The relationship between symptomatic remission and neuropsychological improvement in schizophrenia patients switched to treatment with ziprasidone

Schizophrenia Research 94 (2007) 99 – 106 www.elsevier.com/locate/schres

The relationship between symptomatic remission and neuropsychological improvement in schizophrenia patients switched to treatment with ziprasidone☆ Peter F. Buckley a,⁎, Philip D. Harvey b , Christopher R. Bowie b , Antony Loebel c a b

Medical College of Georgia, United States Mt. Sinai School of Medicine, United States c Pfizer, Inc., United States

Received 22 September 2006; received in revised form 12 December 2006; accepted 14 December 2006 Available online 11 May 2007

Abstract Background: A definition of clinical remission in schizophrenia has recently been proposed. However, it is also known that neuropsychological (NP) impairments may be better predictors of functional outcomes than clinical symptoms. Understanding the relationship between clinical remission and cognitive improvement may be required in order to predict functional improvements, so we examined the development and convergence of clinical remission and neuropsychological improvements in a sample of patients with schizophrenia whose medication was switched to ziprasidone. Methods: One hundred eighty-four patients were switched from their previous treatment with risperidone, olanzapine, or conventional antipsychotics to open-label ziprasidone treatment. One hundred and thirty seven patients were not in remission at baseline and 40 met the clinical criteria for remission at study entry. We rated their symptoms with the PANSS at baseline and after 6 months of treatment. We performed an NP assessment and generated a composite score which was examined for improvements. Results: Of the 184 cases, 48 (26.1% of the total sample) met the remission criteria at baseline. Of these cases, 41 (85%) sustained their remission at the 6-month follow-up. Of the remaining 136 cases, 33% developed remission by the 6-month follow-up. Thus, a total of 55% of the total sample were in remission at the 6-month endpoint. A comparable number of the patients, 34%, improved by 0.5 SD or more in their cognitive performance. Baseline NP performance was not associated with remission at baseline and did not predict achieving remission over time. Further, clinical remission was not correlated with concurrent NP improvements. However, 33 patients achieved clinical remission and improved by 0.5 SD in their NP performance. Implications: After a switch from previous treatment to open-label ziprasidone more than half of patients with schizophrenia experienced sustained clinical remission over 6 months and 32% of the patients achieving remission experienced a concurrent NP improvement. Later research will be required to determine which aspects of improvement (clinical remission and/or cognitive improvements) are required for functional improvements. © 2007 Elsevier B.V. All rights reserved. Keywords: Remission; Response; Treatment; Schizophrenia

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This research was funded by Pfizer, Inc. Peter Buckley and Philip Harvey have served as consultants for Pfizer, Inc. ⁎ Corresponding author. Tel.: +1 706 721 6719; fax: +1 706 721 1793. E-mail address: [email protected] (P.F. Buckley).

0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.12.032

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1. Introduction The extent to which the currently available antipsychotics can deliver meaningful improvements in the lives of patients with schizophrenia is a topic of great academic and (increasingly) public concern (Lieberman et al., 2005; Ragins, 2005). In an effort to move beyond more traditional and symptom-based measures of outcome, several groups have sought to redefine the goals of treatment in more explicit and more meaningful terms— both with respect to overall symptom attainment (Liberman and Kopelowicz, 2005; Andreasen et al., 2005; Leucht et al., 2005) and also the expectations of improved cognitive performance (Harvey et al., 2004a,b). The concept of remission, already well established in the depression literature (Nierenberg and DeCecco, 2001), has gained greater credence. Andreasen and colleagues (2005) have proposed operational criteria for remission in schizophrenia and these incorporate distinct “benchmarks” for symptomatic and functional improvements. Recent application of these criteria to completed treatment studies have shown that a modest proportion of patients can achieve remission at up to 1 year (Lasser et al., 2005) and up to 3 years (Ascher-Svanum et al., 2005). The extent to which our field embraces remission in schizophrenia is also in concert with a broader, more consumer-driven explication of the concept of recovery (Davidson et al., in press). Liberman et al. (2002) have made an initial attempt to operationalize recovery in schizophrenia, based on stringent outcome expectations that include 2 years of symptom remission. Robinson et al. (2004) applied these recovery criteria to patient outcome in a well-characterized first episode schizophrenia treatment sample. They reported that, over the course of 5 years of treatment, 47% of patients attained remission and 14% achieved the recovery criteria. It has also been increasingly acknowledged that cognitive performance is a key mediator of overall functional improvement in schizophrenia (Green, 1996; Harvey et al., 2004a,b). Consistent with other research on the importance of cognition in schizophrenia, cognitive functioning following initial stabilization in the study by Robinson et al. (2004) was associated with attainment of recovery as well as the attainment of longterm symptomatic remission. Although the criteria for remission in the Robinson et al study differed from the recently proposed criteria (Andreasen et al., 2005), the elements were quite similar overall and quite likely to be comparable. It is considerable interest that severity of cognitive impairment in schizophrenia is associated very weakly with clinical symptom severity. For example, in the large-scale (n = 1332) CATIE schizophrenia trial

