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SCHIZOPHRENIA JUST THE FACTS
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
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
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
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
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
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
We will review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
Under the neuroanatomical changes it has been found that the whole brain and grey matter volume is reduced and ventricular volume is increased
These Reductions are specially seen in temporal lobe structures, in particular the hippocampus (correlates with memory impairement), amygdala, and the superior temporal gyri ; also in prefrontal cortex and the thalamus,
Some studies have suggested excess of mixed handedness or reduction in cerebral assymetry in schizophrnia , and this is correlated with younger age at onset.
Some structural alterations such as basal ganglia volume increases have been found which has been correlated to treatment with typical antipsychotics.
These changes imply that there is some thing that has gone wrong with the devlopmental preocess.
In the previous slide we saw the grey matter alterations.. There are some White matter alterations as wel that are seen in schizophernia.. like reduction in corpus callosum fibers.. And this has been correlated with cognitive impairment seen in schizophrenia
In schizophrenia its Not just the number of neurons that is affected but also the connectivity between the neurons is also impaired. I mean not just the quantity, but also the quality of connections is impaired between the neurons, so how to study the quality of connections..??
This quality of connectivity can be studied using imaging studies like DTI (diffussion tensor imaging) { which measures the orientation of water diffusion along the axis of tissue elements, such as axons. }
Fractional anisotropy is one of the measures of the DTI which ranges from 0 (random diffusion) to 1 (unidirectional diffusion);
In schizophrenia FA is seen to be always reduced, specially in white matter tracts like corpus callosum, the cingulum, arcuate fasciculus, and the unicinate fascilulus.
The neuronal disconnectivity may be due to abnormalities in the ultrastructure of myelin sheaths.
This abnormality is found in white matter tracts like corpus callosum, the cingulum, arcuate fasciculus, and the unicinate fascilulus… this may be due to abnormalities in the myelin sheaths.
Neuregulin (NRG1) is one of the genes for oligodendrocyte development and function, so this has been implicated in schizophrenia..
Coming to the alterations in the brain functions..
If a schizophrenia patient is given a cognitive task, then the Dorsolateral prefrontal cortex doesn’t get activated as much as it does in controls.. This is called as hypofrontality..
But the interesting part is that if we control for the performance differences between schizophrenia patient and control then we see that the schizophrenia patients show more prefrontal activity for the similar level of performance… so this shows that the patients put a lot of effort but the response is reduced due to more background noise…
This reduced frontal activity is also seen in relatives of schizophrenics and also in patients who are in prodromal phase of illness, but to a lesser degree..
There are few genes which are implicated in this hypofrontality.. Eg include genes for catechol-O-methyltransferase (COMT) and the metabotropic glutamate receptor (GRM3).. These genes influence the prefrontal signal to noise ratio.
Not just the frontal lobe.. But even in temporal lobe the activation is not sufficient.. But the data is not as robust as it is available for frontal activation..
Suppose a person is receiving a uniform auditory stimuli.. And then v present a deviant stimuli which is different from the uniform auditory stimuli, then there is a prominent negative wave within 100 to 250 milliseconds after the deviant stimuli.
This is called as mismatch negativity, this represents pre-attentive stage and this is seen in the auditory sensory domain and is reduced in schizophrenia patients and their relatives.
This represents NMDA receptor dysfunction
Suppose a patient is receiving a train of repeated stimuli (some thing lik a background noise) then he receives a task relevant, novel stimuli. After around 300 milliseconds of novel stimuli there is a positive wave seen in EEG.. Which reflects that the patient is updating his working memory…
In Schizophrenia this P300 amplitude is consistently reduced… also the P300 latency is increased, suggesting an abnormality in working memory and attention.
Suppose a person receives a random auditory stimuli which is task irrelavent (not novel stimuli) then there is a positive wave on EEG after 50 milliseconds of stimuli this positive wave is called P50..… if the same stimuli is repeatedly given to that person.. Then generally the P50 amplitude decrease gradually.. Which shows that we normally neglect the task irrelavent stimli after repeated presentation of the same, because it is task irrelevant.. It is non significant… which is due to phenomena of sensory gating that occurs in Thalamus…
but in schiophrenia this doesn’t occur.. The P50 wave remains of the same amplitude even after repeated presentation of task irrelevant stimuli.. Which shows that sensory gating in impaired.. This also shows that the task irrelevant stimuli is given the same importance as the task relevant stimuli.. There is no filtering that should occur.
