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The neuropsychology of schizophrenia
Research aspects
The neuropsychology of schizophrenia
What’s new? • Despite admissions that antipsychotic medication is inadequate for the task of treating cognitive impairment, enthusiasm remains in respect of cognitive enhancement in schizophrenia
Ann M Mortimer
• Associations between genes, cognitive deficits, structural parameters, and functional activation are beginning to be elucidated. Even so, heterogeneity remains a prime vexation in establishing an overall position, assisted by the limitations of current cognitive paradigms
Abstract The ubiquity of neuropsychological impairment in schizophrenia is now irrefutable: it is perhaps the most common symptom apart from lack of insight. There is general agreement about what is impaired and what is preserved. Unifying theories of its root cause are beginning to take shape, but its pathophysiological basis is not. Moreover, exactly where neuropsychological impairment fits into an overall model of schizophrenia is less clear. Whether it represents a risk factor, an intrinsic component, a mediator of genetic liability, a fixed or remediable entity is not known. Its natural history is variable and, despite theoretical perspectives, its treatment with antipsychotic and other drugs is far from impressive. Finally, although the impact of neuropsychological impairment on personal and social function is reasonably well established, the relationship is probably much more complex and less exclusive than has been thought.
• Major efforts to elucidate the pathways from cognitive impairment to real-world performance deficit are similarly afflicted, and further complicated by other consequential factors – the rising tide of substance abuse is the latest of these
than go on to develop the disorder.6 Twin studies have demonstrated substantial genetic overlap between cognition and schizophrenia.7 Regarding the neurodevelopmental perspective, a recent study of patients reported an arrest of psychological development according to the Piaget model.8 Supporting the idea that cognitive deficit, however sustained, is a risk factor for schizophrenia is the finding that patients with velocardiofacial syndrome accompanied by neuropsychological impairment, and brain-injured patients with neuropsychological impairment, are the ones who develop schizophrenia; patients with either condition who are free from impairment do not. Associated manifestations of vulnerability to schizophrenia may include neurological and neurophysiological anomaly; combinations of even subtle differences could be predictive of disease onset. Nevertheless, those at high risk of schizophrenia do not demonstrate the levels of impairment typically found within and beyond the first episode. This indicates that prodromal interventions may reduce cognitive impairment, but there is no convincing evidence that early interventions of any kind prevent cognitive decline. As is the case with every other aspect of schizophrenia, there is much heterogeneity of the cognitive profile amongst groups of patients. Some associations have been demonstrated linking functional magnetic resonance imaging parameters to differing neuropsychological profiles.9,10 Genetic research has linked particular single-nucleotide polymorphisms with specific and general neuropsychological deficits,11 and there is some evidence from functional neuro-imaging of association between genotype, working memory performance, and functional activation. Unfortunately, replication is the exception rather than the rule; it is suspected that available neuropsychological tests are not sufficiently specific to ‘map on to’ genetic and activation profiles.12 Even so, the ubiquity and potential utility of cognitive deficit in schizophrenia suggests that it is a core feature of schizophrenia, and ought to be included as a diagnostic criterion.13 It is relevant that dopamine, the target of all antipsychotic drugs, is a powerful regulator and integrator of executive and cognitive functions.14
Keywords cognition; impairment; neuropsychology; schizophrenia
Introduction Cognitive impairment is more common than most other symptoms of schizophrenia; 85% of patients are impaired on comprehensive neuropsychological assessment, compared with 5% of healthy volunteers.1 Almost all patients (98%) have a cognitive deficit according to what is predicted by premorbid estimates.2 Neuropsychological domains affected in schizophrenia include overall cognition, attention, memory, and executive function. Language function and perception are relatively spared. This pattern of deficits may be due to a marked slowing of cognitive processing speed.3 A related ‘core’ process with the potential to explain the pattern of dysfunction is impaired processing of context.4,5 It has been proposed that cognitive approaches hold promise for understanding variability in the neurobiological substrates of schizophrenia. Enhanced genetic risk has been linked to both neuropsychological impairment and symptoms, suggesting that what is inherited is a state of vulnerability manifested by neuropsychological impairment, occurring in many more individuals
Ann M Mortimer FRCPsych DSc is Foundation Chair in Psychiatry at the University of Hull, UK. She qualified in medicine from Leicester University, UK, where she also completed a degree in biochemistry and genetics research. She also runs inpatient rehabilitation services for East Yorkshire and assertive outreach for Hull, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:10
435
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
Given the impact of cognitive deficit on the social function of patients with schizophrenia, important questions remain regarding whether such deficits are remediable by pharmacological or other means. The interrelationships of aspects of schizophrenia, particularly causal associations, remain a matter for conjecture (Figures 1–3). Expanding the argument is the question of risk factors, and how the presence of these impacts upon later manifestations of established illness in the minority who succumb.
