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Impact of risperidone versus haloperidol on activities of daily living in the treatment of refractory schizophrenia
Impact of Risperidone Versus Haloperidol on Activities of Daily Living in the Treatment of Refractory Schizophrenia Robert Paul Liberman, Daniel Gutkind, Jim Mintz, Michael Green, B.D. Marshall Jr, Mary Jane Robertson, and Jeffery Hayden Risperidone has been shown to improve verbal working memory, executive functioning, attention, reaction time, and verbal learning, which, in turn, have been associated with improved functional outcomes. We tested whether risperidone was associated with greater improvements than haloperidol in activities of daily living (ADLs) among persons having treatmentrefractory schizophrenia. In a double-blind, controlled trial of fixed and flexible doses of haloperidol and risperidone, changes in ADLs were operationally monitored on a behavior therapy unit of a state hospital. While no differential effects were noted between risperidone and haloperidol in ADLS, these self-care skills significantly improved as subjects spent longer
times on the behavior therapy unit. Working memory and verbal learning did correlate with improvements in ADLs, independent of drug condition. The contingencies of reinforcement and specific training programs on the behavior therapy unit may have been prepotent for the learning of ADLs, obscuring any differential impact of risperidone. Moreover, ADLs may be governed more by “procedural” learning than by working memory or verbal learning, with the former not differentially influenced by typical verus atypical antipsychotics. Copyright 2002, Elsevier Science (USA). All rights reserved.
C
comes in schizophrenia. In a randomized, clinical trial, we have submitted this hypothesis to a test, using the learning of self-care skills as dependent measures with the same subjects studied by Green et al.9 in their investigation of the neurocognitive effects of risperidone versus haloperidol.
ONTROLLED CLINICAL efficacy trials of antipsychotic drugs have almost exclusively focused on symptomatology as an outcome measure. Medications are seen as effective if they reduce positive symptoms, and/or prevent psychotic relapse and rehospitalization. This unidimensional approach to evaluating the effects of antipsychotic medication has failed to appreciate the interactions between drug and psychosocial treatment effects1 and the effects of medication on neurocognitive and behavioral functioning.2,3 Recent studies have begun to widen the scope of treatment outcome to include community functioning, social problem solving, skills acquisition, and cognitive functioning.2-5 Interestingly, psychotic symptomatology has been found to be unassociated with these other functional outcome domains in many studies,2,4,6 though not all.7 The salutary effects of risperidone over haloperidol in improving the verba1 working memory, verbal learning, attention, reaction time, and executive functioning of persons with treatment refractory schizophrenia have been reported.8-12 Given that improvement in these areas of neurocognitive functioning have been associated with improved functional outcome in correlational studies, the possibility is raised that risperidone-produced improvements in neurocognition might yield advantages in psychosocial functioning for those individuals treated with this novel antipsychotic drug. To date, however, no prospective randomized controlled research has examined this proposed advantage of atypical antipsychotics on functional out-
METHOD
Study Subjects Thirty-six subjects, who gave written informed consent, were recruited from the long-term, psychiatric wards of Camarillo State Hospital. All subjects met DSM-III-R criteria for schizophrenia, based on administration of the Structured Clinical Interview for DSM-III-R, examination of hospital chart notes and past medical records, observation by ward staff, and information from patients’ relatives. All subjects met the criteria for “treatment refractoriness” in schizophrenia, as operationalized by Kane et al.13 In addition, all patients must have tried at least three 6-week periods of treatment with neuroleptic medication from at least two different classes of neuroleptics (at chlorpromazine From the University of California Los Angeles Center for Research on Treatment and Rehabilitation of Psychosis and Psychiatric Rehabilitation Program, Los Angeles, CA. Address reprint requests to Robert Paul Liberman, M.D., UCLA Psych REHAB Program, 300 UCLA Medical Plaza, Los Angeles, CA 90095. Copyright 2002, Elsevier Science (USA). All rights reserved. 0010-440X/02/4306-0020$35.00/0 doi:10.1053/comp.2002.33499
Comprehensive Psychiatry, Vol. 43, No. 6 (November/December), 2002: pp 469-473
