- Email: [email protected]
Impact of newer antipsychotics on outcomes in schizophrenia
CLINICAL THERAF’EUTICSVVOL.
19, NO. 1, 1997
Impact of Newer Antipsychotics Schizophrenia
on Outcomes in
Nicholas A. Keks, MB, PhD Department of Hospital and Community Psychiatry, Alfred Hospital, Prahran, Melbourne, Victoria, Australia
ABSTRACT Functional status in schizophrenia depends in part on cognitive function. Newer antipsychotics, such as risperidone, produce better cognitive function in patients with schizophrenia than do conventional neuroleptics, which implies that the indirect costs of the illness will be less in patients treated with risperidone. A robust decision-analytic model of schizophrenia suggests that the overall cost of treating a patient with risperidone is $11,772.00 per year compared with $13,622.00 per year for haloperidol and that the cost per response is even more favorable toward risperidone-$14,599.00 versus $23,040.00. This model supports the results of naturalistic trials in which risperidone produced better outcomes than did conventional neuroleptics. Overall, the use of the more effective, better tolerated newer antipsychotics should reduce the cost to society of
148
schizophrenia and improve patients’ quality of life. Key words: pharmacoeconomic modeling, schizophrenia, cognitive function, quality of life, cost of schizophrenia.
INTRODUCTION The heterogeneity of schizophrenia with respect to symptoms and course of illness has been recognized since the original conceptualization of Eugen Bleuler. 1 Schizophrenia probably has multiple etiologies, including genetic vulnerability and environmental influences, such as perinatal hypoxia.2 Very broadly, the syndrome can be characterized as a persistent psychosis (often associated with negative symptoms such as alogia, affective flattening, and lack of motivation) that cannot be attributed to a mood disorder, medical illness, or use of drugs.3 Although positive symptoms (delusions, hallucinations, formal thought dis-
0149-2918/97/$3.50
N.A. KEKS
order) and negative symptoms (social withdrawal, alogia, affective flattening, lack of motivation, poverty of thought) are characteristic of schizophrenia,4 other symptoms also occur and often are critical in determining the overall outcome of the illness. Both depression, which can be associated with suicide, and elevation of mood are seen frequently in patients with schizophrenia, as are anxiety and hostility or aggression.5 Cognitive dysfunction also occurs in patients with schizophrenia, particularly those with negative symptoms,6 and is associated with functional impairment. A component of both negative symptomatology and cognitive dysfunction in schizophrenia can be attributed to the use of conventional neuroleptics.’ These “iatrogenic” symptoms can be considered yet another category of manifestations requiring treatment.8 The clinician is therefore faced with the task of addressing a broad spectrum of symptoms in schizophrenia (Table I), with control of these symptoms being the traditional outcome goal in clinical practice. However, there are several other levels of outcome for patients with schizophrenia, some of which are only partly correlated with symptomatic outcomes. Lehman et al9 have recently summarized
Table I. Symptoms
target outcomes for interventions in schizophrenia (Table II). Clinical outcomes that can be assessed include symptoms and behaviors such as self-harm, violence, and substance abuse. Functional status concerns occupational role performance, interpersonal relationships, and self-care. Access to resources and opportunities, such as availability of housing, financial support, work, and safety, are some of the most critical issues for people with chronic schizophrenia. Patient satisfaction and caregiver well-being also must be considered. Clinicians also must consider the economic implications of schizophrenia and its treatment.‘O Costs usually are divided into direct and indirect costs. Direct costs are those associated with treatment. Hospitalization constitutes 70% of direct costs, with drug therapy accounting for only 10% and outpatient care another 20%.” Estimates of indirect costs are more variable, but indirect costs can be at least as high as direct costs. Two broad developments in the treatment of schizophrenia-community treatment programs and newer antipsychotics-are aimed at improving outcomes in general and decreasing the costs of illness and treatment in particular. As care of patients with chronic schizophrenia has
of schizophrenia.
0 Positive symptoms (delusions, hallucinations, formal thought disorders) l Negative symptoms (social withdrawal, alogia, affective flattening, lack of motivation, poverty of thought) l Cognitive dysfunction Mood disturbances Anxiety 0 Iatrogenic symptoms l Hostility and aggression l
l
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CLINICAL THERAPEUTICS”
Table II. Target outcomes for interventions
in schizophrenia.
0 Symptoms l Clinical correlates (substance abuse, suicidality, violence, and hostility) l Functional status l Resources and opportunities (access) 0 Life satisfaction l Family well-being l Patient satisfaction with intervention Adapted from Lehman et a1.9
shifted from hospital to community, the cost-effectiveness of comprehensive, integrated community treatment programs, such as the Program of Assertive Community Treatment in Madison, Wisconsin, has been demonstrated and replicated.‘* These community treatment programs involve a multidisciplinary team available on a 24hour basis that offers crisis intervention, assistance with medication, brief hospitalization in a general hospital, financial and social support, normative housing, social skills training and assistance with basic needs, and support for families and the community. l3 The introduction of newer antipsychotic drugs has also had a profound impact on the treatment of schizophrenia. Clozapine, for example, can improve a broad range of outcomes and result in cost savings.14,15 Risperidone, a serotonin-dopamine antagonist, is the first second-generation antipsychotic to become available for clinical use.16 Risperidone is more effective than conventional neuroleptics for the treatment of positive and negative symptoms of schizophrenia and is less likely than older neuroleptics to cause extrapyramidal side effects at maximally effective doses.17*‘8 This paper selectively examines further evidence concerning outcomes with risperidone in the treatment of schizophrenia.
