Department of Biological Psychiatry, Medical University Innsbruck, Innsbruck, Austria
Bar Ilan University, Ramat Gan, Israel
Department of Biological Psychiatry, Medical University Innsbruck, Austria
Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
Janssen-Cilag GmbH Department for Health Economics, Neuss, Germany
Correspondence: Professor W.W. Fleischhacker, Department of Biological Psychiatry, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Tel: +43 (512) 504 23669; fax: +43 (512) 504 25267; e-mail: wolfgang.fleischhacker{at}uibk.ac.at
Declaration of interest W.W.F. has received research support, consultancy honoraria and fees from Astra Zeneca, BMS, Eli Lilly, Janssen, Otsuka, Pfizer and Sanofi Synthelabo. J.R. has received honoraria and travel support from Johnson and Johnson and other manufacturers of antipsychotics. G.K. has received research support from Janssen.M.E. is an employee of Johnson and Johnson, Belgium and A.M. of Janssen-Cilag, Germany.
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ABSTRACT |
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Aims To examine psychopathology and patient-rated functioning and well-being in patients treated with risperidone.
Method In a 1-year, open-label, international multicentre trial of long-acting risperidone in 615 stable adult patients with schizophrenia, self-rated functioning and well-being were measured every 3 months using the Short Form 36-item questionnaire (SF-36). Psychopathology was quantified using the Positive and Negative Syndrome Scale (PANSS).
Results Significant improvements were found on the SF-36 mental component summary score and vitality and social functioning scales. PANSS and mental component summary scores were moderately correlated.
Conclusions Patient-reported functioning and well-being appear to differ from investigator-rated psychotic symptoms. Patient-rated well-being should be assessed with symptoms to help measure treatment outcomes.
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INTRODUCTION |
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METHOD |
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Participants
Eligible patients were at least 18 years old and had a DSM-IV diagnosis of
schizophrenia (American Psychiatric
Association, 1994). They were required to be symptomatically
stable, as judged by the treating physician, be receiving a stable dose of an
antipsychotic drug for at least 4 weeks before the trial and be in good
general physical health. The main exclusion criteria were substance
dependence, a history of tardive dyskinesia, neuroleptic malignant syndrome or
clinically significant physical abnormalities. Patients who had been treated
with clozapine within 2 months of entry into the trial or with a conventional
depot antipsychotic drug within one treatment cycle were also ineligible.
Study medication
After a 2-week run-in period during which antipsychotic agents other than
risperidone were discontinued, patients were started on oral risperidone at a
daily dosage of 1-6 mg based on the judgement of the treating physician. The
oral dosage was used as a guide to the starting dose of long-acting
risperidone of 25 mg, 50 mg or 75 mg. Supplementation with oral risperidone
was given for 2-3 weeks following the first injection of long-acting
risperidone to provide antipsychotic coverage during the 3-week latency period
after the first injection (Eeredekens et al, 2004). Concomitant
medications that could be initiated or continued, at the discretion of the
investigator, were those to assist sleep, anti-Parkinsonian agents,
antidepressants, mood stabilisers, propranolol for akathisia and
benzodiazepines for agitation and insomnia.
Measures
Both the Positive and Negative Syndrome Scale (PANSS;
Kay et al, 1987;
Kay & Singh, 1989), which
was the primary measure of treatment efficacy, and the Medical Outcomes Study
Short Form 36-item questionnaire (SF-36;
Ware et al, 1993),
which measures patient-rated functioning and well-being, were administered
every 3 months. The SF-36 is a multipurpose generic measure of functional
health and well-being with psychometrically based physical and mental health
summary measures, comprising eight domains which assess the following quality
of life parameters:
Scores range from 0 to 100, with the higher scores indicating a better quality of life. From these eight domains, a physical component summary score (composed of items a-d) and a mental component summary score (composed of items e-h) were calculated and compared with benchmark scores from a general population (Ware, 2003). Scores above or below 50 represent quality of life above or below the population average, respectively. Patients completed the questionnaire prior to being interviewed by the investigator. A 1-month recall was used for all questions. The SF-36 has been found to be suitable for use in multinational studies (Ware et al, 1998).
The Structured Clinical Interview for PANSS (Kay et al, 1987) was used to rate schizophrenia symptoms. In addition to the total PANSS score (sum of all 30 items, maximum score 7 per item), five sub-scales were calculated based on the findings of Marder et al (1997). These sub-scales were:
Sample
A total of 615 patients with schizophrenia were recruited into this trial
(422 men, 193 women). The majority (92%) of them were White, and their mean
age was 42 years (s.e.=0.6, range 18-84). The mean PANSS total score at
baseline was 67.1 (s.e.=0.8). Eighty-seven per cent of the total cohort
completed the first 3 months, and 65% completed the 1-year trial period.
