurodevelopmental models – aberrant neuronal
migration and proliferation
Developmental Derailment models – aberrant
synaptic pruning around adolescence
Neroprogressive theories – based upon neurotoxicity
27

28. EEttiioollooggiiccaall mmooddeellss
Variously posit the role(s) of genetic factors,
abnormal gene expression, and a multitude of
environmental factors.
28

29. NNMMDDAA hhyyppootthheessiiss
Proposed in 1995, NMDA receptors are hypofunctional
Most Integrated theory.
Most consistent with the structural, functional and
electrophysiological abnormalities.
Explains both Positive and negative symptoms.
Explains early, late neurodevelopmental and
neurodegenerative theories
Explains Dopaminergic & GABAergic abnormalities
29

30. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
30

31. Neurobiology –– wwhheerree aarree wwee hheeaaddiinngg ??????
Improvements in nosology - refine the Diagnostic
criteria – incorporate objective measure.
Incorporate neurobiological, neurochemical and and
electrophysiological findings.
 Large multinational studies to confirm/ refute
biomarkers
31

32. PPAARRTT 44

33. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
33

34. Schizophrenia – ffrroomm KKrraaeeppeelliinn ttoo DDSSMM--IIVV--TTRR
 Case descriptions resembling schizophrenia are there since few millennia,
but its definition as disease entity dates back to the mid-19th century.
 Unitary Psychosis (Einheits psychose) –
o German concept of 19th century, lasted till era of Kraeplin (1899).
o all forms of psychosis were surface variations of a single underlying
disease process.
o Unitary Psychosis – Joseph Guislain (1797–1860) – In 1833, he
published Traité Des Phrénopathies ou Doctrine Nouvelle des Maladies
Mentales
o Ernst 1837 – different varieties of mental illness were simply different
stages of a common psychiatric illness i.e Unitary psychosis.
Emphasised spiritual and psychological causes as the etiology
34

35. Schizophrenia – ffrroomm KKrraaeeppeelliinn ttoo DDSSMM--IIVV--TTRR
– Griesinger – As with Zeller, he postulated that melancholia
constituted the primary form of mental illness which then
passed to mania before terminating in dementia.
– Heinrich Neumann - In his book Lehrbuch der Psychiatrie
(Textbook of Psychiatry) of 1859 he proposed that, "There
is only one type of mental disorder. We call it madness
(Irresein).
– Insanity does not possess different forms but different
stages; they are called insanity (Wahnsinn), confusion
(Verwirrheit), and dementia (Blödsinn).
36

36. 19th-century critics ooff UUnniittaarryy ppssyycchhoossiiss
• Karl Kahlbaum –
– 1863 published Die Gruppierung der psychischen Krankheiten (The
Classification of Psychiatric Diseases)
– This text delineated four distinct types of mental illness (vesania):
vesania acuta, vesania typica, vesania progressiva and vesania
catatonica
– He asserted that the unitarian position signalled the "end to all
diagnosis in the field of psychopathology"
• Hecker (1871) – developed the concepts of hebephrenia and cyclothymia.
• These two didn’t agree with concept of Unitary Psychosis.
• Jean-Pierre Falret – in 1851 - published an article describing a condition
he called la folie circulaire (circular insanity),
37

37. 19th-century critics ooff UUnniittaarryy ppssyycchhoossiiss
 Kraepelin - (1899)
o Noted the similarities between catatonia, hebephrenia, and
paranoid dementia. Termed this group as DEMENTIA PRECOX
o He distinguished this group from folie circulaire (which he termed
manic depressive insanity) which was characterized by episodicity,
absence of deterioration, and a more favourable outcome.
o Course and outcome best distinguished psychiatric disease entities
o So he defined schizophrenia on the basis of its onset (in
adolescence or early adulthood), course (chronic and
deteriorating), and outcome (permanent and pervasive
impairment in mental functions)
38

38. 200tthh cceennttuurryy –– ddeeffiinniinngg sscchhiizzoopphhrreenniiaa
Eugen Bleuler – swiss psychiatrist
Coined term schizophenia in 1911
Delusion and Hallucinations were not the essential
symptoms
But disintegration of psychic functions was typical
Bleuler's 4 As – Loosening of association, Blunt
affect, Ambivalence, and Autism
39