150
PHARMACOECONOMIC MODELING A number of approaches can be used to evaluate the economic impact of new drugs.19 Prospective studies, which collect both efficacy and cost data, are often regarded as most informative. However, prospective study protocols make the situation quite artificial, which may be acceptable when evaluating clinical efficacy but can be misleading in terms of cost estimates. Naturalistic studies and beforeafter designs are vulnerable to the influence of confounding variables that cannot be controlled or even identified. Furthermore, these studies may generate findings applicable only to the area or country in which the studies were conducted, given the variations in schizophrenia treatments and costs. However, conducting a pharmacoeconomic study in each different locale would be impractical. Local conditions and costs can be assessed by inputting efficacy data into pharmacoeconomic models. The effect of variations in the different variables can also be investigated by varying the parameters in so-called sensitivity analysis. Davies and Drummond*’ demonstrated the utility of this approach for clozapine in the United Kingdom.
N.A.KEKS
The Australian government requires the submission of pharmacoeconomic analyses before approval of subsidy for a new medication. Such an analysis was done for risperidone, and the results were accepted by the Australian authorities.21T22 The pharmacoeconomic analyses included a meta-analysis of pooled data from six randomized, double-masked trials comparing risperidone with haloperidol. Clinical response was defined as an improvement of at least 20% in global symptomatology. There was a significant difference (13.9%) in the rate of clinical response in favor of risperidone (P < 0.05). The use of anticholinergic drugs was 17.7% less among patients receiving risperidone compared with those receiving haloperidol (P < 0.05). In addition, fewer (12.7%) patients in the risperidone group compared with the haloperidol group withdrew from treatment (P < 0.05). The findings from the meta-analysis were entered into a decision-analytic model that simulated the treatment of patients with chronic schizophrenia over a 2-year period along a range of different pathways. Probabilities were assigned to each pathway based on available clinical data. Resource use was then specified for each pathway and the costs calculated. On the basis of the model, the total cost per patient was estimated at $11,772.00 per year for risperidone and $13,622.00 per year for haloperidol, a difference of $1850.00. With clinical response defined as a 20% reduction in symptoms, the cost per response was $14,599.00 for risperidone and $23,040.00 for haloperidol. The model estimated that risperidone was associated with a 19.7% greater response rate than haloperidol at the end of 2 years. Sensitivity analyses, which varied parameters in the model, demonstrated that the
model was robust. Because hospitalization comprised the largest proportion of costs in this study, the findings of Addington et al23 and Lindstrijm et a124 that risperidone decreased the number of patient days in the hospital also provided strong support for the validity of the Australian model.
COSTS AND BENEFITS OF NEWER ANTIPSYCHOTICS IN NATURALISTIC SETTINGS One objection to data from controlled trials is that the procedures used do not reflect clinical reality. Observations made in naturalistic treatment settings are therefore of particular interest alongside those of scientific trials. In a 2-year, open-label, follow-up study of a double-masked trial comparing haloperidol with risperidone, significant improvements were noted in the patients taking risperidone. 24 Total symptom scores on the Positive and Negative Syndrome Scale and subscale scores for positive, negative, excited, and cognitive factors were lower in patients taking risperidone compared with those taking haloperidol. Patients in the risperidone group also experienced fewer extrapyramidal symptoms than those taking haloperidol. The number of days patients spent in the hospital during the 2 years of risperidone treatment also was significantly reduced (from 150 days to 77 days; P < 0.05). In another naturalistic study, Negron et a125 assessed treatment outcomes in 63 patients who began taking risperidone the first year it became available. Most of these patients had treatment-resistant schizophrenia, schizoaffective disorder, or bipolar mood disorder, For analysis
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CLINICAL THERAPEUTICS”
purposes, the patients were divided into three groups: (1) those discharged within 3 months; (2) those who discontinued risperidone within 3 months; and (3) those who remained in the hospital despite 3 or more months of risperidone therapy. The mean length of illness for all 63 patients was 17 + 10.1 years. They had been continuously hospitalized for a mean of 3.8 f 5.4 years (range, 5 months to 26 years). Most patients received 6 mg/d of risperidone, but one third required more than 12 mg/d. Although 25% of patients needed anticholinergic medication while taking risperidone, 68% had needed anticholinergics when taking conventional neuroleptics during the preceding 3 months. Nine of the 63 patients were discharged within the first 3 months of risperidone treatment (mean treatment time to discharge, 58 f 17 days). The discharge rate tended to be higher for patients with schizophrenia than schizoaffective or bipolar disorder. Patients discharged also were younger, and had a shorter illness duration and length of hospitalization than those remaining in the hospital. Of patients with schizophrenia taking risperidone, 23.8% were discharged from the hospital within 3 months of treatment, whereas the discharge rate in the hospital as a whole during the same period was 11.7%. No discharged patients taking risperidone were readmitted, whereas the general hospital readmission rate at the same time was 30.8%. Forty of the 63 patients taking risperidone remained continuously hospitalized. Of these, 69.2% improved and 10.5% deteriorated as measured by changes in scores on the Clinical Global Impression scale. Forty-six percent required less observation. However, there were no changes in seclusion or in the rate of use of “as-needed” medications.