(Keefe et al., 2006) the correlations between the severity of cognitive deficits at the baseline assessment and positive symptom severity was r = .03, while the correlation with total PANSS scores was r = − .11. The convergence between cognitive impairment, cognitive improvement, and development of clinical remission might be relatively independent. Atypical antipsychotics have been shown to induce some improvements in cognitive functioning (Harvey and Keefe, 2001) although there is some debate about whether this is a direct or indirect effect (Carpenter and Gold, 2002). The magnitude of improvement has been seen to be typically moderate (Woodward et al., 2005) and the relative benefit compared to older antipsychotic medications depends to some extent on the dosing of the conventional comparator. Some evidence suggests that a proportion of patients may have improvements that leave them in the “normal” range after treatment (Harvey et al., 2006). As noted above, post-stabilization cognitive performance predicted a number of features of recovery in first episode patients. It is not known, however, what the relationship would be between cognitive impairment and development of remission in more chronic patients and what the concurrent relationships would be between the development of remission and clinically meaningful cognitive improvements with treatment. This paper presents the results of an extension study of a clinical trial described in two previously published reports (Weiden et al., 2003; Harvey et al., 2004a,b). The study was an open-label switch protocol, where three identical studies examined the transition from one of two atypical antipsychotics (risperidone or olanzapine) or a variety of typical medications to a newer antipsychotic in clinically stable but still symptomatic patients with schizophrenia. Patients were entered into the study either because of concerns about the efficacy or tolerability of their current treatments. Results from the 6-week study found that there were statistically significant improvements in both clinical symptoms (Weiden et al) measured by the Positive and negative syndrome scale (Kay, 1991:PANSS) and in performance on a battery of neuropsychological (NP) tests (Harvey et al., in press). We examined several aspects of the development and course of clinical remission in schizophrenia in our data analyses based on the 6-month follow-up of these patients. First, we examined the development of remission, defined with the Andreasen et al. (2005) criteria, in patients who did not meet the criteria for remission at baseline, both in terms of the proportion of cases who developed remission and patterns of clinical response associated with development of remission.