factors, which may or may not progress; they are independent of the symptoms that, by contrast, do respond to antipsychotic drugs. The poor results of attempts to remediate cognition in established schizophrenia tend to suggest that once decline has taken place that, too, is a fixed entity. Over recent years a further complicating factor has surfaced in the form of alcohol and substance misuse, particularly cannabis. Studies have reported conflicting results with cognitive impairment or enhancement from misusing the same substances.20 There is no overall theoretical or methodological framework within which to study substance effects and their many confounders. It is tempting to ascribe better performance in substance-abusing patients compared to the non-abusing group to the assumption that a certain degree of general cognitive function is required to source and fund their substance use. More severely affected patients may be merely cognitively incapable of that level of organization. Even so, much work continues to find agents that will reverse cognitive impairment in schizophrenia.21 Preclinical models suggest the utility of approaches involving modulation of cholinergic, dopaminergic, and glutamatergic neurotransmission, but their extrapolation to the availability of safe, clinically effective, treatments has not yet come to fruition.22 Such approaches presuppose that the deficit, whatever it is, is reversible. Given the notion of pre-existing cognitive deficit as a risk factor, combined with still poor understanding of the pathophysiology of cognitive decline, this assumption may well prove unsound.
Natural history and treatability of neuropsychological deficit Cognitive impairment is present at onset, rather than being caused by medication, illness progression, and symptoms. Cross-sectional studies find similar levels of impairment in different groups of cooperative patients with schizophrenia despite wide ranges of age and illness duration; comparable levels of deficit have been reported in both first-episode and chronic patients. In the most severely affected patients there is some evidence of slow progressive cognitive decline. Longer duration of illness and greater overall cognitive impairment have been observed along a spectrum of patients, progressing from those with deficits related to the temporal lobe, to patients with frontal lobe deficits, and culminating in those with deficits indicating widespread brain involvement.15 A recent review suggested that deficits present at onset remained stable for 2–5 years before decline began.16 Antipsychotic treatment would appear to have the potential to remediate cognitive impairment, but its effects seem very limited in practice; behavioural interventions are costly and labour intensive, even when effective.17 In early schizophrenia, composite neuropsychological scores failed to improve by even half a standard deviation after antipsychotic drug treatment.18 Observed improvement may simply reflect a practice effect.19 Indeed, although overall symptom severity may be a strong concomitant of deficit, studies that investigated cognitive improvement longitudinally from relapse have demonstrated both positive and negative findings, despite apparent symptomatic recovery in all studies. There appears, therefore, to be no direct link between reduction in symptoms and reduction in neuropsychological deficit, despite numerous cross-sectional associations between symptoms and cognition. This tends to support the notion of these deficits as relatively fixed pre-existing risk
Overall intellectual deficit Schizophrenia is characterized by a general compromise of intellectual function, ranging from a fall in IQ score and poor performance on a wide range of tests, to frank dementia. A recent meta-analysis of 1275 studies of cognition in schizophrenia observed an effect size of schizophrenia of 1.01 for both current and premorbid IQ.23
Attention Attention is not a unitary function: it comprises alertness, orientation to salient stimuli, and executive control of choice of response. One task that involves all three is the digit symbol
Levels of pathology model in schizophrenia Specific brain pathologies: developmental, neurochemical, traumatic, genetic, anatomical, etc.
?
?
?
Neuropsychological dysfunction: dysexecutive syndrome, memory impairment, general intellectual decline, etc.
?
?
?
?
?
Clinical symptoms, neurological symptoms, deficits in personal function, behaviour problems, etc.
Clinical/demographic variables: sex, age, severity, chronicity, etc.
?
Figure 1
PSYCHIATRY 7:10
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© 2008 Elsevier Ltd. All rights reserved.
Research aspects
Independent consequences model in schizophrenia Pathophysiologies
Symptoms
Cognitive impairments
Functional impairment
Functional impairment
Pathophysiologies cause both symptoms and cognitive impairments: symptoms and cognitive impairments are independent of each other, and both give rise to functional deficit
Figure 2
coding task. A recent meta-analysis3 suggested an effect size on performance in schizophrenia of 1.57, greater than in any other test considered. This may well be a result of the overlap with executive processes (see below).
of memory is that all recent reviews and meta-analyses have found consistent deficits in most, if not all, aspects of declarative memory.24 Encoding rather than storage and retrieval (forgetting) is impaired, although in patients with a very severe, chronic condition semantic store is compromised as well.25 It has been suggested that memory disorder is disproportionate to other deficits in cognition in schizophrenia, and that substantial impairments can be found even in patients without any overall clinically significant cognitive compromise, for instance those with normal Mini-Mental State Examination scores. By contrast, non-declarative memory is preserved, unless there is significant general intellectual impairment.