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The remaining 14 patients discontinued risperidone: 10 had a poor response, 3 with bipolar disorder had a manic episode, and 1 had a seizure. Negron et a125 noted that 37% of this group of chronic, treatment-resistant patients were either discharged or required substantially less observation during continued hospitalization. In this study, 50% of patients with bipolar mood disorder or schizoaffective disorder had to discontinue risperidone treatment, a rate much higher than expected. Overall, risperidone treatment resulted in higher discharge rates and lower readmission rates than seen historically with conventional neuroleptics. In another study?‘j the outcomes of patients receiving clozapine or risperidone for more than 2 years from the San Diego County Central Pharmacy were compared. All patients who had been hospitalized, except for the top 10% of hospital bed utilizers, were included in the study. Nineteen patients receiving clozapine and 35 patients taking risperidone were identified and their charts retrospectively reviewed. Outcomes were compared with the year before and the year after the patient began taking clozapine or risperidone. Patients taking clozapine had previously been hospitalized at four times the rate of those taking risperidone. Noncompliance with previous antipsychotic medication was noted in 63% of risperidone patients and 38% of clozapine patients. Patients taking clozapine scored higher on measures of acuity and chronicity than did those receiving risperidone. Costs were calculated for each patient for the year before and the year after risperidone or clozapine treatment was begun. For risperidone, cost savings were $3212.00 per patient. For clozapine, costs increased by $9122.00 per patient. Costs
N.A. KEKS
increased in the clozapine group because these patients required more frequent visits to the hospital, more staff time, and greater use of laboratory facilities. Only one patient each in the risperidone and clozapine groups was hospitalized during the treatment year, representing a significant cost savings compared with previous heavy utilization of hospital services.
QUALITY OF LIFE AND COGNITIVE FUNCTION Health-related quality of life, a complex concept, has been defined as the value assigned to the duration of survival as modified by impairments, functional status, perceptions, and social opportunities influenced by disease, injury, or treat-
Table III. Health-related
quality-of-life
ments.27T28 Bergner 29 has suggested a number of domains for health-related quality of life that focus on specific and general symptoms, emotional status, and various aspects of functional status (Table III). Subjective and objective dimensions must be addressed, and arguably the patient’s perceptions constitute the critical input to these values.30 However, subjective perceptions are complicated in many psychiatric disorders in which insight may be impaired, and a balance between subjective and objective evaluations seems most appropriate. The concept of quality of life is so broad that specific, definable, critical dimensions such as functional status are likely to be more meaningful outcome measures.29 The functional performance of pa-
domains.
Symptoms Functional state Self-care Mobility Physical activity 0 Role activities Household Work l Social functioning Personal interactions Intimacy Community interactions 0 Emotional status Anxiety, stress Depression, loss of control Spiritual well-being 0 Cognition 0 Sleep and rest l Energy and vitality l Health perceptions 0 General life satisfaction
l
l
Reprinted
with permission
from Bergner.29
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CLINICAL THERAPEUTICS”
Table IV. Factors affecting functional
performance
of patients with schizophrenia.
Motivation 0 Understanding of goals 0 Awareness of environment l Strategy and organization 0 Execution 0 Persistence 0 Cessation l
Adapted from FogeL3’
tients with schizophrenia depends on a number of factors (Table IV).31 Motivation has affective, cognitive, and motor aspects and is particularly related to the negative state. However, several other important inputs also relate to cognitive function. Patients must understand the goal of activity and be aware of environmental contingencies. A strategy must be formulated and resources organized to achieve the goal. The action must then be performed and persistently continued until the goal is reached.31 Finally, the action must cease appropriately. Cognitive functions, particularly those involving procedural memory (knowing how to do something) and executive function, are therefore critical to functional performance. The frontal system of the brain supports these cognitive processors and requires intact connections between the prefrontal cortex, striatum, pallidum, and thalamus, which connects back to the frontal cortex. Cognitive deficits observed in schizophrenia are complex, being attributable in part to nonspecific influences such as anxiety but also resulting from the antidopaminergic, sedative, and anticholinergic effects of psychotropic medication.32 “Core” cognitive deficits in schizophrenia concern attention, memory, and executive function.6
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Patients with schizophrenia are often easily distracted and cannot adequately focus and sustain attention. In particular, their voluntary or controlled attention is impaired.32 Procedural and semantic memories are largely intact, but patients often demonstrate impairments in episodic memory and in memory tasks requiring active processing and organization of material. Working memory (the capacity to maintain information during delays while the information is being processed with other mental operations to generate a response) may also be impaired in schizophrenia.33 Executive control functions are cognitive processes that harness simple ideas and behaviors into complex goal-directed behavior.34 Executive dysfunction in schizophrenia is manifested by difficulties in generating and executing plans, impaired problem-solving of new concepts, deficits in abstraction and set shifting, and poor error monitoring.6 Such dysfunction is often demonstrated in research settings using the Wisconsin Card Sorting test and has been attributed to hypofrontal cortical activity in schizophrenia.34 Cognitive dysfunction in schizophrenia is closely linked to negative state manifestations, lack of insight into the illness, and the relationship between patients and their environment. The implications for
N.A.KEKS
medication compliance are substantial; noncompliance can result from cognitive failure (attention, memory, executive dysfunction) or lack of insight, as well as persistent psychosis. By causing functional impairment, cognitive dysfunction can also critically affect occupational and social role performance, ability to participate in relationships, ability to provide for self and perform basic living tasks, and control of behavior damaging to self and others. Problem-solving and crisis management abilities also are impaired. The deleterious effects on most dimensions of quality-of-life measures are apparent. Conventional neuroleptics either worsen or have little net effect on cognitive dysfunction in schizophrenia.32,35 Although some reports indicate that clozapine does not improve cognitive dysfunction and worsens visual memory, probably because of its anticholinergic effects3(j other reports have noted improvements in cognitive function in patients taking this drug.35 In a crossover study comparing risperidone with conventional high-potency neuroleptics in five patients over two 6week phases,37 patients had less attention impairment and improved performance on the Wisconsin Card Sorting test while taking risperidone compared with the conventional neuroleptics. Recent work by Gallhofer et a13*provides interesting comparative data on conventional neuroleptics, clozapine, and risperidone. Eight patients with schizophrenia of less than 2 years’ duration and 8 patients with longer histories were assigned to 1 of 4 groups: off medication for at least 4 days, taking clozapine, taking risperidone, or taking haloperidollfluphenazine. The groups were matched for a variety of characteristics, such as age, gender, and severity and duration of illness. Performance on mazes
testing motor and complex frontal functions were evaluated. Patients taking clozapine or risperidone consistently demonstrated better performance than the other two groups, particularly on the complex frontal mazes that required sequencing and forward planning. In view of the links between cognitive function, functional status, and quality of life, the prospect of improved cognitive function from use of newer antipsychotics constitutes yet another strong argument for the use of these medications in preference to conventional drugs.