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equivalents of 1,000 mg/d or greater) in the previous 5 years, resulting in either no significant symptom improvement or an intolerence to such doses. Patients were excluded from the study if they met any of the following exclusion criteria: (1) presence of any clinically significant neurological disorder; (2) history of serious head injury; (3) physical, cognitive, or language impairment sufficient to bring the validity of clinical scores into question; (4) history of substance abuse within the previous 6 months; (5) a medication history that included a risperidol trial of sufficient length to determine clinical response; (6) treatment with investigational drugs or clozapine within the 4 weeks before study entry or depot neuroleptics within the 8 weeks before study entry; (7) behavior that posed significant danger to self or others; and (8) significant clinical improvement (i.e., total 18-item Brief Psychiatric Rating Scale [BPRS] score ⱕ35) between screening and study entry. Once subjects gave informed consent, they were transferred to the 11-bed Camarillo-University of California Los Angeles Clinical Research Unit, which provided a standardized token economy (social learning) milieu, highly structured training of activities of daily living (ADLs) using “shaping” procedures, and twice-daily training sessions in social and independent living skills. This specialized behavior therapy milieu has been thoroughly described in another publication.14 Points were awarded to subjects for improvements in their selfcare, participation in skills training, and moving to higher levels of responsibility and autonomy. These points could then be exchanged three times daily for privileges, coffee, refreshments, snacks, and other personal items. Procedure During a stabilization phase of 3 weeks, all subjects received 15 to 30 mg of haloperidol. Upon entering the randomized, double-blind phases of the study, subjects first received either 6 mg of risperidone (n ⫽ 18) or 15 mg of haloperidol (n ⫽ 18) for 4 weeks (fixed-dose phase), followed by a 4-week flexible-dose phase. In this flex-dose phase, the treating psychiatrist, while still blind to each patient’s drug condition, was able to adjust the dose in either direction. Mean doses during the flexible-dose phase were 8 mg risperidone and 20 mg haloperidol. Neurocognitive tests, as listed in Table 1, were
LIBERMAN ET AL
Table 1. Neurocognitive Tests Administered in the Risperidone Versus Haloperidol Study During the Fixed- and Flexible-Dose Phases Neurocognitive Tests
Digit Span Distractibility Test (DSDT) California Verbal Learning Test (CVLT) Continuous Performance Test (ds-CPT) (degraded stimulus version) Wisconsin Card Sorting Test (WCST)
Domain of Neurocognition Assessed
Verbal Working Memory Verbal Learning Sustained Attention
Executive Functioning
administered before the stabilization phase, and again after the fixed- and flexible-dose phases. The tests, their rationale, modes of administration, and scoring are described in another publication.15 Assessments of Dependent Variables Throughout the day, nursing staff, who were given intensive training and periodic feedback on their reliability for quality assurance, made observations of subjects’ performance in ADLs: grooming, dressing, room clean-up, and showering. Each of the ADLs was operationally defined. For example, the criteria for proper grooming included brushing teeth (use toothpaste, brush majority of teeth and gum surfaces, rinse toothbrush, replace lid on toothpaste, no food particles visible on teeth), washing hands and face (use soap, apply soap to entire face, hands and wrists, rinse off soap, no visible dirt, soap or wetness on skin), and combing hair (use comb or brush with at least three repetitions over hair, hair not visibly matted or tangled). Scores of 0 to 2 were given for each day’s category of ADLs. Two points were awarded if the person engaged in all of the criteria without prompting; one point for completing the tasks with the aid of prompting and instructions; and zero points if the individual refused to do the task or did not complete all criteria satisfactorily. The reliability of the observational data within each subject was measured by Cronbach’s alpha test and ranged between ␣⫽ .68 (grooming) and ␣⫽ .87 (showering). Subjects in both the risperidone and haloperidol groups did not differ at study entry or during the baseline phase on any of the demographic or clinical characteristics listed in Table 2.
RISPERIDONE v HALOPERIDOL FOR DAILY LIVING
Table 2. Subject Demographic Characteristics for the Risperidone and Haloperidol Conditions Combined Age Gender Age at onset of illness Summary score of 24-item BPRS at baseline Mean points for all ADLs (0-8 pts possible)
37.4 years (7.5) 67% male, 33% female 17.8 years (4.0) 68.2 (14.4) 6.74 (1.0)
NOTE. Data are presented as means and (SD).
