Assessing and Treating Cognitive Impairments in Schizophrenia:
Current and Future
Chun-Yuan Lina,b,c Guochuan E. Tsaid and Hsien-Yuan Lanea, e
a
Institute of Clinical Medical Science, Medical College, China Medical University,
Taichung, Taiwan
b
Department of Psychiatry, Changhua Hospital, Changhua, Taiwan
c
National Changhua University of Education, Changhua, Taiwan
d
Department of Psychiatry, Harbor-UCLA Medical Center
e
Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
** Correspondence:
Hsien-Yuan Lane, MD, PhD
Institute of Clinical Medical Science, Medical College, China Medical University,
Taichung, Taiwan
No.91 Hsueh-Shih Road, Taichung 404, Taiwan
E-mail: hylane@gmail.com
Tel: +886-4-22053366 # 7620
Guochuan E. Tsai and Hsien-Yuan Lane contributed equally as corresponding
authors.
1
Abstract
Schizophrenia is a serious neuropsychiatric disease characterized by positive
symptoms, negative symptoms and cognitive impairments. Evidences have showed
that cognitive impairments sustain in every clinical stage, relate with the liability, may
predict functional outcome in schizophrenia and could be the core symptom of
schizophrenia. The treatment of cognitive impairments in schizophrenia could
alleviate the burden of the illness and has become the subject of intensive research. In
this review, we synthesize current advances of assessing strategies, pharmacological
and non-pharmacological treatments of cognitive impairments in schizophrenia.
According to the registered records of ClinicalTrials.gov, the most widely studied of
these are neurochemical mechanisms related with the dopamine metabolism,
glutamate metabolism , γ-aminobutyric acid (GABA) metabolism, serotonin
metabolism, acetylcholine metabolism , and oxytocin. Despite preclinical data for
putative pro-cognitive drugs, their clinical benefits for schizophrenia patients have
been limited. The small sample sizes and the short treatment duration could be related
with the suboptimal results. Evidences supported the short-term benefits of cognitive
remediation therapy on cognitive domains with small to moderate effects; however,
the small sample sizes and the characteristics of subjects limited the generalization of
the positive results and long-term functional outcome is not clear. Combination
therapy is promising, by integrating pro-cognitive agents and cognitive rehabilitation
programs or combining two kinds of pro-cognitive agents via different mechanisms.
Future studies should investigate the pro-cognitive drugs’ long-term efficacy, rebound
deterioration in psychosis/cognition following discontinuation, and related biomarkers
of functional outcome.
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Introduction
Schizophrenia is one of the most serious neuropsychiatric diseases in the world,
influencing 1% of the global population(1). The symptom complexes of disease
liability in schizophrenia are positive symptoms (delusions and hallucinations),
negative symptoms (anhedonia, asociality, and amotivation) and cognitive
impairments (memory, attention, and executive dysfunction). Most people with
schizophrenia cope with symptoms throughout their lives and often rely on others for
help. The families and society are also affected by schizophrenia, and the direct and
indirect costs of schizophrenia are great(2). In this review, we synthesize current
advances of assessing strategies, pharmacological and non-pharmacological
treatments of cognitive impairments in schizophrenia. Articles were identified through
a literature search in MEDLINE. The search covered the period from January 1990 to
February 2012. The keywords were “schizophrenia” (in title) combined with
“cognitive” (in title/abstract) and the additional filters were “journal article, full text
available, humans, and English language”. The search produced 4081 articles and
2257 were excluded after title examination. Then, the following criteria guided the
inclusion of studies in the review if: (1) the sample consisted of schizophrenia patients
according to a recognized criterion-based diagnostic system such as DSM or ICD; (2)
for clinical trials: the study used standardized and reliable clinical scales and cognitive
tasks; (3) the study was published in a peer-reviewed journal. Finally, 191
publications were enrolled for the authors to review.
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Cognitive impairments: core symptoms of schizophrenia
Significant cognitive impairment including working memory, attention, visual
memory, executive function and social cognition were observed in the subjects of
prodromal psychosis(3). Prior to onset of psychosis, cognitive dysfunction is evident
in pre-schizophrenia subjects during childhood and importantly, the cognitive
impairments are associated with the vulnerability to psychosis among the unaffected
high-risk subjects (3, 4). In the early course of schizophrenia, cognitive impairment is
present in the drug naïve patients(5) and even in those patients with intact intellectual
function(6). Moreover, cognitive functioning is independently correlated with the
post-onset relapses of first-episode psychoses(7). In the chronic stage of
schizophrenia, cognition does not consequentially improve following relief from acute
psychotic episode(8). Impaired cognitive function is associated with social and
adaptive functioning in geriatric schizophrenia patients, particularly for those with
long illness duration(9). More so than other dimensions, cognitive impairment is
thought to be the core manifestation of schizophrenia for the pervasive persistence at
each course of the illness and the predictive utility for the daily functioning of
patients(10, 11).
The relationships between positive, negative and mood symptoms and cognitive
symptoms have been equivocal in both cross-sectional and longitudinal studies
(12-15). A recent meta-analytic review of 58 cross-sectional studies enrolling 5,009
individuals (94% with schizophrenia, 3% with schizoaffective disorder, and 3% with
other psychotic disorders; mean age and mean illness duration ranged from 19.1 to
51.9 years and 4.8 to 28.9 years, respectively) showed that negative and disorganized
dimensions were significantly but modestly associated with cognitive deficits. In
contrast, positive and depressive symptom dimensions did not show any relationship
with any neuropsychological domain(16).
