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Cognitive Functioning, Physical Health and Early Non-response in Schizophrenia
with disability in schizophrenia, impeding an individual’s ability to live Table 1: Seven Domains of Cognition in Schizophrenia
independently, undertake vocational activities and function socially.
The National Institutes of Health (NIH) in the US is currently investing
Working memory
heavily in the Measurement and Treatment Research to Improve
Attention
Cognition in Schizophrenia (MATRICS.ucla.edu) and Treatment Units
Verbal learning and memory
Visual learning and memory
for Research on Neurocognition and Schizophrenia (TURNS.ucla.edu)
Reasoning and problem-solving
initiatives: programmes dedicated to evaluating the effects of novel
Speed of processing
compounds on improving cognition and, by association, functional
Social cognition
outcome. In this regard, animal models have proved extremely
valuable in the exploration of neurocognitive impairments in Figure 1: Effect of Sub-chronic Phencyclidine on
schizophrenia, not only revealing the underlying implications
Reversal Learning
in disease neurobiology, but also suggesting potential mechanisms by A
which atypical antipsychotics exert their efficacies in specific
100
cognitive domains. This article will review the current understanding
of cognitive functioning in schizophrenia, discussing recent pre-
80
clinical research into antipsychotic medications and the treatment
60
***
goals of cognitive functioning from a clinical perspective.
40
Cognitive Impairment as a
Therapeutic Goal in Schizophrenia
20
Percentage correct responding
Cognitive impairment is common early in schizophrenia, and appears
0
to be fully developed by the time of the first episode. Recent data
Initial Reversal
indicate that while the profile of cognitive impairments is present
Sub-chronic vehicle Sub-chronic PCP
similarly in schizophrenic, schizo-affective, psychotic major depressive
B
disorder and psychotic bipolar disorder patients, it is the level of 30
impairment that differs between the disorders, with schizophrenia
presenting with the greatest severity of impairment.
2
Moreover, there
20
is a poor association between symptomatic treatment and functional
success. The Hillside Hospital study enrolled patients during their first
episode, treated them according to a medication algorithm and Lever presses 10
measured the rate of recovery as defined by symptomatic outcomes
(clinical remission of positive and negative symptoms) and functional
0
outcomes (adequate social/vocational functioning).
3
Clinical remission
Veh PCP Veh PCP
was sustained for at least two years by 56.7% of patients, but
Initial Reversal
functional recovery for at least two years was somewhat lower, at
Correct Incorrect
37.9%. More remarkably, only 13.7% of patients achieved full recovery The effects of sub-chronic phencyclidine (PCP) 2mg/kg twice daily for seven days on initial
after a follow-up of five years. Importantly, better cognitive
and reversal task performance in the reversal learning test (A) and lever-pressing in the
initial and reversal phases (B). Source: Abdul-Monim, 2007.
14
performance was associated with full recovery, adequate
social/vocational function and symptom remission.
3
Despite the fact mimics the cognitive domains as well as negative symptoms of
that the vast majority of patients in this study had clinical symptoms schizophrenia. The animal model should map the relevant cognitive
that were manageable with antipsychotics, almost 85% of these first- domains, have good predictive validity with demonstrated drug and
episode patients never recovered from their first episode. Although clinical efficacies and, importantly, incorporate aspects of the
clinical remission of positive and negative symptoms was observed, underlying pathology and neurobiology of schizophrenia.
the lack of functional recovery greatly highlights functional disability as
a major unresolved clinical issue in schizophrenia. With a correlation The N-methyl-D-aspartic acid (NMDA) receptor hypofunction
between enhanced cognition and improved functional outcome, the hypothesis of schizophrenia proposes that dysregulation or
following question arises: If you treat cognitive dysfunction, whether disturbance of the glutamatergic system leads to hypofrontality,
pharmacologically or behaviorally, will the resulting clinical response particularly with respect to the dopaminergic system in the striatum
include reductions in disability? and frontal cortex.
4–6
This NMDA hypofunction is reproduced in animal
models using phencyclidine (PCP), a non-competitive antagonist of
Animal Models of Cognitive Impairment the NMDA receptor.
7
Sub-chronic PCP administration induces a
The goals of schizophrenia treatment in the realm of cognition are neurobiological effect; levels of the calcium-binding protein
primarily to avoid further deterioration of existing cognitive deficits parvalbumin, which serves as a marker for the gamma-aminobutyric
and secondarily to normalise existing deficits. The MATRICS initiative acid (GABA) interneurons, are reduced in the brains of PCP-treated
has identified seven domains of cognitive function that are affected rats, particularly in the hippocampus – a deficit often observed in
in schizophrenia (see Table 1), some of which have been successfully schizophrenic patients post mortem.
8–10
Levels of brain-derived
reproduced in animal models. However, the normalisation of neurotrophic factor (BDNF) are also reduced in PCP-treated rats;
cognitive deficits is a much more difficult area to study, and few reductions in BDNF have previously been implicated in schizophrenia
validated disease models exist. Therefore, the development of pathogenesis, leaving neurons susceptible to insult.
11,12
The basic
an animal model allows for a system within the laboratory that sub-chronic PCP treatment regimen involves seven days of treatment
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