Data Analysis Within-subject changes in performance of ADLs were measured by subtracting each subject’s mean score on each of the four ADLs (grooming, dressing, room clean-up, showering) at study completion from his/her score at study entry. One-way analyses of variance were then conducted to test differences between drug conditions on changes in performance of ADLs from study entry to study conclusion. Spearman correlations were computed to examine the relation between neurocognitive functioning and an overall composite measure that integrated all ADLs. In addition, general linear mixed-model regression analyses (SAS Proc MIXED) were conducted to evaluate possible interactions between neurocognitive performance and ADLs across the two time periods (fixed dose/flexible dose) in the study. RESULTS
Activities of Daily Living There were no statistically significant differences between drug conditions for any of the categories of daily living skills, nor for the sum of activities across all domains (dressing ⫹ grooming ⫹ room clean-up ⫹ showering). However, subjects in both drug conditions showed statistically significant improvements from the start to the finish of the study in showering (t ⫽ 2.24, df ⫽ 27, P ⫽ .034) and grooming (t ⫽ 2.77, df ⫽ 27, P ⫽ .01). Modest improvements (though not statistically significant) from the baseline phase to the end of the study were also found in the other two activities of daily living (dressing and room cleanup). Thus, there was evidence from this evaluation that ADLs improved during subjects’ stay on the Clinical Research Unit, suggesting that the Unit’s token economy and skills training program may
471
have had a salutary effect on these behavioral dimensions, regardless of the drug treatment condition. Relationship Between Neurocognitive and Functional Measures No significant differences were found between drug conditions for any of the ADLs and neurocognitive performance. Spearman correlations between neurocognitive performance and ADLs are shown in Table 3 across both drug conditions. A summary score was derived from the Digit Span Distractibility Test (DSDT) by summing the distraction and nondistraction conditions because these two conditions correlated highly in both dosage phases (fixed: r ⫽ .87, df ⫽ 33, P ⫽ .0001; flexible: r ⫽ .76, df ⫽ 32, P ⫽ .0001). During the fixed-dose phase of the study, the following neurocognitive measures had statistically significant relationships with the functional behaviors comprising ADLs: DSDT with overall ADLs; California Verbal Learning Test (CVLT) with overall ADLs. During the flexible-dose phase of the study, the following statistically significant relationships emerged: DSDT with overall ADLs; CVLT with overall ADLs. It should be emphasized that these relationships were found for the fixed and flexible phases of the medication trial when subjects in both the risperidone and haloperidol conditions were combined. In addition to these simple analyses within each medication phase, a general linear, mixed-model, regression analysis with repeated measures (fixed and flexible phases) was done to obtain maximal statistical power across the two time periods and evaluate possible interactions between medication
Table 3. Spearman Correlations Between Neurocognitive Tests and Overall Score on Activities of Daily Living ADLs
Neurocognitive Measure
Fixed
Flexible
WCST ds-CPT CVLT DSDT
0.12 0.19 0.58* 0.48*
0.36 0.23 0.66† 0.62†
NOTE. The specific number of subjects for whom test data were available during fixed and flexible dose phases of medication varied between 25 and 33. Data are pooled for both risperidone and haloperidol groups. *P ⬍ .01. † P ⬍ .001.
