Quality of Life in Schizophrenia: A Comparison of Instruments

Transcription

1 Quality of Life in Schizophrenia: A Comparison of Instruments by Joyce A. Cramer, Robert Rosenheck, Weichun Xu, Jonathan Thomas, William Henderson, and Dennis S. Charney for the Department of Veterans Affairs Cooperative Study Qroup on Clozapine in Refractory Schizophrenia Abstract Health-related quality of life in schizophrenia can be assessed by direct patient response or by a rating based on a structured interview. This study compares both types of instruments using a series of five standards: (1) sensitivity to change over time, (2) sensitivity to treatment effect, (3) correlation with symptom severity, (4) correlation with global clinical ratings, and (5) correlation with other measures of healthrelated quality of life. Four hundred and twenty-three inpatients with schizophrenia participating in a clinical trial comparing clozapine and haloperidol (VA Cooperative Study in Health Services #17) were evaluated using multiple measures of health-related quality of life (Lehman Quality of Life Interview; Heinrichs- Carpenter-Hanlon Quality of Life Scale; Strauss- Carpenter Level of Function scale, and clinical response.) The Quality of Life Interview showed less sensitivity to change and treatment effect, as well as lower correlations with all other measures than the Quality of Life Scale and the Level of Function scale. The latter scales showed high sensitivity to both change and treatment effect, and moderate-high correlations with other measures and with each other. The Quality of Life Scale and the Level of Function scale rater assessments appeared to be substantially more sensitive to subtle change and treatment effects than the patient-reported Quality of Life Interview for clinical trials. Health-related quality of life in schizophrenia is a more heterogeneous concept than previously appreciated. Keywords: Schizophrenia, quality of life, clinical trial, functional status, symptoms. Schizophrenia Bulletin, 26(3): ,2000. HRQOL encompasses several major dimensions including psychological status, functional abilities, subjective wellbeing, social interactions, economic status, vocational status, and physical status. Several factors have led to the recent interest in HRQOL as an outcome measure. A large population of persons with severe and persistent mental illness that had previously been maintained in institutions is now living in the community with various levels of support. The effectiveness of various programs ranging from simple pharmacological therapy or day programs to intensive case management must be evaluated not only in terms of clinician ratings of symptomatology, but also in terms of overall HRQOL. The development of new antipsychotic medications has fostered additional interest in HRQOL as a measure of improvement related to treatment. HRQOL information can also be used by government agencies and managed care providers as a basis for allocation of resources to the most effective treatments. In view of the modest and sometimes incomplete efficacy of medications in controlling the symptoms of schizophrenia, researchers and clinicians have looked toward HRQOL assessments as an additional measure of treatment success. Lehman (1995) outlined some of the conceptual issues faced in the assessment of HRQOL in mental illness. Major components that can be measured objectively are levels of function in the community, whereas subjective assessments are appropriate for domains related to well-being. Some aspects of HRQOL are considered generic because they assess general issues that are appropriate across a broad spectrum of illnesses (e.g., general physical function and emotional status). However, disease-specific instruments often are needed because they allow a specialized approach to the particular types of problems that are pertinent to the population to be studied (e.g., social activity and daily activities for schizophrenia Assessment of health-related quality of life (HRQOL) has become an important aspect in the evaluation of treatment programs for people with chronic severe schizophrenia. Send reprint requests to Ms. J.A. Cramer, VA Connecticut Healthcare System (G7E), 950 Campbell Ave., West Haven, CT ; e- mail: joyce.cramer@yale.edu. 659