P50 deficits are correlated with abnormalities in alfa-7 nicotinic receptors, which also explains the high incidence of nicotine dependence.
Suppose v hear a sudden loud sound then v are going to have a startle reflex.... But if the same loud sound comes again for the second time after around 60-120 milliseconds then the startle reflex is muted.. This phenomena is called as prepulse inhibition..
But in schizophrenic patients this doesnot occur.. That is prepulse inhibition is reduced reflecting impaired sensory gating at thalamus… this is due to dysfunction of NMDA receptors
Normally, humans are able to capture the image of a moving object and maintain the image on the fovea even while the image continues moving. This is done through the pursuit eye movements..
In schizophrenia this smooth pursuit movement is impaired with abnormal “catch-up” saccades.
Pursuit deficits have been found to be related to reduced function in the extraretinal motion processing pathway
These pursuit abnormalities are both correlated with functioning of prefrontal lobe.
There are some sleep abnormalities seen in schizophrenia which include reduction in Total as wel as NREM sleep.. And increased wake time..
There is also reduction in stage 2 REM latency..
Sleep alterations in schizophrenia may differ from those in depression, {which is characterized by REM latency reductions and increases in REM density }
Usually the neuronal activity in the brain is synchronized which improves the communication with in and across different brain regions..
This Can be measured using EEG activity
this is abnormal in schizophrenia
This reduced synchrony is correlated with thought disorder, conceptual disorganization, visual hallucinations and attention deficits..
We saw the anatomical and physiological changes.. Now Coming to the neurochemical alterations seen in schizophrenia..
Magnetic resonance spectrosopy is the imaging method that helps us to evaluate the neurochemistry.
N-acetyl aspartate (NAA) and Membrane phospholipid (MPL) are the two important metabolites that are studied
N-acetyl aspartate (NAA), is considered as a marker of the formation and/or maintenance of myelin.. Where as membrane phospholipid (MPL) metabolites show the integrity of dendrites and synapse
In schizophrenia these two molecules are seen to be decreased which suggests that there is defective mylination and synapse formation… so the connectivity between the neurons is compromised
PME and NAA changes are also seen in offsprings, and even before the onset of illness, so might be used as a sort of marker after some years..
There are some neurotransmitter changes in schizophrenia.. Which we all know wel..
One of the key NT is Dopamine – its alteration is well known, and it is a Oldest theory which says that the dopamine excess leads to schizophrenia. This is based on the indirect evidence from D2 blokcing antipsychotics. This theory explained occurrence of positive symptoms but was not able to explain the cognitive and negative features of schizophrenia which are due to deficiency of dopamine in mesocortical tracts.
Glutamate is one more NT implicated in the causation of schizophrenia, it is proposed that in schizophrenia there is deficient glutamate mediated excitatory neurotransmission via NMDA receptors. This is supported by the fact that NMDA receptor antagonists like phencyclidine (PCP) and ketamine induce psychotic symptoms, both positive and negative symptoms. Post-mortem studies of schizophrenia patients have shown that NMDA receptor are decreased in prefrontal cortex and the hippocampus
Even GABA is also implicated in schizophrenia… and patients have consistently shown reduced levels of GABA in prefrontal cortex, so GABAa receptors may be upregulated as a compensatory response… and GABA levels correlate with impairment in working memory..
There are few more NTs implicated.. It is seen that the muscarinic receptors are seen to be decreased in schizophrenics.. Which suggests some abnormality with acetylcholine concentration.
Seratonin is also implicated.. Even though direct evidence of serotonergic dysfunction is lacking, the antipsychotics acting via 5HT2 , 3 and 6 suggest that seratonin might have a role to play in schizophrenia.
what are the neuroendocrinal changes seen in schizophrenia..
Among these HPA axis dysregulation is most common and very important alteration…
this can be measured using Dexamathosone suppression test.. which is negative in patients of schizophrenia.. That is the dexamethasone administration fails to supress cortisol levels.
Elevated cortisol levels correlate with greater symptom severity, impaired cognition and ventricular enlargement.. This also leads to decreased hippocampus size.
