Neurocognition in Schizophrenia

Dr Parth GoyalSecond Year Resident

Department of Psychiatry

History• Cognitive deficits in schizophrenia have

been identified as early as Kraeplin's original description of "dementia praecox," meaning cognitive decline with onset in youth.

• They are widely suggested to be a core feature of schizophrenia with increasing support for including impairments in cognition in the diagnostic criteria of the illness.

Reasons why its important ?

• Sz affects various domains of cognition

• Schizophrenics on an average perform 1-2 SD below healthy controls on tests of cognition

• Adversely impacts day-to-day functioning of patients

Practical Relevance • Cognitive impairments are associated with

poor functional outcomes in patients

• This includes:

• a) Difficulty in community functioning

• b) Inability to maintain successful employment

• c) Difficulty in problem solving skills.

Areas Affected• Vigilance

• Verbal Memory

• Visual Memory

• Speed Of Processing

• Reasoning & Problem Solving

• Verbal Fluency

• Immediate & Working Memory

• Social Cognition

Efforts to understand these deficits?

• The NIMH undertook a very comprehensive study titled “MATRICS”, Measurement and Treatment to Improve Cognition in Schizophrenia, to evaluate cognition in Sz.

• It evaluated more than 1000 patients on various cognitive domains in a variety of conditions.

• The “CATIE”, Clinical Anti-Psychotic Trial of Intervention Effectiveness study was done to assess the effects of anti psychotics on a variety of domains in schizophrenia.

Finding of MATRICS• SZ patients perform poorly in all domains of

cognition with a SD of 1-2.

• The impairment in performance is more or less constant over time

• Most patients have impairment before the onset of the first episode psychosis

• There is a further decline in cognitive performance after the first episode of psychotic symptoms.

Comparison b/w Various Subjects.

Findings of CATIE• Cognitive decline is present before the

initiation of anti-psychotic treatment

• The AP do little to reverse the changes

• The maximum benefit has been shown with the use of perfenazine

• Newer AP’s do not provide any sustainable benefit over the older AP’s in context to cognitive changes.

Vigilance• The first domain to be tested on cognitive

assessment is that of Vigilance:

• Def: Ability to maintain attention over time.

• Test: Continuous Performance Test

• Performance: Perform poorly as compared to healthy controls

Test Procedure (CPT)• 2-4 digit numbers are shown sequentially

@ 1/sec

• Patient instructed to press the key/mouse when he sees an identical number as the one presented before on the screen.

Real Life Difficulties • Patients unable to maintain vigilance

encounter a number of problems:

• a) Difficulty following social conversation

• b) Inability to follow instructions

• c) Difficulty performing simple activities like watching tv or reading.

Verbal Learning and Memory

• Def: This is the memory a/w a) Learning of new information b) Retaining new information c) Recalling new information

• Test: California Verbal Memory Test

• Results: Patients have more difficulty in learning new things than in recalling.

Test Procedure (CVLT)

• Patients are given 15 names and are asked to recall them afterwards.

• This is true even for more interesting events like stories.

Trial Number Healthy Controls Schizophrenics

1st 8/15 5/15

5th 13/15 9/15

Real Life Difficulties • Patients experience severe social and

occupational deficits

• Since verbal memory is routinely required in this ever changing world, deficits on this cognitive domain severely impair the patients ability to deal with the changes constantly required at work place.

Visual Learning and Memory

• Def: This is domain a/w learning, retaining and recalling visual information in its shape, form, content and position.

• This domain is found to be the least impaired in schizophrenia than other domains

Test Procedure

• Patients are asked to

• a) draw a figure from memory

• b) indicate among an array of figures which was presented previously.

Real life Difficulties

• The impairments in this domain are strongly correlated with functional outcomes and can affect patients in all of the ways mentioned previously.

Reasoning & Problem Solving

• Def: Ability of a person to logically navigate through problems and take a decision appropriate to the situation

• Test: Wisconsin Card Sorting Test

• Result: Perform poorly as compared to healthy controls

• This test also measures vigilance and visual memory.

Test Procedure(WCST)

• The patient is given a deck of cards and is asked to sort the cards on the basis of three parameters

• 1) Colour

• 2) Form

• 3) Number

• Patients with Sz or with frontal lobe dysfunction exhibit perseveration on this test.

• This lead to the formulation of the “Frontal hypo function hypothesis of SZ”

Real life Difficulties

• Patients who perform poorly on this test show impairments in all fronts of life

• Primarily these impairments stem from a decreased ability to adapt to changes in real life situations.