2 Schizophrenia Bulletin, Vol. 26, No. 3, 2000 J.A. Cramer et al. patients). A review of scales from the literature of published instruments developed for assessment of severely mentally ill populations demonstrates a diversity of approaches (Cramer and Spilker, 1998). Most instruments are either patient-based or clinician-based assessments of a variety of aspects of HRQOL that are compromised in schizophrenia. The central components among most instruments include social, psychological, and adaptive functioning. During the design of a multicenter clinical trial comparing clozapine and haloperidol (Rosenheck et al. 1997), we chose to include three HRQOL instruments. These widely used instruments were (1) the Lehman Quality of Life Interview (LQLI; Lehman et al. 1982, 1986, 1988), (2) the Heinrichs-Carpenter-Hanlon Quality of Life Scale (HQLS; Heinrichs et al. 1984), and (3) the Strauss- Carpenter Level of Function (SLOF; Strauss and Carpenter, 1977), a brief precursor of the HQLS. The LQLI was selected because it uses a direct response by the patient for a wide variety of issues. Its simplicity was appealing in the context of a multicenter clinical trial. The instrument has been widely used in health services research and community-based outcome assessments. The HQLS was selected because it had been used in other clinical trials of atypical antipsychotic medications. Earlier clozapine trials had based outcomes on HQLS so that improvement in HQLS scores was considered the gold standard for effectiveness (Meltzer et al. 1990). The LQLI was designed to assess general quality of life (not HRQOL) in patients with severe mental illnesses (Lehman 1995). Initial studies were performed with patients in board and care homes, supervised community residences, and psychiatric hospitals (Lehman 1982, 1986, 1988). The advantage of the LQLI is the simplicity of administration of the structured questionnaire. Interviewers need not have extensive clinical skills, and need only brief instructions for administration of the instrument. The generic nature of the items expands the focus beyond problems experienced in schizophrenia, making the instrument useful across a variety of disorders and allowing comparisons with the general population. A disadvantage is that patients with schizophrenia often have difficulty making judgments as required, as noted by interviewers in our program, who expressed concern that severely ill schizophrenia patients were not able to reflect on the "terrible to delighted" range of responses offered for the subjective items. The HQLS was designed to assess a rater-based evaluation of Interpersonal Relations, Instrumental Role, Intrapsychic Foundations, and Commonplace Objects and Activities. The major impediments in implementation of HQLS ratings are the lengthy administration and the need to train clinically skilled interviewers carefully and to maintain rigorous interrater reviews. The purpose of this report is to compare these instruments based on five standards: (1) sensitivity to change over time, (2) sensitivity to treatment effect, (3) correlation with symptom severity, (4) correlation with global clinical ratings, and (5) correlation with other HRQOL instruments. Comparisons among HRQOL instruments were based on data from a large, welldefined population of patients with treatment-refractory schizophrenia who were evaluated by trained interviewers. Methods Sample. Four hundred and twenty-three patients with a verified DSM-IIl-R diagnosis of schizophrenia who were treatment-resistant inpatients in a Department of Veterans Affairs (VA) medical center psychiatry unit were invited to participate in a 1-year clinical trial (VA Cooperative Study in Health Services #17). Patients were randomized to 1 year of treatment with either clozapine or haloperidol at optimal dose, based on individual titration. The study is described in detail by Rosenheck et al. (1997). The status of "treatment resistance" was defined as having little or no improvement with at least two standard antipsychotic medications at 1000 mg chlorpromazine equivalents (unless limited by adverse effects) and current severe symptoms verified by Brief Psychiatric Rating Scale scores (Overall and Gorham 1962). Measures. Patients were evaluated at the time of enrollment into the clinical trial using multiple measures of HRQOL (LQLI, HQLS, SLOF), symptomatology (Positive and Negative Symptom Scale [PANSS], Kay et al. 1987), and clinical global measures (Global Assessment Scale [GAS], Endicott et al. 1976; Clinical Global Impression [CGI], Guy 1976). Quality of Life Interview. The LQLI (Lehman et al. 1982, 1986, 1988) is a structured self-report interview designed to be administered by a trained nonclinical interviewer. It contains 143 items in subscales, requiring approximately 50 minutes for completion. The instrument intersperses objective questions of levels of function for which specific responses are requested, with parallel subjective questions of life satisfaction that are answered using a Likert scale of seven anchors ranging from "terrible" to "delighted." The seven Objective Subscales quantify specifics of living situation, daily activities, family relationships, social relations, finances, work-school issues, legal-safety issues, and health issues. The six Subjective Subscales assess satisfaction with living situation, family relations, social relations, leisure activities, finances, legal-safety issues, work-school issues, health, and overall quality of life. Subscale scores are calculated as the mean of items in each scale. There is no total score. 660