Memory impairment in schizophrenia Memory overall is classified into declarative and non-declarative types, sometimes referred to as explicit and implicit memory respectively. Declarative memory includes episodic memory – what most people would call memory; in other words, memories of personally experienced events with a time and place context. The other major subdivision of declarative memory is semantic memory, what most people would call knowledge, consisting of culturally shared remembered facts without time or place connotations. Non-declarative memory function includes unconscious processes such as priming and classical conditioning. It also includes procedural memory, that is, cognitive or motor skills that become automated by repeated practice; a good example is driving a car. Some parts of memory function are further divided, for instance verbal versus non-verbal memory, working memory versus long-term memory, recall versus recognition memory, etc. Some types of memory can be broken down into encoding, storage and retrieval. The ‘take home message’ in respect
Working memory deficits Working memory can be considered as an extension of shortterm memory span (7 ± 2 items). It holds auditory and visual information ‘online’ (the phonological loop and the visuospatial sketchpad), manipulated by a ‘central executive’. Although memory span is normal, central executive function is impaired: maintenance and manipulation of what is contained in the phonological loop and the visuospatial sketchpad is faulty. There is a substantial body of opinion that working memory deficit may be at the core of a range of cognitive deficits in schizophrenia, as it is crucial to so many cognitive tasks.
Domains model in schizophrenia: causality and patterns of association are variable or unknown Positive symptoms
Cognitive and attentional disturbance
? Functional impairment
Deficit (negative) symptoms Neurological symptoms
Figure 3
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© 2008 Elsevier Ltd. All rights reserved.
Research aspects
schizophrenia and their results. The potential to reverse cognitive impairment may be severely limited by poorly understood pathophysiological factors, despite assumptions about treatability based on preclinical neuroscience. Therefore, control of symptoms, prevention of relapse, and rehabilitative strategies aiming to maximize personal and social function must remain the mainstay of treatment in schizophrenia. It seems highly unlikely that any treatment will ever succeed in retrieving premorbid levels of cognition, or turn the clock back on personal and social function. ◆
Deficits in executive (frontal lobe) function Executive function is even less of a unitary concept than attention. A distributed set of cortical networks based in, but not limited to, the frontal lobes facilitates the maintenance or shifting of cognitive responses, guiding a behavioural sequence to its overall goal. Such executive control must draw on memory of the past and anticipation of the future environment, generation of and choice between behavioural alternatives, and modification of planning according to ongoing feedback. Numerous tests, the best known being the Wisconsin Card Sorting Test, are performed poorly by patients with schizophrenia.3 Executive dysfunction, particularly set shifting and error monitoring, is particularly related to lack of insight in psychotic disorder in general.26
References 1 Palmer B, Heaton R, Paulsen J. Is it possible to be schizophrenic and neurologically normal? Neuropsychology 1997; 11: 437–47. 2 Keefe R, Eesley C, Pie M. Defining a cognitive function decrement in schizophrenia. Biol Psychiatry 2005; 57: 688–91. 3 Dickinson D, Ramsey M, Gold J. Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry 2007; 64: 532–42. 4 Hemsley D. The development of a cognitive model of schizophrenia: placing it in context. Neurosci Biobehav Rev 2005; 29: 977–88. 5 Barch D. What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience 2006; 139: 73–84. 6 Byrne M, Clafferty B, Cosway R, Grant E, Hodges A, Whalley H. Neuropsychology, genetic liability, and psychotic symptoms in those at high risk of schizophrenia. J Abnorm Psychol 2003; 112: 38–48. 7 Toulopoulou T, Picchioni M, Rijsdijk F, et al. Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Arch Gen Psychiatry 2007; 64: 1348–55. 8 Torres A, Olivares J, Rodriguez A, Vaamonde A, Berrios G. An analysis of the cognitive deficit of schizophrenia based on the Piaget developmental theory. Compr Psychiatry 2007; 48: 376–79. 9 Osuji I, McGarrahan A, Mihalakos P, Garver D, Kingsbury S, Cullum C. Neuropsychological functioning in MRI-derived subgroups of schizophrenia. Schizophr Res 2007; 92: 189–96. 10 Nestor P, Onitsuka T, Gurrera R, et al. Dissociable contributions of MRI volume reductions of superior temporal and fusiform gyri to symptoms and neuropsychology in schizophrenia. Schizophr Res 2007; 91: 103–106. 11 Burdick K, Goldberg T, Funke B, et al. DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 2007; 89: 169–72. 12 Joyce E, Roiser J. Cognitive heterogeneity in schizophrenia. Curr Opin Psychiatry 2007; 20: 268–72. 13 Keefe R, Fenton W. How should DSM-IV criteria for schizophrenia include cognitive impairment? Schizophr Bull 2007; 33: 912–20. 14 Nieoullon A, Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol 2003; 16(Suppl. 2): S3–S9. 15 Kremen W, Seidman L, Faraone S, Toomey R, Tsuang M. Heterogeneity of schizophrenia: a study of individual neuropsychological profiles. Schizophr Res 2004; 71: 307–21. 16 Ojeda N, Sanchez P, Elizagarate E, et al. Course of cognitive symptoms in schizophrenia: a review of the literature. Actas Esp Psiquiatr 2007; 35: 263–70.