39. 200tthh cceennttuurryy –– ddeeffiinniinngg sscchhiizzoopphhrreenniiaa
 Karl Jasper – (1946) described psychopathology
 Kurt Schneider (1959) defined 11 first-rank symptoms which he
considered pathognomonic of schizophrenia
 Three people gave definition of schizophrenia.
 Kraepelin - did not provide specific criteria for its diagnosis but
emphasized longitudinal course and outcome.
 In contrast, both Bleuler and Schneider provided specific cross-sectional
criteria.
 Current definitions of schizophrenia (in ICD-10 & DSM-IV-TR)
incorporate Kraepelin’s chronicity, Bleuler’s negative symptoms,
and Schneider’s positive symptoms,
40

40. 200tthh cceennttuurryy –– ddeeffiinniinngg sscchhiizzoopphhrreenniiaa
 By the 1960s, the Bleulerian viewpoint had become dominant in
the USA while the Kraepelinian and Schneiderian concepts broadly
prevailed in the rest of the world.
 ICD -8 & ICD –9 emphasized on positive symptoms, chronicity, and
poor outcome as defining features of schizophrenia
 The DSM-II defined schizophrenia it on the basis of “loss of ego
boundaries”.
 In DSM – III there was Marked changes in definition (narrow
definition) of schizophrenia.
 From DSM III to DSM III-R to DSM IV to DSM IV-TR the definition has
been gradually widened and currently both ICD 10 and DSM IV-TR
definitions are almost the same
41

41. 42

42. CCuurrrreenntt ccoonncceepptt ooff SScchhiizzoopphhrreenniiaa
Likely that schizophrenia is not a singular disease
entity and it has got many individual diseases.
There are several etiological & pathophysiological
processes appearing relevant to its development
Precise delineation of this constellation of distinct
“individual diseases” that are part of this entity is not
possible at present.
43

43. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
44

44. Clinical features –– PPoossiittiivvee SSyymmppttoommss
Delusions and hallucinations
Delusion –
o Varying degree of persistence, systematised, bizarre,
influence functioning
o Schindarian 1st rank symptoms (Delusion of control,
thought insertion, withdrawal and broadcasting )are
classically linked to schizophrenia
o Percecutory delusion and delusion of reference are most
common.
o Influenced by socio cultural background
45

45. Clinical features –– PPoossiittiivvee SSyymmppttoommss
Hallucinations –
o can occur in any of the five sensory modalities,
o auditory hallucinations are the most common.
o Schneiderian 1st rank symptoms Voices conversing among
themselves or commenting on the patient are
characteristic .
o But threatening voices speaking to the person are more
common.
Dopaminergic hyperactivity in mesolimbic tract causes
positive symptoms, which are most responsive to
antipsychotic medications
46

46. Clinical ffeeaattuurreess –– NNeeggaattiivvee ssyymmppttoommss
 Blunting or loss of a range of affective and conative functions.
o Abulia (loss of motivation)
o Alogia (poverty of speech)
o Anhedonia (inability to experience pleasure)
o Avolition (lack of initiative)
o Apathy (lack of interest), and
o Asociality (reduced social drive)
 Negative symptoms – can be either 10 or 20
 10 Negative symptoms may develop at Prodromal phase, psychotic-phase,
or in deteriorative phase.
 The pathophysiology of negative symptoms is poorly understood
 Relatively treatment-refractory and debilitating symptoms
47

47. Disorganization of tthhiinnkkiinngg aanndd bbeehhaavviioorr
 ‘Formal thought disorder’- fragmentation of the logical,
progressive, and goal-directed nature of normal thought process.
 Mild circumstantiality to tangentiality to incoherence and word
salad.
 Positive formal thought disorder – derailment and neologisms
 Negative formal thought disorder – poverty of thought content
 FTD - direct expression of loosening of association
 Seen in minority of schizophrenics.
 More prominent during acute exacerbations, relatively persistent,
and associated with poor outcomes.
48

48. MMoooodd ssyymmppttoommss
Depression is common in schizophrenia,
May be part of the prodrome, the florid phase, follow an
acute episode (postpsychotic depression)
more severe in those with comorbid substance use disorders
Several mechanisms contribute to development of depression
in schizophrenic illness-it is an integral part of the illness, its
appearance may correspond to the development of insight, it
can be due to another disorder such as major depression co-occurring
with schizophrenia, or it might reflect an adverse
effect of antipsychotic medications
49