3 Quality of Life in Schizophrenia Schizophrenia Bulletin, Vol. 26, No. 3, 2000 Quality of Life Scale. The HQLS (Heinrichs et al. 1984) is a semistructured interviewer-administered scale containing 21 items in four subscales, requiring approximately 45 minutes for completion. The structure of the instrument establishes a series of topics to be explored with the patient by the interviewer, using specified sample probes. Each item is then rated on a seven-point scale (0-6) for which descriptive anchors are provided. High scores reflect normal or unimpaired function, and low scores reflect severe impairment of function. The subscales are as follows: Interpersonal Relations (eight items): Household, friends, acquaintances, social activity, social network, social initiative, withdrawal, sociosexual behavior. Instrumental Role (four items): Occupational role, work functioning, work level, work satisfaction. Intrapsychic Foundations (seven items): Sense of purpose, motivation, curiosity, anhedonia, aimless inactivity, empathy, and emotional interaction. Common Objects and Activities (two items): Commonplace objects, commonplace activities. Subscale scores are calculated as the mean scores for items in each scale. A total score is calculated as the sum of all subscale scores. Level of Function Scale. The SLOF (Strauss and Carpenter 1977) is a semistructured interviewer-administered scale containing nine items in four domains, requiring approximately 20 minutes for completion. The items fall into four domains with higher scores (on a five-point scale, 0-4) reflecting better functioning. The subscales are Social Contacts (frequency and quality of social contacts), Work (quantity and quality of useful work), Symptomatology (absence of symptoms and recent hospitalization), and Function (fullness of life and overall level of function). Subscale scores are calculated as the mean scores for items in each scale. A total score is calculated as the sum of all subscale scores. Positive and Negative Symptom Scale. The PANSS (Kay et al. 1987) is administered as a Structured Clinical Interview (Opler and Ramirez 1992). The instrument assesses symptomatology in three subscales reflecting positive, negative, and general symptoms, as well as a total score. The 30 items are scored from absent (0) to extreme problem (6). Completion requires approximately 30 minutes. Global Assessment Scale and Clinical Global Impression. GAS and CGI ratings were based on the clinician's estimate of the patient's current level of function. GAS ratings were made for the usual condition in past week (Endicott et al. 1976). GAS scores are based on a 100-point scale with ten defined anchors serving as examples of clinical condition (higher scores indicate better functioning). The CGI score is a Likert scale ranging from normal (0) to extremely ill (6) (Guy 1976). Training, Administration, and Reliability. Research coordinators at each of the 15 participating centers were trained to become proficient raters for all instruments. The LQLI was administered by raters who were instructed on presentation of the questions to patients in a standardized format without bias. Raters were trained extensively in the administration of the HQLS using videotapes and team ratings of patients. The rater who interviewed the patient using the HQLS probes then asked additional questions in order to rate the SLOF. Similar training was accomplished for the PANSS. Interrater reliability was reevaluated quarterly to maintain consistency among raters. Videotaped examples rated annually by the entire group showed excellent agreement (Cicchetti et al. 1997; Rosenheck et al. 1997). The same rater administered the battery of instruments in one or two sessions, depending on patient tolerance. The sequence of administration was LQLI, HQLS, and SLOF, followed by PANSS, CGI, GAS, and other assessments for the clinical trial. Statistical Analyses. Several tests of validity were used. Sensitivity to change and to differences between clozapine and haloperidol treatment was measured by effect sizes. Effect size for change over time was calculated as mean scores at 12 months minus mean scores at baseline, divided by the standard deviation at baseline. Effect size for treatment was calculated as mean clozapine score minus mean haloperidol score at 12 months, divided by the standard deviation of the entire sample at baseline. The statistical significance of change from baseline to 12 months was evaluated with repeated measures analysis of variance. ANCOVAs in which the 12-month measures were dependent variables evaluated differences between treatment groups; baseline values were included as covariates. Some patients discontinued the assigned study medication because of lack of efficacy or adverse effects and received open treatment with clozapine, haloperidol, or other standard medications, as clinically indicated. Since these crossovers could affect study comparisons, the effect size calculations included only the 232 patients who remained on the randomized treatment for 1 year (excluding 90 patients whose treatment changed during followup). Pearson correlation coefficients were used to evaluate correlations of HRQOL measures with symptom severity (PANSS), correlations with global clinical measures (GAS, CGI), and correlations among related HRQOL domains at baseline and 12 months. Effect sizes and correlations of greater than or equal to 0.4 were considered high, were considered moderate, and less than 0.2 were considered low. 661