CONCLUSIONS Pharmacoeconomic modeling is a useful alternative to retrospective pharmacoeconomic analyses and add-on limbs of prospective trials that often are unrepresentative of real psychiatric practice. A decision-analytic model using real data for risperidone was robust and suggested that patients treated with risperidone could be expected to respond better than those treated with haloperidol and would be less likely to be noncompliant. Risperidone was also less expensive than haloperidol when the overall cost of schizophrenia was assessed, and the cost per response was markedly less (by more than 30%) for risperidone compared with haloperidol. In addition, the improved cognitive function associated with the use of risperidone should lead to improved quality of life, as has been demonstrated with clozapine. 39 Furthermore, improved cognitive function and fewer side effects lead to better social functioning, which in turn reduces indirect costs and enhances a patient’s ability to benefit from rehabilitation programs, thereby increasing the likelihood that the patient can live in the
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community after discharge from the hospital. Conventional neuroleptics are likely to impair cognition further in patients with schizophrenia. In contrast, improved cognitive function can be expected with the use of risperidone.
Address correspondence to: Nicholas A. Keks, MB, PhD, Department of Hospital and Community Psychiatry, Alfred Hospital, Commercial Road, Prahran 3 181, Melbourne, Victoria, Australia.
REFERENCES
1. Andreasen NC, Carpenter WT. Diagnosis
and classification of schizophrenia. SC&Ophr Bull. 1993;19:199-214. 2. Carpenter WT, Buchanan RW. Schizophrenia. NEJM. 1994;330:681-690. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 4. Andreasen NC, Flaum M. Schizophrenia: The characteristic symptoms. Schizophr Bull. 1991;17:274-279. 5. Cutting J. Descriptive psychopathology. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell; 1995. 6. Gold JM, Harvey PD. Cognitive deficits in schizophrenia. Psychiatr Clin North Am. 1993;i6:29.5-311. 7. Keks NA, Burrows GD. New medications for the schizophrenics. Med J Aust. 1994; 16053-54.
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8. Keks NA. Schizophrenia. Pharm. 1996;26:93-96.
Aust J Hosp
9. Lehman AF, Thompson JW, Dixon LB, Scott JE. Schizophrenia: Treatment outcomes research-editors’ introduction. Schizophr Bull. 1995;21:561-566. 10. Rupp A, Keith S. The costs of schizophrenia. Assessing the burden. Psychiatr Clin North Am. 1993;16:413-423. 11 Souetre E. Health economic considerations in the treatment of schizophrenia. Presented at the 8th Congress of the European College of Neuropsychopharmacology; September 30 to October 4, 1995; Venice, Italy. 12. Goldberg D. Cost-effectiveness studies in the treatment of schizophrenia: A review. Schizophr Bull. 1991;17:453-459. 13. Test MA, Knoedler WI-I, Allness DJ, et al. Long-term community care through an assertive continuous treatment team. In: Tamminga CA, Schulz SC, eds. Schizophrenia Research. New York: Raven Press; 1991:239-246. 14. Meltzer HY. Dimensions of outcome with clozapine. Br J Psychiatry. 1992;160: 46-53. 15. Meltzer HY, Cola P, Way L, et al. Costeffectiveness of clozapine in neurolepticresistant schizophrenia. Am J Psychiatry. 1993;150:1630-1638. 16. Leysen JE, Janssen PMF, Megens AA, Schott A. Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry. 1994;55:5-12. 17. Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-
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controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol.
1993; 13:25-40.
18. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry.
1994;151:825-835.
26. Thompson D. Cost and benefit analysis for clozapine and risperidone. Presented at the 149th annual meeting of the American Psychiatric Association; May 4-9, 1996; New York, New York. 27. Patrick D, Erickson P. Health Status and Health
Policy:
Allocating
Resources
to
Health Care. New York, NY: Oxford Uni-
19. Maynard A, Bloor K. Economic evaluation of mental health services. Curr Opin Psychiatry. 1995;8:122-125. 20. Davies L, Drummond M. Assessment of the costs and benefits of drug therapy for treatment-resistant schizophrenia in the United Kingdom. Br J Psychiatry 1993; 162:3842.
