Susan R. McGurk

The role of cognition in vocational functioning in schizophrenia

Schizophrenia is associated with long-term unemployment. Cognitive dysfunction, rather than clinical symptoms, may be the most important factor in the ability to work for patients with this disorder. To evaluate the relationship of clinical symptoms and cognitive functioning to work status, thirty patients with schizophrenia, who were participants in a vocational rehabilitation program, were evaluated with a comprehensive neuropsychological battery and assessment of psychopathology. Subjects were classified as being in stable full-time, part-time or unemployed work status for at least a year. Univariate analysis indicated that patients who were working full-time were significantly better educated, more likely to be treatment-resistant, more likely to be treated with an atypical antipsychotic medication, had more positive symptoms, and were engaged in work tasks which were more cognitively complex than the part-time employed and unemployed work groups. An ANCOVA controlling for education demonstrated that the full-time employed group performed significantly better than the unemployed group on measures of executive functioning, working memory and vigilance; and significantly better than the part-time group on measures of vigilance and executive functioning. Although negative symptoms did not significantly relate to work status in the univariate analysis, a multiple regression indicated that negative symptoms, level of education, and executive functioning differentiated the work groups. These results suggest that poor premorbid function, negative symptoms and cognitive dysfunction are significantly associated with unemployment in schizophrenia.

Cognitive functioning, symptoms, and work in supported employment: a review and heuristic model

OBJECTIVE Supported employment has been shown to improve the employment outcomes of clients with severe mental illness (SMI), but many clients who receive this service still fail to achieve their vocational goals. There is a need to better understand how illness-related impairments interfere with work, and how supported employment services deal with those impairments in order to improve the employment outcomes of clients with SMI. METHOD We conducted a review of research on the relationship between cognitive functioning, symptoms, and competitive employment in clients with SMI. Based on this review, we developed a heuristic model of supported employment that proposes specific interactions between cognitive factors, symptoms, vocational services, and employment outcomes. RESULTS The review indicated that cognitive functioning and symptoms were strongly related to work in studies of general psychiatric samples. In studies of clients participating in vocational rehabilitation programs, associations between cognitive functioning, symptoms, and work were also present, but were attenuated, suggesting that vocational rehabilitation compensates for the effects of some cognitive impairments and symptoms on work. We describe a heuristic model of supported employment that posits specific and testable effects of cognitive domains and symptoms on vocational services and employment outcomes. CONCLUSIONS Supported employment appears to work by compensating for the effects of cognitive impairment and symptoms on work. The model may serve as a guide for research aimed at understanding how supported employment works, and for developing supplementary strategies designed to improve the effectiveness and cost-effectiveness of supported employment services.

The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone

BACKGROUND Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period. METHODS Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score. RESULTS We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period. CONCLUSIONS This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications may have neurocognitive benefits at low doses that are neutralized or reversed at higher doses.

Work, Recovery, and Comorbidity in Schizophrenia: A Randomized Controlled Trial of Cognitive Remediation

Employment is central to the concept of recovery in severe mental illness. However, common comorbid conditions present significant obstacles to consumers seeking employment and benefiting from vocational rehabilitation. We review research on the effects of three common comorbid conditions on work and response to vocational rehabilitation, including cognitive impairment, substance abuse, and medical conditions, followed by research on vocational rehabilitation. We then present the results of a randomized controlled trial evaluating the effects of adding cognitive remediation to a vocational rehabilitation program compared with vocational rehabilitation alone in 34 consumers with severe mental illness. Consumers who received both cognitive remediation and vocational rehabilitation demonstrated significantly greater improvements on a cognitive battery over 3 months than those who received vocational rehabilitation alone and had better work outcomes over the 2-year follow-up period. Substance abuse was associated with worse employment outcomes, but did not interact with treatment group, whereas medical comorbidity was not related to work outcomes. More research is warranted to evaluate the interactions between substance abuse and medical comorbidity with vocational rehabilitation and cognitive remediation.

