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Targeted Cognitive Training and Real-World Outcomes in Schizophrenia

3 August 2009. New research suggests that cognitive training can achieve impressive results in schizophrenia, although some antipsychotic drugs may limit its effectiveness, and societal influences may shape real-world outcomes. In two new studies, Sophia Vinogradov, of the University of California at San Francisco, and colleagues find that a neuroscience-based training program substantially improves cognitive outcomes in patients with schizophrenia, producing gains that may last six months. In a third study, Vinogradov and associates warn that anticholinergic effects of antipsychotic drugs may undermine the training. A person’s environment might, too; a team led by Philip Harvey, of the Emory University School of Medicine, finds that most subjects with schizophrenia live independently in rural Sweden but not in New York City, despite similar ability levels.

Cognitive deficits often appear before, and independently of, other symptoms of schizophrenia (for a review of cognition in schizophrenia, see Bowie and Harvey, 2005; also see SRF related news story; SRF news story). They respond only modestly, if at all, to antipsychotic drugs (see SRF related news story), making training designed to improve their cognitive processes or to compensate for impaired functions an attractive option. According to a 2007 meta-analysis (McGurk et al., 2007), such training can moderately improve cognitive performance, but may fail to improve patients’ real-world functioning unless they also receive treatment that targets their psychosocial functioning.

Perceive it to retrieve it
Vinogradov's group thought that cognitive training might work better if it took its cue from the latest neuroscience findings (see SRF live discussion). In their paper in the July American Journal of Psychiatry, first author Melissa Fisher of the University of California at San Francisco and colleagues write, “Prior cognitive remediation, approaches have not specifically targeted impaired perceptual processes, although a growing body of research has identified a number of early sensory deficits in schizophrenia and has related them to higher-order cognitive impairments” (see SRF related news story).

Fisher and colleagues designed the program to target early auditory and working memory processes, with the hope of also enhancing verbal memory and overall cognition. As they explain it, “The basic notion is that by improving the speed and accuracy of information processing in the auditory system, higher-order functions such as verbal encoding and verbal memory retrieval have more reliable signals on which to operate.”

The study examined 55 outpatients with chronic schizophrenia who had undergone randomization to either the training program or a control condition. The stand-alone cognitive training challenged subjects to make progressively harder auditory distinctions as their performance improved. Correct responses earned “rewards” of points and animations. Since studies suggest that people with schizophrenia can benefit from practice (McGurk et al., 2007), those in the training program received an hour of computer-based training daily, five days a week, until they had received 50 hours total. Control subjects played computer games for the same amount of time.

The researchers chose most of their cognitive measures based on the recommendations of the (MATRICS [Measurement and Treatment Research to Improve Cognition in Schizophrenia]; for information specifically about the cognitive battery, see Nuechterlein et al., 2008). Even though both subject groups began the study with similar cognitive performance, over time the training group improved more than controls in verbal working memory, verbal learning, verbal memory, and global cognition. Training-related effect sizes topped 0.85 for global cognition, verbal learning, and verbal memory, surpassing those found in the earlier meta-analysis (McGurk et al., 2007).

Fisher and colleagues offer an explanation for the program’s apparent success: “As the auditory cortex responds to the psychophysical training, a more salient verbal signal is ‘fed forward’ into working memory operations; this then permits more efficient and accurate encoding of the verbal information.” In a commentary in the same issue, Michael Green of the University of California, Los Angeles, commends the researchers for basing the intervention on neuroplasticity models and for using MATRICS-recommended measures of cognition, which should facilitate comparing their results with those from other studies (see SRF related news story). Despite these strengths, he wondered whether the program would help patients function in the real world.

The nitty-gritty
Along with the training’s effects on functional outcomes, other questions hung in the air: How long would the benefits last? Would further training help patients more? In a follow-up study published online by Schizophrenia Bulletin on March 5, first author Fisher, Vinogradov, and colleagues addressed these questions.

The study focused on 32 clinically stable patients with schizophrenia who had been randomly assigned to either the cognitive training or control conditions described above. After they finished their 50 sessions of auditory training, 10 of the 22 subjects in the training group received 50 more hours of training. This added training aimed to improve visual processing and cognitive control.

From baseline to post-training to the six-month follow-up, the training group's performance improved more than that of control subjects on verbal learning and memory and on cognitive control. Verbal memory did not improve in this study, contrary to the earlier one. All domains except verbal memory showed a large, positive effect of training from baseline to the post-training assessment, and a medium-to-large effect from baseline to six months later.

