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Editorials   |    
Understanding the Glass Ceiling for Functional Outcome in Schizophrenia
CAMERON S. CARTER, M.D.
Am J Psychiatry 2006;163:356-358. doi:10.1176/appi.ajp.163.3.356

Despite the widespread availability of medications that suppress psychosis and prevent relapse, most patients with schizophrenia function poorly in the community and few lead fully independent lives. This has led researchers to identify factors other than psychosis that are associated with poor functional outcome. Perhaps not surprisingly, impaired cognition has emerged as a highly reliable predictor of poor functional outcome in schizophrenia. Performance on a range of cognitive tasks has been shown to be associated with poor social and occupational functioning (1). Addressing this and other treatment-refractory aspects of schizophrenia, such as negative symptoms, as well as reconfiguring our system of care to emphasize early intervention and access to rehabilitation services (see the related editorial by William Carpenter in this issue of the Journal, p. 353), are essential steps if we are to move beyond symptom control and relapse prevention and toward improved functional outcome in this illness.

The insight that impaired cognition underlies much of the functional disability in schizophrenia is well timed in view of the explosion of new knowledge over the past decade regarding how the brain supports cognitive and emotional processing and how this is modulated neuropharmacologically and by experience. To capitalize on this new knowledge and translate it into therapies, a number of steps must be taken (2). First, the specific cognitive mechanisms that fail in schizophrenia need to be identified, together with the process by which these deficits lead to functional disability. Second, the neural systems underlying impaired cognition in schizophrenia need to be identified. Knowledge from animal models and basic human pharmacological and imaging studies can then provide targets for modulating impaired cognitive networks and inform the development of both pharmacological and psychosocial therapies.

Four articles in this issue of the Journal take important steps toward this goal. Schneider and colleagues (p. 442) report results of a behavioral study that sought to better characterize the cognitive mechanisms underlying abnormal processing of emotional faces in schizophrenia. In their experiment, subjects viewed faces and had to decide whether a particular emotion was being expressed (happiness, sadness, anger, or fear, respectively); whether a face was from a person older or younger than 30; and, finally, whether a face was one that was viewed during previous testing. The authors report that although patients were impaired on all tasks, they were significantly more impaired on the emotion discrimination measure. Patients were able to correctly identify the presence of a particular emotion, but they falsely identified the presence of the target emotion when it was not present at a higher rate than healthy subjects. This bias to misidentify an emotion may be related to the social deficits of patients with schizophrenia. The authors propose additional experiments to tease out whether patients have an inability to benefit from the context provided by a string of judgments about the presence of a particular emotion (i.e., a cognitive or decision-making deficit) from a disturbance in perceiving emotional content, and they have developed a version of their task for future functional magnetic resonance imaging (fMRI) studies of the brain circuitry associated with emotional face processing in schizophrenia.

To understand how altered cognitive processes actually lead to poor functional outcome in schizophrenia, Sergi and colleagues (p. 448) used a statistical technique called structural equation modeling. This allowed them to take performance measures from a task that measured perceptual processes, one that measured socially relevant cognition by requiring subjects to make a social inference, and systematic measures of social and occupational functioning and test models of the relationships among performance on these measures. These authors have contributed extensively to the literature relating cognition to poor outcome, and in this study they examine whether the effects of impaired cognition are mediated through poor social cognition, as measured by the social perception task. This was indeed the case. The model that included mediation of the effects of perceptual deficits on functional outcome through social task performance was more robust than the model that considered the direct relationship between impaired perceptual processing and functional outcome. This provides a potentially very important insight into how basic cognitive deficits may be expressed as poor performance on measures of higher-level social inference and, ultimately, poor outcome in daily life. This insight may directly inform treatment approaches targeting this cascade of deficits.

Another mechanistic study in this issue of the Journal, by Onitsuka and colleagues (p. 455), combines behavioral as well as brain-based (event-related potentials recorded from the scalp surface and structural MRI) measurements to link cognitive deficits in schizophrenia to brain pathology. They compared subjects with and without schizophrenia using a visual classification task and report that the N170, an event-related potential that is thought to index object identification and is particularly responsive during face identification, was most markedly reduced in schizophrenia for these stimuli, compared with other objects. They also report that the reduction in this signal in patients was correlated with the volume of the right posterior fusiform gyrus, a region of the ventral temporal lobes important for face identification and thought to play a role in generating the N170. Following a similar logic to that of the Sergi et al. study, Onitsuka et al. propose that altered structure and function of temporal areas involved in face identification may contribute to social deficits in schizophrenia.