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Second, we examined the course of patients who met the remission criteria at baseline, in terms of the proportion of cases who sustained their remission and the general patterns of clinical symptom in those cases. Third, we examined the prevalence of hypothetically “clinically significant” cognitive improvements, presenting the prevalence of cases who improved by 0.5 and 1.0 standard deviations in their cognitive functioning over the 6-month period, acknowledging that we have no way to determine if patients truly received a clinical benefit. Fourth, we examined the relationship between cognitive functioning at baseline prior to the switch and remission status. Finally, we examined the convergence between the occurrence of clinically significant cognitive improvements and development and maintenance of clinical remission. While the 6-month period is too short to expect changes in major functional milestones, concurrent changes in cognitive functioning and clinical remission may have positive prognostic significance. 2. Methods 2.1. Subjects This study is a report of an extension of a 6-week open-label study (see Weiden et al., 2003; Harvey et al., 2004a,b) of stable schizophrenia outpatients who were switched to ziprasidone from conventional medications, olanzapine, or risperidone. Eligible patients were diagnosed with schizophrenia or schizoaffective disorder, as defined in the Diagnostic and Statistical Manual for Mental Disorders — Fourth Edition (DSM-IV) and between the ages of 18–55, with at least an 8th grade reading level. Additionally, patients were taking oral doses of antipsychotic medication within 25% of the recommended daily dose for a minimum of 3 months, with no history of treatment resistance. Major exclusion criteria were the presence of other current DSM-IV Axis-I disorders not in remission, a history of treatment resistance, urine toxicology positive for illicit drugs or a history of psychoactive substance abuse or dependence not in current remission, more than moderate depression as indicated by ratings on the Montgomery–Asberg Depression Rating Scale (Montgomery and Åsberg, 1979), or treatment with psychoactive medications other than antipsychotics. Patients provided written informed consent and all procedures were approved by institutional review boards at each site. Patients were recruited from multiple treatment sites within the United States. Patients who were receiving treatment with conventional antipsychotic medications, risperidone, or olanzapine were eligible. Two hundred

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and seventy stable outpatients with schizophrenia or schizoaffective disorder were switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or tolerability, as determined by the investigator at each of the research sites. After screening and baseline assessments, patients were placed on oral ziprasidone (40 mg b.i.d. for 2 days, followed by flexible dosing between 20 mg b.i.d. and 80 mg b.i.d. for the next 40 days), and their previous antipsychotic was discontinued or tapered within 7 days. Anticholinergics and benzodiazepines were administered as needed but were prohibited in the 12 hours before cognitive testing. At the completion of the 6-week efficacy trial, patients who had completed the study were offered the opportunity to participate in a one-year extension to assess the efficacy and tolerability of ziprasidone. The entire baseline cognitive battery was repeated at 6 months. Of the 270 patients who were switched at baseline, 185 entered the extension study, with 184 of these providing cognitive data at 6 months or earlier termination. Cognitive assessments were performed at baseline, while patients were receiving their previous medication, at the close of the 6-week trial, and again at 6 months during the continuation trial. As we reported before in a previous publication examining different features of this database (Harvey et al., 2006), there were no statistically significant differences between cases who entered the extension study and those who did not on PANSS total, positive, or negative symptoms, any of the cognitive variables, or any of the demographic factors. 2.2. Clinical assessment and remission criteria The main clinical assessments were carried out with the PANSS, which was administered weekly at Baseline through 6 weeks and then again at months 3 and 6, as well as at early termination. We used the PANSS items criteria for remission. In order to meet criteria for remission, subjects had to have scores of 3 (Mild) or less on all of the critical PANSS items presented in Table 1. This determination was made at the 6-month follow-up of the patients, thus requiring that patients be in remission 6 months after initiating treatment with ziprasidone. 2.3. Cognitive assessments These assessments covered domains of verbal learning and memory, attention and vigilance, executive functions, and language skills.

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Table 1 Critical PANSS items for the definition of remission • Delusions (P1) • Hallucinations (P3) • Unusual thought content (G9) • Conceptual disorganization (P2) • Mannerisms and posturing (G5) • Blunted affect (N1) • Social withdrawal (N4) • Lack of spontaneity (N6)

Verbal learning and memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT; Spreen and Strauss, 1998). The critical dependent measures are total learning for Trials 1 to 5 and Long-Delay Recall. Attention and vigilance were assessed with three tasks: the Digit Span Distraction Test (DSDT, Green et al., 1997), the Continuous Performance Test, Identical Pairs version (CPT-IP; Cornblatt et al., 1989) and the Trail Making test, part A (Reitan and Wolfson, 1993). The DSDT is a commonly used test of memory span and resistance to distractibility. In the CPT-IP, a commonly used test of vigilance, patients are asked to press a computer response key whenever the same four-digit target stimulus occurs twice in a row. In Trail Making Test, Part A, patients are instructed to connect, in ascending order and as quickly as possible, a series of circles containing numbers. Verbal fluency was assessed with two measures. Phonological fluency was measured with the Controlled Oral Word Association Test (COWAT; Spreen and Strauss, 1998), subjects are asked to name, in 60 s, items that begin with the letters F, A, then S. Semantic fluency was measured with the animal naming test (Spreen and Strauss, 1998). Executive functioning was measured with several tests. In part B of the Trail Making Test, the circles contain numbers and letters, patients are instructed to alternate between numbers and letters.