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For acutely ill schizophrenia inpatients, improvement in cognitive functions was
related with improvements in positive symptoms but not in negative symptoms over 6
months(13). Improvement in positive symptoms but not negative symptoms was
associated with improvements in cognitive domains of executive function , spatial
memory, concentration/speed , and global cognition in a study in 42 schizophrenia
patients during their first 4-5 years of illness duration(17), however improved
negative symptoms but not psychotic or disorganized symptoms were related with
improved verbal cognition in another 5-year follow-up cohort of
fifty-four
first-episode and recent-onset schizophrenia patients (18). For chronic schizophrenia
(illness duration of 13.9-20.5 years), change in positive or negative symptoms was not
related to change in cognition longitudinally (19, 20). Different characteristics of
patients may contribute to the conflicting results of the relationship between changes
in symptoms and cognitive functioning in schizophrenia.
Collectively, negative symptoms may be associated with the levels of cognitive
deficits and a poor cognitive outcome but the correlation between negative symptoms
and change in cognition was reduced longitudinally. Moreover, cognitive impairment
in schizophrenia is not merely side effects of medication or disease chronicity but a
prominent and stable domain throughout the course of schizophrenia, even as positive
symptoms fluctuate. It sustains in every clinical stage, relates with the liability, and
may predict functional outcome in schizophrenia (21-23).
Assessment tests of cognitive impairments in schizophrenia
Among patients with schizophrenia, cognitive impairments have been identified
in almost every measurable cognitive ability domain, from basic to higher order
cognition(24, 25). It has been suggested that cognitive impairments may represent the
candidate endophenotypes in the search for genes conferring risk for schizophrenia
(26-28). Therefore, it is important to establish a more refined description of cognitive
5
impairments by using neuropsychological measures(28).
Various batteries have been introduced to assess the cognitive deficits of
schizophrenia patients (Table 1), such as Treatment Research to Improve Cognition in
Schizophrenia Consensus Cognitive Battery (MCCB)(10), the Brief Assessment of
Cognition in Schizophrenia (BACS)(29), Cognitive Drug Research computerized
assessment system (CDR)(30), CogTest Battery(31), and Cambridge
Neuropsychological Test Automated Battery (CANTAB)(32). To develop efficient
tool with brief administration and scoring time, portability, repeatability, and
availability for the design of clinical trials of drugs for cognitive impairment in
schizophrenia, Treatment Research to Improve Cognition in Schizophrenia
(MATRICS)(10) initiative facilitated the development of MCCB. The creation of
MCCB is an important step because well-defined measures have been chosen to
comprise cognitive domains that best characterized schizophrenia. MCCB includes 7
domains: (1) speed of processing (2) sustained attention (3) working memory, verbal
and nonverbal (4) verbal learning and memory (5) visual learning and memory (6)
reasoning and problem solving, and (7) social cognition.
The 1st to 6th domains were defined as neurocognition, the processes of linking
and appraising information, while the 7th domain of social cognition, measured by
Mayer–Salovey–Caruso Emotional Intelligence Test Version 2.0 (MSCEIT V2.0)(33,
34), was defined the mental operations underlying social interactions such as the
perception, interpretation, and generation of responses to the intentions and behaviors
of others(35). Neurocognition and social cognition are related, but different
constructs(36). Research on social cognition in schizophrenia has focused on 4
domains: perceiving emotions, using emotions to facilitate thought, understanding
emotions, and managing emotions in self and others. Cumulative data showed that
social cognition may mediate the relationship between neurocognition and functional
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outcomes(37). MATRICS defined social cognition and neurocognition as an integral
whole of cognitive function in schizophrenia and the managing emotions component
was selected for its relatively stronger relationship to functional status(33, 38).
The MCCB has become the standard assessment tool for assessing cognitive
dysfunction in schizophrenia, however the predominant population in the studies has
been older, chronic, and mainly male schizophrenia patients(39), further endeavors to
recruit larger and diverse samples and to ensure versions with the cross-cultural
adaptability for different countries are necessary.
Biomarkers reflecting on cognitive impairments
At present, the diagnosis of schizophrenia relies on descriptive behavioral and
symptomatic information, and specific biomarker is lacking. Establishing biomarkers
those reflect on cognitive impairment, a primary role in the pathophysiology of
schizophrenia, with sensitivity, specificity and availability deserves further
investigation.
Genetics modalities
Susceptibility genes may increase risk for schizophrenia through baneful effects
on cognitive processes. Several genes those regulate neural development,
dystrobrevin-binding protein 1 (DTNBP1) gene(40),
catechol-O-methyltransferase (COMT) gene(41) ,brain derived neurotrophic factor
(BDNF) gene(42-44), Disrupted in schizophrenia 1 (DISC1) gene(45), and D-amino
acid oxidase activator gene (DAOA, G72)(46) have garnered as potential contributors
to impaired cognition in schizophrenia. The majority of these studies measured
schizophrenia patients’ cognitive domains, and genotyped the patients for specific
SNPs and then investigated the associations of alleles with either general or specific
cognitive measures. For examples, schizophrenia patients who carried the DTNBP1
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haplotype showed significantly greater P1 of the visual evoked potential (VEP) deficit
than patients who were non-carriers (40) ; higher loading of the COMT 158 Met allele
was associated with better neurocognitive performance among patients with chronic
schizophrenia while (41) while the Val allele is associated with impaired working
memory and general cognitive decline(28) ;the Met allele at the val66met
polymorphism in the BDNF gene was associated with impaired working memory
performance(47) and visuospatial dysfunction(44) ; and DISC1 genotype was related
to rapid visual search and verbal working memory in schizophrenia(45). Although the
studies are beset with small sample sizes, heterogeneous ethnic origin, and
unequivocal cognitive test methods so that consistent and specific effect of genotypes
on cognitive impairment in schizophrenia remain variable, genetics modalities
provided promising evidence that variation in particular genes could affect neural
development and function and further explained the heterogeneity of cognitive
impairments in patients with schizophrenia.