These three studies have in common the more precise identification of the relationship between treatment-refractory cognitive deficits in schizophrenia and poor functional outcome, setting the stage for a more detailed understanding of the underlying neural substrates and potential therapeutic targets. A fourth study in this issue of the Journal, by Andrews and colleagues (p. 463), takes this next step. They used fMRI and tasks that engage working memory and episodic memory, which are well-characterized cognitive systems that are impaired in schizophrenia. They performed an innovative, high-resolution analysis of activation in subregions of the thalamus known to integrate the frontal and temporal cortical elements of brain circuits that support these functions. Two subregions, the dorsomedial and anterior nuclei, showed reduced activation correlated with poorer task performance. These data converge with data from other studies showing altered thalamic structure and function in schizophrenia (3, 4). The interpretation of Andrews et al. can be informed by many new developments in cellular and molecular neuroscience regarding the development and function of thalamic-cortical circuits (5, 6) and their role in the synchronization of neuronal activity, which appears to be essential for normal cognition.

An example of a new therapy that is informed by the mechanistic approach exemplified in these studies is cognitive enhancement therapy (7). Cognitive enhancement therapy combines computer-based cognitive training with groups that allow patients to develop and practice social skills. Cognitive enhancement therapy produces sustained functional improvements in patients with schizophrenia. Further refinements of this approach will benefit greatly from better specification of the cognitive systems that are impaired in schizophrenia and of their expression as disabling social and occupational deficits. Furthermore, there is now great interest in developing procognitive drugs for schizophrenia (2, 8). Linking cognitive impairments in schizophrenia to specific neural systems will accelerate this process by allowing the psychopharmacology of cognition in schizophrenia to be informed by the wealth of new knowledge from basic neuroscience regarding the function and neuropharmacology of these circuits.

Research that increases our understanding of the mechanisms underlying poor functional outcome in schizophrenia is necessary to guide treatment development to help patients get beyond their "glass ceiling." The combination of behavioral, electrophysiological, and structural and functional brain imaging approaches used in these four papers exemplifies the progress that is now being made in this direction.

Address correspondence and reprint requests to Dr. Carter at the University of California, Davis, Imaging Research Center, 4701 X St., Sacramento, CA 95817;  cameron.carter@ucdmc.ucdavis.edu (e-mail).

Green MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry  1996; 153:321–330
[PubMed]
 
Carter CS: Applying new approaches from cognitive neuroscience to enhance drug development for the treatment of impaired cognition in schizophrenia. Schizophr Bull  2005; 31:810–815
[PubMed]
[CrossRef]
 
Jones EG: Cortical development and thalamic pathology in schizophrenia. Schizophr Bull  1997; 23:483–501
[PubMed]
 
Andreasen NC, Arndt S, Swayze VW II, Cizadlo T, Flaum M, O’Leary D, Ehrhardt JC, Yuh WTC: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science  1994; 266:294–298
[PubMed]
[CrossRef]
 
Jones EG: The Thalamus—Revisited. New York, Cambridge University Press (in press)
 
Lewis D, Hashimoto T, Volk D: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci  2005; 6:312–324
[PubMed]
[CrossRef]
 
Hogarty GE, Flesher S, Ulrich R, Carter M, Greenwald D, Pogue-Geile M, Keshavan M, Cooley S, DiBarry A, Garrett A, Parepally H, Zoretich R: Cognitive enhancement therapy for schizophrenia: effects of a 2 year randomized trial on cognition and behavior. Arch Gen Psychiatry  2004; 61:866–876
[PubMed]
[CrossRef]
 
Harvey PD, Green MF, Keefe RS, Velligan DI: Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. J Clin Psychiatry  2004; 65:361–372
[PubMed]
[CrossRef]
 
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References

Green MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry  1996; 153:321–330
[PubMed]
 
Carter CS: Applying new approaches from cognitive neuroscience to enhance drug development for the treatment of impaired cognition in schizophrenia. Schizophr Bull  2005; 31:810–815
[PubMed]
[CrossRef]
 
Jones EG: Cortical development and thalamic pathology in schizophrenia. Schizophr Bull  1997; 23:483–501
[PubMed]
 
Andreasen NC, Arndt S, Swayze VW II, Cizadlo T, Flaum M, O’Leary D, Ehrhardt JC, Yuh WTC: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science  1994; 266:294–298
[PubMed]
[CrossRef]
 
Jones EG: The Thalamus—Revisited. New York, Cambridge University Press (in press)
 
Lewis D, Hashimoto T, Volk D: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci  2005; 6:312–324
[PubMed]
[CrossRef]
 
Hogarty GE, Flesher S, Ulrich R, Carter M, Greenwald D, Pogue-Geile M, Keshavan M, Cooley S, DiBarry A, Garrett A, Parepally H, Zoretich R: Cognitive enhancement therapy for schizophrenia: effects of a 2 year randomized trial on cognition and behavior. Arch Gen Psychiatry  2004; 61:866–876
[PubMed]
[CrossRef]
 
Harvey PD, Green MF, Keefe RS, Velligan DI: Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. J Clin Psychiatry  2004; 65:361–372
[PubMed]
[CrossRef]
 
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+

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