Post-mortem studies have shown that brain weight is reduced , ventricles enlarge, and there is loss of cerebral asymmetry
They also show Reduction in the number of dendritic spines. There's also a reduction in markers of axon terminals, such as synaptophysin.
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
So we finished with the anatomical, physiological and biochemical alteration of schizophrenia..
How do these facts help us
They Help us to understand the etiology,
These endophenotypes are midpoints between the genetic composition (i.e genome) and symptoms (phenome.)
they may help us identify the genes responsible for schiz..even though v have not traced the genes.. V may trace them with the help of these endophenotypes.
Is there any value of these biomarkers in the diagnosis of schizophrenia ???
As per (DSM-III R) a diagnosis of schizophrenia required that it cannot be established that an organic factor initiated and maintained the disease.. Which actually contradicts the whealth of evidence present at this point of time.. V can see that there are many candidate genes coming up and there are many anatomical, physiological and biochemical alterations in schizophrenia.. So its very much wrong to conclude that there is no organic cause…
So DSM-IV moved a bit away from this opinion of schizophrenia being a totally non organic condition... And viewed Schizophrenia as an idiopathic, or primary psychotic disorder rather than as a “non-organic” disorder as DSM-III R implied. And still they didnt had any of the biomarkers in the diagnostic categories.. And the diagnosis was entirely dependent on the phenomenology
The reason for non inclusion of biomarkers is that they are very expensive.. They are non specific, can be seen in bipolar & schizoaffective as well.. Non sensitive, not all the patients of schizophrenia show these signs.
So we need to identify robust biomarkers which can be used cost effectively in clinical setting and we need to incorporate these biomarkers, which can be one or more neurocognitive, neuroimaging or psychophysiological markers in the diagnostic criterias of schizophrenia and this will facilitate more objective and neuroscientifically based approaches to diagnosis.
These biomarkers May also help us to predict the variation in the course, outcome and treatment response.. At this point they do not do so.. But hoped to do so in future
There are some data to suggest that Prefrontal structural changes and neurochemical alterations help us predict the outcome after the first psychotic episode.
While these biomarkers promise us many things, but none of the biomarkers have found any strong foothold in clinical practice.. It is all still in the theory and nothing has influenced the clinical practice..
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
We just saw many many facts about schizophrenia.. They tell us that….. most of the research has consolidated the past facts that were known, with a bit of new knowledge added in neurobiology.
The research in schizophrenia has made progression from the study of crude measures such as 5-HIAA (indole acetic acid) and HVA(Homovanilic acid) (metabolites of serotonin and dopamine, respectively) in CSF to elucidation of specific circuits and receptors.
Now lets see how these facts have been integrated into some models,
These facts have helped us form some Pathophysiological models of schizophrenia (which explains us “what is exactly wrong” with the neurobiology in the illness)
Based upon the observation of antipsychotics efficacy, NEUROCHEMICAL theories were formed, which initially implicated DOPAMINE as the main reason but later on glutamate, GABA, seratonin were also implicated
Gradually with the advent of neuroimaging and neuropathological studies Neuroanatomical theories were formed, which implicated structural and functional alterations in brain as the basic pathophysiology.{ Examples include the alterations in association cortex, aberrant inter-hemispheric connectivity as evident by loss or reversal of hemispheric asymmetry, or corpus callosal alterations, Cortico–thalamic connections…}
These facts have also helped us to form some Theories of pathogenesis which have explain us nature and timing of pathology
Initially it was proposed that there is something wrong with neuronal migration and proliferation during developmental stages which were called as neurodevelopmental model
But later on people assumed that there is something wrong with the neuronal pruning.. That usually occurs in adoloscent age.. so they named it as model of developmental derailment ..
Then came neuroprogressive theories which were based upon neuronal excitotoxicity or neurochemical sensitization as the cause for the deterioration that is seen in schizophrenia
Based upon these facts we also have Etiological models which address the question of “why” these changes occur in schizophrenia
These models implicate genetic factors, abnormal gene expression and a multitude of environmental factors as the reason for schizophrenia.
So to summarise we saw many basic facts.. Then we saw the models which were deduced from these facts.. And these models are also many.. So which of these models in the right one???? That’s actually a difficult question to answer because each model explains a part of scizophrenia.. But not the whole thing.. .. So authors propose that we should integrate these individual models and come up with a model that explains most of the things..