49. Motor ssyymmppttoommss aanndd ccaattaattoonniiaa
Slowing of psychomotor activity is common in schizophrenia
is usually associated with negative and depressive symptom
clusters.
Excessive motor activity, often apparently purposeless, is
more often associated with exacerbations of positive
symptoms. Which can range from simple isolated movements
of posturing, mannerisms, and stereotypies to more complex
patterns of motion as observed in various catatonic states
catatonia can present as either stupor or excitement, and is
characterized by echolalia, echopraxia, automatic obedience,
waxy flexibility, and extreme negativism.
50

50. CCooggnniittiioonn
Cognitive impairments are highly prevalent
Cognitive deficit is of a generalized nature with additional
impairments in specific domains (i) episodic memory,
(ii)Processing speed, (iii)verbal fluency, (iv)attention,
(v)executive functions, (vi)working memory and (vii) social
cognition
Cognitive deficits are present even in the premorbid phase
Increase with the first psychotic episode
Only Modest partial improvement with antipsychotics
Cognitive Impairment - poor social & vocational outcomes
51

51. AAnnxxiieettyy
Anxiety is a prominent symptom early in the course of
the illness
But anxiety disorders are viewed as “comorbidity” with
rather than a clinical expression of schizophrenia.
This may be an artefact of our current nosological system
Anxiety disorders (in particular, comorbid social phobia,
obsessive–compulsive disorder, and panic disorder) are
common in schizophrenia and adversely impact outcome
52

52. IImmppaaiirreedd IInnssiigghhtt
 Most of the patients believe that they have no illness
 This correlates with the functional outcomes
MMiinnoorr PPhhyyssiiccaall aabbnnoorrmmaalliittiieess
 subtle morphological abnormalities of little functional or cosmetic
significance in the head, face, hands, or feet.
 Higher frequency among schizophrenics compared to general population
and mark developmental aberrations, reflect prenatal insults.
 They show no association with overall illness severity or any symptom
domain
 Exhibit some degree of familiality
 Dermatoglyphic abnormalities are consistently described in schizophrenia,
reflecting ectidermal origin
 Their precise relevance to schizophrenia is unclear. 53

53. Neurological signs: ““hhaarrdd”” aanndd ““ssoofftt””
“Hard” signs that reflect impairments in motor, sensory, or
reflex functions which are localizable
“soft” nonlocalizing deficits that do not implicate a specific
brain region.
hard neurological signs include hypoalgesia, impaired
olfactory function, and oculomotor abnormalities.
Olfactory Dysfuction - impairments in odor identification,
recognition, and discrimination; predicts episode in high risk
individuals, present in unaffected relatives as well, correlates
with severity of b=negative symptoms.
54

54. SSoofftt nneeuurroollooggiiccaall ssiiggnnss
Include impairments in motor dexterity, presence of primitive
reflexes or cortical release signs, difficulties in proper
sequencing of complex motor tasks, and deficits in sensory
integration.
Not specifically localizable but putatively implicate the
cerebellum, frontal lobe, prefrontal cortex, and the parietal
lobe respectively.
Correlate with cognitive, negative and disorganization
symptoms
leftward shift in handedness, with a greater prevalence of
left-handedness and mixed-handedness.
55

55. OOnnsseett aanndd ccoouurrssee
 Premorbid phase – subtle and nonspecific cognitive, motor and/or social
dysfunction
 Prodromal phase – attenuated positive symptoms declining function
 1st Psychotic episode – formal onset of schizophrenia,
 Initial decade of illness – repeated episodes with partial and variable
improvement
 First 5 years – most pronounced decline in functional capacity
 Stable phase or plateau – less prominent psychotic symptoms, more
prominent negative symptoms and stable cognitive deficits.
 Recovery of varying degrees occur at any stage of the illness unlike
Kraepelin’s perspective of progressive deterioration,
 Significant proportion of individuals with schizophrenia exhibit substantial
improvement
56