Clinical relevance of neuropsychological dysfunction in schizophrenia Earlier work claimed that specific types of neuropsychological performance and deficit predicted aspects of personal and social function. Despite its potential usefulness in the prediction of care needs, this work has not been translated into routine initiatives in patient care. It is clear that numerous other factors make a marked contribution to ‘real-world’ skills and the motivation that leads to their use. For instance, it was recently demonstrated that the contribution of neuropsychological performance to real-world skills was mediated by its influence on ‘functional capacity’, in other words the formal assessment of specific life skills under optimal conditions, something that may have much in common with certain neuropsychological tests themselves. Furthermore, depression and negative symptoms also predicted real-world skills, independently of functional capacity.27 Moreover, an initiative to produce evaluation protocols for cognition, functional capacity, and real-world skills, with an ultimate objective of application to pharmacological treatment effects, reported similar dissociation between real-world skills and the rest.28 Finally, premorbid risk, in terms of borderline of reduced intellectual functioning, adversely affected every aspect of schizophrenia observed in a recent large study29 and predicted function 10 years later.30
Conclusion Neuropsychological deficit in schizophrenia is ubiquitous and almost certainly related to risk and pathophysiology. Current tests of cognitive function lack specificity and precision, but understanding of the individual components of cognitive function is increasing. As a result, unifying theories about the core deficit in schizophrenic cognitive function are beginning to emerge. Research that integrates genetic analysis and cognitive evaluation with structural and functional neuro-imaging is beginning to reveal clinicopathological correlations of great interest. However, associations of cognitive deficit with personal function, social function, and symptoms are further removed. Complex and unclear, these relationships continue to defy attempts at simplification. Other factors may impact more cogently on these important aspects of patient outcome, affect, and personality, representing the most likely prospects here. Unfortunately, current drug and psychological treatments appear to have little impact on neuropsychological deficits in
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Research aspects
17 Bowie C, Jaga K. Methods for treating cognitive deficits in schizophrenia. Expert Rev Neurother 2007; 7: 281–87. 18 Keefe R, Sweeney J, Gu H, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early schizophrenia: a randomized double-blind 52-week comparison. Am J Psychiatry 2007; 164: 1061–71. 19 Goldberg T, Goldman R, Burdick K, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 2007; 64: 1115–22. 20 Coulston C, Perdices M, Tennant C. The neuropsychology of cannabis and other substance use in schizophrenia: review of the literature and critical evaluation of methodological issues. Aust N Z J Psychiatry 2007; 41: 869–84. 21 Carter C, Barch D. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia. Schizophr Bull 2007; 33: 1131–37. 22 Buchanan R, Freedman R, Javitt D, Abi-Dargham A, Lieberman J. Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007; 33: 1120–30. 23 Fioravanti M, Carlone M, Vitale B, Cinti M, Clare L. A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychol Rev 2005; 15: 73–95. 24 Reichenberg A, Harvey P. Neuropsychological impairments in schizophrenia: integration of performance-based and brain imaging findings. Psychol Bull 2007; 133: 833–58. 25 Laws K, Al-Uzri M, Mortimer A. Lexical knowledge degradation in schizophrenia. Schizophr Res 2000; 45: 123–31. 26 Aleman A, Agrawal N, Morgan K, David A. Insight in schizophrenia and neuropsychological function: meta-analysis. Br J Psychiatry 2006; 189: 204–12.
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27 Bowie C, Reichenberg A, Patterson T, et al. Determinants of realworld functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am J Psychiatry 2006; 163: 418–25. 28 Harvey P, Cornblatt B. Pharmacological treatment of cognition in schizophrenia: an idea whose method has come. Am J Psychiatry 2008; 165: 163–65. 29 Chaplin R, Barley M, Cooper S, et al. The impact of intellectual functioning on symptoms and service use in schizophrenia. J Intellect Disabil Res 2006; 50: 288–94. 30 van Winkel R, Myin-Germeys I, De Hert M, Delespaul P, Peuskens J, Van Os J. The association between cognition and functional outcome in first-episode patients with schizophrenia: mystery resolved? Acta Psychiatr Scand 2007; 116: 119–24.
Practice points • Neuropsychological impairment constitutes a risk factor for schizophrenia and worsens during the illness course • There are deficits in general intellect, memory, executive function, attention, and working memory. Language, nondeclarative memory, and perception are relatively preserved • Assumptions that cognitive impairment is treatable may not be true in many patients • Personal and social function rely on much more than neuropsychological performance • Substances of abuse also affect cognitive function
439
© 2008 Elsevier Ltd. All rights reserved.