Neuroimaging modalities
Neuroimaging assessments, including morphometric neuroimaging and
functional neuroimaging, have played a prominent role in the quest to identify the
brain systems responsible for cognitive dysfunction in schizophrenia. Whereas
morphometric neuroimaging assessments such as computer tomography (CT)
and magnetic resonance imaging (MRI) allow for detailed visualization of the brain
structure, functional neuroimaging assessments, such as positron emission
tomography (PET), functional magnetic resonance imaging (fMRI), and magnetic
resonance spectroscopy (MRS) further investigators to evaluate both brain structure
and activity in the brain more closely. For examples, meta-analysis of diffusion-tensor
imaging (DTI) studies identified fractional anisotropy reductions of left frontal lobe
and temporal lobe in schizophrenia and supported that in addition to gray matter
8
deficits, disruption of white matter integrity may be affected in schizophrenia(48) and
findings from resting-state fMRI have supported that schizophrenia patients and their
healthy first-degree relatives have impaired connectivity from DLPFC to its
coordinated regions including the bilateral caudate, left middle/inferior frontal gyrus,
left precentral gyrus, and right cerebellum(49).
The study of cognitive impairments with neuroimaging tools may be potential
biomarkers of schizophrenia by identifying the neurophysiologic connections of
cognitive impairments. There are evidences that linked impairments of key cognitive
domains to brain dysfunction including working memory(50) and episodic memory
with hypofrontality(51), executive function with deficits in dorsolateral prefrontal
cortex (DLPFC) (49), anterior cingulate cortex (ACC) and mediodorsal nucleus of the
thalamus(52) and poorer verbal working memory performance with decreased white
matter integrity between prefrontal and parietal cortices (53). Moreover,
Subramaniam et al demonstrated that cognitive training generalized to an untrained
higher-order operation and produced a significant improvement in its correlation of
fMRI activity in patients with schizophrenia(54), suggesting that neuroimaging tools
could be used as the outcome measurement s for pro-cognitive agents or programs. To
date, the quality of neuroimaging has dramatically increased so investigators are able
to evaluate neurodevelopmental abnormalities and neurodegenerative changes in the
brain by combining structural and functional measures(55). Therefore, the capacity to
test the relationship of cognitive symptoms and brain abnormalities (including both
structure and dynamics) in schizophrenia is promising. For examples, MRS providing
chemical composition, neurotransmitter levels, and neuronal integrity in living tissue
is increasingly applied to characterize tissue-based chemical or metabolic
abnormalities in schizophrenia; the majority of brain image studies on cognitive
deficits are to approach the connections of activity/volume in a brain region of interest
9
(ROI) during cognitive tasks in schizophrenia patients and healthy controls
respectively. However, there is a considerable inconsistency caused by heterogeneous
subjects across studies and methodological differences in various cognitive tasks,
image processing and quality assurance protocols(55). Besides unifying image
operations and cognitive tasks during image survey, further studies will need to
identify more homogeneous subject groups and follow patients longitudinally
throughout the illness stages to understand the role of neurophysiologic disturbances
and further, to develop specific imaging biomarkers for aligned use in trials of
cognitive dysfunction in schizophrenia.
Peripheral modalities
Blood is the safe and maybe the most available route to develop biomarker of
schizophrenia. For the examples of excitatory amino acids (EAA), Hashimoto et al
(56) reported that serum levels of D-serine and the ratio of D-serine to total serine in
patients with schizophrenia are significantly decreased in schizophrenia patients than
in healthy subjects. Decreased plasma glycine levels, lower glycine/serine ratio and
higher homocysteine levels were found in schizophrenia patients than in comparison
subjects (57). Higher serum level of D-serine was associated with more symptom
improvements of positive, negative and cognitive symptoms in a D-serine add-on
treatment for schizophrenia patients(58). Another example is brain-derived
neurotrophic factor (BDNF), in a 50 hours computerized auditory training that
enrolled chronic schizophrenia patients and matched healthy comparison subjects,
serum BDNF levels were significantly increased in schizophrenia subjects after
neurocognitive training, and the authors suggested that serum BDNF levels may serve
as a peripheral biomarker for the effects cognitive enhancement in schizophrenia(42).
These finding suggested that EAA levels (D- serine level and glycine level) and
BDNF levels may be promising convenient peripheral markers for schizophrenia and
10
changes of the levels may reflect the improvement of the clinical and cognitive
symptoms.
Pharmacotherapy based on biological aspects of cognitive impairment in
schizophrenia
A number of diverse etiological hypotheses including neurodevelopmental,
neurodegenerative, immunological, inflammatory, infectious and metabolic
pathophysiological mechanisms for schizophrenia have been proposed(59). Evidences
show that schizophrenia is a polygenic disorder in which the multiple susceptibility
genes act together with environmental stressors in increasing vulnerability. Many of
the susceptibility genes identified for schizophrenia are responsible for regulating
neuronal connectivity and synaptogenesis(60) that are associated with learning and
memory indicating pathophysiology of cognitive impairments could be the important
etiology of schizophrenia. Although improving cognitive function is crucial, the effect
of present psychotherapeutic medication, typical and atypical antipsychotics, for
cognitive impairments in schizophrenia is controversial (61-63).
Cognition is a highly complex CNS function depends upon interconnectivity of
multiple CNS systems. Whereas models of the pathophysiology of schizophrenia per
se emphasize excessive signaling in subcortical dopamine (DA) pathways, the
accumulating research supported a link between schizophrenia and functional and
anatomical dysconnectivity that lead structural changes of association fibers at the
cellular level and aberrant control of synaptic plasticity at the synaptic level(64).
Besides dopamine pathway, a diverse palette of neurotransmitters, such as glutamate,
gamma-aminobutyric acid (GABA), and acetylcholine influence cognitive
performance(65). These neurochemical systems constitute a large, heterogeneous set
of potential targets for novel therapeutic agents to remediate cognition in
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schizophrenia.