So to summarise we saw many basic facts.. Then we saw the models which were deduced from these facts.. And these models are also many.. So which of these models in the right one???? That’s actually a difficult question to answer because each model explains a part of scizophrenia.. But not the whole thing.. .. So authors propose that we should integrate these individual models and come up with a model which can explain maximum facts on its own..
NMDA hypothesis is one such model which is most integrative theory.. was proposed in 1995, according to this theory the NMDA receptors are considered to be hypofunctional..
This theory has the power to explain most of the structural, functional and electrophysiological abnormalities..
This also explains both positive and negative symptom production..
This also Explains early, late neurodevelopmental and neurodegenerative theories.
This also explains Dopaminergic & GABAergic abnormalities seen in schizophrenia
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
So with so much of advances made in the neurobiology of schizophrenia where are we heading exactly..
Authors propose that we should make improvements in nosology and refine the diagnostic criterias to include objective measure.. After which we may be able to better identify the neurobiological processes..
Large multinational studies may have to be conducted that cofirm/refute the current hypothesis on biomarkers
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
Although case descriptions resembling schizophrenia go back a few millennia, its consideration as a disease entity dates back to the mid-19th century
Unitary Psychosis was the concept that was popular in 19th-century in German psychiatry.. It lasted till the era of Emil Kraepelin, this concept considered that all forms of psychosis were surface variations of a single underlying disease process. According to this, there were no distinct disease entities in psychiatry but they were only variants of a single universal madness and the boundaries between these variants were fluid.
Unitary Psychosis 1st described by German psychiatrisât named Joseph Guislain (1797–1860) – In 1833 in his book………………………. he proposed a complex system of psychiatric classification which had almost a hundred different mental states. He proposed that all the mental disorders arise from one of the 4 basic pathologies and all the disorders go through7 successive stages of progressive deterioration 1st of which is MANIA and the last one is DEMENTIA
Ernst Albrecht von Zeller – again a german psychiatrist - In 1837 he proposed that different varieties of mental illness were simply different stages of a common psychiatric illness i.e Unitary psychosis
Griesinger – German Psychiatrist - student of zeller - he postulated that melancholia constituted the primary form of mental illness which then passed to mania before terminating in dementia. This was his concept of unitary psychosis.
Heinrich Neumann - In his 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).
Karl Kahlbaum – German Psychiatrist, four distinct types of mental illness.. Among which catatonia was one of the types..
Hecker (1871) who was a student of Kahlbaum, worked with Kahlbaum and studied young psychotic patients and defined hebephrenia and cyclothymia.
These two peple didn’t agree with concept of unitary psychosis
Jean-Pierre Falret – a french psychiatrist he described a condition called as la folie circulaire (circular insanity), which is synonymous to current diagnosis of BPAD.
Kraeplin a germen psychiatrist - Noted the similarities between catatonia, hebephrenia, and paranoid dementia, concluded that all of them had adolescent or early adult onset, all had tendency to deteriorate over the period of time, and all ended with mental dullness or dementia, Termed this group as DEMENTIA PRECOX
He distinguished this group (which he called dementia praecox) from folie circulaire (which he termed manic depressive insanity) which was characterized by episodicity, absence of deterioration, and a more favourable outcome.
Kraepelin was of opinion that course and outcome best distinguished psychiatric disease entities
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)
Then came Eugen Bleuler – a swiss psychiatrist
He Coined the term schizophenia in 1911
According to Delusion and Hallucinations were not the essential symptoms
But disintegration of psychic functions was typical of schizophrenia..
He empasised on 4 As – Loosening of association, Blunt affect, Ambivalence, and Autism
Karl Jasper – (1946) described psychopathology and wrote a book on it
Kurt Schneider (1959) defined 11 first-rank symptoms which he considered pathognomonic of schizophrenia
so in total 3 people gave definitions 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 to diagnose schizophrenia.
Current definitions of schizophrenia (in ICD-10 & DSM-IV-TR) incorporate Kraepelin’s chronicity, Bleuler’s negative symptoms, and Schneider’s first rank symptoms..
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”.
Due to these factors there was descripency among the rates of diagnosis of schizophrenia between US and rest of the world
So what do the current concept of schizophrenia tel us..