The neuropsychology of schizophrenia
What’s new? • Despite admissions that antipsychotic medication is inadequate for the task of treating cognitive impairment, enthusiasm remains in respect of cognitive enhancement in schizophrenia
Ann M Mortimer
• Associations between genes, cognitive deficits, structural parameters, and functional activation are beginning to be elucidated. Even so, heterogeneity remains a prime vexation in establishing an overall position, assisted by the limitations of current cognitive paradigms
Abstract The ubiquity of neuropsychological impairment in schizophrenia is now irrefutable: it is perhaps the most common symptom apart from lack of insight. There is general agreement about what is impaired and what is preserved. Unifying theories of its root cause are beginning to take shape, but its pathophysiological basis is not. Moreover, exactly where neuropsychological impairment fits into an overall model of schizophrenia is less clear. Whether it represents a risk factor, an intrinsic component, a mediator of genetic liability, a fixed or remediable entity is not known. Its natural history is variable and, despite theoretical perspectives, its treatment with antipsychotic and other drugs is far from impressive. Finally, although the impact of neuropsychological impairment on personal and social function is reasonably well established, the relationship is probably much more complex and less exclusive than has been thought.
• Major efforts to elucidate the pathways from cognitive impairment to real-world performance deficit are similarly afflicted, and further complicated by other consequential factors – the rising tide of substance abuse is the latest of these
than go on to develop the disorder.6 Twin studies have demonstrated substantial genetic overlap between cognition and schizophrenia.7 Regarding the neurodevelopmental perspective, a recent study of patients reported an arrest of psychological development according to the Piaget model.8 Supporting the idea that cognitive deficit, however sustained, is a risk factor for schizophrenia is the finding that patients with velocardiofacial syndrome accompanied by neuropsychological impairment, and brain-injured patients with neuropsychological impairment, are the ones who develop schizophrenia; patients with either condition who are free from impairment do not. Associated manifestations of vulnerability to schizophrenia may include neurological and neurophysiological anomaly; combinations of even subtle differences could be predictive of disease onset. Nevertheless, those at high risk of schizophrenia do not demonstrate the levels of impairment typically found within and beyond the first episode. This indicates that prodromal interventions may reduce cognitive impairment, but there is no convincing evidence that early interventions of any kind prevent cognitive decline. As is the case with every other aspect of schizophrenia, there is much heterogeneity of the cognitive profile amongst groups of patients. Some associations have been demonstrated linking functional magnetic resonance imaging parameters to differing neuropsychological profiles.9,10 Genetic research has linked particular single-nucleotide polymorphisms with specific and general neuropsychological deficits,11 and there is some evidence from functional neuro-imaging of association between genotype, working memory performance, and functional activation. Unfortunately, replication is the exception rather than the rule; it is suspected that available neuropsychological tests are not sufficiently specific to ‘map on to’ genetic and activation profiles.12 Even so, the ubiquity and potential utility of cognitive deficit in schizophrenia suggests that it is a core feature of schizophrenia, and ought to be included as a diagnostic criterion.13 It is relevant that dopamine, the target of all antipsychotic drugs, is a powerful regulator and integrator of executive and cognitive functions.14
Keywords cognition; impairment; neuropsychology; schizophrenia
Introduction Cognitive impairment is more common than most other symptoms of schizophrenia; 85% of patients are impaired on comprehensive neuropsychological assessment, compared with 5% of healthy volunteers.1 Almost all patients (98%) have a cognitive deficit according to what is predicted by premorbid estimates.2 Neuropsychological domains affected in schizophrenia include overall cognition, attention, memory, and executive function. Language function and perception are relatively spared. This pattern of deficits may be due to a marked slowing of cognitive processing speed.3 A related ‘core’ process with the potential to explain the pattern of dysfunction is impaired processing of context.4,5 It has been proposed that cognitive approaches hold promise for understanding variability in the neurobiological substrates of schizophrenia. Enhanced genetic risk has been linked to both neuropsychological impairment and symptoms, suggesting that what is inherited is a state of vulnerability manifested by neuropsychological impairment, occurring in many more individuals
Ann M Mortimer FRCPsych DSc is Foundation Chair in Psychiatry at the University of Hull, UK. She qualified in medicine from Leicester University, UK, where she also completed a degree in biochemistry and genetics research. She also runs inpatient rehabilitation services for East Yorkshire and assertive outreach for Hull, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:10
435
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
Given the impact of cognitive deficit on the social function of patients with schizophrenia, important questions remain regarding whether such deficits are remediable by pharmacological or other means. The interrelationships of aspects of schizophrenia, particularly causal associations, remain a matter for conjecture (Figures 1–3). Expanding the argument is the question of risk factors, and how the presence of these impacts upon later manifestations of established illness in the minority who succumb.