Speed of Processing• Def: Ability to automatically and fluently

perform relatively easy cognitive tasks especially when high mental efficiency is required.

• Test: Wechsler Adult Intelligence Scale Digit Symbol Test

• Result: Patients perform poorly as compared to healthy controls.

Test Procedure(WAIS-DST)

• Each number 1-9 is associated with a different simple symbol

• Subjects are required to copy as many symbols a/w numerical in 90 secs.

• Patients with SZ show sever deficits on this test and the performance on this test has accounted for the maximum variance in the overall composite score on the CATIE study.

Real Life Difficulties

• 1) Reduced ability of patients to keep up with “Task related Jobs”

• 2) Increased “social latency” which hampers relationships.

Verbal Fluency• Def: It is a cognitive function that facilitates

information retrieval from memory.

• Successful retrieval requires executive control over cognitive processes such as selective attention, selective inhibition, mental set shifting, internal response generation and self monitoring.

• Tests: There are two different tests, each to test phonological and semantic fluency

• Results: Patients perform significantly worse than their healthy counter parts

Test Procedure

• Phenomenological Fluency: Name as many objects starting from a single letter e.g. “a” in 60 seconds.

• Sementic Fluency: Category based. E.g. name as many animals as you can in 60 seconds starting with the letter “c”

Real life Difficulties

• Hampers social and vocational rehabilitation

• Makes communication difficult and awkward.

Immediate/Working Memory

• Def: Immediate memory is the amount of information that is held online to perform a specific task.

• Working memory: Memory that can be subjected to some manipulation while being held online

• Also includes the visuo-spatial memory.

• These domains can be tested on routine MSE/MMSE tests and are severely impaired in patients with SZ.

Real life Circumstances

• They are the core components of neuro-cognitive impairment

• Causes impairments in other cognitive domains like:

• attention

• planning

• memory

• intelligence

• IT is also closely related to the “Hypofrontality Hypothesis”

Social Cognition • Refers to how people process social information

especially its encoding, storage, retrieval and application to social situations.

• This domain of cognition is associated with understanding the context of conversations based on an accurate interpretation of facial expression, social cues and eye movements.

• This domain is severely impaired in SZ and the theory concerning the same is called “Theory of Mind (ToM)”.

• Many studies have been done to measure and objective this impairment.

Course of Cognitive Impairment

• Significant deficits present in childhood f/b decline prior to 1st episode.

• Generally stable, not progressive

• Deficits of around 1-2 SD from healthy controls

• Can serve as an early predictor for detecting SZ in “high risk and ultra high risk” persons.

Course of Cognitive Impairment in Sz.

Genetics• Clear Heritable component

• First degree relatives have impaired performance on a number of tasks.

• Genetic Factors >> Environmental Factors

• A number of genes and SNP’s have been implicated in the genesis. No single gene has been identified yet.

Deficits in Children and Follow Back Studies in SZ

• “Follow Back Method” has been used in a number of studies to assess the temporal relationship and change in cognition in SZ.

• a) UK National Survey of Health and Development Study

• b) Swedish Army Study

• c) Iowa Test Study

• d) Israeli Draft Board Registry.

Relationship of Neuro cognitive Changes to Sz

Symptoms • The question of the hours is:

• “Is it possible that the impairments that are seen on these test could be due to the symptoms of Sz (positive and negative), rather than them being an indicator of pure cognitive dysfunction?”

Cognition and Positive Symptoms.

• If these impairments were due to positive symptoms then they should reverse when the symptoms are controlled

• Similiar impairments are not seen in patients with other psychotic illness like Bipolar Mood Disorder.

• In the CATIE study, more than 91% patients were able to complete the neurocognitive tasks and the over all correlation b/w positive symptoms and impaired cognition was nearly zero.

• The potential confounds: a) Patients too psychotic to be tested; b) Low temporal stability and reliability of these symptoms.

Cognitive Impairments and Negative symptoms

• Neuro-cognitive impairments (NCI) are significantly correlated with negative symptoms

• Motor outcomes strongly related

• A/b/w reduced motivation and poor performance of tests is complex.

• Increase in pupil size is seen in Sz patients while performing tests, indicating that patients are engaged neuro cognitively. However the results on the test are not convincing

Contd. • There is compelling evidence to suggest that poor

performance on these tests, causes low reward expectation which in turn enhances low motivation.