4 Schizophrenia Bulletin, Vol. 26, No. 3, 2000 J.A. Cramer et al. Results At the baseline assessment, all 423 subjects were inpatients because of refractory psychosis, with high symptomatology scores (PANSS mean score 91 ± 15 clozapine; 92 ± 15 haloperidol). At 12 months 94 percent of the 322 evaluable patients were outpatients, with significantly reduced symptomatology (PANSS mean score 79 clozapine, 84 haloperidol, difference p = 0.02). The largely male (98%) VA population was 43 ± 8 years of age, had 12 ± 2 years of education, and had an ethnic distribution of 66 percent white, 30 percent black, and 4 percent Hispanic. The mean age of onset of schizophrenia was 22 ± 5 years. Instrument Sensitivity and Relationships With External Standards Sensitivity to change over time. The effect size was calculated to represent the sensitivity of each subscale component and the overall instrument in demonstrating a difference between baseline and 12 months. Four of seven subjective and three of six objective LQLI subscales showed statistically significant changes over time (table 1, column 2). Subjective scales showing significant change included leisure and family relations (both p = , but large effect size only for leisure), residence (p = 0.02), finances (p = 0.01), and general quality of life (p < ). Objective scales that showed significant change over time, also with small effect sizes, included activities (p = ), victimization (p < 0.05), and social function (p < 0.01). The HQLS and SLOF, in contrast, were highly sensitive to change, as were the global clinical assessments (all p < ), with moderate to high effect sizes. Sensitivity to treatment effect. The effect size also was calculated to represent the sensitivity of each subscale component and overall instrument in demonstrating a difference between clozapine and haloperidol at 12 months (table 1, column 3). LQLI had low sensitivity, with only one of seven subjective scales (finances, p ) and none of seven objective scales achieving statistical significance. HQLS and SLOF both had high sensitivity to treatment group differences, as did the global clinical assessments (p < ) with moderate to high effect size. Correlation with symptoms. PANSS symptom ratings were included for comparison with non-quality of life assessments in the expectation that improvement with symptoms might be reflected in improved HRQOL. Table 2, column 2, shows that none of the LQLI subscales reached even moderate correlations with PANSS total scores (average correlation subjective = 0.04, objective = 0.09). In contrast, HQLS and SLOF showed high correlations with PANSS. Correlations with global clinical ratings. As seen with PANSS scores, none of the LQLI subscales was even Table 1. Effect sizes Measure LQLI subjective subscales Residence Leisure Family relations Social relations Finances Safety Effect size over time * -1.12** 0.20** *** 0.04 General quality of life 0.21" LQLI objective subscales Residence Activities Function Family contacts Social contacts Victimization Physical health HQLS SLOF PANSS GAS CGI 0.20 ** -0.21*** * ** 0.89** -0.93** -0.78** Effect size between drugs * *** 0.484*** *** 0.560** *** Note. CGI = Clinical Global Impression, GAS = Global Assessment Scale, HQLS = Heinrichs-Carpenter-Hanlon Quality of Life Scale, LQLI = Lehman Quality of Life Interview, PANSS = Positive and Negative Symptom Scale, SLOF = Strauss-Carpenter Level of Function. 1 Effect size over time includes all patients in both treatment groups. 2 Effect size between drugs includes patients in each treatment group. * p < 0.05; " p < 0.001; *** p< 0.01 moderately correlated with CGI or GAS scores (average correlation subjective = 0.04, objective = 0.08). HQLS and SLOF, in contrast, showed moderate to high correlations and effect sizes with CGI and GAS scores. Discussion These data demonstrate several differences among HRQOL instruments in meeting the five criteria examined in this investigation. The LQLI was the least sensitive and robust instrument in all five areas: sensitivity to change over time, sensitivity to treatment effect between medica- 662