It conveys that schizophrenia is not a single disease entity but a entity that has many individual diseases with distinct etiology, pathology and pathophysiology..
But at this point it is not possible to delineate these “individual diseases”
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
Positive symptoms include Delusions and hallucinations
Several different kinds of delusions can occur which can have varying degrees of persistence and systematization, and these influence the individual's functioning to varying degree.
although first-rank symptoms (delusions of control, thought insertion, withdrawal and broadcasting) all are traditionally linked to schizophrenia, most common once are delusions of reference and percecution
The content of delusion is influenced by the socio cultural background
Hallucinations can occur in any of the five sensory modalities, although auditory hallucinations are the most common. Voices conversing among themselves or commenting on the patient are considered characteristic (Schneiderian first-rank symptoms), but threatening or accusatory voices speaking to the person are more common.
although first-rank symptoms Voices conversing among themselves or commenting on the patient are characteristic of schizophrenia, most common once are threatening or accusatory voices speaking to the person
Negative symptoms involve a blunting or loss of a range of affective and conative functions.
Negative symptoms can be either 10 or 20 … 10 is intrinsic to the disease & 20 is due to neuroleptics, environmental deprivation or depression
Disorganised thinking leads to ‘Formal thought disorder’ refers to fragmentation of the logical, progressive, and goal-directed nature of normal thought process.
It can range in severity from the relatively mild circumstantiality and tangentiality to the more severe incoherence and word salad
Thought disorder can be positive as wel as negative
According to Bleuler (1911) FTD is direct expression of loosening of association
Even though described as pathognomonic by Bleular disorganised thinking is Seen in minority of schizophrenics and is also seen in few manics. So it is not senstive enough to diagnose schizophrenia.
Cognitive impairments are highly prevalent
MATRICS was the study done to assess the cognitive symptoms.
Cognitive deficits are present even in the premorbid phase of schizophrenia, they increase during the first episode of psychosis and then improve only partially with the treatment
Cognitive Impairment predicts poor social & vocational outcomes
“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.
Even Kraepelin (1919) and Bleuler (1911) both had noted the reduced sensitivity to pain in patients with schizophrenia which is nothing but hypoalgesia
a high prevalence of olfactory dysfunction in patients with schizophrenia, with impairments in odor identification,
recognition, and discrimination. Impairment of olfactory function has been found to predict likelihood of developing schizophrenia among individuals at high-risk, similar olfactory deficits are observed in first-degree relatives, and the severity of olfactory deficits has been found to be associated with the severity of negative symptoms
Now coming to the course of schizophrenia.. Usually patients of schizophrenia will have a premorbid phase with subtle and nonspecific cognitive, motor and social dysfunction
Next occurs the prodromal phase characterized by attenuated positive symptoms and declining functional capacity.
Then occurs the first psychotic episode which marks the formal onset of schizophrenia,
then the initial decade of schizophrnia is generally charecterised by repeated episodes of psychosis with partial and variable improvement.
The decline in functional capacity is most pronounced in the first five years after a first episode of psychosis
Then comes a stable phase or plateau, when psychotic symptoms are less prominent and negative symptoms with cognitive deficits become more prominent.
Coming to recovery part.. It can occur at any stage of the illness to a varying degree. Kraepelin had proposed that schizophrenia has invariably a deteriorative course ending up in mental dulllness or DEMENTIA… but that’s not true because significant proportion of patients show good improvement
Now coming to prodromal phase.. It is the period of the time that precedes the first psychotic episode.. During this period the patients will have subthreshold psychotic symptoms, along with cognitive deficits, negative symptoms, few mood symptoms, and decline in functional capacity.
Usally this lasts from few months to years.. On an average lasts 5 year
Then the positive symptoms starts appearing gradually.. And usually positive symptoms accumulate for one year before a psychiatrist is consulted
So v saw the stages of schizophrenia.. How it progresses through premorbid and prodromal stages.. So can v exactly predict if a person is going to develop a psychotic episode… no.. V cant.. Because only 1/6 of patients in prodromal stage go on to have a psychotic episode which is far too less..
But there is one positive hope in predicting the episode.. People with more severe positive symptoms and more social impairemnt are more likely to develop an episode.. But again the question is how to define that “more severe positive symptoms and more social impairemnt ” what is the exact cut offf… ??