factors, which may or may not progress; they are independent of the symptoms that, by contrast, do respond to antipsychotic drugs. The poor results of attempts to remediate cognition in established schizophrenia tend to suggest that once decline has taken place that, too, is a fixed entity. Over recent years a further complicating factor has surfaced in the form of alcohol and substance misuse, particularly cannabis. Studies have reported conflicting results with cognitive impairment or enhancement from misusing the same substances.20 There is no overall theoretical or methodological framework within which to study substance effects and their many confounders. It is tempting to ascribe better performance in substance-abusing patients compared to the non-abusing group to the assumption that a certain degree of general cognitive function is required to source and fund their substance use. More severely affected patients may be merely cognitively incapable of that level of organization. Even so, much work continues to find agents that will reverse cognitive impairment in schizophrenia.21 Preclinical models suggest the utility of approaches involving modulation of cholinergic, dopaminergic, and glutamatergic neurotransmission, but their extrapolation to the availability of safe, clinically effective, treatments has not yet come to fruition.22 Such approaches presuppose that the deficit, whatever it is, is reversible. Given the notion of pre-existing cognitive deficit as a risk factor, combined with still poor understanding of the pathophysiology of cognitive decline, this assumption may well prove unsound.
Natural history and treatability of neuropsychological deficit Cognitive impairment is present at onset, rather than being caused by medication, illness progression, and symptoms. Cross-sectional studies find similar levels of impairment in different groups of cooperative patients with schizophrenia despite wide ranges of age and illness duration; comparable levels of deficit have been reported in both first-episode and chronic patients. In the most severely affected patients there is some evidence of slow progressive cognitive decline. Longer duration of illness and greater overall cognitive impairment have been observed along a spectrum of patients, progressing from those with deficits related to the temporal lobe, to patients with frontal lobe deficits, and culminating in those with deficits indicating widespread brain involvement.15 A recent review suggested that deficits present at onset remained stable for 2–5 years before decline began.16 Antipsychotic treatment would appear to have the potential to remediate cognitive impairment, but its effects seem very limited in practice; behavioural interventions are costly and labour intensive, even when effective.17 In early schizophrenia, composite neuropsychological scores failed to improve by even half a standard deviation after antipsychotic drug treatment.18 Observed improvement may simply reflect a practice effect.19 Indeed, although overall symptom severity may be a strong concomitant of deficit, studies that investigated cognitive improvement longitudinally from relapse have demonstrated both positive and negative findings, despite apparent symptomatic recovery in all studies. There appears, therefore, to be no direct link between reduction in symptoms and reduction in neuropsychological deficit, despite numerous cross-sectional associations between symptoms and cognition. This tends to support the notion of these deficits as relatively fixed pre-existing risk
Overall intellectual deficit Schizophrenia is characterized by a general compromise of intellectual function, ranging from a fall in IQ score and poor performance on a wide range of tests, to frank dementia. A recent meta-analysis of 1275 studies of cognition in schizophrenia observed an effect size of schizophrenia of 1.01 for both current and premorbid IQ.23
Attention Attention is not a unitary function: it comprises alertness, orientation to salient stimuli, and executive control of choice of response. One task that involves all three is the digit symbol
Levels of pathology model in schizophrenia Specific brain pathologies: developmental, neurochemical, traumatic, genetic, anatomical, etc.
?
?
?
Neuropsychological dysfunction: dysexecutive syndrome, memory impairment, general intellectual decline, etc.
?
?
?
?
?
Clinical symptoms, neurological symptoms, deficits in personal function, behaviour problems, etc.
Clinical/demographic variables: sex, age, severity, chronicity, etc.
?
Figure 1
PSYCHIATRY 7:10
436
© 2008 Elsevier Ltd. All rights reserved.
Research aspects
Independent consequences model in schizophrenia Pathophysiologies
Symptoms
Cognitive impairments
Functional impairment
Functional impairment
Pathophysiologies cause both symptoms and cognitive impairments: symptoms and cognitive impairments are independent of each other, and both give rise to functional deficit
Figure 2
coding task. A recent meta-analysis3 suggested an effect size on performance in schizophrenia of 1.57, greater than in any other test considered. This may well be a result of the overlap with executive processes (see below).
of memory is that all recent reviews and meta-analyses have found consistent deficits in most, if not all, aspects of declarative memory.24 Encoding rather than storage and retrieval (forgetting) is impaired, although in patients with a very severe, chronic condition semantic store is compromised as well.25 It has been suggested that memory disorder is disproportionate to other deficits in cognition in schizophrenia, and that substantial impairments can be found even in patients without any overall clinically significant cognitive compromise, for instance those with normal Mini-Mental State Examination scores. By contrast, non-declarative memory is preserved, unless there is significant general intellectual impairment.
