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. Hallucinations3. 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 engagementContinuity of careAppropriate lifestyleFamily supportVocational 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 2007Paliperidone (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 requirePromotion of independenceStability in social networksConsistency of careAddressing 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

Healthcare

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