Tolerability, safety and efficacy have been reported elsewhere
(Fleischhacker et al,
2003), and suggest that in schizophrenia patients with stable
symptoms can achieve further improvement in terms of both safety and efficacy
by having their medication switched to long-acting risperidone.
Statistical analysis
The primary analysis of the study explored changes in self-rated
functioning and well-being from baseline at 12 weeks, 24 weeks, 36 weeks and
50 weeks and at end-point. Changes from baseline in self-rated functioning and
well-being, as measured by the SF-36, were analysed for each measurement point
and for the last observation for each patient using a paired samples
t-test. Differences on the SF-36 between population norms and study
participants are expressed as effect size scores using Cohen's formula
(Cohen, 1976), which consists
of subtracting the mean differences of the two groups and dividing it by the
pooled standard deviation. Cohen
(1976) has termed effect sizes
of 0.20-0.50 as small, 0.50-0.80 as medium and greater than 0.80 as large. For
example, an effect size of 0.20 corresponds to the difference between the
heights of 15-year-old and 16-year-old girls in the USA, an effect size of
0.50 corresponds to the difference between the heights of 14-year-old and
18-year-old girls and an effect size of 0.80 corresponds to the difference
between the heights of 13-year-old and 18-year-old girls
(Cohen, 1976).
A second planned analysis examined the overlap of self-rated functioning and well-being as measured by the four SF-36 mental health domains and the mental component summary scores, and psychopathology as measured by the five PANSS sub-scale scores. This was done by examining correlations of the measures and then by maximum likelihood factor analysis with promax rotation. The number of factors was determined by examining the scree plots. Factor analysis permitted a test of the extent to which the PANSS sub-scale scores and SF-36 mental health domain scores overlapped and the goodness of fit of the factor model obtained. Root mean square error of approximation (RMSEA) was used to indicate the goodness of fit; values below 0.1 are considered to be a good fit and those below 0.05 a very good fit (Steiger, 1989).
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RESULTS |
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Improvement in self-rated functioning and well-being during antipsychotic treatment
Table 2 presents mean change
on the SF-36 domains and summary scores. On the physical health measures there
was no significant change to end-point based on last value carried forward
when examining all participants. On the mental health measures there were
significant improvements at all time points on the mental component summary,
the vitality score and, with the exception of week 12 (P=0.08), also
on social functioning. On role - emotional there were
significant improvements at all time points but not at end-point derived by
last observation carried forward analysis.
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Association of self-rated functioning and well-being and PANSS
Table 3 shows the
correlations of the mental component summary, and the four SF-36 mental health
domain scores it comprises, with the PANSS sub-scale scores at baseline and
the correlations among change from baseline to end-point on these measures. At
baseline and on change, the highest correlations were found between the PANSS
anxiety/depression scale and the SF-36 domain general mental
health; at baseline the correlation coefficient was r= -0.53
and for change it was r= -0.42. Correlations of PANSS
anxiety/depression with mental component summary were 0.49 at baseline and
0.36 for the change scores. Despite the fact that both the total PANSS score,
as presented elsewhere (Fleischhacker
et al, 2003), and the mental component summary score of
the SF-36 improved significantly over the course of the trial, changes in the
two measures were only moderately correlated (r= -0.4).
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To examine further the extent to which the domains measured by the two instruments overlapped, maximum likelihood factor analysis was conducted with promax rotation. The factor analysis included the five PANSS sub-scales and the four SF-36 mental health domains. Analyses of the baseline data and change scores both produced two factors, one of which was associated with the five PANSS sub-scales, the other with the four mental health domains of the SF-36. At baseline the factors cumulatively accounted for 47.2% of the variance and, for change to end-point, for 39.5% of the variance. The correlation between the factors at baseline was r= -0.34, suggesting that the SF-36 and PANSS have an overlap of 12% at baseline. For change to end-point the correlation was r= -0.52, suggesting an overlap of 27%. The factor plot presenting the results of the factor analysis for the baseline measures is presented in Fig. 1. The mental health domains of the SF-36 were more tightly clustered than the sub-scales of the PANSS.
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DISCUSSION |
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Baseline illness severity and outcome
Even though our study recruited symptomatically stable patients, baseline
scores (particularly in the mental health domains) were significantly below
population norms. Improvements both in psychopathology and in the mental
health domains and the mental component summary score during treatment with
long-acting risperidone were apparent early in treatment and were maintained
throughout the long-term treatment period. Given that the population in this
study were required to be physically healthy, the physical component summary
score and scores on its individual physical health domains (physical
functioning, role - physical, bodily pain and general health) were high at
baseline and approached normative scores. Consequently, the effect of
treatment on the physical components of the SF-36 was modest over the course
of the study, which may reflect the fact that treatment with long-acting
risperidone generally induces few side-effects that might interfere with the
subjective physical well-being of patients with schizophrenia. These findings
are consistent with the observed increments in a smaller double-blind,
placebo-controlled study, involving more severely symptomatic patients with
schizophrenia treated with long-acting risperidone for a shorter period
(Nasrallah et al,
2004).