When they looked at the dose-response relationship, Fisher and colleagues noted that only the group that completed 100 training sessions improved more than controls on global cognition and processing speed at six months. “Thus, it appears that a longer training period, or additional training of visual and cognitive control processes, may be required to drive improvements in speed of processing,” they write.

Treatment tradeoffs
Unfortunately, patients may not reap the full benefits of cognitive training if they are taking antipsychotic medications that cause anticholinergic effects. Acetylcholine dysfunction, thought to loom large in Alzheimer’s disease, may also contribute to schizophrenia-related cognitive deficits (Gray and Roth, 2007). In the July 1 American Journal of Psychiatry in Advance, Vinogradov and colleagues describe the effects of anticholinergic activity on training outcome in 49 outpatients with schizophrenia.

At baseline, higher serum anticholinergic activity correlated with worse performance on tests of verbal working memory, and verbal learning and memory, but not on other MATRICS-based cognitive measures. After 50 sessions of auditory training, anticholinergic activity correlated with lesser gains in global cognition. In fact, serum anticholinergic activity explained 20 percent of the variance in global cognition change, more than age, intelligence, or symptom severity.

“It appears that if we wish to maximize patients’ response to rehabilitation, we must take care to minimize their anticholinergic burden,” the researchers conclude. They suggest that clinicians weigh the anticholinergic effects of drugs such as clozapine, olanzapine, quetiapine, benztropine, and some first-generation antipsychotics before prescribing them.

Worldly influences
Improving patients’ lives might require more than skills training; after all, what people can do and what they actually do often differ. In a 1997 study of older patients with schizophrenia in New York and London, Harvey and colleagues found evidence that environmental factors lead to divergent outcomes in subjects with similar levels of impairment (Harvey et al., 1997).

In the July American Journal of Psychiatry, another Harvey-led team presents findings of a recent cross-national study. It examined functional capacity—the ability to perform daily living activities—and real-life outcomes in outpatients with schizophrenia or schizoaffective disorder who lived in vastly different places. It compared 244 subjects in New York City or its close suburbs with 146 subjects in a mostly rural part of Sweden called Trollhättan.

To measure functional capacity, the study used two subscales of the University of California, San Diego, Performance-Based Skills Assessment (UPSA) battery. These UPSA-B subscales, which parallel UPSA total scores, assess the ability to manage money and communicate. Information about real-world outcomes came from subjects themselves, their case managers, and their charts. It included whether subjects had reached milestones such as living independently and being at least partly financially responsible, working for pay, and being married or widowed.

Results showed that the two groups resembled each other in functional capacity. Even so, and despite similar vocational and social outcomes, their residential outcomes diverged drastically. In particular, 80 percent of the Swedish patients lived independently and at least contributed to their own financial support, versus only 46 percent of the New Yorkers. The New York patients were much likelier than their counterparts in rural Sweden to live in restricted settings. In the Swedish group, UPSA-B scores did not differentiate those living independently, in a restricted setting, or in a non-restricted setting without financial responsibility, but they did in the United States.

As to the specific environmental factors that might cause different life stories to unfold in patients with similar abilities, Harvey and colleagues point to differences in social service systems in the two places. In Trollhättan, disabled persons with schizophrenia receive more generous financial aid from the government than do those living in the costly New York area. Harvey and colleagues write, “These differences in social support for people with mental illness have a clear and strong signal in terms of real-world functional outcomes.” Such environmental differences might even determine the real-life effects of cognitive training.—Victoria L. Wilcox.

Fisher M, Holland C, Merzenich MM, Vinogradov S. Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009 July;166(7):805-811. Abstract

Green MF. New possibilities in cognition enhancement for schizophrenia. Am J Psychiatry. 2009 July;166(7):749-752. Abstract

Fisher M, Holland C, Subramaniam K, Vinogradov S. Neuroplasticity-based cognitive training in schizophrenia: an interim report on the effects 6 months later. Schizophrenia Bulletin Advance Access. 2009, March 5. Abstract

Vinogradov S, Fisher M, Warm H, Holland C, Kirshner MA, Pollock BG. The cognitive cost of anticholinergic burden: Decreased response to cognitive training in schizophrenia. Am J Psychiatry in Advance. 2009, July 1. Abstract

Harvey PD, Helldin L, Bowie CR, Heaton RK, Olsson A-K, Hjärthag F, Norlander T, Patterson TL. Performance-based measurement of functional disability in schizophrenia: A cross-national study in the United States and Sweden. Am J Psychiatry. 2009 July; 166(7):821-827. Abstract

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