21. Davies A. Efficacy, safety and cost effectiveness of risperidone versus haloperidol. I. Meta-analysis. Data on file, JanssenCilag, Beerse, Belgium, 1995. 22. Davies A. Efficacy, safety and cost effectiveness of risperidone versus haloperidol. II. Cost-effectiveness. Data on file, Janssen-Cilag, Beerse, Belgium, 1995. 23. Addington DE, Jones B, Bloom D, et al. Reduction of hospital days in chronic schizophrenic patients treated with risperidone: A retrospective study. Clin Ther: 1993;15:917-926. 24. Lindstrijm E, Eriksson B, Hellgren A, et al. Efficacy and safety of risperidone in the long-term treatment of patients with schizophrenia. Clin Thel: 1995;17:402+12. 25. Negron AE, Leiderman EA, Parkadavil M, et al. Naturalistic outcome of risperidone treatment in an academic state hospital setting. Presented at the seventh annual meeting of the New York Office of Mental Health; December 7-9, 1994; Albany, New York.
versity Press; 1993. 28. Reviaki DA, Murray M. Assessing health related quality of life outcomes of drug treatments for psychiatric disorders. CNS Drugs. 1994; 1:465476. 29. Bergner M. Quality of life, health status and clinical research. Med Care. 1989;27 (Suppl3):S148-S156. 30. Awad AG, Hogan TP. Subjective response to neuroleptics and the quality of life: Implications for treatment outcome. Acta Psychiatr
Stand.
1994;89:27-32.
31. Fogel BS. A neuropsychiatric approach to impairment of goal-directed behaviour. Presented at the 149th annual meeting of the American Psychiatric Association; May 4-9, 1996; New York, New York. 32. Goldberg TE, Gold JM. Neurocognitive deficits in schizophrenia. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell; 1995:146-162. 33. Royall DR. Neuroanatomy, measurement and clinical significance of the executive cognitive functions. Presented at the 149th annual meeting of the American Psychiatric Association; May 4-9, 1996; New York, New York. 34. Weinberger DR, Berman KF, Zec RF. Physiologic significance of dorsolateral prefrontal cortex in schizophrenia. I: Regional cerebral blood flow evidence. Arch Gen Psychiatry.
1986;43:114-124.
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35. Lee MA, Thompson PA, Meltzer HY. Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry. 1994;55: 82-87. 36. Goldberg TE, Greenberg RD, Griffin SJ, et al. The effect of clozapine on cognition and psychiatric symptoms in patients with schizophrenia. Br J Psychiatry. 1993;162: 4348. 37. Goldberg TE, Daniel DG, Pickar D, et al. Differential effects of risperidone and con-
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ventional neuroleptics on neurocognition: A pilot study. Abstract. 38. Gallhofer B, Bauer I-l, Lis S, et al. Cognitive dysfunction in schizophrenia: Comparison of treatment with atypical antipsychotic agents and conventional neuroleptic drugs. Eur Neuropsychopharmacol. 1996; 6(Suppl 2):S2-13-S2-20. 39. Meltzer HY, Cola P, Way L, et al. Cost effectiveness of clozapine in neurolepticresistant schizophrenia. Am J Psychiatry. 1993;150:1630-1638.
19, NO. 1, 1997
Impact of Newer Antipsychotics Schizophrenia
on Outcomes in
Nicholas A. Keks, MB, PhD Department of Hospital and Community Psychiatry, Alfred Hospital, Prahran, Melbourne, Victoria, Australia
ABSTRACT Functional status in schizophrenia depends in part on cognitive function. Newer antipsychotics, such as risperidone, produce better cognitive function in patients with schizophrenia than do conventional neuroleptics, which implies that the indirect costs of the illness will be less in patients treated with risperidone. A robust decision-analytic model of schizophrenia suggests that the overall cost of treating a patient with risperidone is $11,772.00 per year compared with $13,622.00 per year for haloperidol and that the cost per response is even more favorable toward risperidone-$14,599.00 versus $23,040.00. This model supports the results of naturalistic trials in which risperidone produced better outcomes than did conventional neuroleptics. Overall, the use of the more effective, better tolerated newer antipsychotics should reduce the cost to society of
148
schizophrenia and improve patients’ quality of life. Key words: pharmacoeconomic modeling, schizophrenia, cognitive function, quality of life, cost of schizophrenia.