Many strategies for developing pro-cognitive agents in schizophrenia have been
proposed and the recently popular approaches are on putative agents that may directly
or indirectly enhance neuroplasticity. These include research on pro-cognitive agents
those enhance neurotransmission (e.g., cholinesterase inhibitors), stimulate or inhibit
brain receptors (e.g., NMDA receptor glycine site agonists). According to the
registered records of ClinicalTrials.gov (66), the most widely studied of these are
neurochemical mechanisms related with the dopamine metabolism, glutamate
metabolism , GABA metabolism, serotonin metabolism, acetylcholine metabolism ,
and oxytocin (Table 2).
Dopamine targets
Dopamine D1 receptor agonists
Davis et al provided a mechanism to propose that schizophrenia is characterized by
frontal hypodopaminergia resulting in striatal hyperdopaminergia(67). While exposure
to dopamine D2 receptor agonists induces psychotic symptoms and that conventional
antipsychotic drugs block subcortical D2 receptors, a deficit in cortical dopamine
transmission at D1 receptors may be associated with cognitive impairments of
executive function and working memory in schizophrenia(68). Dopamine D1 receptor
agonists/partial agonists have been putative targets for cognition enhancement for the
localization of D1 receptors in prefrontal cortex (PFC) profoundly may be associated
with higher cognitive function. PFC regulation behavior, thought, and working
memory and dopamine depletion may induce PFC cognitive impairment in animals
(69). Impairments of working memory and executive functioning domains have been
linked with decreased PFC dopamine signaling(70).A single subcutaneous dose of
dihydrexidine, a D1 selective agonists, was safe and increased prefrontal brain
perfusion in patients with schizophrenia in a pilot study(71). However, there are some
12
flaws need to be overcome: D1 receptor agonists have not been shown to exert any
cognitive improvement in human, chronic treatment with a D1 agonist may lead to
down-regulation of D1 receptors and may exacerbate cognitive dysfunction, and
direct-acting D1agonists on peripheral D1 receptors could lead to hypotensive
effects(72).
Catechol-O-methyltransferase inhibitor
Catechol-O-methyltransferase (COMT) methylates catecholamines and COMT
may be important for the breakdown of PFC dopamine levels, particularly during
performance of PFC-dependent tasks(73). Given the role of indirect
dopamine-activating regulation, the use of COMT inhibitors is another tractable
therapeutic target for cognitive impairments in schizophrenia. For examples, cognitive
performance was improved following inhibition of COMT with tolcapone, a COMT
antagonist, in rat(73). Clinical trials have been conducted to test the effects of COMT
inhibition on cognition in schizophrenia. Notably, tolcapone increased prepulse
inhibition (PPI) and improved performance in working memory tasks only in the
COMT Val158Met G/G group of healthy male subject suggesting that the efficacy may
be in condition of special pharmacogenetic background(74).
Glutaminergic targets
Glutamate is the most important excitatory amino acid in central nervous system
among mammalian animals, and affects the exercise and emotion function. There is
evidence supporting that deficient glutamatergic functioning is associated with
full-scale symptoms in schizophrenia(58). Moreover, many of susceptibility genes for
schizophrenia regulate synaptogenesis at glutamate synapses and glutamate
neurotransmission(60).
NMDA receptor antagonist
Agents acting at the glutamate system were the most frequently studied class of
13
pro-cognitive drugs since enhanced glutamate release from presynaptic neurons and
activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors assist long-term
potentiation (LTP) induction which is critical for strengthening synaptic plasticity and
facilitating learning(72). NMDA receptor is the most fine-defined glutamate receptor,
could modulate synaptic plasticity, memory, and cognition(75) and the dysfunction of
NMDA receptor might cause the lost of neuroplasticity and cognition
impairments(76). NMDA receptor antagonists could not only cause positive, negative,
and cognitive symptoms of schizophrenia in healthy subjects but also deteriorate
positive and negative symptoms in schizophrenic patients(77, 78). The important role
played by NMDA receptors in both the pathophysiology of schizophrenia and
neuronal plasticity suggest that enhancement of NMDA receptor function may cope
with the cognitive impairments in schizophrenia. NMDA receptor channels could be
functioned through glutamate and glycine sites and excitotoxicity could be prevented
while the glycine sites of NMDA receptor are enhanced (79, 80). These treatments
safely facilitate NMDA receptor function with agonists of the NMDA
receptor-associated glycine site included: D-serine(58, 81), glycine(82-84),
D-alanine(85), D-cycloserine(86, 87).
GlyT-I glycine transporter I (GlyT-1) inhibitor
Besides the action of agonists, NMDA receptor function also can be safely
enhanced indirectly with Glycine transporter I (GlyT-1) inhibitor. GlyT-1 inhibitor is
importnat in the process of NMDA glutamatergic neurotransmission(88, 89); the
glycine supply to synapse could be incresed through sarcosine by blocking the
reuptake of glycine(90). GlyT-1inhibitor has been one of the most promising
approaches for pro-cognitve agents via enhancing NMDA receptor function. For
example, sarcosine, an endogenous GlyT-1 inhibitor, alone or combined with other
antipsychotics could improve schizophrenia patients’ positive, negative, and
14
cognitive symptoms while comparing with placebo(91, 92). Another exapmle is
bitopertin, which is currently in a number of phase III clinical trials comparing its
effect on the symptoms of schizophrenia with placebo(93). From previous research
aimed on schizophrenia patients, it was suggested that D-Serine(58), glycine(94, 95),
and sarcosine(91) might modify part of cognitive function. However, study on the
efficacy of these NMDA enhancers for cognitive impairments in schizophrenia using
comprehensive tool such as MCCB is limited(96). Since glutamate metabolism ,
especially NMDA receptor paly an important role in plasticity and memory, further
approaches of cognitive enhancements associated with NMDA receptors are needed.