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LIBERMAN ET AL
condition and activities of daily living. The model included the DSDT, CVLT, drug condition, and drug treatment phase as independent measures with interactions. These analyses confirmed the association of the DSDT and CVLT with ADLs, only when subjects in both drug conditions were combined. The main effects for the DSDT and CVLT with the composite score for activities of daily living were F ⫽ 7.4, P ⫽ .01, and F ⫽ 6.4, P ⫽ .02, respectively. The other two neurocognitive assessments (degraded stimulus Continuous Performance Test [ds-CPT] and the Wisconsin Card Sorting Test [WCST]) did not bear significant relationships with the changes in functional behaviors of subjects on the ward. DISCUSSION
Why did risperidone, found by others8,9,12 to differentially improve several neurocognitive functions when compared with haloperidol, not differentially improve activities of daily living in our analysis? A possible explanation for the lack of differences may be that the Unit’s system of behavioral shaping and contingencies of reinforcement had a prepotent effect on the subjects’ adherence to performing their own ADLs regardless of drug condition. This explanation was supported by the improvements in ADLs as subjects increased the duration of their residency on the Unit, possibly reflecting the learning that took place over time. In a “triple blind” study of antipsychotic medications and functional ward behaviors conducted in a social learning program16 that resembled the Clinical Research Unit, the point or token system was more powerful than medications in producing behavioral improvements in regressed, chronic mental patients. An alternative, but not mutually exclusive explanation may be that ADLs are more habitual and are not so dependent on the higher level neurocognitive functions such as working memory and verbal learning which are differentially affected by atypical antipsychotics. “Implicit“ or ”procedural“
learning that takes place largely outside of conscious awareness and has been shown to operate relatively normally in schizophrenia17 may be more responsible for determining ADLs but less differentially influenced by risperidone and haloperidol. Recently reported findings suggest that atypical antipsychotic drugs, despite their favorable effects on neurocognition, have not been associated with better vocational outcomes.18,19 In one of these studies, 82 schizophrenia-spectrum patients receiving either risperidone or olanzapine versus conventional antipsychotics were followed for up to 2 years. Patients from both medication conditions worked for an average of 4 weeks, with 13% of both groups attaining competitive employment.18 There is a growing body of evidence to suggest that improvements in neurocognitive functioning are stronger predictors of functional outcome than are improvements in psychotic symptomatology.2,6 Recall memory has been specifically associated with behavioral skill acquisition.4 As clinical psychopharmacology extends its reach to the study of neurocognitive processes and functional activities of life, the relationships among antipsychotic drugs, information processing, and instrumental and social role behavior will become clearer. At this time, we are simply “opening doors” for this much needed progression in research to take place. Recently published studies of neurocognition in schizophrenia may generate more promising hypotheses that can identify the specific neurocognitive variables or functions that have specific ratelimiting control over specific instrumental and social behaviors of persons with schizophrenia.20-22 As research on neurocognitive pharmacology proceeds, it will be important for investigators to comprehend that medications are never administered, ingested, metabolized or have their effects in a socioenvironmental vacuum. The interactions of drug and psychosocial treatment effects must be considered in the design and interpretation of the outcomes of treatment.23
REFERENCES 1. Falloon IRH, Liberman RP. Interactions between drug and psychosocial therapy in schizophrenia. Schizophr Bull 1983;9: 543-554. 2. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153:321-330. 3. Marder SR, Wirshing SC, Mintz J, McKenzie J, Johnston K, Eckman TA, et al. Two-year outcome of social skills training
and group psychotherapy for outpatients with schizophrenia. Am J Psychiatry 1996;153:1585-1592. 4. Corrigan PW, Wallace CJ, Schade ML, Green MF. Learning medication self-management skills in schizophrenia: relationships with cognitive deficits and psychiatric symptoms. Behav Ther 1994;25:5-15. 5. Flynn SW, MacEwan GW, Altman S, Kopala LC, Fredrikson DH, Smith GN, et al. An open comparison of clozapine and