INTRODUCTION The heterogeneity of schizophrenia with respect to symptoms and course of illness has been recognized since the original conceptualization of Eugen Bleuler. 1 Schizophrenia probably has multiple etiologies, including genetic vulnerability and environmental influences, such as perinatal hypoxia.2 Very broadly, the syndrome can be characterized as a persistent psychosis (often associated with negative symptoms such as alogia, affective flattening, and lack of motivation) that cannot be attributed to a mood disorder, medical illness, or use of drugs.3 Although positive symptoms (delusions, hallucinations, formal thought dis-
0149-2918/97/$3.50
N.A. KEKS
order) and negative symptoms (social withdrawal, alogia, affective flattening, lack of motivation, poverty of thought) are characteristic of schizophrenia,4 other symptoms also occur and often are critical in determining the overall outcome of the illness. Both depression, which can be associated with suicide, and elevation of mood are seen frequently in patients with schizophrenia, as are anxiety and hostility or aggression.5 Cognitive dysfunction also occurs in patients with schizophrenia, particularly those with negative symptoms,6 and is associated with functional impairment. A component of both negative symptomatology and cognitive dysfunction in schizophrenia can be attributed to the use of conventional neuroleptics.’ These “iatrogenic” symptoms can be considered yet another category of manifestations requiring treatment.8 The clinician is therefore faced with the task of addressing a broad spectrum of symptoms in schizophrenia (Table I), with control of these symptoms being the traditional outcome goal in clinical practice. However, there are several other levels of outcome for patients with schizophrenia, some of which are only partly correlated with symptomatic outcomes. Lehman et al9 have recently summarized
Table I. Symptoms
target outcomes for interventions in schizophrenia (Table II). Clinical outcomes that can be assessed include symptoms and behaviors such as self-harm, violence, and substance abuse. Functional status concerns occupational role performance, interpersonal relationships, and self-care. Access to resources and opportunities, such as availability of housing, financial support, work, and safety, are some of the most critical issues for people with chronic schizophrenia. Patient satisfaction and caregiver well-being also must be considered. Clinicians also must consider the economic implications of schizophrenia and its treatment.‘O Costs usually are divided into direct and indirect costs. Direct costs are those associated with treatment. Hospitalization constitutes 70% of direct costs, with drug therapy accounting for only 10% and outpatient care another 20%.” Estimates of indirect costs are more variable, but indirect costs can be at least as high as direct costs. Two broad developments in the treatment of schizophrenia-community treatment programs and newer antipsychotics-are aimed at improving outcomes in general and decreasing the costs of illness and treatment in particular. As care of patients with chronic schizophrenia has
of schizophrenia.
0 Positive symptoms (delusions, hallucinations, formal thought disorders) l Negative symptoms (social withdrawal, alogia, affective flattening, lack of motivation, poverty of thought) l Cognitive dysfunction Mood disturbances Anxiety 0 Iatrogenic symptoms l Hostility and aggression l
l
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CLINICAL THERAPEUTICS”
Table II. Target outcomes for interventions
in schizophrenia.
0 Symptoms l Clinical correlates (substance abuse, suicidality, violence, and hostility) l Functional status l Resources and opportunities (access) 0 Life satisfaction l Family well-being l Patient satisfaction with intervention Adapted from Lehman et a1.9
shifted from hospital to community, the cost-effectiveness of comprehensive, integrated community treatment programs, such as the Program of Assertive Community Treatment in Madison, Wisconsin, has been demonstrated and replicated.‘* These community treatment programs involve a multidisciplinary team available on a 24hour basis that offers crisis intervention, assistance with medication, brief hospitalization in a general hospital, financial and social support, normative housing, social skills training and assistance with basic needs, and support for families and the community. l3 The introduction of newer antipsychotic drugs has also had a profound impact on the treatment of schizophrenia. Clozapine, for example, can improve a broad range of outcomes and result in cost savings.14,15 Risperidone, a serotonin-dopamine antagonist, is the first second-generation antipsychotic to become available for clinical use.16 Risperidone is more effective than conventional neuroleptics for the treatment of positive and negative symptoms of schizophrenia and is less likely than older neuroleptics to cause extrapyramidal side effects at maximally effective doses.17*‘8 This paper selectively examines further evidence concerning outcomes with risperidone in the treatment of schizophrenia.
150
PHARMACOECONOMIC MODELING A number of approaches can be used to evaluate the economic impact of new drugs.19 Prospective studies, which collect both efficacy and cost data, are often regarded as most informative. However, prospective study protocols make the situation quite artificial, which may be acceptable when evaluating clinical efficacy but can be misleading in terms of cost estimates. Naturalistic studies and beforeafter designs are vulnerable to the influence of confounding variables that cannot be controlled or even identified. Furthermore, these studies may generate findings applicable only to the area or country in which the studies were conducted, given the variations in schizophrenia treatments and costs. However, conducting a pharmacoeconomic study in each different locale would be impractical. Local conditions and costs can be assessed by inputting efficacy data into pharmacoeconomic models. The effect of variations in the different variables can also be investigated by varying the parameters in so-called sensitivity analysis. Davies and Drummond*’ demonstrated the utility of this approach for clozapine in the United Kingdom.
N.A.KEKS
The Australian government requires the submission of pharmacoeconomic analyses before approval of subsidy for a new medication. Such an analysis was done for risperidone, and the results were accepted by the Australian authorities.21T22 The pharmacoeconomic analyses included a meta-analysis of pooled data from six randomized, double-masked trials comparing risperidone with haloperidol. Clinical response was defined as an improvement of at least 20% in global symptomatology. There was a significant difference (13.9%) in the rate of clinical response in favor of risperidone (P < 0.05). The use of anticholinergic drugs was 17.7% less among patients receiving risperidone compared with those receiving haloperidol (P < 0.05). In addition, fewer (12.7%) patients in the risperidone group compared with the haloperidol group withdrew from treatment (P < 0.05). The findings from the meta-analysis were entered into a decision-analytic model that simulated the treatment of patients with chronic schizophrenia over a 2-year period along a range of different pathways. Probabilities were assigned to each pathway based on available clinical data. Resource use was then specified for each pathway and the costs calculated. On the basis of the model, the total cost per patient was estimated at $11,772.00 per year for risperidone and $13,622.00 per year for haloperidol, a difference of $1850.00. With clinical response defined as a 20% reduction in symptoms, the cost per response was $14,599.00 for risperidone and $23,040.00 for haloperidol. The model estimated that risperidone was associated with a 19.7% greater response rate than haloperidol at the end of 2 years. Sensitivity analyses, which varied parameters in the model, demonstrated that the
model was robust. Because hospitalization comprised the largest proportion of costs in this study, the findings of Addington et al23 and Lindstrijm et a124 that risperidone decreased the number of patient days in the hospital also provided strong support for the validity of the Australian model.
