Schizophrenia

Schizophrenia –
Recent Updates
14th
January, 2015

Methodology of Literature Review
 Search Terms
– Different combinations of following terms:
‘schizophrenia’, ‘psychosis’, ‘recent updates’, ‘changes in
classification’, ‘community interventions’, ‘psychosocial’,
‘epidemiology’, ‘genetics’, ‘neurobiology’, ‘treatment’,
‘phenomenology’, etc. were used
 Search Engines
– PubMed, Google Scholar, Cochrane
 Time Period
– Last 7 years (2008 to 2014)
 Books Reviewed
– Comprehensive Textbook of Psychiatry, 9th
Edition;
Advances in Schizophrenia Research, 2009
Ms. Jinu Abraham, IMHANS, Calicut 2

Presentation Outline
 Introduction
– Definition
 Changing Classifications
– DSM-V
– Major Changes
– Research Domain Criteria
 Phenomenology
– Delusions
– Hallucinations
– Negative Symptoms
 Epidemiological Aspects
– Global Burden of Illness
– Burden of Illness
– Treatment Gap
– Issues in Epidemiological
Studies
– Cross Cultural Aspects
– Migration
 Neurobiology
– Genetics
– Epigenetics
– Neurobiology
– Imaging Research

Presentation Outline…contd
 Interventions
– Prevention Strategies
– Early Phase Interventions
– Pharmacotherapy
– Introduction to
Antipsychotics
– Newer Antipsychotics
– PORT Treatment
Recommendations
– Adjunctive Pharmacological
Agents
– M.A.T.R.I.C.S.
– Psychosocial Interventions
– Community Interventions
 Course and Outcome
– Deficit Syndrome
– Co-morbidities

INTRODUCTION

Definition
“Schizophrenia is characterized by disordered
cognition, including a “gain of–function” in
psychotic symptoms and a “loss of–function” in
specific cognitive functions, such as working and
declarative memory, but without the progressive
dementia that characterizes classical
neurodegenerative disorders.”
- (CTP, 9th
Ed.)

CHANGING CLASSIFICATIONS

DSM-V
 Schizophrenia Spectrum and Other Psychotic
Disorders
 Criteria A: Characteristic Symptoms
– Two (or more) of the following, each present for a
significant portion of time during a one-month
period (or less if successfully treated). At least one
of these should include 1-3
1. Delusions
2. Hallucinations
3. Disorganized Speech

DSM-V…contd
4. Grossly Disorganized or Catatonic Behavior
5. Negative Symptoms (i.e. diminished emotional
expression or avoilition)
 Criteria B: Social/Occupational Dysfunction
 Criteria C: Duration of 6 Months
 Criteria D: Schizoaffective and Mood Disorder
exclusion
 Criteria E: Substance/General Medical Condition
exclusion

DSM-V…contd
 Criteria F: Relationship to Global Developmental
Delay or Autism Spectrum Disorder
– If there is a history of autism spectrum disorder or
other communication disorder of childhood onset,
the additional diagnosis of schizophrenia is made
only if prominent delusions or hallucinations are
also present for at least one month (or less if
successfully treated).

Major Changes
 Elimination of bizarre delusions and Schneiderian
‘first-rank’ hallucinations
 Clarity regarding negative symptoms
 Requirement of minimum two characteristic
symptoms
 Elimination of subtypes and psychopathological
dimensions
 Distinction of course specifiers
 Harmonization with ICD 11
– (Tandon, et al., 2013)

Research Domain Criteria
 Current diagnostic system not informed by
breakthroughs in genetics and molecular, cellular and
systems neuroscience
 RDoC project (NIMH):
– “Develop, for research purposes, new ways of
classifying mental disorders based on dimensions of
observable behavior and neurobiological measures”
 Interfaces with genomics, neuroscience and
behavioral science explicating etiology and
suggesting new treatments
- (NIMH, 2014)

PHENOMENOLOGY

Delusions
 Cognitive models of positive psychotic symptoms
- (Garety, Kuipers, Fowler, Freeman, & Bebbington, 2001)
(Freeman, et al., 2008)

Delusions…contd
 50% variability in levels of paranoia in population
is due to genes
- (Zavos, et al., 2014)
 Worry plausible factor in occurrence of paranoid
thinking
– Worry Intervention Trial
- (Freeman, et al., 2012 & Freeman, et al., 2014)

Delusions…contd
 Interpersonal sensitivity –
– ‘feeling vulnerable in the presence of others due to the
expectation of criticism or rejection’
High in patients with persecutory delusions and those at high
risk of psychosis
- (Bell & Freeman, 2014; Freeman, Pugh, Vorontsova, Antley, & Slater, 2010 & Masillo, et
al., 2012)
 Higher levels of paranoia associated with less analytic,
experiential and rational reasoning
– ‘Belief inflexibility’
Failure to consider alternative explanations, resistance to
hypothetical contradiction
- (Freeman, Evans, & Lister, 2012, Freeman, Lister, & Evans, 2014 & So, et al.,
2012)