56. OOnnsseett aanndd ccoouurrssee
Demarcation between various phases of schizophrenia is
imprecise
The distinction between premorbid & prodromal symptoms is
based on the unproven assumption premorbid impairments
reflect precursors or risk factors but prodromal symptoms are
earliest manifestation.
Half of the patients in Prodrome phase do not go on to
develop schizophrenia
Onset of first episode – insidious or ill-defined
Psychotic manifestations are often not clearly episodic; and
there is enormous variation in the progression of the
57

57. PPrreemmoorrbbiidd pphhaassee
 Range of developmental behavioral, emotional and cognitive
problems,
 Premorbid impairments in academic and social function.
 Delays in motor development, attentional dysfunction, deficits in
receptive language, poor academic achievement, social isolation,
and emotional detachment
 Poor premorbid function is associated with an early age of onset of
psychosis and greater severity of negative and cognitive symptoms
during the illness.
 Symptoms during premorbid period may show pathophysiology of
schizophrenia, they are neither universally present in nor specific.
58

58. PPrrooddrroommee pphhaassee
 “Prodrome” – Period of time preceding the first onset of psychosis
 Subthreshold psychotic symptoms, along with cognitive deficits, negative
symptoms, mood symptoms, and decline in functioning
 May last from months to years, with a mean of ∼5 years.
 Positive symptoms accumulate for about 1 year prior to initial clinical
contact.
 Only 1/6th of patients having prodrome progress to schizophrenia
 Positive hope :- more severe positive symptoms and more social
impairment are more likely to develop an episode.
 But how to define “more severe positive symptoms” and “more social
impairment ” ….. ????????
 Various pharmacological psychological approaches tried in this group,
results are mixed.
59

59. Onset of illness and the initial ppssyycchhoottiicc eeppiissooddee
Defining the onset – difficult, due to variation in defination
For practical purposes – development of frank psychotic
symptoms mark the onset of episode.
Usual age of onset – between 15-45yrs of age
Early age of onset (b20 years) and a very early-onset (b13
years) manifest worse premorbid function, more severe
negative and disorganization symptoms, greater cognitive
deficits, and inferior overall prognosis
Substance use and life stressors can precipitate the episode
60

60. Onset of illness and the initial ppssyycchhoottiicc eeppiissooddee
Onset in females is 5-7 yrs later in females compared to males
Age-at-onset distribution is unimodal for men but bimodal for
women with a peak of 18–30 years for both genders but an
additional second peak later in life among females.
Compared to men, women have better premorbid
functioning, express more affective symptoms and less
negative symptoms, manifest less cognitive impairment, have
lower rates of completed suicide, respond better to
treatment, and have a better overall prognosis
61

61. Chronicity aanndd rreeccoovveerryy:: ppllaatteeaauu pphhaassee
Course – characterised by exacerbations and remissions, with
varying recovery between the episodes.
Exacerbations – triggered by stress, nonadherence to
treatment, substance abuse.
 Positive symptoms tend to become less severe and negative
symptoms more prominent.
Cognitive symptoms are generally stable
Mood symptoms vary in severity in partial association with
psychotic symptoms.
62

62. Chronicity aanndd rreeccoovveerryy:: ppllaatteeaauu pphhaassee
Approximately A quarter of patients exhibit full
psychopathological remission, and about half show social
remission which is in contrast to what kreaplin proposed
Untreated psychosis – biologically noxious (Unproven
hypothesis)
Duration of untreated psychosis – extent of deterioration
Following initial episodes – Plateau course reached with
stable deficits
Antipsychotics – do they modify long term course ???
63

63. OOuuttccoommee aanndd ccoommoorrbbiiddiittiieess
Outcome – variable. And influenced by many factors
Predictors of better outcome include acute onset of illness,
better premorbid function, superior cognitive function,
absence of substance abuse, female gender, and a later age
of onset
Individuals with schizophrenia exhibit increased mortality,
high risk of suicide, increased rates of a range of comorbid
medical and psychiatric illnesses, reduced likelihood of
employment, and impairments in quality of life
64

64. MMoorrttaalliittyy
Mortality rates double the general population
Lifespan is reduced by approximately 15–20 year
Causes for increased mortality
o Suicide – 25% cases
o Accidents – 10% cases
o General medical condition – Cardiovascular disease
Among males – suicide leading case of death
Among females – cardiovascular disease is leading cause
65