DAAO (D-amino acid oxidase) inhibitor
Another hopeful agent for treating schizophrenia is D-amino acid oxidase
(DAAO) inhibitor. DAAO, presents in mammals’ liver, kindney and brain(97), is the
main metabolic enzyme that decreases the effect of D-amino acids, like D-serine and
D-alanine(98, 99). When the activity of DAAO is restrained, the metabolism of
D-amino acids could be retarded so the additional way to reinforce NMDA receptor is
to restrain the activity of DAAO (58, 100). A randomized double blind trial has
showed that DAAO inhibitor modified cognitive function in chronic schizophrenia
patients (101), supporting the safety and pro-cognitive potential of DAAO inhibitor.
Since this is the first positive result among NMDA receptor- related clinical trials
using MCCB, further studies should be encouraged.
AMPA-receptor-positive modulation
The other indirect enhancement of NMDA receptor is activating glutamatergic
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.
Postsynaptic AMPA receptors provide the primary depolarization to activate NMDA
receptors, while NMDA receptors are required for cooperation of AMPA receptors to
15
process synaptic plasticity(72). Therefore, activation of AMPA receptors to enhance
glutamatergic transmission may be important for learning and memory. However,
AMPA receptors rapidly desensitize after activation. To avoid desensitization of
AMPA receptors, ampakines, allosteric potentiators of AMPA receptors function, are
managed as treatments for enhancing cognition in schizophrenia. The use of
ampakines were found to inhibit receptor deactivation and potentiate LTP and
improve performance of memory tasks in rodents(72). In a 4-weeks clinical trial of 21
schizophrenia patients on clozapine, coadministration of the ampakine CX-516
yielded significant improvements in memory and attention(102), however, in a larger
trial of 105 schizophrenia patients on atypical antipsychotics, CX-516 augmentation
was well tolerated but not show clear beneficial effects(103). Suboptimal does and
short half-life of CX-516 and short trial duration may contribute to the inconsistent
findings. Ampakines are heterogeneous with different potency, half-life and
pharmacodynamic effects, thus, besides CX-516, other AMPA-receptor-positive
modulation is still a highly active area of research.
Cholinergic targets
Acetylcholine is a critical mediator of learning and memory and degeneration of
the cholinergic neurons has been recognized as a part of the pathophysiology of
Alzheimer’s disease (AD). Cholinergic approach has been the main therapy for
cognitive decline in AD(104). In schizophrenia patients, anticholinergic drugs are
usually prescribed to patients taking antipsychotics to control extrapyramidal
symptoms induced by antipsychotic medication. Serum anticholinergic activity in
schizophrenia patients showed a significant association with impaired cognitive
performance and was significantly associated with a lowered response to cognitive
training(105). Taken together, cholinergic targets have been widely introduced to treat
cognitive impairment in schizophrenia.
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Nicotinic acetylcholine receptors
Agonists at nicotinic acetylcholine receptors increase in cholinergic activity and
may thereby benefit attention capacity, the variable of cognitive performance(106).
Nicotinic acetylcholine receptors (nAChR) and G-protein coupled muscarinic
receptors are the two receptor classes of acetylcholine. The two nAChR subtypes,
heteropentameric α4β2nAChRs and homopentameric α7nAChRs, are highly localized
within brain regions associated with mediating cognitive function, have received
much attention. The drugs targeting α4β2nAChR (106) and α7nAChRs(107) have
been tested for the role in cognitive dysfunction but the results of nAChR
agonists/partial agonists on cognition enhancement in patients with schizophrenia
were mixed.
Potential benefits for cognitive impairments and negative symptoms of
α7nAChRs (TC-5619) for in schizophrenia was reported recently (108). Of note, in
line with studies regarding cognitive improvements after nicotine administration in
patients with schizophrenia(109), the results of TC-5619 on the working memory
improvement were statistically significant smokers with schizophrenia. Other ongoing
trials may help to elucidate the uniqueness of nicotinic agonist treatments for
schizophrenia patients who are regular cigarette smokers.
Muscarinic acetylcholine receptors
Muscarinic acetylcholine receptors (mAChR) are classified into five subtypes
(M1 to M5) based on intracellular signaling pathways. The M1 mAChR, M4 mAChR,
and M2 mAChR expressed within the CNS predominantly and involved in regulating
the effects of Ach(110). M1 mAChR received much attention as a potential drug
target to improve learning and memory. Unfortunately, it is difficult to develop
selective agents for the different muscarinic receptor subtypes. No mAChR agonist,
however, has undergone successful clinical development, except a 4-week small pilot
study, schizophrenia subjects treated with xanomeline, a muscarinic agonist with
17
relative functional in vitro selectivity for the M1 and M4 receptor, showed
improvements in measures of verbal learning and short-term memory function(111).
Acetylcholinesterase inhibitors (AChEIs)
Acetylcholinesterase is the enzyme responsible for metabolizing acetylcholine in
the synaptic cleft. Inhibition of the enzyme via acetylcholinesterase inhibitors
(AChEIs) delays the breakdown of acetylcholine and elevates cholinergic
transmission. AChEIs including donepezil, rivastigmine and galantamine (a relative
lower potency AChEI with allosteric nicotinic receptor modulation properties) have
become the first line pharmacotherapy for mild to moderate AD though the treatment
effects on daily living activities and behavior are partially(104). Potential benefits of
AChEIs adjunctive therapy in cognitive impairments in schizophrenia was supposed,
however, there is weak clinical evidence that AChEIs benefit for schizophrenia in
randomized, placebo-controlled studies (112, 113).