COSTS AND BENEFITS OF NEWER ANTIPSYCHOTICS IN NATURALISTIC SETTINGS One objection to data from controlled trials is that the procedures used do not reflect clinical reality. Observations made in naturalistic treatment settings are therefore of particular interest alongside those of scientific trials. In a 2-year, open-label, follow-up study of a double-masked trial comparing haloperidol with risperidone, significant improvements were noted in the patients taking risperidone. 24 Total symptom scores on the Positive and Negative Syndrome Scale and subscale scores for positive, negative, excited, and cognitive factors were lower in patients taking risperidone compared with those taking haloperidol. Patients in the risperidone group also experienced fewer extrapyramidal symptoms than those taking haloperidol. The number of days patients spent in the hospital during the 2 years of risperidone treatment also was significantly reduced (from 150 days to 77 days; P < 0.05). In another naturalistic study, Negron et a125 assessed treatment outcomes in 63 patients who began taking risperidone the first year it became available. Most of these patients had treatment-resistant schizophrenia, schizoaffective disorder, or bipolar mood disorder, For analysis
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purposes, the patients were divided into three groups: (1) those discharged within 3 months; (2) those who discontinued risperidone within 3 months; and (3) those who remained in the hospital despite 3 or more months of risperidone therapy. The mean length of illness for all 63 patients was 17 + 10.1 years. They had been continuously hospitalized for a mean of 3.8 f 5.4 years (range, 5 months to 26 years). Most patients received 6 mg/d of risperidone, but one third required more than 12 mg/d. Although 25% of patients needed anticholinergic medication while taking risperidone, 68% had needed anticholinergics when taking conventional neuroleptics during the preceding 3 months. Nine of the 63 patients were discharged within the first 3 months of risperidone treatment (mean treatment time to discharge, 58 f 17 days). The discharge rate tended to be higher for patients with schizophrenia than schizoaffective or bipolar disorder. Patients discharged also were younger, and had a shorter illness duration and length of hospitalization than those remaining in the hospital. Of patients with schizophrenia taking risperidone, 23.8% were discharged from the hospital within 3 months of treatment, whereas the discharge rate in the hospital as a whole during the same period was 11.7%. No discharged patients taking risperidone were readmitted, whereas the general hospital readmission rate at the same time was 30.8%. Forty of the 63 patients taking risperidone remained continuously hospitalized. Of these, 69.2% improved and 10.5% deteriorated as measured by changes in scores on the Clinical Global Impression scale. Forty-six percent required less observation. However, there were no changes in seclusion or in the rate of use of “as-needed” medications.
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The remaining 14 patients discontinued risperidone: 10 had a poor response, 3 with bipolar disorder had a manic episode, and 1 had a seizure. Negron et a125 noted that 37% of this group of chronic, treatment-resistant patients were either discharged or required substantially less observation during continued hospitalization. In this study, 50% of patients with bipolar mood disorder or schizoaffective disorder had to discontinue risperidone treatment, a rate much higher than expected. Overall, risperidone treatment resulted in higher discharge rates and lower readmission rates than seen historically with conventional neuroleptics. In another study?‘j the outcomes of patients receiving clozapine or risperidone for more than 2 years from the San Diego County Central Pharmacy were compared. All patients who had been hospitalized, except for the top 10% of hospital bed utilizers, were included in the study. Nineteen patients receiving clozapine and 35 patients taking risperidone were identified and their charts retrospectively reviewed. Outcomes were compared with the year before and the year after the patient began taking clozapine or risperidone. Patients taking clozapine had previously been hospitalized at four times the rate of those taking risperidone. Noncompliance with previous antipsychotic medication was noted in 63% of risperidone patients and 38% of clozapine patients. Patients taking clozapine scored higher on measures of acuity and chronicity than did those receiving risperidone. Costs were calculated for each patient for the year before and the year after risperidone or clozapine treatment was begun. For risperidone, cost savings were $3212.00 per patient. For clozapine, costs increased by $9122.00 per patient. Costs
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increased in the clozapine group because these patients required more frequent visits to the hospital, more staff time, and greater use of laboratory facilities. Only one patient each in the risperidone and clozapine groups was hospitalized during the treatment year, representing a significant cost savings compared with previous heavy utilization of hospital services.
QUALITY OF LIFE AND COGNITIVE FUNCTION Health-related quality of life, a complex concept, has been defined as the value assigned to the duration of survival as modified by impairments, functional status, perceptions, and social opportunities influenced by disease, injury, or treat-
Table III. Health-related
quality-of-life
ments.27T28 Bergner 29 has suggested a number of domains for health-related quality of life that focus on specific and general symptoms, emotional status, and various aspects of functional status (Table III). Subjective and objective dimensions must be addressed, and arguably the patient’s perceptions constitute the critical input to these values.30 However, subjective perceptions are complicated in many psychiatric disorders in which insight may be impaired, and a balance between subjective and objective evaluations seems most appropriate. The concept of quality of life is so broad that specific, definable, critical dimensions such as functional status are likely to be more meaningful outcome measures.29 The functional performance of pa-
domains.