65. SSuuiicciiddee
 Approximately one-third attempt suicide one or more times.
 Risk of suicide highest early in the course of the illness, particularly
in association with better premorbid function and good insight
 Factors that increase the risk of suicide
o Coexisting depressive disorder,
o History of previous suicide attempts,
o Substance abuse, Male gender,
o Poor treatment adherence and response,
o Higher medical comorbidity,
o Akathisia
o Impulsivity.
 Clozapine reduces risk of suicide. 66

66. VViioolleenntt bbeehhaavviioouurr
Majority of individuals with schizophrenia are not
violent.
Disproportionately more likely to be victims of
violence.
Small statistically significant relationship exists
between schizophrenia and violent.
Severity of positive symptoms, comorbid substance
use and impulsivity explain this relationship
67

67. CCoommoorrbbiidd ppssyycchhiiaattrriicc ddiissoorrddeerrss
Anxiety and depressive syndromes – common
comorbidities
Social phobia - 20% , obsessive–compulsive disorder
- 15%, generalized anxiety disorder - 10%, and panic
disorder, specific phobic disorder, and post-traumatic
stress disorder 5% each.
Anxiety symptoms will need separate therapeutic
attention in most cases.
68

68. CCoommoorrbbiidd iinntteelllleeccttuuaall ddiissaabbiilliittyy
Approximately 3–5% of individuals with intellectual
disability have co-occurring schizophrenia and they
exhibit higher mortality rates and greater disability
than persons with schizophrenia alone.
69

69. CCoommoorrbbiidd ssuubbssttaannccee aabbuussee
 Strong association between schizophrenia and substance abuse present
and association is bidirectional.
 Substance abuse increases psychotic symptoms ; schizophrenia associated
with increased prevalence of substance use
 Distinguishing substance-induced psychosis from schizophrenia is difficult
particularly during the 1st episode of psychosis if substance use present.
 Alcohol, nicotine, and cannabis abuse are very common.
 They worsening of psychosis, and limit the effectiveness of antipsychotics.
 Cannabis acts as a risk factor for schizophrenia or atleast precipitates in
predisposed people.
 Nicotine dependence – 5 times more common among schizophrenic
patients compared to general population
70

70. MMeeddiiccaall ccoo--mmoorrbbiiddiittyy
 Contribute to about 60% of the excess mortality seen
 An increased prevalence of several comorbid medical conditions
 Under-recognition and inadequate treatment of comorbid medical
conditions
 Increased risk of cardiovascular disease (because of obesity,
hyperlipidemia, diabetes, smoking, sedentary life style, adverse effects of
some antipsychotic medications, and other factors)
 Under recognition or late recognition of the cardiovascular problem
(because of inadequate reporting of symptoms, poor access to medical
care, & reduced quality of actual medical care)
 Increased likelihood of complications of treatment (because of increased
vulnerability, poor quality of treatment, treatment interactions, and other
factors)
71

71. Lower risk ooff ssoommee mmeeddiiccaall iillllnneesssseess
Reduced occurrence of cancers, rheumatoid arthritis and type
1 diabetes mellitus among schizophrenics
May be due to common Etiological or pathophysiological
factor simultaneously increases the risk of schizophrenia
while decreasing the likelihood of cancer.
These findings may generate testable new hypotheses about
the etio-patho- physiology of schizophrenia.
72

72. Impact of schizophrenia on iinnddiivviidduuaall && ssoocciieettyy
Increased unemployment and homelessness
2/3rd of affected persons have never been married.
Significantly reduced quality of life.
Increased family burden
In comparison to families of patients with other chronic
diseases, families of patients with schizophrenia report higher
subjective and objective burden also lower support from the
social network and professionals
73

73. OOvveerrwwiieeww ooff pprreesseennttaattiioonn
From findings to facts of schizophrenia
What the known facts can tell us
Towards integration: from facts to models
Neurobiology of schizophrenia: way ahead
Evolution of the concept of schizophrenia from
Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
74

74. RReeccoonncceeppttuuaalliizziinngg sscchhiizzoopphhrreenniiaa
 It is premature to dump the very concept of schizophrenia,
 But we should discard the current construct, disassemble its
components, and reconstruct a more valid and meaningful entity.
 shortcomings with the current term of schizophrenia.
o First, its clinical manifestations are very diverse and this
heterogeneity is not explained with current term
o Second, schizophrenia is most likely not a single disease entity -
there are several etiological factors and pathophysiological
mechanisms.
o Third, its boundaries are ill-defined and it needs to be better
described and demarcated
75