γ-aminobutyric acid (GABA) targets
GABA is the main inhibitory neurotransmitter and GABA receptors are the
principal inhibitory neurotransmitter receptors in human CNS. Frontocortical GABA
interneurons and pyramidal cells integrate inputs from modulators controlling
cognitive function, including monoamines, acetylcholine and glutamate(114). GABA
type A (GABAA ) receptors modulate emotions, cognition, and muscle tone and are
targets of clinically used drugs, such as anxiolytics, sedatives, and hypnotics(115). A
disturbance in cortical GABAA receptor signaling connected with schizophrenia was
reported and it has been proposed that full positive allosteric modulators of α2, α3 or
α5 subunit subtype that are unrelated to the current uses of benzodiazepines may
provide therapeutic potential for the defect cognition in schizophrenia(114). MK-0777,
a relatively selective agonist at the GABAAα2 subtype, induced reversal of
ketamine-induced working memory impairments by the GABAA alpha2/3 agonism in
18
primates(116) and improvement of prefrontal-mediated delayed memory in
schizophrenia in a small sample size trial(117). In contrast with the promising
preliminary data, it was recently reported that MK-0777 did not have an improvement
in cognition of schizophrenia subjects in a large, multi-site, randomized clinical trial
and the authors suggested that a more potent partial agonist with greater intrinsic
activity at the GABAA α2 site might be needed for cognitive enhancement in
schizophrenia (118).
Serotonergic targets
5-hydroxytryptamine (Serotonin, 5-HT) transporters are widely distributed in the
brain areas linked to memory such as the hippocampus, frontal cortex and
striatum. Serotonin acts through several 5-HT receptors in the brain to modulate
dopaminergic neurotransmission(119) and the ultimate effect of 5-HT/DA interactions
has been posited as the main feature of atypical antipsychotics such as clozapine and
benefit to negative and cognitive deficits(120). 5-HT1A receptor agonists, 5-HT2C
receptor agonists, 5-HT6 receptor antagonists and 5-HT7 receptor ligands may
contribute to beneficial effects on schizophrenia including negative cognitive
symptoms (120, 121). It is also noteworthy that some selective 5-HT2A receptor
antagonists blocked the cognition-damage effects (prepulse inhibition) of NMDA
receptor antagonist in rats so that 5-HT2A antagonistic actions may normalizing
NMDA receptor function and thereby improve cognition in schizophrenia(122). In
addition, 5-HT4 receptor agonists and 5-HT6 receptor antagonists have shown
enhancing cholinergic transmission and 5-HT6 receptor antagonism also have shown
enhancing neurotransmission at glutamatergic neurons(72).
Taken together, studies suggest an intimate association between 5-HT receptors
and dopamine, acetylcholine and glutamine systems and imply that the modulation of
serotonin neurotransmission may prove value in the treatment of disorders involving
19
glutamatergic /dopamine /cholinergic dysfunction such as schizophrenia. However the
preclinical and clinical literatures are mixed regarding whether 5-HT agonists or
antagonists enhance cognition. Among the limited clinical feedbacks, a study of 6
weeks administration of tandospirone, a 5-HT1A partial agonist, augmented with
typical antipsychotic drugs enhanced verbal memory in 26 outpatients with
schizophrenia(123) but a risk for exacerbating positive symptoms of 5-HT agonist in
schizophrenia was a concern(72). To date, no compound aimed at 5-HT receptors
solely benefits cognitive function in schizophrenia patients. Moreover, many
approved atypical antipsychotics have 5-HT2A antagonist and 5-HT1A partial agonist
actions, it is unlikely that atypical antipsychotics have powerful efficacy of improving
cognition in schizophrenia. These results demonstrate that additional clinical studies
are needed.
Oxytocin and others
Oxytocin is released from the posterior pituitary in response to sexual
stimulation, uterine dilatation, nursing, and, in some situations, stress(124). Animal
studies connected oxytocin with social recognition, pair bonding, and parental
behavior while human studies associated oxytocin with facial emotion perception,
trust, and coping with stress(124, 125). Oxytocin may play important role in social
behavior and emotion regulation in humans and dopaminergic or glutamatergic
systems appear to mediate these effects(124).There have been growing trials on
oxytocin in neuropsychiatric disorders in recent 5 years. Single-dose infusion of
oxytocin showed improvements in affective speech comprehension in autistic
spectrum disorders(125), 2 weeks of intranasal oxytocin administration may improve
social cognition in schizophrenia(126). Moreover, 3 weeks of twice-daily intranasal
oxytocin adjunctive to standard antipsychotic medications caused reductions on the
Positive and Negative Symptom Scale and Clinical Global Impression-Improvement
20
Scale in schizophrenia subjects may support that oxytocin exhibits antipsychotic
properties(127). However, the sample size was very small and the trial duration was
brief in these studies. An important concern is that amnesic effects have been reported
in humans treated with oxytocin(128), although better verbal memory performance
with 3 weeks adjunctive intranasal oxytocin in schizophrenia subjects was reported
recently(129). Further comprehensive studies about the impact of oxytocin on both
social cognition and neurocognition in schizophrenia are needed.
Histamine H3 receptor antagonist (66), dopamine and noradrenaline-reuptake
transporter inhibitors, selective noradrenaline-reuptake inhibitor(130, 131),
wakefulness-promoting agent(132) have been also introduced as pro-cognitive agents
in schizophrenia, however, robust positive effect has not been reported yet(66).
We identified 59 published clinical trials on pro-cognitive drugs in schizophrenia
patients through the Pubmed website from January 1990 to February 2012 using the
terms ‘‘schizophrenia and dopamine agonists ’’, ‘‘schizophrenia and COMT ’’,
‘‘schizophrenia and glutamate’’, ‘‘schizophrenia and acetylcholine’’, ‘‘schizophrenia
and γ-aminobutyric acid ’’, ‘‘schizophrenia and serotonin ’’, ‘‘schizophrenia and
oxytocin ’’, ‘‘schizophrenia and histamine’’, ‘‘schizophrenia and norepinephrine’’, and
‘‘schizophrenia and stimulant’’. Positive results of modest to moderate degrees of
diverse cognitive improvement in 31 researches were reported, while negative results
were reported in 28studies (Supplemental Figure). Although the trend of bias of more
positive results on publications of newer experimental agents is unapparent, it should
be noted that according to the analysis of completed clinical trials of potential
pro-cognitive drugs in schizophrenia by Keefe et al(39), suboptimal statistical power
is a critical methodological issues. Therefore ongoing efforts should be made to
increase the probability of identifying pro-cognitive treatments in schizophrenia.