5 Quality of Life in Schizophrenia Schizophrenia Bulletin, Vol. 26, No. 3, 2000 Table 2. Correlations between HRQOL measures and clinical measures at baseline Measure TOT-PANSS CGI GAS LQLI subjective subscales Residence Leisure Family Social relations Finances Legal-safety General quality of life Mean subjective LQLI objective subscales Residence Activities Function Family contact Social contact Victimization Physical health Mean objective HQLS SLOF 0.107* 0.178*" *** *** *" ** * *** "* * * *** *** 1 Note. CGI = Clinical Global Impression, GAS = Global Assessment Scale, HQLS = Heinrichs-Carpenter-Hanlon Quality of Life Scale, LQLI = Lehman Quality of Life Interview, SLOF = Strauss-Carpenter Level of Function, TOT-PANSS = Positive and Negative Symptom Scale total scores. 1 High correlation. 2 Moderate correlation. * p < 0.05; ** p < 0.01; *** p s tions, correlation with symptom severity, correlation with global clinical ratings, and correlation with other HRQOL measures. Thus, the LQLI does not appear to be as sensitive an instrument for use in clinical trials as the HQLS and SLOF. The three HRQOL instruments appear to measure different constructs using distinct approaches: (1) subjective patient assessments, (2) objective patient activity reports, and (3) external rater assessments. 1. LQLI subjective assessments evaluate subjective experiences by asking the patient to make judgments. This is an important dimension of HRQOL because it highlights the consumer's perspective. These areas, important as they are, appear to be less affected by clinical changes occurring over time or by clozapine treatment. Other investigators have noted that people living under harsh or adverse conditions often become resigned to their situation and may develop low expectations for themselves that may reduce their appreciation of small changes (Sen 1992, Atkinson et al. 1997). 2. LQLI objective subscales measure HRQOL as operationalized by concrete activities. These areas also showed little or no effect from medication, no correlation with clinical measures, little effect of time, and poor correlations with interview-based assessments. Although symptomatology and subjective reports of HRQOL improved over time, limited differences were seen in actual performance of daily activities. As with subjective judgments of HRQOL, operationalized activity measures also show limited time and treatment effects. 3. A third dimension of HRQOL is based on external rater assessments of patient functional status. These ratings appear to be most sensitive to change and to treatment effects, and most highly correlated with other measures (all of which were also rater based). A limitation of these external measures of HRQOL is that ratings may be contaminated by the rater's simultaneous observations of symptoms and side effects. Thus, while external evaluation of HRQOL is more sensitive than internal objective or subjective ratings, it is a less pure assessment of HRQOL. We now present a more detailed discussion of the performance of each scale. LQLI. It may be argued that the LQLI performed poorly because of the highly symptomatic population. To evaluate this possibility, we examined correlations between the LQLI, HQLS, and SLOF for groups of patients stratified by their baseline PANSS scores (low range 57-91, high range ). Few correlations reached moderate levels for either group, except for moderate correlations with LQLI objective residence, housing, activities, family contacts, and social contacts. The pattern of correlations was similar at baseline and 12 months, with higher levels of correlation in the groups with more symptomatology (higher PANSS scores). SLOF and HQLS correlated highly at both times and for all groups. These differences may be explained as a function of the entrenched deprivation of the subject that might lead the person to minimize differences over time (Sen 1992). Atkinson et al. (1997) noted that patient reports could be influenced by emotional withdrawal and lack of family ties and social contacts, as well as by poor insight that could lead to minimization of the impact of their illness in many domains. As health care providers, we tend to judge functional status from the viewpoint of symptoms. Thus, 663

6 Schizophrenia Bulletin, Vol. 26; No. 3, 2000 J.A. Cramer et al. patients whose symptomatology is florid (high PANSS scores) or who have severe adverse effects (e.g., extrapyramidal symptoms) are judged as not doing well. In contrast, patients might have very different value judgments for their condition, reflecting their accommodation to decrements in HRQOL and function. Thus, patient responses to subjective questions on the LQLI might correlate poorly with rater assessments on the HQLS or SLOF. Lehman (1993) commented on the difficulty for clinicians to appreciate that HRQOL perceived by patients differs from their social norms. Nonetheless, the LQLI question on global HRQOL was moderately to highly correlated with most subjective scales. This simple question might be a good indicator of overall subjective HRQOL in this model. Lehman et al. (1997) described use of the LQLI in a longitudinal study of homeless persons with severe mental illness. In this population, all subjective subscales improved