Defining the onset of schizophrenic illness can be difficult because of variations in definition of onset (first sign of mental disturbance, first positive symptom, first evidence of social dysfunction, first clinical contact, or first hospitalization) and the usually continuous process of illness evolution from prodrome to overt psychosis
For practicle purpose the development of frank psychotic symptom like (hallucinations, delusions, disorganized speech or behavior, and negative symptoms) marks the onset of schizophrenia..
Substance use and life stressors can precipitate the episode, but no specific trigger identified so far.
Although the lifelong risk of schizophrenia is similar in men and women, the onset of the illness on average occurs about 5–7 years later in females
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
Classically, the course is characterized by exacerbations and remissions, with psychotic symptoms resolving to varying extents between these episodes across patients and through the course of the illness .
Psychotic exacerbations can be triggered by stress, nonadherence to treatment, or substance abuse.
As the illness progresses Positive symptoms tend to become less severe and negative symptoms more prominent over the long-term course of the illness.
Cognitive symptoms are generally stable over the course of the illness while mood symptoms vary in severity in partial association with psychotic symptoms.
What if we don’t treat the psychosis.. Is it going cause any harm to the patient ????..... Literature says yes.. Because untreated psychosis is considered to be noxious to neurons and results in progressive brain loss. And the Duration of untreated psychosis determines the extent of deterioration as wel.
Approximately A quarter of patients exhibit full psychopathological remission, and about half show social remission which is in contrast to what kreaplin proposed
Usually after the initial psychotic episodes – a Plateau course is reached when the patient will mostly have stable deficits.. But still sometime complete recovery do occur.
During the episodes of psychosis antipsychotics do improve functional outsome by improving the positive symptoms.. But do they really modify the long term course ???.. The answer to this remains unclear..
The extent of deterioration appears to be related, in part, to the duration of untreated psychosis
As discussed in previous slides Outcome in schizophrenia is variable, can range from full recovery to partial recovery to sever deficits
And this outcome is influenced by several factors like for example circumstances under which the illness started, characteristics of the illness, premorbid personality and functioning, available treatments, the social setting, and environmental factors.
The factors that predict better outcome in schizophrenia include acute onset of illness, better premorbid function, superior cognitive function, absence of substance abuse, female gender, and a later age of onset
Compared to General population Individuals with schizophrenia have got 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
Mortality rates in schizophrenia is double the general population
Lifespan of a schizophrenia patient is reduced by approximately 15–20 year
Causes for increased mortality include
Suicide – 25% cases
Accidents – 10% cases
General medical condition – Cardiovascular disease
Among males – suicide leading case of death
Among females – cardiovascular disease is leading cause
We often see pateints of schizophrenia ending up with an suicidal attempt.. It May be due to command hallucinations or some other reason..
This suicidal attempt is seen in Approximately one-third of patients of schizophrenia
Risk of suicide highest early in the course of the illness, and particularly if the patient had good premorbid functioning and good insight.
There are few factors that help us in predicting the risk of suicide which I have listed out..
Clozapine is known to decrease suicides..
In contratry to the popular belief of psychotic patients being violent..Majority of individuals with schizophrenia are not violent… infact they are more likely to be victims of violence
However, a small relationship does exists between schizophrenia and violent behaviour, it is statistically significant as wel.. It is dependent upon the severity of positive symptoms, comorbid substance use and impulsivity.
As per Literature incidence of schizophrenia is increased in patients of intellectual disability but not incidence of bipolar illness or unipolar depression,…so there is some correlation between intellectual disability and schizophrneia..
Approximately 3–5% of individuals with intellectual disability have co-occurring schizophrenia and they have got higher mortality rates and greater disability than persons with schizophrenia alone.
Coming to the comorbid substance abuse.. There is strong association between schizophrenia and substance use.. And the association is bidirectional..
So there is increased prevelence of substance use disorders in schizophrenics.. Also substance use increases the psychotic symptoms...
Suppose a patient comes with 1st episode of psychosis with substance use disorder starting before the onset of psychotic symptoms.. Then it becomes difficult to say whether that person is having primary psychotic disorder or it is substance induced psychotic disorder.. Which can be only decided upon long term folllow ups.