The Wisconsin Card Sorting Test (WCST; Heaton et al., 1993) is a commonly used test of executive functioning, which measures cognitive flexibility, maintenance of a cognitive set, and working memory. In the present study, the critical dependent variable is the number of categories attained. For the present study in order to examine changes from baseline, performance on all cognitive variables at baseline were transformed to z-scores (mean = 0, SD = 1) to provide a standard metric with which to evaluate change with treatment. Scores were adjusted so that positive values reflect improvement from baseline. These scores were not corrected for demographic factors, because there was no healthy comparison sample, and some of these tests are experimental measures that do have extensive normative data available. In these analyses, the z-scores for all of the cognitive tests were averaged, unweighted, into a single composite score. This is a typical procedure, consistent with that to be used with the MATRICS neurocognitive battery (Green et al., 2004). In order to ensure that we were not missing important information about any of the cognitive variables, we performed analyses with the individual cognitive items as well as the composite score. 2.4. Methods for determining remission Patients were characterized as meeting criteria for remission or not at baseline, 6-week assessment, and 6month assessment. In order to evaluate the sustained nature of remission we will report data on cases who were in remission at baseline and those who were in remission at 6 months. Since the cognitive assessment data were not available at the 3-month clinical assessment and because the proposed remission criteria require 6-month stability data, we did not use those clinical data as an intermediate endpoint. For purposes of the data analyses, we used the 6-month endpoint to classify subjects as in persistent remission.

Table 2 Demographic and baseline characteristics

Men (%) Mean age in years (range) Schizophrenia (%) Receiving antiparkinsonian Medications pre-study (%) Mean (SD) PANSS Mean (SD) S–A

Conventional (n = 108)

Olanzapine (n = 104)

Risperidone (n = 58)

70 39.3 (18–61) 75 58

63 36.0 (19–57) 69 11

67 37.2 (18–61) 83 26

67.5 (16.3) 2.5 (3.1)

65.6 (16.7) 1.5 (2.7)

71.0 (18.7) 1.6 (2.3)

Note. PANSS: Positive and Negative Syndrome Scale Total Score. S–A: Simpson–Angus.

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2.5. Data analyses We computed the proportion of cases that developed and sustained remission, as well as the proportion of cases that had cognitive improvements of 0.5 and 1.0 SD from baseline scores. Repeatedmeasures Analysis of Variance (ANOVA) was used to examine the baseline and 6-month scores for the PANSS Positive, Negative, and General Subscales. Similarly, a repeated-measures ANOVA was used to compare the cognitive composite score from baseline to endpoint across remission status. 3. Results Descriptive characteristics of the sample at baseline are presented in Table 2. These data are for all of the patients who entered the study and not just those who completed the 6-month extension. 3.1. Development of remission Of the 184 cases, 48 (26.1% of the total sample) met the remission criteria at baseline. Of these cases, 41 (85% of the cases who started in remission) sustained their remission at the 6-month follow-up. Of the remaining 136 cases, 60 (33% of the total sample) developed remission by 6 weeks and sustained it at the 6-month follow-up. Thus, a total of 101 of 184 cases (55% of the total sample) were in remission at the 6-month endpoint. No cases that were not in remission at the 6-week assessment were in remission at the 6-month endpoint. 3.2. PANSS correlates of remission Repeated-measures analysis of variance was used to examine PANSS positive, negative, and general scores at baseline and endpoint, with three subject groups compared: those who sustained remission, those who developed remission, and those who did not develop remission. Patients who were in remission at baseline and lost their remission were not examined in these analyses because of the small number (7) of subjects. These scores are presented in Fig. 1 and the results were similar for all three symptom dimensions. For all three dimensions, there was a statistically significant two-way interaction of Time (baseline to endpoint) × Group. For all three dimensions, Tukey Least Signficant Difference (LSD) follow-up tests found the same pattern of results: only subjects who developed remission manifested a change (p b .01) in their clinical