Combined Cognitive Remediation and Functional Skills Training for Schizophrenia: Effects on Cognition, Functional Competence, and Real-World Behavior

OBJECTIVE Cognitive remediation is an efficacious treatment for schizophrenia and, when used within broader psychosocial treatments, improves transfer to real-world behavior change. The authors examined whether cognitive remediation effectively generalizes to functional competence and real-world functioning as a standalone treatment and when combined with a functional skills treatment. METHOD Outpatients with schizophrenia (N=107) were randomly assigned to receive cognitive remediation, functional adaptation skills training, or combined treatment, with cognitive remediation preceding functional skills training. Clinical symptoms, neurocognition, social competence, functional competence, and case-manager-rated real-world behavior were assessed at baseline, at end of treatment, and at a 12-week durability assessment. RESULTS Neurocognition improved, with durable effects, after cognitive remediation but not after functional skills training. Social competence improved both with functional skills training and with combined treatment but not with cognitive remediation alone. Improvements in functional competence were greater and more durable with combined treatment. Cognitive remediation alone did not produce significant improvements in real-world behavior, but when combined with functional skills training, statistically significant improvements from baseline to end of treatment and follow-up were observed in community or household activities and work skills. Number-needed-to-treat analyses suggest that as few as three cases are required for treatment to induce a meaningful improvement in functional skills. CONCLUSIONS In a short intervention, cognitive remediation produced robust improvements in neurocognition. Generalization to functional competence and real-world behavior was more likely when supplemental skills training and cognitive remediation were combined.

A randomized controlled trial of cognitive remediation among inpatients with persistent mental illness.

OBJECTIVE This study evaluated the feasibility and efficacy of a cognitive remediation program in improving cognitive and work functioning for intermediate- to long-stay psychiatric inpatients. METHODS Eighty-five inpatients with predominantly DSM-IV-defined schizophrenia were randomly assigned to cognitive remediation or to a control condition. The cognitive remediation program consisted of 24 hours of computerized practice over a 12-week period and a weekly discussion group to facilitate transfer of cognitive skills to daily activities. A computer control group received similar hours of staff and computer exposure without cognitive training exercises. A comprehensive neuropsychological battery was administered at baseline and posttreatment. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline, midtreatment (six weeks), and posttreatment (12 weeks) and at six- and 12-month follow-ups. Work functioning was tracked during a 12-month follow-up period. RESULTS The average number of 45-minute sessions completed was 23. Patients in the cognitive remediation group demonstrated significantly greater improvements over three months than the control group in the composite measure of overall cognitive functioning, psychomotor speed, and verbal learning. In addition, patients who received cognitive remediation worked more weeks than the control group over the 12-month follow-up period. Patients in both groups showed significant and comparable improvements over the follow-up period on the positive, activation, and depression subscales of the PANSS. CONCLUSIONS Cognitive remediation was a feasible treatment for this group of inpatients and more effective at improving cognitive functioning than a computer control intervention. Longer-term follow-up indicated that cognitive remediation was associated with better work outcomes, suggesting benefits in psychosocial functioning.

GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia.

γ‐Aminobutyric acid (GABA), the principal inhibitory neurotransmitter of CNS, has been consistently implicated in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD). Two isoforms of GAD have been identified and have been named GAD65 and GAD67 based on their apparent molecular weights. In this study, GAD65 and GAD67 mRNA and protein levels were measured by using real‐time RT‐PCR and immunoblotting, respectively, in post‐mortem brain tissue from the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of the elderly persons with schizophrenia and matched normal controls. In addition, the mRNA expression of GAT‐1, one of the principal transporters of GABA, was also studied in the same subjects. Expression of GAD65 and GAD67 mRNA in the DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT‐1 mRNA was unchanged. Although the levels of GAD65 and GAD67 messages were increased in schizophrenia subjects, the proportion of the two GAD isoforms remained constant in controls and schizophrenics. In the human DLPFC, GAD65 mRNA was found to be expressed significantly less than the message for GAD67, approximately 16% of that observed for GAD67. On the contrary, the abundance of GAD65 protein in the DLPFC was about 350% of that observed for GAD67. The results suggest a substantial dysregulation of GAD mRNA expression in schizophrenia and, taken together with the results of protein expression studies, raise the possibility that both cortical and subcortical GABA function may be compromised in the disease.

mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics

L‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors (AMPARs) mediate the majority of the fast excitatory transmission in the CNS. To determine whether gene expression of AMPARs and/or AMPAR binding proteins, which control response/sensitivity of AMPAR‐bearing neurons to glutamate, are altered in schizophrenia, mRNA expression and abundance of AMPAR subunits (GluR1–4) and several AMPAR binding proteins (SAP97, PICK1, GRIP, ABP) were measured in the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of elderly schizophrenia patients (n = 36) and matched normal controls (n = 26) by quantitative real‐time PCR. The mRNA expression of GluR1, GluR4, and GRIP in the DLPFC and expression of the GluR4, GRIP, and ABP in the occipital cortex were significantly elevated in schizophrenics. GluR1 and ABP mRNA expression in the occipital cortex and GluR2, GluR3, SAP97, and PICK1 expression in either cortical area were not significantly altered. The data also demonstrated significant differences in the abundances of mRNAs encoding GluR1–4 subunits (GluR2 > GluR3 > GluR1 > GluR4) and of AMPAR binding proteins (SAP97 > PICK1 > GRIP > ABP) in both diagnostic groups. GluR2 (58–64%) and GluR3 (24–29%) were the major components of the AMPAR mRNA in both cortical areas, implying that the major AMPAR complexes in the human cortex are probably those containing GluR2 and GluR3 subunits. Small but significant differences in the amounts of GluR2, GluR3, and GRIP mRNAs were detected between the two cortical areas: more GluR3 and GRIP but less GluR2 were detected in the DLPFC than in the occipital cortex.

Cognitive functioning and employment in severe mental illness.

This study compared cognitive functioning and symptomatology of unemployed, supported employed, and independently employed clients with severe mental illness. Unemployed clients who wanted to work (N = 21) were compared with clients working in supported employment programs (N = 17) and clients who had been working independently for at least 1 year (N = 23) on a neuropsychological battery and the Positive and Negative Syndrome Scale. Clients who were unemployed had more severe symptoms and worse cognitive functioning on both positive and negative symptoms, and almost all domains of cognitive functioning. Supported employed clients had more severe psychotic symptoms and worse working memory than independently employed clients, but did not differ in negative symptoms or the other domains of cognitive functioning, including attention/concentration, psychomotor speed, verbal learning and memory, or executive functions. Finally, job complexity was correlated with impaired executive functions among clients working independently, but not in supported employment. Severe symptoms and cognitive impairment may interfere with the ability of some clients with severe mental illness to obtain competitive work. Supported employment programs appear to work by helping clients compensate for problematic symptoms and cognitive impairment and, to a lesser extent, by finding or developing environmental niches in which these impairments do not impede their ability to perform the necessary job tasks.

The longitudinal relationship of clinical symptoms, cognitive functioning, and adaptive life in geriatric schizophrenia

Cognitive dysfunction is increasingly being recognized as a major contributor to the adaptive impairment seen in most patients with schizophrenia. Reported here is a prospective longitudinal evaluation of the relationship between cognitive and adaptive functioning in elderly patients with schizophrenia. It was hypothesized that baseline cognitive and negative, but not positive symptoms, would be predictive of cross-sectional impairment and longitudinal outcome. Subjects were 168 elderly patients with schizophrenia, free of major neurological disorders, who were residents of a long-term psychiatric facility. Subjects were assessed at baseline and again an average of 15months later. The PANSS was used to assess the severity of symptoms of schizophrenia. Cognitive symptoms were assessed using the components of the CERAD cognitive battery. Social and adaptive functioning was assessed using the SAFE scale. Spearman correlations were determined among clinical variables, and the rank ordering of prediction of SAFE scale scores at follow-up was determined using a stepwise regression procedure. At follow-up, adaptive life skills correlated with cognitive performance and negative symptoms (Spearman rho values 0. 41-0.57, all p values <0.0001), but not positive symptoms (r=0.09, n. s.). Among cognitive tasks, verbal learning and memory were most highly correlated with adaptive skills at follow-up. These results confirm and extend previous studies that indicate that cognitive impairments are predictive, both cross-sectionally and longitudinally, of adaptive life skills in persons with schizophrenia. Negative symptoms, but not positive symptoms, were correlated with impaired adaptive skills. Taken together, these results underscore the need to develop more effective treatments for cognitive and negative symptoms in schizophrenia.