Symptoms Functional state Self-care Mobility Physical activity 0 Role activities Household Work l Social functioning Personal interactions Intimacy Community interactions 0 Emotional status Anxiety, stress Depression, loss of control Spiritual well-being 0 Cognition 0 Sleep and rest l Energy and vitality l Health perceptions 0 General life satisfaction
l
l
Reprinted
with permission
from Bergner.29
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Table IV. Factors affecting functional
performance
of patients with schizophrenia.
Motivation 0 Understanding of goals 0 Awareness of environment l Strategy and organization 0 Execution 0 Persistence 0 Cessation l
Adapted from FogeL3’
tients with schizophrenia depends on a number of factors (Table IV).31 Motivation has affective, cognitive, and motor aspects and is particularly related to the negative state. However, several other important inputs also relate to cognitive function. Patients must understand the goal of activity and be aware of environmental contingencies. A strategy must be formulated and resources organized to achieve the goal. The action must then be performed and persistently continued until the goal is reached.31 Finally, the action must cease appropriately. Cognitive functions, particularly those involving procedural memory (knowing how to do something) and executive function, are therefore critical to functional performance. The frontal system of the brain supports these cognitive processors and requires intact connections between the prefrontal cortex, striatum, pallidum, and thalamus, which connects back to the frontal cortex. Cognitive deficits observed in schizophrenia are complex, being attributable in part to nonspecific influences such as anxiety but also resulting from the antidopaminergic, sedative, and anticholinergic effects of psychotropic medication.32 “Core” cognitive deficits in schizophrenia concern attention, memory, and executive function.6
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Patients with schizophrenia are often easily distracted and cannot adequately focus and sustain attention. In particular, their voluntary or controlled attention is impaired.32 Procedural and semantic memories are largely intact, but patients often demonstrate impairments in episodic memory and in memory tasks requiring active processing and organization of material. Working memory (the capacity to maintain information during delays while the information is being processed with other mental operations to generate a response) may also be impaired in schizophrenia.33 Executive control functions are cognitive processes that harness simple ideas and behaviors into complex goal-directed behavior.34 Executive dysfunction in schizophrenia is manifested by difficulties in generating and executing plans, impaired problem-solving of new concepts, deficits in abstraction and set shifting, and poor error monitoring.6 Such dysfunction is often demonstrated in research settings using the Wisconsin Card Sorting test and has been attributed to hypofrontal cortical activity in schizophrenia.34 Cognitive dysfunction in schizophrenia is closely linked to negative state manifestations, lack of insight into the illness, and the relationship between patients and their environment. The implications for
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medication compliance are substantial; noncompliance can result from cognitive failure (attention, memory, executive dysfunction) or lack of insight, as well as persistent psychosis. By causing functional impairment, cognitive dysfunction can also critically affect occupational and social role performance, ability to participate in relationships, ability to provide for self and perform basic living tasks, and control of behavior damaging to self and others. Problem-solving and crisis management abilities also are impaired. The deleterious effects on most dimensions of quality-of-life measures are apparent. Conventional neuroleptics either worsen or have little net effect on cognitive dysfunction in schizophrenia.32,35 Although some reports indicate that clozapine does not improve cognitive dysfunction and worsens visual memory, probably because of its anticholinergic effects3(j other reports have noted improvements in cognitive function in patients taking this drug.35 In a crossover study comparing risperidone with conventional high-potency neuroleptics in five patients over two 6week phases,37 patients had less attention impairment and improved performance on the Wisconsin Card Sorting test while taking risperidone compared with the conventional neuroleptics. Recent work by Gallhofer et a13*provides interesting comparative data on conventional neuroleptics, clozapine, and risperidone. Eight patients with schizophrenia of less than 2 years’ duration and 8 patients with longer histories were assigned to 1 of 4 groups: off medication for at least 4 days, taking clozapine, taking risperidone, or taking haloperidollfluphenazine. The groups were matched for a variety of characteristics, such as age, gender, and severity and duration of illness. Performance on mazes
testing motor and complex frontal functions were evaluated. Patients taking clozapine or risperidone consistently demonstrated better performance than the other two groups, particularly on the complex frontal mazes that required sequencing and forward planning. In view of the links between cognitive function, functional status, and quality of life, the prospect of improved cognitive function from use of newer antipsychotics constitutes yet another strong argument for the use of these medications in preference to conventional drugs.
CONCLUSIONS Pharmacoeconomic modeling is a useful alternative to retrospective pharmacoeconomic analyses and add-on limbs of prospective trials that often are unrepresentative of real psychiatric practice. A decision-analytic model using real data for risperidone was robust and suggested that patients treated with risperidone could be expected to respond better than those treated with haloperidol and would be less likely to be noncompliant. Risperidone was also less expensive than haloperidol when the overall cost of schizophrenia was assessed, and the cost per response was markedly less (by more than 30%) for risperidone compared with haloperidol. In addition, the improved cognitive function associated with the use of risperidone should lead to improved quality of life, as has been demonstrated with clozapine. 39 Furthermore, improved cognitive function and fewer side effects lead to better social functioning, which in turn reduces indirect costs and enhances a patient’s ability to benefit from rehabilitation programs, thereby increasing the likelihood that the patient can live in the
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community after discharge from the hospital. Conventional neuroleptics are likely to impair cognition further in patients with schizophrenia. In contrast, improved cognitive function can be expected with the use of risperidone.
Address correspondence to: Nicholas A. Keks, MB, PhD, Department of Hospital and Community Psychiatry, Alfred Hospital, Commercial Road, Prahran 3 181, Melbourne, Victoria, Australia.
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