21
Non-pharmacological cognitive remediation therapy
Various psychosocial cognitive rehabilitation and enhancement programs ( also
often referred to as cognitive remediation therapy), that provide computerized
exercises, therapist-guided instruction, and group discussions to link training
exercises to everyday life have been introduced to remediate the cognitive
impairments in schizophrenia(133). The benefit of cognitive remediation therapy was
built upon repetitive training to enhance neuroplasticity of the brain(134) and
supported by the improved performance of neuropsychological test and the
accompanied neuroimaging change(135) and biological change(42). Meta-analytic
reviews supported the short-term benefits of cognitive remediation therapy on
cognitive domains with small to moderate effect(133, 136), and limited longitudinal
studies showed improvements in several cognitive domains endured at 6-12
months(137). In addition, higher dose and more broad-spectrum training programs
may be necessary to drive enduring gains of cognitive remediation therapy(137). It
should be noted that the small sample sizes and the characteristics of subjects (mostly
male patients, narrowed age distribution in mid-thirties, and requests of low symptom
severity and educational levels of enrolling for trials) (133, 136) limited the
generalization of the positive results and it is not yet clear whether or not cognitive
remediation therapy results in improved long-term functional outcome. The duration
and intensity/dose, and programs/strategies of cognitive remediation therapy have
been variable across studies since there has been rapid multiplication of new and
adapted cognitive remediation approaches. Long-term maintenance of cognitive
effects, the effectiveness of transferring to real-world functional competence and the
ideal duration/dose of cognitive rehabilitation programs remain unclear.
Nevertheless, the effectiveness of cognitive remediation is providing opportunity for
improving everyday functioning of schizophrenia patients.
22
It is interesting that cognitive remediation therapy that provided more
comprehensive integration with neurocognitive and psychosocial rehabilitation that
included coaching strategies and adjunctive social rehabilitation showed greater
effects on functioning (133, 135, 136), so there is a need to understand mediators and
moderators of the synergic benefit. Social cognition may impact the functional
outcome of independent living skills because intact social skills are vital for
negotiating good interpersonal interactions in real world(36). Neurocognitive
impairments may have an deleterious effect on social cognition and thereby social
cognition mediated neurocognition and functional outcome(35). Programs implant
social skill training may be a way to enhance the efficacy of cognitive remediation
therapy programs or even pro-cognitive agents.
Combination therapy
Augmentation of antipsychotics with combining of pro-cognitive agents and
cognitive rehabilitation programs would be expected to maximize the benefits of
cognitive improvement. Although the first study(96) of combined pharmacotherapy
(D-serine) and cognitive remediation therapy reported that while cognitive retraining
resulted in a significant improvement in verbal working memory, D-Serine or the
combination of D-Serine and cognitive retraining did not show any significant effect
on the global cognitive improvement in schizophrenia subjects. Since the safety and
tolerability were good in the combination therapy, future studies using higher doses of
D-serine or other pro-cognitive agents, along with the newer cognitive remediation
strategies has been encouraged(96). Another promising strategy is to combine with
two kinds of pro-cognitive agents via different mechanisms; however the safety and
tolerability should be investigated carefully.
Conclusions
Despite preclinical bench data, there has been limited positive clinical feedback
23
for current putative pro-cognitive drugs target in humans. Add-on, placebo-controlled,
double-blind design was predominant across the completed trials those tended to have
a small sample size (the majority was less than 50 subjects), to have a shorter study
duration (ranged from 2-24 weeks, 8 weeks was in the majority), to be an add-on trial,
and use a single cognitive outcome measure. There has been limited robust effect on
cognitive improvement so far for current pro-cognitive agents. The possible
methodological reasons, the limited sample sizes and the short treatment duration,
could be related with the suboptimal results of little changes in cognitive scores(39).
Moreover, to obtain robust and consistent effects, studies of pro-cognitive agents in
schizophrenia conducted in subjects who are younger, at an earlier stage of illness, or
have less severe cognitive impairments are necessary(138). Besides pharmacotherapy,
the benefit of cognitive remediation therapy is promising, however, the generalization
of the positive results has been limited and the variable programs across studies need
further integration. Combination therapy, by integrating pro-cognitive agents and
cognitive rehabilitation programs or combining two kinds of pro-cognitive agents via
different mechanisms is hopeful if safety and tolerability will be investigated
carefully.
Given the broad pattern of cognitive impairments, from attention and working
memory to social cognition in schizophrenia, the efficacy on a single dimension, such
as working memory, would not suffice to predict the effect on overall cognitive
improvement. Therefore, the lately ongoing trials with adequate sample size, with
comprehensive outcome measurement to meet adopted standards for cognitive
assessments and longer duration may be promising for investigating enhancement of
cognition with positive results in schizophrenia. Furthermore, more future studies
should be intensively focused on investigating the long-term efficacy, identity of
multinational sites, the rebound deterioration in psychosis/cognition following the
24
discontinuation, and co-outcomes of related biomarkers and daily functioning
improvement.
