Cognitive Deficits in

Schizophrenia: An Evidence
Based Approach
Dr. Umesh.
S
CIP Ranchi

My whole mental power has disappeared, I

have sunk intellectually below the level of a
beast(a patient with schizophrenia, quoted by
Kraepelin, 1919, p. 25).

Dementia praecox and paraphrenia. Robert E. Krieger Publishing Co. Inc.,

Huntington, NY pp 25

Introduction
Traditionally, significant cognitive deficits was thought to
manifest only in burnt out cases with schizophrenia (SZ).
It is becoming evident that masked or marked
cognitive deficits in schizophrenia is

the norm of the illness

often pre-dates
Influence overall functioning
60-65% of the SZ patients have a significant impairment
in neurocognitive functioning (Rund et al, 2006)

Rund BR, Sundet K, Asbjrnsen A, Egeland J, Landr NI, Lund A, Roness A, Stordal KI, Hugdahl K. Neuropsychological test
profiles in schizophrenia and nonpsychotic depression. Acta Psychiatrica Scandinavica. 2006 Apr 1;113(4):350-9.

Cognition
Ulric Gustav Neisser,
father of cognitive
psychology defined
cognition as
the mental process (activity) of knowing: the
acquisition,
organization,
and
use
of
knowledge

y
t
i
l
a
r
t
n
e
C
of
n
o
i
t
i
n
g
o
C
Diverse
Array of
Domains

Attentio
n
Working
Memory
Processing
Speed
Inhibitio
n
Reasoning and
Problem Solving
Visual and verbal
learning and
memory
Social Cognition

COGNITIVE RESEARCH IN
SCHIZOPHRENIA
early clinical observations that
occurred in
the beginning of the 1900s

E
M
assessment-based
A
C
E
R
IT
E
approaches that
E
H
R
E
W
H
D
W
emerged after World War
N
?
A
?
?
M
E
O
II
W
R
F
E
AR
the more recent era ( last 20
years) cognitive research has
emerged as a neuroscience
discipline

Publications

Cognition Deficits in
Schizophrenia

Keefe R and Philip D. Novel Antischizophrenia Treatments. In Handbook of Experimental Pharmacology Eds Geyer & Gross. 2012

Neurodevelopmental
OR
Neurodegenerative?

Neurodevelopment: An Extended
Process
Developmental fixed lesion occurring most commonly in the
second trimester of intrauterine life
Basic cognitive functions

Crystallized cognitive skills

Developmental processes (arborisation and myelination)

continue at least through the first two post-natal decades
complex executive functions

Fluid cognitive skills

G
A
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R
NEU

Measures of cognitive functioning correlate with

measures of brain structure in patients with
schizophrenia.
If progressive brain tissue loss occurs over the
course of schizophrenia, one might predict that
this would be accompanied by progressive
deterioration in cognition

THIS DOES NOT APPEAR TO BE THE

CASE

Brain matter lost in schizophrenia is related to a

combination of
1. (early) neurodevelopmental processes
reflected in intracranial volume reduction
2. llness progression reflected in grey matter
volume reduction

 Studies show global and specific aspects of

cognitive deficits in schizophrenia once the
diagnosis is established.
Cognitive deficits are stable over time for
periods of up to ten years except for verbal
memory deficits which is progressive (Bozikas
& Andreos, 2011; Bora & Murray, 2014).
Further studies are needed to confirm
especially the domains of executive function.
It

is

still

unclear

when

the

decline

Neurobiology of Cognitive Deficits

in SZ
Brain is too complex to understand

Assembling
difficult and may in
Cognition isjigsaw
one of itsisfunctions
part underlie why various models have
Current
understanding
is not enough
to decipher
failed
to restore
cognitive
functions
in the
cognitive
deficits holistically.
targeted
population
(Cope et al, 2016).
Brain Imaging
Neural oscillations
Molecular targets
Animal models

Neuroimaging
Imaging studies of schizophrenia
have used a variety of tasks that
probe elements of cognitive
functions using functional imaging.
A meta-analysis that included
executive function domains tested,
patients consistently showed
hypoactivation of dorsolateral,
medial prefrontal regions, dACC
and thalamus.

 Cognitive functions essentially emerge from the

coordinated activity of distributed neuronal
populations that are dynamically configured on
the backbone of anatomical connections(neural
synchrony).
Schizophrenia involves in a disruption of the
dynamic activity of neural processes in various
large-scale networks (Uhlhaas & Singer, 2015).

Neural Oscillations
Theta ( 47 Hz) frequencies are related to episodic
memory and driven by hippocampal regions in
coordination with the prefrontal cortex (PFC).
The activity of GABAergic interneurons in the PFC is
reflected in the gamma oscillations (3080 Hz), which
is linked to attention and working memory.
The synchronization of , and rhythms across
regions of the brain represents a neural code that
modulates top-down cortical control of cognitive
processes (Millan et al, 2012; Ulhaas & Singer, 2015).
Millan MJ, Agid Y, Brne M, Bullmore ET, Carter CS, Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, Dubois B. Cognitive
dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews Drug discovery. 2012
1;11(2):141-68.

Event related Potentials

Event-related potentials (ERP)are voltage fluctuations
in the EEG that are time-locked to internal or external
events (stimuli, responses, decisions).
Some ERP components like p300 and MMN have been
linked with specific transmitter-receptor systems like
serotonin, glutamate and GABA (Heekeren et al,
2008).
ERPhave great potential asbiomarkersthat could be
used to improve the development of procognitivetreatments forschizophrenia (Luck & Kappenma,
2011).
Heekeren HR, Marrett S, Ungerleider LG. The neural systems that mediate human perceptual decision making. Nature
reviews neuroscience. 2008 Jun 1;9(6):467-79.
Luck SJ, Kappenman ES, editors. The Oxford handbook of event-related potential components. Oxford university press; 2011
Nov 17.

