SCHIZOPHRENIA JUST THE FACTS

Schizoprenia Just the factsSchizoprenia Just the factsPart 3 & 4Part 3 & 4

Dr. B C MALATHESHJuniour Resident - 3

R. Tandon et al. / Schizophrenia Research 110 (2009) 1–23

M.S. Keshavan et al. / Schizophrenia Research 106 (2008) 89–107

Overwiew of presentationOverwiew of presentationFrom findings to facts of schizophreniaWhat the known facts can tell usTowards integration: from facts to modelsNeurobiology of schizophrenia: way aheadEvolution of the concept of schizophrenia from

Kraepelin to DSM-IV-TR Clinical features of schizophreniaReconceptualizing schizophrenia

2

Neuroanatomical correlatesNeuroanatomical correlates 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

White matter pathology and disconnectivityWhite matter pathology and disconnectivityWhite 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

Alterations in in vivo brain functionAlterations in in vivo brain function 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

Alterations in brain physiologyAlterations in brain physiologyMismatch negativity (MMN)P300 event-related potentials (ERP)P50 DeficitPre-pulse inhibition (PPI)Eye movement (EM) abnormalitiesSleep abnormalitiesAlterations in neural synchrony

6

Mismatch negativity (MMN)Mismatch negativity (MMN)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

P300 Evoked PotentialP300 Evoked PotentialThis 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

Sensory Gating (P50) DeficitSensory Gating (P50) DeficitIn 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

Pre-pulse inhibition (PPI)Pre-pulse inhibition (PPI)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

Eye movement (EM) abnormalitiesEye movement (EM) abnormalitiesNormally, 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

Sleep abnormalitiesSleep abnormalitiesReductions 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

Neural Synchronization DeficitsNeural Synchronization DeficitsFrequently the neuronal activity is synchronized in

brain and this is a means of communication within and across brain regions.

Can be measured using EEG activityThis is Reduced in schizophreniaReduced synchrony is correlated with thought

disorder, conceptual disorganization, visual hallucinations and attention deficits .

13

Neurochemical alterations – in vivo studiesNeurochemical alterations – in vivo studies 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

Neurochemical alterations – Neurochemical alterations – NeurotransmitterNeurotransmitter Dopamine –

o Oldest theory, much of evidence indirecto 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

Neurochemical alterations – Neurochemical alterations – NeurotransmitterNeurotransmitter Gamma amino butyric acid (GABA)

o Reduced levels of GABA in prefrontal cortexo GABAa receptors are upregulated o Correlated with impairment in working memory.

Other Neurotransmitterso decreases in muscarinic receptors o direct evidence of serotonergic dysfunction is lacking, but

different serotonin receptors play important role in treatment of schizophrenia.

16

Neurochemical alterations – NeuroendocrineNeurochemical alterations – NeuroendocrineHPA axis dysregulation is commonDexamethasone non-suppression - significantly

higher in schizophrenicsElevated cortisol levels - greater symptom severity,

impaired cognition and ventricular enlargementElevated cortisol levels - decrease hippocampus size

17

Neuropathological changesNeuropathological changesPost-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

What do the facts tell usWhat do the facts tell usHelp us elucidating the etiologyThese 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

Value of biomarkers in diagnosisValue of biomarkers in diagnosis 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

Value of biomarkers in predictionValue of biomarkers in predictionMay help us chart the phenotypic variation in the

course, outcome and treatment responsePrefrontal structural and neurochemical alterations –

predict outcome after the first psychotic episode.Many promises but nothing in clinical practice.

23



24

Towards integration: from facts to modelsTowards integration: from facts to modelsPast observations consolidated and new additions in

neurobiologyProgression from crude measures like 5-HIAA and

HVA (metabolites of serotonin and dopamine, respectively) to specific circuits and receptors.

25

Pathophysiological model Pathophysiological model 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

Theories of pathogenesisTheories of pathogenesisNeurodevelopmental models – aberrant neuronal

migration and proliferationDevelopmental Derailment models – aberrant

synaptic pruning around adolescenceNeroprogressive theories – based upon neurotoxicity

27

Etiological modelsEtiological modelsVariously posit the role(s) of genetic factors,

abnormal gene expression, and a multitude of environmental factors.

28

NMDA hypothesisNMDA hypothesisProposed in 1995, NMDA receptors are hypofunctionalMost Integrated theory.Most consistent with the structural, functional and

electrophysiological abnormalities.Explains both Positive and negative symptoms.Explains early, late neurodevelopmental and

neurodegenerative theoriesExplains Dopaminergic & GABAergic abnormalities

29



30

Neurobiology – where are we heading ???Neurobiology – where are we heading ???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

PART 4PART 4



33

Schizophrenia – from Kraepelin to DSM-IV-TRSchizophrenia – from Kraepelin to DSM-IV-TR 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

– 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).