Fig. 1. Clinical symptoms as a function of remission status.

symptoms from baseline to endpoint. There were no differences at baseline between cases not in remission that eventually did and did not develop remission on any

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of the three PANSS dimensions. There were no differences at endpoint between cases who sustained remission for the 6-month period and those who developed remission during the period on any of the three PANSS dimensions. 3.3. Cognitive functioning and remission Cognitive composite scores at baseline and endpoint as a functional of remission status are presented in Fig. 2. The repeated-measures ANOVA found a statistically significant effect of time, F(1175) = 13.88, p b .001, and no significant interaction of remission status by time of assessment, F(1175) = .47, p = .62. This finding suggests that subjects with and without remission improve in their cognitive functioning in an essentially equivalent manner and that there were no

baseline differences as a function of likelihood of developing remission. This finding was replicated in a post hoc analysis, where a t-test was used to compare the baseline cognitive scores of cases who were and were not in remission at endpoint, t(175) = .21, p = .84. Finally, we compared every cognitive variable with the same data analytic strategy. For none of the variables was there a significant interaction of remission status by time of assessment, indicating that the global score analyses were not overlooking any important relationships with remission on the part of individual cognitive domains. 3.4. Clinical significant cognitive changes and remission status Patients were characterized by whether they manifested improvements in the composite cognition score of at least 0.5 SD or 1.0 SD. The prevalence of these changes in presented in Fig. 2 as well. We examined differences in the likelihood of improving at least 0.5 SD in cognitive functioning across the remission groups with a 2 (remission status at endpoint) × 2 (cognitive improvement yes/no) chi-square test. The group differences were non significant χ2(1) = 1.62, p = .14, indicating that there were no statistically association between the likelihood of development of remission and the likelihood of experiencing potentially meaningful cognitive improvements. However, the rate of clinically significant cognitive improvements in the remitted group, 32%, indicated that there were a total of 33 patients out of the initial sample of 184 who both maintained remission for 6 months and experienced a clinically significant improvement in their cognitive functioning. We did not perform these analyses with individual cognitive items, because of the large number comparisons that would have been involved. 4. Discussion

Fig. 2. Cognitive functioning and remission status.

There are several findings of importance in this study. After 6 months of sustained treatment with a new atypical antipsychotic medication over half of the subjects met clinical criteria for remission. Second, patients who started in remission sustained their remission at a rate of 85%. This rate of sustained remission is exactly the same as in the recent report on sustained remission with long-acting atypical therapy (Lasser et al., 2005). Further, a worsening of as little as one point on the PANSS on any of the eight defining criteria could have led to a designation of lost remission, making this a very conservative criterion and

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highlighting the robust nature of the maintained remission. Third, about 20% of the subjects in the sample experienced both clinically significant improvements in their cognitive functioning and a remission of their symptoms that was present at the 6-month endpoint. Thus, these data converge to suggest that a number of patients with schizophrenia experience wideranging long-term benefits from their transition to a newer atypical medication, when switched because of previous lack of efficacy or problems in tolerability. Baseline cognitive functioning did not predict the presence or development of remission. Although these results do not replicate the findings of Robinson et al. (2004), there are several differences between the samples that account for this discrepancy. Most important, the Robinson et al. patients were experiencing their first episode and they were assessed at the time of their first stabilization with antipsychotic treatments. The convergence between symptomatic remission and clinically significant cognitive change was minimal and this finding is consistent with earlier reports suggesting that symptomatic remission does not guarantee improvement in functional status or recovery from the illness. Our results highlight the need to consider all aspects of the illness when evaluating treatment response (see Harvey et al., 2004a,b), weighting functional outcomes and cognitive impairments as important features of the illness. Our also results suggest that it is very difficult to predict which patients would develop remission. Cognitive impairment was not a predictor, as noted above. In addition, baseline severity of symptoms in the patients not in remission at baseline did not predict either, as there was no difference in severity of any symptoms between those cases who developed remission with treatment and those who did not. At the endpoint, the cases that developed remission were indistinguishable from those who were remission in terms of symptom severity as well. Thus, we cannot point to any features of the patients in this study that is predictive of their likelihood of development of remission based on initial presentation. Functional recovery is not addressed by these data, because of the brief nature of the study. Future research, such as the studies to be conducted in the TURNS project (Buchanan et al., 2005), will include performance-based measures of functional capacity. Changes in these ecologically valid measures may predict changes in real-world outcomes. It needs to be understood, however, that functional recovery in schizophrenia also requires consideration of environmental factors, such as opportunities for performance of func-