Memory impairment in schizophrenia Memory overall is classified into declarative and non-declarative types, sometimes referred to as explicit and implicit memory respectively. Declarative memory includes episodic memory – what most people would call memory; in other words, memories of personally experienced events with a time and place context. The other major subdivision of declarative memory is semantic memory, what most people would call knowledge, consisting of culturally shared remembered facts without time or place connotations. Non-declarative memory function includes unconscious processes such as priming and classical conditioning. It also includes procedural memory, that is, cognitive or motor skills that become automated by repeated practice; a good example is driving a car. Some parts of memory function are further divided, for instance verbal versus non-verbal memory, working memory versus long-term memory, recall versus recognition memory, etc. Some types of memory can be broken down into encoding, storage and retrieval. The ‘take home message’ in respect
Working memory deficits Working memory can be considered as an extension of shortterm memory span (7 ± 2 items). It holds auditory and visual information ‘online’ (the phonological loop and the visuospatial sketchpad), manipulated by a ‘central executive’. Although memory span is normal, central executive function is impaired: maintenance and manipulation of what is contained in the phonological loop and the visuospatial sketchpad is faulty. There is a substantial body of opinion that working memory deficit may be at the core of a range of cognitive deficits in schizophrenia, as it is crucial to so many cognitive tasks.
Domains model in schizophrenia: causality and patterns of association are variable or unknown Positive symptoms
Cognitive and attentional disturbance
? Functional impairment
Deficit (negative) symptoms Neurological symptoms
Figure 3
PSYCHIATRY 7:10
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© 2008 Elsevier Ltd. All rights reserved.
Research aspects
schizophrenia and their results. The potential to reverse cognitive impairment may be severely limited by poorly understood pathophysiological factors, despite assumptions about treatability based on preclinical neuroscience. Therefore, control of symptoms, prevention of relapse, and rehabilitative strategies aiming to maximize personal and social function must remain the mainstay of treatment in schizophrenia. It seems highly unlikely that any treatment will ever succeed in retrieving premorbid levels of cognition, or turn the clock back on personal and social function. ◆
Deficits in executive (frontal lobe) function Executive function is even less of a unitary concept than attention. A distributed set of cortical networks based in, but not limited to, the frontal lobes facilitates the maintenance or shifting of cognitive responses, guiding a behavioural sequence to its overall goal. Such executive control must draw on memory of the past and anticipation of the future environment, generation of and choice between behavioural alternatives, and modification of planning according to ongoing feedback. Numerous tests, the best known being the Wisconsin Card Sorting Test, are performed poorly by patients with schizophrenia.3 Executive dysfunction, particularly set shifting and error monitoring, is particularly related to lack of insight in psychotic disorder in general.26
References 1 Palmer B, Heaton R, Paulsen J. Is it possible to be schizophrenic and neurologically normal? Neuropsychology 1997; 11: 437–47. 2 Keefe R, Eesley C, Pie M. Defining a cognitive function decrement in schizophrenia. Biol Psychiatry 2005; 57: 688–91. 3 Dickinson D, Ramsey M, Gold J. Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry 2007; 64: 532–42. 4 Hemsley D. The development of a cognitive model of schizophrenia: placing it in context. Neurosci Biobehav Rev 2005; 29: 977–88. 5 Barch D. What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience 2006; 139: 73–84. 6 Byrne M, Clafferty B, Cosway R, Grant E, Hodges A, Whalley H. Neuropsychology, genetic liability, and psychotic symptoms in those at high risk of schizophrenia. J Abnorm Psychol 2003; 112: 38–48. 7 Toulopoulou T, Picchioni M, Rijsdijk F, et al. Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Arch Gen Psychiatry 2007; 64: 1348–55. 8 Torres A, Olivares J, Rodriguez A, Vaamonde A, Berrios G. An analysis of the cognitive deficit of schizophrenia based on the Piaget developmental theory. Compr Psychiatry 2007; 48: 376–79. 9 Osuji I, McGarrahan A, Mihalakos P, Garver D, Kingsbury S, Cullum C. Neuropsychological functioning in MRI-derived subgroups of schizophrenia. Schizophr Res 2007; 92: 189–96. 10 Nestor P, Onitsuka T, Gurrera R, et al. Dissociable contributions of MRI volume reductions of superior temporal and fusiform gyri to symptoms and neuropsychology in schizophrenia. Schizophr Res 2007; 91: 103–106. 11 Burdick K, Goldberg T, Funke B, et al. DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 2007; 89: 169–72. 12 Joyce E, Roiser J. Cognitive heterogeneity in schizophrenia. Curr Opin Psychiatry 2007; 20: 268–72. 13 Keefe R, Fenton W. How should DSM-IV criteria for schizophrenia include cognitive impairment? Schizophr Bull 2007; 33: 912–20. 14 Nieoullon A, Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol 2003; 16(Suppl. 2): S3–S9. 15 Kremen W, Seidman L, Faraone S, Toomey R, Tsuang M. Heterogeneity of schizophrenia: a study of individual neuropsychological profiles. Schizophr Res 2004; 71: 307–21. 16 Ojeda N, Sanchez P, Elizagarate E, et al. Course of cognitive symptoms in schizophrenia: a review of the literature. Actas Esp Psiquiatr 2007; 35: 263–70.