Hallucinations
 Occurring in 60%–70% of people with schizophrenia,
auditory hallucinations most common
 Also, occurs in 15% of healthy population
– (Boksa, 2009)
 Neurophysiological approaches to study auditory
hallucinations
– Assessments of State
– Assessments of Trait
– Mechanistic Studies of Trait
– (Ford, et al., 2012)

Hallucinations…contd
 International Consortium on Hallucination
Research [InCoHR]
– Contribution of disease-related process
– Novel theoretical cognitive framework
– Neurobiological substrates
– Hallucination-related alterations in
neurophysiology
– Review of different treatment options
– (Waters, 2012)

Negative Symptoms
 Consensus statement 2006 (NIMH) suggest five categories of
negative symptoms
– Avolition
– Anhedonia
– Affective blunting
– Social withdrawal
– Alogia
- (CTP, 9th
Ed.)
 Limitations of current instruments
– Item content, outdated; does not incorporate contemporary
research findings
– Reflects conceptually distinct domains that are not necessarily
part of negative symptom domain
– Include behavioral referents of what are essentially experiential
deficits
– (Blanchard, et al., 2011)

Negative Symptoms…contd
 Collaboration to Advance Negative Symptom
Assessment in Schizophrenia
– Inclusive development process
– Scale refinement in iterative data-driven process
 Initial test
– Good reliability
– Excellent convergent validity
– Discriminant validity
– (Forbes, et al., 2010)

EPIDEMIOLOGICAL ASPECTS

Global Burden of Illness
 Disability-adjusted life year (DALY)
– 1 DALY = 1 year of healthy life lost in given
population, due to combined effects of disability
and premature mortality
– (Whiteford et al., 2013)

Global Burden of Illness…contd
 In 2010, mental and substance use disorders
accounted for 183.9 million DALYs or 7.4% of all
DALYs worldwide
– Schizophrenia 7.4%

Burden of Illness
 Life expectancy decreased (15-12 years)
– long-lasting negative health habits
– disease- and treatment-related metabolic disorders
– increased frequencies of cardiovascular diseases
 Co-existing depression - adverse consequence on course,
progression, morbidity and mortality
 Cognitive impairment
 Social impairment
– Stigmatisation
– Lack of corresponding awareness within professional and
social spheres
 Considerable caregiver burden
– (Millier, et al., 2014)

Treatment Gap
 Treatment Gap for Schizophrenia, including non
affective psychoses, across the world – 32.2%
- (WHO, 2004)
 Systematic World Psychiatry Association Survey
suggest strategies to reduce gap:
– Task shifting to non-specialist providers
– Increase in specialist mental health resources to provide
effective and sustained supervision and support
– Decentralization of specialized mental health resources
– (Tempier, et al., 2010)

Issues in Epidemiological Studies
 Incidence
– estimated annual number of first-onset cases in
defined population per 1,000 persons at risk
 Objective biomarkers lacking, onset defined
– point in time when clinical manifestations become
recognizable and can be diagnosed according to
specified criteria
 Data on incidence and outcome scarce, especially
in LAMICs
– (CTP, 9th
Ed.)

Cross Cultural Aspects
 WHO undertaken three multi-country
epidemiological studies
– Determine prevalence, cultural expression, natural
history and outcome at multiple sites throughout
industrialized and developing world
 International Pilot Study of Schizophrenia (IPSS)
– Nine countries
– Prevalence roughly equal in all sites
– Better outcome in developing countries
– (WHO, 1973)

Cross Cultural Aspects…contd
 International Study of Schizophrenia (ISoS)
– Incorporated IPSS and DOSMeD cohorts
– Findings consistent, outcome differentials favor
developing countries, remained robust
– (Hopper &Wanderling, 2000)
 Acute onset and catatonic subtype more common
in traditional rural communities
– Over-diagnosis in developing countries?
• Organic psychoses (tropical communicable diseases,
TLE), ATPD, culture-bound syndromes and
affective disorders
– (CTP, 9th
Ed.)Ms. Jinu Abraham, IMHANS, Calicut 28

Migration
 High incidence rate (6.0 per 1,000) found in
African Caribbean population in UK
– Includes second generation migrants also
– No excess morbidity in indigenous populations
 “Horizontal” increase in risk
– Environmental factor boosting penetrance of
predisposing genes carried?
 Psychosocial hypotheses are being explored
– (CTP, 9th
Ed.)