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tional skills and support and encouragement of functional gains. It has been shown in two randomized clinical trials delivering computer-based cognitive remediation that cognitive enhancement can reliably lead to improvements in the critically important realworld outcome of employment (Wexler and Bell, 2005; McGurk et al., 2005). There are several limitations of this study. It has proven difficult to define how much cognitive change is required in order to be functionally relevant and our choice of indices for cognitive improvements (0.5 SD or more) is based on consensus and not necessarily on empirical data regarding potential for functional improvement. Without a comparison sample of either healthy controls or untreated patients we cannot exclude the possibility that the cognitive changes reflect an effect of repeated testing, such as a practice effect. Since some of the tests that we employed do not have extensive norms, we could not characterize our patients at baseline in terms of exactly how cognitively impaired they were and analyze the data on that basis. For the tests where norms are available (i.e., the RAVLT, Verbal Fluency, Trail Making, and WCST), it appears as if the patients on average are in the impaired range (see Harvey et al., 2004a,b for a discussion of this issue in the short-term efficacy analyses and Harvey et al., 2006 for a study of a subset of these tests at 6 months in a different sample). Six months is too short a study for definitive evaluation of recovery, relapse prevention, and functional improvements. Longer-term follow-ups would be required for such evaluations. As noted in the earlier reports on this study, the open-label nature of the study is a limitation that could be overcome with double-blind methods and data were not collected on the specific reasons (efficacy vs. tolerability) for the switches. Lasser et al. (2005), who presented the first report on remission with long-term treatment, also used open-label methods. In conclusion, the results of this study indicate that patients who are switched to a new atypical medication and manifest adherence to treatment for a 6-month period have a 50% or greater change of experiencing remission at the end of the period, consistent with previous studies of long-acting medications. Further, about 20% of the patients experienced both cognitive improvements and remission, despite the fact that development of remission was not predicted by baseline cognitive functioning and development of remission and cognitive improvements were not inter-related. Again, these data suggest the need to consider all aspects of improvement with treatment in schizophrenia, in order to focus on recovery from the illness.