Clinical relevance of neuropsychological dysfunction in schizophrenia Earlier work claimed that specific types of neuropsychological performance and deficit predicted aspects of personal and social function. Despite its potential usefulness in the prediction of care needs, this work has not been translated into routine initiatives in patient care. It is clear that numerous other factors make a marked contribution to ‘real-world’ skills and the motivation that leads to their use. For instance, it was recently demonstrated that the contribution of neuropsychological performance to real-world skills was mediated by its influence on ‘functional capacity’, in other words the formal assessment of specific life skills under optimal conditions, something that may have much in common with certain neuropsychological tests themselves. Furthermore, depression and negative symptoms also predicted real-world skills, independently of functional capacity.27 Moreover, an initiative to produce evaluation protocols for cognition, functional capacity, and real-world skills, with an ultimate objective of application to pharmacological treatment effects, reported similar dissociation between real-world skills and the rest.28 Finally, premorbid risk, in terms of borderline of reduced intellectual functioning, adversely affected every aspect of schizophrenia observed in a recent large study29 and predicted function 10 years later.30
Conclusion Neuropsychological deficit in schizophrenia is ubiquitous and almost certainly related to risk and pathophysiology. Current tests of cognitive function lack specificity and precision, but understanding of the individual components of cognitive function is increasing. As a result, unifying theories about the core deficit in schizophrenic cognitive function are beginning to emerge. Research that integrates genetic analysis and cognitive evaluation with structural and functional neuro-imaging is beginning to reveal clinicopathological correlations of great interest. However, associations of cognitive deficit with personal function, social function, and symptoms are further removed. Complex and unclear, these relationships continue to defy attempts at simplification. Other factors may impact more cogently on these important aspects of patient outcome, affect, and personality, representing the most likely prospects here. Unfortunately, current drug and psychological treatments appear to have little impact on neuropsychological deficits in
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Research aspects
17 Bowie C, Jaga K. Methods for treating cognitive deficits in schizophrenia. Expert Rev Neurother 2007; 7: 281–87. 18 Keefe R, Sweeney J, Gu H, et al. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early schizophrenia: a randomized double-blind 52-week comparison. Am J Psychiatry 2007; 164: 1061–71. 19 Goldberg T, Goldman R, Burdick K, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 2007; 64: 1115–22. 20 Coulston C, Perdices M, Tennant C. The neuropsychology of cannabis and other substance use in schizophrenia: review of the literature and critical evaluation of methodological issues. Aust N Z J Psychiatry 2007; 41: 869–84. 21 Carter C, Barch D. Cognitive neuroscience-based approaches to measuring and improving treatment effects on cognition in schizophrenia. Schizophr Bull 2007; 33: 1131–37. 22 Buchanan R, Freedman R, Javitt D, Abi-Dargham A, Lieberman J. Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007; 33: 1120–30. 23 Fioravanti M, Carlone M, Vitale B, Cinti M, Clare L. A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychol Rev 2005; 15: 73–95. 24 Reichenberg A, Harvey P. Neuropsychological impairments in schizophrenia: integration of performance-based and brain imaging findings. Psychol Bull 2007; 133: 833–58. 25 Laws K, Al-Uzri M, Mortimer A. Lexical knowledge degradation in schizophrenia. Schizophr Res 2000; 45: 123–31. 26 Aleman A, Agrawal N, Morgan K, David A. Insight in schizophrenia and neuropsychological function: meta-analysis. Br J Psychiatry 2006; 189: 204–12.
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27 Bowie C, Reichenberg A, Patterson T, et al. Determinants of realworld functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am J Psychiatry 2006; 163: 418–25. 28 Harvey P, Cornblatt B. Pharmacological treatment of cognition in schizophrenia: an idea whose method has come. Am J Psychiatry 2008; 165: 163–65. 29 Chaplin R, Barley M, Cooper S, et al. The impact of intellectual functioning on symptoms and service use in schizophrenia. J Intellect Disabil Res 2006; 50: 288–94. 30 van Winkel R, Myin-Germeys I, De Hert M, Delespaul P, Peuskens J, Van Os J. The association between cognition and functional outcome in first-episode patients with schizophrenia: mystery resolved? Acta Psychiatr Scand 2007; 116: 119–24.
Practice points • Neuropsychological impairment constitutes a risk factor for schizophrenia and worsens during the illness course • There are deficits in general intellect, memory, executive function, attention, and working memory. Language, nondeclarative memory, and perception are relatively preserved • Assumptions that cognitive impairment is treatable may not be true in many patients • Personal and social function rely on much more than neuropsychological performance • Substances of abuse also affect cognitive function
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