Among the different substances of abuse.. Alcohol, nicotin and cannabies are very common in schizophrenia.. They worsen psychosis and decrease effectiveness of antipsychotic drugs
Cannabies itself acts as a risk factor for schizophrenia or atleast it precipitates schizophrenia in predisposed individuals.
Nicotine dependence is 5 times more common in schizophrenia compared to general population..
Medical comorbidities play a very important role in deciding the mortality in schizophrnics.. As much as 60% of increased mortality risk is attributed to medical comorbidities.. There is increase prevalence of several medical conditions.. And these conditions tend to be not detected early and treated early..
Among the medical comorbidities… cardiovascular diseases appear to be most common in psychiatric partients, the reasons for it are varied which can be metabolic side effects of psychotropics, sedentary life, obesity hyperlipedimia.. These cardiovascular diseases are also detected late because of under reporting of symptoms, poor quality of health care received.. So there is incresed chances of having the complications..
There are some reports suggesting that occurrence of few medical conditions like Cancers, rheumatoid arthritis and type 1 diabetes mellitus may be lower in schizophrenia.
These findings may help us to identify a common etiologic or pathophysiologic factor that has led simultaneously to increased risk of schizophrenia while decreasing the likelihood of few medical conditions.
These findings actually lead us to generate new hypotheses about the etio-patho- physiology of schizophrenia, which can be tested and confirmed
So what is the impact of schizophrenia on society and the individual…
Schizophrenics are Lilly to be unemployed and homeless
2/3rd schizphrenia patients are unmarried.
Schizophrenis Significantly reduced the quality of life.
There is 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
review major findings from the domains of brain structure, chemistry, physiology and neuropathology
What the known facts can tell us about the etiology, pathology, treatment, prognosis..
Then we integrate these facts into models of etiology, pathophysiology and pathogenesis..
Neurobiology of schizophrenia: way ahead.. What all can be done ahead in this field in the future..
Evolution of the concept of schizophrenia from Kraepelin to DSM-IV-TR
Clinical features of schizophrenia
Reconceptualizing schizophrenia
Authors say that it is premature and early to dump the very concept of schizophrenia,
But we should definatly discard the current construct, dis - assemble its components, and reconstruct a more valid and meaningful entity.
There are few shortcomings with the current term of schizophrenia.
First, its clinical manifestations are very diverse and this heterogeneity is not explained with current term
Second, schizophrenia is most likely not a single disease entity - there are several etiological factors and pathophysiological mechanisms.
Third, its boundaries are ill-defined and it needs to be better described and demarcated
So its clear that current term SCHIZOPHRENIA has many shortcoming.. So how to reconceptualize it.. Heterogenesity of schizophrenia is one such shortcoming with schizophrenia that needs to b reconceptualised …
ICD-10 and DSM IV TR have provided us withnthe subtypes (which include paranoid, simple, catatonic, disorganised, undiffrentiated)
But there are problems with these subtypes they are unstable over the course of illness.. Person with paranoid features in current episode may have disorganised features in the next episode.. They do not guide clinician in deciding then treatment options, they so not explain any etiology or pathophysiology.
So author advices to abandon these subtypes, which has been done in DSM V.. And has adviced few dicotomus subtypes which have better clinical utility lik..
How to solve mystery of heterogeneity of schizophrenia?
Authors have given some suggestions to solve the basis behind the heterogeneity
They have suggested that Cross sectional heterogeneity in clinical expression, that is constellation of symptoms we see, may be resolved by identifying distinct psychopathological dimensions;
Then the Etiological and pathophysiological heterogeneity, may solved by identifying clear pathways mapping to particular phenotypic dimensions (or psychopathologic dimension)
The Longitudinal heterogeneity in course and outcome of schizophrenia may be understood by studying the effects of pathoplastic factors like development, aging, and neural repair processes on particular stage of schizophrenia.
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.
As we just saw schizophrenia is constellation of symptoms.. No two patients of schizophrenia are same.. And this clinical diversity can be because of pathophysiological and etiological heterogeneity..
So It is likely that schizophrenia not a single disease entity but is group of phenotypically similar disease entities or syndromes..
And With current knowledge it is difficult to demarcate these separate entities… may be when we map each psychopathologic dimension to a particular intermediate phenotype then we will be able to recognise these separate disease entities with distinct course and treatment options..