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References Andreasen, N.C., Carpenter Jr., W.T., Kane, J.M., Lasser, R.A., Marder, S.R., Weinberger, D.R., 2005. Remission in schizophrenia: Proposed criteria and rationale for consensus. Am. J. Psychiatry 162, 441–449. Ascher-Svanum, H., Zhu, B., Faries, D., Kinon, B., Kane, J.M., 2005. Type of symptom remission and treatment outcomes in the longterm treatment of patients with schizophrenia. Neuropsychopharmacology S112 (abstract). Buchanan, R.W., Davis, M., Goff, D., et al., 2005. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr. Bull. 311, 5–19. Carpenter Jr., W.T., Gold, J.M., 2002. A new view of therapy for cognition in schizophrenia. Biol. Psychiatry 51, 969–971. Cornblatt, B.A., Lenzenweger, M.F., Erlenmeyer-Kimling, L., 1989. The continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients. Psychiatry Res. 29, 65–85. Davidson, L., O'Connell, M., Tondora, J., Styron, T., Kangas, K., in press. The top ten concerns about recovery encountered in mental health system transformation. Psychiatr. Serv. Green, M.F., 1996. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153, 321–330. Green, M.F., Marshall Jr., B.D., Wirshing, W.C., et al., 1997. Does risperidone improve verbal working memory in treatment resistant schizophrenia? Am. J. Psychiatry 154, 799–804. Green, M.F., Nuechterlein, K.H., Gold, J.M., et al., 2004. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol. Psychiatry 565, 301–307. Harvey, P.D., Keefe, R.S.E., 2001. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am. J. Psychiatry 158, 176–184. Harvey, P.D., Green, M.F., Keefe, R.S.E., Velligan, D.I., 2004a. Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. J. Clin. Psychiatry 65, 361–372. Harvey, P.D., Meltzer, H.Y., Simpson, G.S., et al., 2004b. Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia. Schizophr. Res. 66, 101–114. Harvey, P.D., Green, M.F., Bowie, C.R., Loebel, A., 2006. The dimensions of clinical and cognitive change in schizophrenia: evidence for independence of improvements. Psychopharmacology (Berl) 187, 356–363. Harvey, P.D., Bowie, C.R., Loebel, A., in press. Neuropsychological normalization with long-term atypical antipsychotic treatment: results of a 6-month, randomized, double-blind comparison of ziprasidone vs. olanzapine. J. Neuropsychiatry Clin. Neurosci. Heaton, R.K., Chelune, C.J., Talley, J.L., Kay, G.G., Curtiss, G., 1993. Wisconsin Card Sorting Test Manual-Revised and expanded. Psychological. Assessment. Resources, Odessa, FL.

Kay, S.R., 1991. Positive and Negative Syndromes in Schizophrenia. Brunner/Mazel, New York. Keefe, R.S., Bilder, R.M., Harvey, P.D., et al., 2006. Baseline neurocognitive deficits in the CATIE Schizophrenia Trial. Neuropsychopharmacology 31, 2033–2046. Lasser, R.A., Bossie, C.A., Gharabawai, G., Kane, J.M., 2005. Remission in schizophrenia: data from a one-year study of risperidone long-acting injectible. Schizophr. Res. 77, 215–227. Leucht, S., Kane, J.M., Kissling, W., Etschel, E., Engel, R.R., 2005. What does the PANSS mean? Schizophr. Res. 79, 231–238. Liberman, R.P., Kopelowicz, A., 2005. Sustained remission of schizophrenia. Am. J. Psychiatry 162, 173. Liberman, R.P., Kopelowicz, A., Ventura, J., Gutkind, D., 2002. Operational criteria and factors related to recovery from schizophrenia. Int. Rev. Psychiatry 14, 256–272. Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with schizophrenia. N. Engl. J. Med. 353, 1209–1223. McGurk, S.R., Mueser, K.T., Pascaris, A., 2005. Cognitive training and supported employment for persons with severe mental illness: one-year results from a randomized controlled trial. Schizophr. Bull. 31, 898–909. Montgomery, S.A., Åsberg, M., 1979. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382–389. Nierenberg, A.A., DeCecco, L.M., 2001. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J. Clin. Psychiatry 62 (suppl 16), 5–9. Ragins, M., 2005. Should the CATIE study be a wakeup call? Psychiatr. Serv. 56, 1489. Reitan, R.M., Wolfson, D., 1993. The Halstead–Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation, 2nd edition. Neuropsychology Press, Tucson, AZ. Robinson, D.G., Woerner, M.G., McMenamin, M., Mendelowitz, A., Bilder, R.M., 2004. Symptomatic and functional improvement from a first episode of schizophrenia or schizoaffective disorder. Am. J. Psychiatry 161, 473–479. Spreen, O., Strauss, E., 1998. A compendium of neuropsychological tests: administration, norms, and commentary. Oxford University Press, New York. Weiden, P.J., Simpson, G.S., Potkin, S.G., et al., 2003. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J. Clin. Psychiatry 64, 580–588. Wexler, B.E., Bell, M.D., 2005. Cognitive remediation and vocational rehabilitation for schizophrenia. Schizophr. Bull. 31, 931–941. Woodward, N.D., Purdon, S.E., Meltzer, H.Y., Zald, D.H. A meta– analysis of neuropsychological change to change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int. J. Neuropsychopharmacol. 8, 457–472.