Overall

Electrophysiological
studies
confirms
that
cognitive deficits in schizophrenia are not related
to localized brain lesions per se, but rather to
disturbed functional connectivity between various
brain structures.

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Loss
Loss of
of top-down
top-down cognitive
cognitive control
control
PRTC-Parietal cortex ventral anterior (VA) and medial dorsal (MD)

Molecular targets
Cognitive deficits can be rectified or compensated.
But if network shifts from the molecular level to systems
level rectification becomes questionable.
Early treatment using one or more molecular targets is
crucial.
The primary molecular targets identified includes
1. Dopamine receptors
2. Serotonin receptors
3. Nicotinic and muscarinic acetylcholine receptors
4. Glutamatergic receptors
5. GABA receptors.

 Cognitive deficits correlate with a decline in

dopamine in the prefrontal cortex, primarily at the
level of D1 receptors and imbalance of D1 and D2
receptors in the prefrontal cortex
D1 stimulation are essential for working memory
function.
D1 receptor activity follows the inverted-U
dose-response curve, where either too little or too
much D1 stimulation impairs working memory.

The role of HT1A

5-HT1A receptor agonism has
been suggested to enhance
cognition (executive function
and verbal memory).
5-HT1A agonists selectively
stimulate 5-HT1A receptors
located
on
GABA
interneurons in the PFC
This diminishes the activity
of GABA neurons, leading to
disinhibition of Glu neurons
to augment DA release in the
PFC (improves cognition)

Glutamate and cognition

The impairment in
network activation,
connectivity and
interaction are related to
disruptions in
glutamatergic signaling
specifically through
hypofunctioning NMDA
receptor.
A MRS study found
reduction in thalamic and
prefrontal cortex
glutamate levels during a

Antipsychotics and Cognition

Hill SK, Bishop JR, Palumbo D, Sweeney JA. Effect of second-generation antipsychotics on cognition: current issues
and future challenges. Expert review of neurotherapeutics. 2010;10(1):43-57. doi:10.1586/ern.09.143.

Trajectory of improvement
(Based on animal model)
5HT1A

Schreiber R, Newman-Tancredi A. Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis
through 5-HT 1A receptor activation. Neurobiology of learning and memory. 2014 30;110:72-80.

 Earlier, CATIE trial found perphenazine superior to

olanzapine and risperidone at the 18 month
endpoint in improvement of cognition.
A recent longitudinal study found improvement of
cognitive score with low dose haloperidol similar to
those found with risperidone or olanzapine.
Olanzapine produced significantly more cognitive
benefits than haloperidol at short term (12 weeks),
but they failed to demonstrate cognitive changes at
1 and 2 years

The magnitude of the putative cognitive advantages

of SGAs have regressed from robust and modest
effect sizes in early open-label, to modest and at
times negligible effect sizes in double-blind
controlled trials (Hill et al, 2010).

Practice effect.
Industry sponsored clinical trials investigating the cognitive
effects of antipsychotic drugs have rarely addressed the
potential confound of practice effects (Goldberg et al, 2007)
Moreover, it is unclear whether equivalent practice effects
should be expected of first-episode or those with chronic
long-standing illness
Hence, the combination of neuropsychological and
electrophysiological methods may be beneficial for the
understanding of mechanisms of cognitive enhancement
and prediction of functional outcome (Sumiyoshi et al,
2013).
Goldberg TE, Goldman RS, Burdick KE, et al. Arch. Gen. Psychiatry.
2007;64(10):11151122

Cognitive remediation training (CRT)

CRT has been found to improve cognitive
functioning and influence neural plasticity.
Improvement was elicited with increased activity
in the lateral
and medial prefrontal cortex (PFC),
.
parietal cortex, insula, and the caudate and
thalamus.
A recent meta-analysis has found benefits of CRT
associated with increased activation in the left
PFC and thalamus (Ramsay & McDonald, 2015)

Ramsay IS, MacDonald AW. Brain correlates of cognitive remediation in schizophrenia: activation
likelihood analysis shows preliminary evidence of neural target engagement. Schizophrenia bulletin.
2015 Mar 23:sbv025.

The interface of motivation and

cognition

Fervaha G, Zakzanis KK, Foussias G, Graff-Guerrero A, Agid O, Remington G. Motivational deficits and cognitive
test performance in schizophrenia. JAMA psychiatry. 2014 Sep 1;71(9):1058-65.

Tests assessing
neurocognition

Measurement
and
Treatment
Research to Improve Cognition in
Schizophrenia
(MATRICS)
Consensus
Cognitive
Battery
(MCCB)
Launched by the National Institute of Mental Health in
2008 (Nuechterlein et al, 2008)
Comprehensive cognitive function evaluation of
schizophrenia in the context of clinical trials (as
composite measures with neural correlates).

Conclusion

Cognitive impairment is the prime driver of

significant disabilities in occupational and social
functioning in patients with schizophrenia.

There has been several prominent negative

treatment trials, negative studies of add-on
treatments which has made researchers focus on
various novel molecules.

Assessment of neurocognitive functions using

neuropsychological measures along with neural
correlates would help to understand cognitive deficits
in a better way and one might expect a good
cognitive enhancer for SZ in the near future.

Thank You