NEUROBIOLOGY

Genetics
 High heritability, upto 80%
- (Sullivan, et al, 2003)
 Genome-wide association studies state increased risk
with NRGN and 2NF8044 genes
Common genes, small effect
Rare genes, large effect
Environmental factors and
gene-environment interactions

Epigenetics
 Gene environment interactions
 Proven results on interaction between cannabis use
and AKT1 gene on risk of psychosis
- (Di Forti, et al, 2012)
 Inconsistent associations
– fetal hypoxia and hypoxia-related genes on volume of
hippocampus
– childhood trauma and variants of serotonin transporter on
cognitive functioning
– childhood trauma and COMT gene on cognitive
functioning

Neurobiology
 Nuanced role of dopamine,
pointing to importance of
other neurotransmitters
 Hypofunction of NMDA
glutamatergic receptor
 Glutamate models explain
cognitive symptoms

Neurobiology…contd
 Abnormal maturation of
prefrontal networks
– Pre-post synaptic
abnormalities in inhibitory
neurons disturb
neurodevelopmental
processes
 Cognitive deficits
– Disturbance in myelination
and inhibitory control of
synaptic pruning

Neurobiology…contd
 Exposure to infectious or inflammatory agents in
utero
– Oxidative stress elevated in schizophrenia
 Autoimmune dysfunction
– Immune system activation (cytokines elevation, etc.)
seen in psychoses
– Anti NMDA-receptor encephalitis -
– Auto-antibodies- neuronal proteins
– Bi-directional association with common autoimmune
diseases
- (Song, et al, 2013; Finke, et al, 2012; Zandi, et al, 2011; Benros, et al, 2012)

Imaging Research
 Conceptualizes
schizophrenia as disorder of
brain connectivity
– Subtle structural alterations
– enlargement of third and
lateral ventricles
– reductions in whole-brain
gray matter volume
– reductions in temporal,
frontal and limbic regions
- (Shepherd, et al, 2012)

Imaging Research…contd
– Reduced activation of
dorsolateral prefrontal cortex
during tasks of executive
function
– (Minzenberg, et al, 2009)
– White matter changes in
frontal and temporal lobes
that imply decreased
connectivity
- (Yao, et al, 2013)

 Challenge: Translate neuroimaging findings into
clinical settings
 Search for Biomarkers
– Research underway to integrate imaging
modalities with genetic electrophysiological and
clinical data

INTERVENTIONS

Prevention Strategies
 No scientically established interventions for
primary prevention
– (Brown, A. S., & McGrath, 2011)
 Apart from positive family history, our ability to
identify those at-risk currently poor
 Reducing risks of obstetric complications
 New Scales
– Bonn Scale for the Assessment of Basic Symptoms

Early Phase Interventions
 Ultra High Risk State
– Attenuated positive and negative symptoms
– several years to months before schizophrenia
 Approx. 35% convert to schizophrenia
- (Ruhrmann, et al, 2010)
 Neuroanatomical, neurophysiological,
neurocognitive and neurohormonal changes
Changes proximal to onset of psychosis
Early recognition and intervention targeted to
pathophysiological processes needed

Early Phase Interventions…
 UHR
– Psychosocial intervention or supplementation with
eicosapentaenoic acid
– Pharmacological approach if needed (aripiprazole
best choice)
 FEP
– Both psychosocial and pharmacology
– Second generation antipsychotics

Early Phase Interventions…
 CPEP
– Minimize risk of relapse and disability, maximize
social and functional recovery
– Focus on
Maximizing chances of treatment engagement
Continuity of care
Appropriate lifestyle
Family support
Vocational recovery and progress

Introduction to Antipsychotics
 Antipsychotic drugs mainstay of treatment
– Adverse effects and suboptimal outcomes led to
development of second-generation antipsychotics
(SGAs)
 CATIE (Clinical Antipsychotic Trials in Intervention
Effectiveness); CUtLASS (Cost Utility of the Latest
Antipsychotic drugs in Schizophrenia Study)
Except for adverse effects as a reason for
discontinuation, differences minimal
do not markedly differ from FGAs regarding
compliance, quality of life and effectiveness

Newer Antipsychotics
 Introduced since 2007
Paliperidone (Invega, Ortho-McNeil-Janssen),
Iloperidone (Fanapt, Vanda)
Asenapine (Saphris, Organon)
Lurasidone (Latuda, Sunovion)

PORT Treatment Recommendations
 Schizophrenia Patient Outcome Research Team
(PORT)
– Strong empirical support for FGAs and SGAs in
acute and maintenance treatment
– Clozapine for treatment-resistant positive
symptoms, hostility and suicidal behaviors
- Kreyenbuhl, et al, 2011

Adjunctive Pharmacological Agents
 Agents stimulating NMDA glutamate receptor
may ameliorate negative symptoms
- Patil, et al, 2007
 Information on use of adjunctive pharmacological
agents and treatment of co-occurring substance
abuse
 Pro-cognitive medications
– dopaminergic, nicotinergic, glutamatergic,
GABAergic and other novel targets
– Larger, more rigorous studies needed