75. Heterogeneity iiss tthhee pprroobblleemm ttoo bbee ssoollvveedd
 ICD-10 and DSM IV TR have provided us with the subtypes
 Subtypes are unstable over the course of illness, do not help in treatment
decisions, do not explain etiology or pathophysiology.
 So author advices to abandon these subtypes
 Alternative dichotomous approaches to subtype schizophrenia have been
proposed:
o Process v/s reactive
o good prognosis v/s bad prognosis,
o Early onset v/s late onset,
o Positive v/s negative,
o Developmental v/s Degenerative,
o Deficit v/s Nondeficit.
76

76. Heterogeneity iiss tthhee pprroobblleemm ttoo bbee ssoollvveedd
How to solve mystery of heterogeneity of schizophrenia?
Cross sectional heterogeneity in clinical expression may be
resolved by identifying distinct psychopathological
dimensions;
Etiological and pathophysiological heterogeneity may solved
by identifying clear pathways mapping to particular
phenotypic dimensions (or psychopathologic dimension)
Longitudinal heterogeneity in course may be understood by
studying the pathoplastic effects of development, aging, and
neural repair processes on particular stage of schizophrenia
77

77. Dimensions ooff sscchhiizzoopphhrreenniiaa aanndd
IInntteerrmmeeddiiaattee pphheennoottyyppeess
Schizophrenia - has range of dimensions (positive, negative,
disorganization, cognitive, mood, motor),
The severity and relative proportions vary across patients
and through the course of the illness.
These symptom dimensions, may actually reflect distinct etio-pathogenetic
processes.
78

78. Is sscchhiizzoopphhrreenniiaa oonnee ddiisseeaassee oorr mmaannyy??
o Clinical diversity due to pathophysiological and etiological
heterogeneity.
o Neither a single disease entity and nor is it a circumscribed
syndrome, likely to be a conglomeration of phenotypically
similar disease entities and syndromes.
o With current knowledge – difficult to demarcate these
separate entities.
79

79. Longitudinal heterogeneity && ssttaaggiinngg ooff iillllnneessss
The premorbid stage (stage 0)
o Varying degrees of risk for developing schizophrenia (based
on genetic features, environmental exposures, behavior, and
social function) but without any clinical evidence.
o The implication is that reducing the “psychosis load” may
decrease the risk of developing schizophrenia
o Reduce other risk factors or enhance protective factors.
o Population-level strategies would be of particular importance
in reducing overall risk
80

80. Longitudinal heterogeneity && ssttaaggiinngg ooff iillllnneessss
 The prodrome (stages Ia and Ib)
o Clinical expression of some of these risk factors (stages Ia) and the
manifestation of basic or sub-threshold psychotic symptoms (stages
Ib)
o A specified set of interventions may prevent the progression to
psychosis
o The prodrome represents a reversible stage in schizophrenia, with
stage Ia being less likely to devolve into schizophrenia than the later
stage Ib
o Antidepressant medications, GABA-ergic agents , cognitive behavior
therapy, and low-dose antipsychotics in the late prodrome may be
of particular utility in this stage of the illness.
81

81. Stage II
o indicates the prior occurrence of at least one full psychotic
episode without deterioration during remission.
o The implication is that although the threshold for psychosis
has been crossed, the deterioration generally associated with
schizophrenia has not occurred.
o Treatment at this stage can benignly “reshape the course” of
the psychotic disorder
82
Longitudinal heterogeneity && ssttaaggiinngg ooff iillllnneessss

82.  Stage III
o Denotes the appearance of inter-episode deficits in conjunction
with psychosis.
o The implication is that while some irreversible deficits associated
with schizophrenia have occurred, additional potentially
preventable deterioration can still occur and this warrants effective
control of psychosis to limit such deterioration.
 Stage IV (Fig. 3)
o Implies that substantial deterioration may have occurred and that
treatments can at best be symptomatic and rehabilitative.
83
Longitudinal heterogeneity && ssttaaggiinngg ooff iillllnneessss

83. 84