over 12 months followup, while changes in objective items were seen in daily activities, frequency of family and social contacts, and employment rates over the year. We also found statistically significant effect sizes for many LQLI subscales comparing baseline to 1-year assessments. These data suggest that patients with severe and persistent schizophrenia can differentiate and report change over time, although neither study showed significant treatment group differences on the LQLI. HQLS. Sensitivity to change over time and between treatments was robust for the HQLS and SLOF. Interim assessments at 3, 6, and 9 months showed similar patterns of sensitivity for both instruments. The HQLS was used as a primary outcome in this trial (Rosenheck et al. 1997) where HQLS total scores were significantly improved among patients who stayed on clozapine for 12 months compared to the haloperidol group (p = 0.003). The ability of trained clinician-raters to spend adequate time interviewing and probing patients about each item likely enhanced the reliability of ratings. The HQLS could be considered a gold standard research instrument for assessment of HRQOL in severely ill schizophrenia patients when administered by trained clinical raters. The high correlations between HQLS and SLOF suggest that the SLOF might be a substitute for the longer interview. However, we do not know if the SLOF would have performed as well if it had been administered separately and without the structure of the longer HQLS interview. Comparisons Between LQLI and HQLS. Lehman et al. (1993) compared the LQLI and HQLS, describing correlations among subscales and test-retest reliability in 59 patients with schizophrenia. However, completion of instruments on different days makes it difficult to interpret the data. In contrast to our findings of low correlations, they found moderate correlations between the HQLS and LQLI subscales of overall HRQOL, family contacts, social contacts, and daily activities. We also examined interrelationships among the LQLI and HQLS subscales, finding results similar to use of the total HQLS score. As indicated by Lehman et al. (1993), the two instruments are not highly convergent, in part because they have different underlying constructs for most subscales. We found good external validation for HQLS and SLOF, but not for LQLI when compared with concurrently administered PANSS, GAS, and CGI ratings. PANSS scores were significantly correlated with HQLS and SLOF, but not with LQLI subscales. One consideration is that LQLI is the only instrument that excludes clinician judgment. The implications of differing results depending on the type of instrument is problematic. The issue can be partially resolved by recalling the caveat that instrument selection should depend on the setting (e.g., managed care outcome assessments might best focus on community living [Lehman, 1995]). Using statistical analyses on which to make comparisons differs from an analysis of clinically important correlations or outcomes. The amount of change in any instrument score needs to be anchored in the clinical framework of "What is a detectable difference?" We are looking at how clinicians rated patients on a global scale (e.g., unchanged, better, worse) in conjunction with HQLS scores. (Cramer et al., in press) Concluding Comments. In summary, these data suggest that LQLI may not be a primary instrument for clinical trials for severely ill schizophrenia patients because it is not sensitive to subtle differences in treatment as are the HQLS and SLOF. Such patients may be functioning at a consistently low level from which change is not readily discernable. Activities and contacts with people might be too limited to provide adequate information for the questionnaire. All of these factors should help explain the low correlations with HQLS, PANSS, CGI, and GAS interview-based data. However, it should be understood that responses that do not match expected social norms may still accurately reflect the patient's personal perspective. Nonetheless, caution is needed in interpreting the high correlations among symptom and rater-based HRQOL assessments because they were rated by the same clinician. Each of these instruments thus addresses a different aspect of HRQOL. Selection depends on the major issue to be studied. As shown in this report, individual measures provide different conclusions. To maximize the chance of demonstrating a difference between therapeutic interventions, a rater-based instrument appears to be the best choice. However, to document either client-evaluated status or objective manifestations of change in behavior, the LQLI would be the preferred instrument, although it is less likely to show significant change. The high correlations between 664