Schizophrenia – from Kraepelin to DSM-IV-TRSchizophrenia – from Kraepelin to DSM-IV-TR

36

19th-century critics of Unitary psychosis19th-century critics of Unitary psychosis• 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

19th-century critics of Unitary psychosis19th-century critics of Unitary psychosis 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 entitieso 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

2020thth century – defining schizophrenia century – defining schizophreniaEugen Bleuler – swiss psychiatristCoined term schizophenia in 1911Delusion and Hallucinations were not the essential

symptomsBut disintegration of psychic functions was typicalBleuler's 4 As – Loosening of association, Blunt

affect, Ambivalence, and Autism

39

2020thth century – defining schizophrenia century – defining schizophrenia 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

2020thth century – defining schizophrenia century – defining schizophrenia 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

Current concept of SchizophreniaCurrent concept of SchizophreniaLikely 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



44

Clinical features – Positive SymptomsClinical features – Positive Symptoms 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

Clinical features – Positive SymptomsClinical features – Positive Symptoms 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

Clinical features – Negative symptomsClinical features – Negative symptoms 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

Disorganization of thinking and behaviorDisorganization of thinking and behavior ‘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

Mood symptomsMood symptoms 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

Motor symptoms and catatoniaMotor symptoms and catatonia 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

CognitionCognition 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

AnxietyAnxietyAnxiety is a prominent symptom early in the course of

the illnessBut 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

Impaired InsightImpaired Insight Most of the patients believe that they have no illness This correlates with the functional outcomes

Minor Physical abnormalitiesMinor Physical abnormalitiesMinor Physical abnormalitiesMinor Physical abnormalities 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

Neurological signs: “hard” and “soft”Neurological signs: “hard” and “soft” “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

Soft neurological signsSoft neurological signs 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

Onset and courseOnset and course 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

Onset and courseOnset and course 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

Premorbid phasePremorbid phase 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

Prodrome phaseProdrome phase “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

Onset of illness and the initial psychotic episodeOnset of illness and the initial psychotic episode 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

Onset of illness and the initial psychotic episodeOnset of illness and the initial psychotic episode 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

Chronicity and recovery: plateau phaseChronicity and recovery: plateau phase 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

Chronicity and recovery: plateau phaseChronicity and recovery: plateau phase 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

Outcome and comorbiditiesOutcome and comorbidities 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

MortalityMortality Mortality rates double the general population Lifespan is reduced by approximately 15–20 year Causes for increased mortality

o Suicide – 25% caseso Accidents – 10% caseso General medical condition – Cardiovascular disease

Among males – suicide leading case of death Among females – cardiovascular disease is leading cause

65

SuicideSuicide 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 Akathisiao Impulsivity.

Clozapine reduces risk of suicide.

66

Violent behaviourViolent behaviourMajority 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

Comorbid psychiatric disordersComorbid psychiatric disordersAnxiety and depressive syndromes – common

comorbiditiesSocial 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

Comorbid intellectual disabilityComorbid intellectual disabilityApproximately 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

Comorbid substance abuseComorbid substance abuse 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

Medical co-morbidityMedical co-morbidity 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

Lower risk of some medical illnessesLower risk of some medical illnesses 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-pathophysiology of schizophrenia.

72

Impact of schizophrenia on individual & societyImpact of schizophrenia on individual & society 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



74

Reconceptualizing schizophreniaReconceptualizing schizophrenia 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

Heterogeneity is the problem to be solvedHeterogeneity is the problem to be solved 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 reactiveo 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

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

Heterogeneity is the problem to be solvedHeterogeneity is the problem to be solved

Dimensions of schizophrenia and Dimensions of schizophrenia and Intermediate phenotypesIntermediate phenotypes

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

Is schizophrenia one disease or many?Is schizophrenia one disease or many?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

Longitudinal heterogeneity & staging of illnessLongitudinal heterogeneity & staging of illness 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

Longitudinal heterogeneity & staging of illnessLongitudinal heterogeneity & staging of illness 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

Stage IIo 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 & staging of illnessLongitudinal heterogeneity & staging of illness

Stage IIIo 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 & staging of illnessLongitudinal heterogeneity & staging of illness

SCHIZOPHRENIA JUST THE FACTS

Health & Medicine

Transcript of SCHIZOPHRENIA JUST THE FACTS