Correlation results in the light of previous studies
In this study correlations between objective symptom ratings and subjective
ratings of functioning and well-being at baseline were only modest. Also,
although patients in this trial improved both in terms of SF-36 mental health
domain scores and the PANSS scores
(Fleischhacker et al,
2003), there was only a moderate correlation between changes
measured on the PANSS and the SF-36.
We are not aware of any other published data on perceived functioning and well-being, as measured by the SF-36, in clinically stable patients with schizophrenia treated with novel antipsychotic drugs. The SF-36 was, however, used in another published large-scale study in this area, conducted by Tunis et al (1999) in a large cohort of people with schizophrenia who participated in a clinical trial of olanzapine v. haloperidol. The trial sample consisted of patients who had clinically significant psychosis and who had demonstrated less than an optimal response to their previous medication. The study found that the SF-36 exhibited good reliability and validity among people with schizophrenia. Tunis et al (1999) also found that, compared with population norms, the study participants had marked deficits in the SF-36 domains in general health, vitality, general mental health, social functioning and in both physical and emotional role limitation; furthermore, correlations between the Brief Psychiatric Rating Scale total score and the SF-36 domain scores were non-significant for all physical component scores and ranged from -0.20 to -0.31 for the mental health domain scores (vitality, r= -0.21; social functioning, r= -0.29; role - emotional, r= -0.20; general mental health, r= -0.31). Similar to our study, these correlations suggested - also in poorly responding patients - little overlap between the psychopathology measures and the SF-36 mental health domains; however, the association of each component of the SF-36 with specific BPRS item clusters was not examined, thus not allowing more detailed examination of the association of change in symptoms as rated in a clinical interview and changes in patients' perceived mental and physical health.
These results support our finding that patient-reported improvement in functioning and well-being is a different outcome dimension from investigator-rated improvement of psychopathology, which suggests that it is advisable to use more than just one method when assessing outcomes.
Limitations
The major limitation of our study was that it did not have a control group,
so that although improvements in well-being were noted it is not possible to
know whether these changes would have occurred in the absence of treatment
with long-acting risperidone. Still, regardless of any potential drug effects,
the finding that symptom improvement, as measured by an observer-based rating
scale, has little in common with subjectively experienced functioning and
well-being still stands. Another limitation of the study is that the SF-36 is
a generic instrument used across all disease states, and its usefulness in
schizophrenia is constrained by the fact that it does not adequately cover the
social domains, notably social functioning and psychosocial reintegration,
that are relevant outcomes in this illness. On the other hand, the SF-36 is a
patient-rated instrument that is well validated and sensitive to changes in
the level of functioning in schizophrenia
(Russo et al, 1998;
Tunis et al, 1999). It is short, simple, practical and widely used, with associated normative data
to enable comparisons with the general population.
Implications for further research
There is evolving evidence that in comparison with conventional
antipsychotics, novel antipsychotics are more effective in improving
health-related quality of life in patients with schizophrenia
(Hamilton et al,
2000; Cook et al,
2002; Karow & Naber,
2002). This may be a reflection of the efficacy, tolerability and
relapse prevention benefits of these drugs over conventional drugs
(Csernansky et al,
2002; Sartorius et al,
2002,
2003;
Leucht et al, 2003).
Whatever the cause of these improvements, this outcome domain is very relevant
to people with schizophrenia.
Given the importance of health-related quality of life, particularly among people with schizophrenia, and the apparent lack of overlap between symptom improvement and improvement in this domain, future clinical trials of antipsychotic medications should routinely apply measures such as the SF-36, optimally in conjunction with a disease-specific, patient-rated instrument. Studies are also needed of the extent to which perceived functioning and well-being are associated with longer-term outcomes such as relapse. In addition, more work is needed in identifying which domains and measures of health-related quality of life are most germane to treating schizophrenia.
In summary, maintenance treatment with long-acting risperidone appears to contribute to an improvement of outcomes beyond a reduction of symptoms in patients with schizophrenia. Clinically meaningful improvements were observed in our study participants; these findings for self-rated functioning and well-being are distinct from symptomatic improvement. Therefore, patient functioning and well-being are relevant parameters to assess in addition to symptom improvement.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication June 15, 2004. Revision received October 4, 2004. Accepted for publication October 9, 2004.
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