7 Quality of Life in Schizophrenia Schizophrenia Bulletin, Vol. 26, No. 3, 2000 HQLS and SLOF scores suggest that the SLOF might be a substitute for the longer HQLS interview. However, we do not know if the SLOF would have performed as well if it had been administered separately, and without the structure of the longer HQLS interview. HRQOL as evaluated by external raters appears to show greater propensity for improvement than personal evaluation by patients of either their subjective or objective HRQOL. These results suggest that HRQOL is a more heterogeneous concept than has been previously appreciated. References Atkinson, M.; Zibin, S.; and Chuang, H. Characterizing quality of life among patients with chronic mental illness: A critical examination of the self-report methodology. American Journal of Psychiatry, 154:99-105, Cicchetti, D.V.; Showalter, D.; and Rosenheck, R. A new method for assessing interexaminer agreement when multiple ratings are made on a single subject: Applications to the assessment of neuropsychiatric symptomatology. Psychiatry Research, 72:51-63, Cramer, J.A.; Rosenheck, R.; Xu, W.; Henderson, W.; Thomas, J.; Charney, D.; for the Department of Veterans Affairs Cooperative Study on Clozapine in Refractory Schizophrenia. Detecting improvement in symptomatology and quality of life in schizophrenia Schizophrenia Bulletin, in press. Cramer, J.A., and Spilker, B. Quality of Life and Pharmacoeconomics: An Introduction. Philadelphia, PA: Lippincott-Raven, pp Endicott, J.; Spitzer, R.L.; Fleiss, J.L.; and Cohen, J. The Global Assessment Scale: A.procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry, 33: , Guy, W. Clinical global impression. In: Guy, W, ed. ECDEU Assessment Manual for Psychopharmacology. (DHEW Publication No. ADM ) Rockville, MD: National Institute of Mental Health, pp Heinrichs, D.W.; Hanlon, T.E.; and Carpenter, W.T., Jr. The Quality of Life Scale: An instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin, 10(3): , Kay, S.R.; Fiszbein, A.; and Opler, L.A. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2): , Lehman, A.F. The quality of life interview for the chronically mentally ill. Evaluation and Program Planning, 11:51-62, Lehman, A.F. Measuring quality of life in a reformed health system. Health Affairs, 14:90-101, Lehman, A.F.; Dixon, L.B.; Kernan, E.; DeForge, B.R.; and Postrado, L.T. A randomized trial of assertive community treatment for homeless persons with severe mental illness. Archives of General Psychiatry, 54: , Lehman, A.F.; Possidente, S.; and Hawker, F. The quality of life of chronic patients in a state hospital and in community residences. Hospital and Community Psychiatry, 37: , Lehman, A.F.; Postrado, L.T.; and Rachuba, L.T. Convergent validation of quality of life assessments for persons with severe mental illnesses. Quality of Life Research, 2: , Lehman, A.F.; Ward, N.C.; and Linn, L.S. Chronic mental patients: The quality of life issue. American Journal of Psychiatry, 10: , Meltzer, H.Y.; Burnett, S.; Bastani, B.; and Ramirez, L.F. Effects of six months of clozapine treatment on the quality of life of chronic schizophrenia patients. Hospital and Community Psychiatry, 41: , Opler, L.A., and Ramirez, P.M. Structured Clinical Interview for the PANSS (SCI-PANSS). Toronto, Canada: Multi-Health Systems, Overall, J.E., and Gorham, D.R. The Brief Psychiatric Rating Scale. Psychological Reports, 10: , Rosenheck, R.; Cramer, J.; Xu, W.; Thomas, J.; Henderson, W.; Frisman, L.; Fye, C; and Charney, D. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. New England Journal of Medicine, 337: , Sen, A. Inequality Reexamined. Cambridge, MA: Harvard University Press, p. 55. Strauss, J.S., and Carpenter, W.T., Jr. Prediction of outcome in schizophrenia: HI. Five year outcome and its predictors. Archives of General Psychiatry, 34: ,1977. Acknowledgments This study was supported by the Department of Veterans Affairs Health Services Research and Development Service. We thank Jennifer Cahill for programming support. Clozapine Cooperative Study #17 investigators were John Grabowski, M.D. (Allen Park, MI); Denise Evans (Augusta, GA); Lawrence Herz (Bedford, MA); George Jurgus (Brecksville, OH); Sidney Chang (Brockton, MA); Lawrence Dunn (Durham, NC); John Crayton (Hines, IL); William Lawson (Little Rock, AK); Richard Douyon (Miami, FL); Edward Allen (Montrose, NY); John Lauriello (Palo Alto, CA); Michael Peszke (Perry Point, MD); Jeffrey Peters (Pittsburgh, PA); Janet Tekell (San 665

8 Schizophrenia Bulletin, Vol. 26, No. 3, 2000 J.A. Cramer et al. Antonio, TX); and Joseph Erdos (West Haven, CT). C. Fye (Albuquerque, NM) participated at the Pharmacy Coordinating Center. The Authors Joyce A. Cramer, B.S., Robert Rosenheck, M.D., and Dennis S. Charney are members of the VA Connecticut Healthcare System, West Haven, CT, and of the Yale University School of Medicine, Department of Psychiatry, New Haven, CT. Weichun Xu, Jonathan Thomas, and William Henderson are members of the VA Cooperative Studies Program Coordinating Center, Hines, IL. All are members of the Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. 666