M.A.T.R.I.C.S.
 Current antipsychotics little or no effect on
negative symptoms and cognitive impairment
 Measurement and Treatment Research to Improve
Cognition in Schizophrenia (MATRICS)
– Development of consensus for measuring
cognition in clinical trials
– NIMH-FDA consensus on trial design
– FDA advice regarding path to drug approval
– Recommendations for promising molecular targets

Psychosocial Interventions
 Unmet needs to be assessed in evaluation
– Healthcare Needs: Complications and Co-
morbidities
–Related to negative symptoms
–Adverse effects of medication
–Substance abuse
–Life style issues
–Medical problems
–Compliance issues

Psychosocial Interventions…contd
 Psychosocial and Economic Needs
– Differ according to socio-cultural environment
– Daily activities, need for company and intimate
relationships affected by stigma and social
exclusion
– Patients using long term services require
Promotion of independence
Stability in social networks
Consistency of care
Addressing theme of loss

Functional Recovery
 Objective dimensions of recovery
– remission of symptoms and patient’s return to
socio-occupational functioning
– BPRS and PANSS
 Subjective dimensions of recovery
– life satisfaction, hope, knowledge about illness,
and empowerment
– Liberman, et al, 2002

Therapy
 4 treatments focused on, all differ in their
selection of treatment targets
– Social Skills Training
– Cognitive Behavioral Therapy
– Cognitive Remediation
– Social Cognition Training

Social Skills Training
 Has well established history but…
 Outcome domains of earlier studies affected by
multiple variables
 Kurtz and Mueser (2008), suggest SST affects:
– Social skills knowledge
– Social and daily living skills
– Functioning in community
– Relapse

Cognitive Behavior Therapy
 Faulty cognitive appraisal + Early learning
experience = Negative mood states
 Core Components
– Engagement and assessment
– Coping enhancement
– Developing shared understanding of experience of
psychosis
– Working of delusions and hallucinations
– Addressing mood and negative self evaluations
– Managing risk of relapse and social disability
- Garety, et al, 2000

Cognitive Behavior Therapy…contd
 Small to medium effect on:
– Treatment of positive and negative symptoms
– Mood
– Community functioning

Cognitive Remediation
 Treatment of cognitive deficits characterized by two
approaches:
– Cognition enhancing
– Compensatory
 Cognition enhancement approach based on
neuroplasticity model of brain development
– Cognition enhancement training
– Cognitive remediation therapy
– NEAR approach
Pre-post training gains noted in global cognition,
executive, occupational and social functioning

Cognitive Remediation…contd
 Compensatory approach targets functional deficits
but with consideration of cognitive impairments
– Errorless training
– Cognitive adaptation training
Improvements noted in error elimination,
medication and appointment adherence, grooming
and hygiene, care of living space and leisure and
social activities

Social Cognition Training
 Social cognition defined as,
– “the ability to construct representations of the relations
between oneself and others, and to use those
representations flexibly to guide social behavior”
- Adolphs R., 2011
 Deficits in areas of:
– Affect perception
– Social perception
– Attributional style
– Theory of mind

Social Cognition Training…contd
 2 types of studies
– ‘broad treatment’, embeds SCT within multi-
component training packages
– ‘targeted treatment’, employs SCT to target social
cognition
 Social Cognitive and Interpersonal Training found
to improve social networks and cause fewer
aggressive incidents

Community Interventions
 Assertive Community
Treatment
 Banyan Model
 Community Psychiatry

COURSE AND OUTCOME

Prognosis
 10% commit suicide
 Deficit Syndrome
– Multiple negative symptoms + careful history
suggesting enduring symptoms
– Poor prognosis regarding full functional recovery
– CTP, 9th
Ed.

Cannabis Use
 Psychoactive constituent delta-9-THC
– produces euphoric high, feeling of relaxation and
intensification of sensation, can cause some short-
lived schizophrenic symptoms
– (D’Souza, 2009)
 Reduction in cannabis use
– Currently no evidence for any psychological
therapy or medication, being better than standard
 Results of review limited as trial sizes were small
and data poorly reported

Smoking
 Among mentally ill, smoking prevalence highest
in Schizophrenia (approx 70-80%)
 Ill effects
– Financial burden
– Smoking-related morbidity and mortality
 Not just ‘bad habit’ but self medication of clinical
symptoms and side effects of antipsychotic drugs

Conclusions
 Current understanding of schizophrenia has
expanded dramatically in last two decades
 Research in the neurobiology has led to questions
regarding the essential aspects of the diagnosis
itself
 More focus on the functional aspects in addition
to ‘symptoms’ of schizophrenia

THANK YOU

Schizophrenia

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