25
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Table 1. Batteries of assessing the cognitive impairments in schizophrenia
Battery
Domains (constructs)
Treatment Research to Improve Cognition in Schizophrenia Speed of processing
Consensus Cognitive Battery
Sustained attention
(MCCB)
References
(10)
Working memory, verbal and
Verbal
learning and memory
nonverbal
Visual learning and memory
Reasoning and problem solving
Social cognition
Brief Assessment of Cognition in Schizophrenia
Working memory
(BACS)
Motor speed
(29)
Verbal fluency
Attention and speed of information
Cognitive Drug Research Computerized
Executive functions
processing
Attention
Assessment System (CDR)
Working memory
(30)
Episodic Memory
CogTest Battery
Speed of Processing
(31)
Selective and Sustained Attention
Working Memory
Declarative Memory
Executive Function
Set Shifting
Conflict Functions
Language and Spatial Skills
Motor Speed and Laterality
Social Cognition
Cambridge Neuropsychological Test
Visual memory
Automated Battery (CANTAB)
Attention and reaction time
Verbal memory
Decision making and response
Executive function
control
Emotion recognition
Working memory
37
(32)
Table 2. Targets and clinical feedbacks for putative pro-cognitive agents in schizophrenia
Circuitries
Molecular action ( drug targets)
Feedbacks on cognition in schizophrenia
Potential adverse effects*
References
Dopamine metabolism Dihydrexidine
compounds
Tolcapone
Example
D1 selective agonists
Single dose: ↑prefrontal brain perfusion
Nausea, flushing dizziness, and hypotensive effects
(71, 72)
COMT inhibitor
Unavailable in schizophrenia
Hepatotoxicity in treating Parkinson's disease **
(74)
Glutamate metabolism Glycine
NMDA Glycine site agonists
Weak↑cognitive symptoms, MCCB unavailable
Renal toxicity in rats at high doses**
(83, 94)
D-serine
NMDA Glycine site agonists
Weak↑cognitive symptoms, MCCB unavailable
Upper digestive tract discomfort and drowsiness
(58)
D-cycloserine
NMDA glycine site agonism/partial agonist
Inactive in global cognitive functioning
Confusion, dizziness, headache, somnolence,
(86)
Sarcosine
NMDA Glycine reuptake inhibitors
Weak↑cognition symptoms, MCCB unavailable
Fatigability, hypersomnia, sedation, and tachycardia
(91, 92)
Benzoate
D-amino acid oxidase blocker
↑neurocognition
Weight gain, insomnia and tachycardia
(101)
CX-516
Positive modulators of glutamatergic
Pilot trial↑memory and attention
Insomnia, fatigue, heartburn,
(102)
aminomethylphosphonic acid (AMPA)
Larger trial: inactive
abdominal discomfort and hypertension
(103)
and seizure in treating tuberculosis**
Acetylcholine
TC-5619
Alpha-7 nicotinic receptor partial agonist
↑working memory in smokers
Constipation, nausea and insomnia.
(108)
metabolism
Xanomeline
Muscarinic M1, M4 receptors agonists
Pilot trial↑verbal learning and short-term memory
Nausea, vomiting, and other gastrointestinal distress
(111)
Donepezil
Cholinesterase inhibitors
(112, 113)
Selective GABAA receptor
Inactive
function in global cognitive functioning
Pilot trial↑memory
Dizziness and muscle cramp
MK-0777
Somnolence, brushing, hyper salivation
(117)
(GABA) metabolism
α2,3 subunit partial agonist
Larger trial: inactive in MCCB
Serotonin metabolism Tandospirone
5HT1A partial agonists
Pilot trial ↑working memory and verbal memory
γ-aminobutyric acid
(118)
Nausea, diarrhea, headache, dizziness, and restlessness
(123)
Dimebon
5-HT6 antagonist
Trend of ↑working memory and attention
Oxytocin
Oxytocin
Oxytocin receptor agonist
Pilot trial intranasal oxytocin↑social memory
Amnestic effects and endocrine side effects
(126)
Pilot trial intranasal oxytocin↑verbal memory
cause by intravenous administration
(129)
Others
MK0249
H3 receptor antagonist
Inactive in attention, episodic memory,
Insomnia, anxiety, nausea and headache
(66)
(130)
(121)
and working memory
Atomoxetine
Note:
Selective noradrenaline-reuptake inhibitor
Inactive in cognitive performance, but was associated
Decreased appetite, dry mouth, nausea, vomiting,
dizziness, fatigability, and mood swings
Reboxetine
Selective noradrenaline-reuptake inhibitor
with
increases in left dorsolateral PFC and PCC.
with increases
Inactive in visual-spatial memory, sustained attention
As
above dizziness, fatigability and mood swings.
vomiting,
(131)
Armodafinil,
Wakefulness-promoting agent
Inactive in global cognitive functioning
Diarrhea, headache, muscle spasm, and restlessness
(132)
Modafinil
restlessness
38
* No dropout was due to severe adverse effect in current available clinical trials .
**No detrimental changes in clinical laboratory parameters in clinical trials.
Abbreviations:
COMT: Catechol-O-methyltransferase ; NMDA: N-methyl-D-aspartate
MCCB: Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery
DLPFC: dorsolateral prefrontal cortex PCC: posterior cingulate cortex
39
Supplemental Figure
Ratios of positive and negative results of clinical trials focused on pro-cognitive effect in schizophrenia, by different circuitries.
Abbreviations:
GABA: γ-aminobutyric acid
Legend of supplemental figure
59 published clinical trials with cognitive improvement as the primary or secondary outcome of schizophrenia subjects through searches of the
Pubmed website using the terms ‘‘schizophrenia and dopamine agonists ’’, ‘‘schizophrenia and COMT ’’, ‘‘schizophrenia and glutamate’’,
‘‘schizophrenia and acetylcholine’’, ‘‘schizophrenia and γ-aminobutyric acid ’’, ‘‘schizophrenia and serotonin ’’, ‘‘schizophrenia and oxytocin ’’,
‘‘schizophrenia and histamine’’, ‘‘schizophrenia and norepinephrine’’, and ‘‘schizophrenia and stimulant’’ were identified from January 1990 to
February 2012. Positive results of modest to moderate degrees of cognitive improvement in 31 researches were reported, while negative results
were reported in 28 studies.
40
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