• At 1 year interval, both symptoms are a/w poor performance, but are not predictive of each other. If negative symptoms were to cause this impairment, then a longitudinal relationship is to be expected

• Differentially NCI are more strongly a/w poor functional outcomes and adaptive changes than are negative symptoms

Summary (Correlation with Negative Symptoms)• Cross sectional correlation of negative

symptoms and NCI has been “consistently” reported

• Magnitude: Modest

• Directionality: Not well understood

• Enough evidence for both ends of the spectrum.

Treatment of NCI• Large amount of research is going into

understanding the exact neurobiology, thus giving us better pharmacological targets in the future.

• Treatment with AP’s (1st Gen) has been shown to cause lethargy, somnolence and EPS, all of which impair cognition

• In addition the anti cholinergic given to often control these symptoms, exacerbate cognitive impairments by causing confusion.

Contd.• The CATIE study compared the efficacy of 4

different second gen AP in NCI.

• The anti-psychotics studied were olanzapine, risperdione, ziprasidone and quetiapine.

• These were compared against perfanzine.

• The end result: Effects of AP’s was negligible.

Cognitive Remediation.

• Cognitive remediation is an intervention that seeks to enhance the neuro-cognitive skills in patients relevant to their recovery goals.

• Learning-based behavioural skills designed to enhance neuro and/ or social cognitive skills.

• Based on drills & strategies

• Ultimate goal: generalisation to improve psychosocial outcomes

• Innovations:-Incorporate new generation of computerised cognitive training -Integrate CR with skills training,-Apply techniques to enhance motivation and learning duringCR

Compensatory Approach

Two main approaches: Compensatory and Restorative.

Compensatory approaches utilise environmental supports and adaptive strategies to bypass cognitive deficits and improve target behaviours and functional outcomes in individuals with schizophrenia

Restorative Approach

• Cognitive enhancement therapy (CET) is a multi-component cognitive remediation approach, is an e.g. of Restorative Approach.

• CET is designed to provide enriched cognitive experiences through targeted and integrated neuro-cognitive and social-cognitive training.

Contd.The focus is on enhancing both "bottom-up" processing of critical social stimuli, with "top-down" executive control over distracting information and emotional arousal.Through the integration of computer-based cognitive exercises in attention, training, and problem-solving, with an active social-cognitive group experience designed to facilitate perspective-taking, gistful processing of information, and social context appraisal, CET is thought to provide the requisite experiences needed to enhance neural processing and achieve adult cognitive milestones.

Results• A/w medium effect sized for cognitive and

functional outcomes

• Better if incorporated with

• a) Psychosocial rehabilitation programs

• b) Incorporate strategy teaching and other methods.

PsychopharmacologyThe etiologic and phenomenological complexity of neuro-cognitive deficits in schizophrenia may be better served by psychopharmacological agents that

(i) target neurotransmitter systems proximal in the causal chain to neurocognitive deficits

(ii) enhance distal survival processes in the central nervous system—neurogenesis, neuronal growth, synaptogenesis, and connectivity

(iii) counteract the negative effects of aberrant neurodevelopment in schizophrenia, such as neuroinflammation and oxidative stress.

Agents that counteract Neuro inflammation and Oxidative stress.

Results so Far• Consistent positive improvements in neuro-cognition

have “not” been found with psychopharmacological treatment in people with schizophrenia.

• Clearly, the neurobiological basis of neuro-cognitive deficits in schizophrenia is quite complex, not limited to a single target but several interconnected signalling systems.

• The variable aetiology and phenomenology of neuro-cognitive dysfunction in schizophrenia may very well contribute to the limited efficacy of enhancing drugs.

Indian Numbers• India vs. US- no significant gender differences in Indian

sample vis a vis reproductive indices (n=224 -I and 144- US) (Bhatia et al 2002)

• New Delhi- 34% lower occupations, + 20% unemployed, 39% drift lower. (Bhatia Chakraborty et al 2008)

• Chennai: Social but not cognitive deficits related to work dysfunction. (Srinivasan & Tirupati 2005)

• Wandering aimlessly: 22% (Jakhar 2012)• Cognitive deficits in chronic Sz in India similar to those in

Western studies. N=100 (Srinivasan et al 2005)• Poor Cognitive test performance related to impaired:

Self-care, occupational role, social role, and family roleInversely correlated to negative symptoms.

Thank You.