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risperidone in treatment-resistant schizophrenia. Pharmacopsychiatry 1998;31:25-29. 6. Smith TE, Hull JW, Romanelli S, Fertuck E, Weiss KA. Symptoms and neurocognition as rate limiters in skills training for psychotic patients. Am J Psychiatry 1999;156:18171818. 7. Stip E, Lussier I. The effect of risperidone on cognition in patients with schizophrenia. Can J Psychiatry 1996;41(2 Suppl):S35-40. 8. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25:233-255. 9. Green MF, Marshall BD, Wirshing WC, Ames D, Marder SR, McGurk S, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154:799-804. 10. Earnst KS. Taylor SF, Smet IC, Goldman RS, Tandon R, Berent S. The effects of typical antipsychotics, clozapine, and risperidone on neuropsychological test performance in schizophrenia. Schizophr Res 1999;40:255-256. 11. Berman I, Klegon D, Fiedosewicz H, Chang H. The effect of novel antipsychotics on cognitive functioning. Psychiatr Ann 1999;29:643-646. 12. Addington J, Addington D. Neurocognitive functioning in schizophrenia: a trial of risperidone versus haloperidol. Can J Psychiatry 1997;42:983-991. 13. Kane J, Honigfeld G, Singer J, Meltzer H, Group CCS. Clozapine for the treatment-resistant schizophrenic: a doubleblind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-796. 14. Glynn SM, Liberman RP, Bowen L, Kuehnel TG, Marshall BD, Gnanamuthu S. The Clinical Research Unit at Camarillo State Hospital. In: Corrigan PW, Liberman RP (eds). Behavior Therapy in Psychiatric Hospitals. New York, NY: Springer, 1994:39-60. 15. Harvey PD, Keefe RFE. Studies of the cognitive changes
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in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 2001;158:176-184. 16. Paul GL, Tobias LT, Holly BL. Maintenance psychotropic drugs in the presence of active treatment programs: a triple blind withdrawal study with long-term mental patients. Arch Gen Psychiatry 1972;27:106-115. 17. Kern RS, Green MF, Wallace CJ. Declarative and procedural learning in schizophrenia: a test of the integrity of divergent memory systems. Cognit Neuropsychiatry 1997;2:3950. 18. Meyers PS, Bond GR, Tunis SL, McCoy ML. Comparisons between atypical and traditional antipsychotics in work outcome for clients in a psychiatric rehabilitation program. Psychiatr Serv. In Press. 19. Aquila R. Vocational outcomes associated with conventional vs. atypical antipsychotic medications. Presented at the Annual Meeting of the American Psychiatric Association; May 16-20, 1999; Chicago, IL. 20. Kern RS, Green MF, Marshall BD, Wirshing WC, Wirshing D, McGurk S, et al. Risperidone vs. haloperidol on reaction time, manual dexterity, and motor learning in treatment-resistant schizophrenia patients. Biol Psychiatry 1998;44: 726-732. 21. Kee KS, Kern RS, Green MF. Perception of emotion and neurocognitive functioning in schizophrenia: what’s the link? Psychiatry Res 1998;81:57-65. 22. Spaulding WD, Fleming SK, Reed D, Sullivan M, Storzbach D, Lam M. Cognitive functioning in schizophrenia: Implications for psychiatric rehabilitation. Schizophr Bull 1999; 25:275-290. 23. Liberman RP, Marder SR, Marshall BD Jr, Mintz J, Kuehnel TG. Biobehavioral therapy: Interactions between pharmacotherapy and behavior therapy in schizophrenia. In: Wykes T, Tarrier N, Lewis S (eds). Outcome and Innovation in Psychological Treatment of Schizophrenia. London, UK: Wiley, 1998:179-199.
times on the behavior therapy unit. Working memory and verbal learning did correlate with improvements in ADLs, independent of drug condition. The contingencies of reinforcement and specific training programs on the behavior therapy unit may have been prepotent for the learning of ADLs, obscuring any differential impact of risperidone. Moreover, ADLs may be governed more by “procedural” learning than by working memory or verbal learning, with the former not differentially influenced by typical verus atypical antipsychotics. Copyright 2002, Elsevier Science (USA). All rights reserved.
C
comes in schizophrenia. In a randomized, clinical trial, we have submitted this hypothesis to a test, using the learning of self-care skills as dependent measures with the same subjects studied by Green et al.9 in their investigation of the neurocognitive effects of risperidone versus haloperidol.
ONTROLLED CLINICAL efficacy trials of antipsychotic drugs have almost exclusively focused on symptomatology as an outcome measure. Medications are seen as effective if they reduce positive symptoms, and/or prevent psychotic relapse and rehospitalization. This unidimensional approach to evaluating the effects of antipsychotic medication has failed to appreciate the interactions between drug and psychosocial treatment effects1 and the effects of medication on neurocognitive and behavioral functioning.2,3 Recent studies have begun to widen the scope of treatment outcome to include community functioning, social problem solving, skills acquisition, and cognitive functioning.2-5 Interestingly, psychotic symptomatology has been found to be unassociated with these other functional outcome domains in many studies,2,4,6 though not all.7 The salutary effects of risperidone over haloperidol in improving the verba1 working memory, verbal learning, attention, reaction time, and executive functioning of persons with treatment refractory schizophrenia have been reported.8-12 Given that improvement in these areas of neurocognitive functioning have been associated with improved functional outcome in correlational studies, the possibility is raised that risperidone-produced improvements in neurocognition might yield advantages in psychosocial functioning for those individuals treated with this novel antipsychotic drug. To date, however, no prospective randomized controlled research has examined this proposed advantage of atypical antipsychotics on functional out-
METHOD
Study Subjects Thirty-six subjects, who gave written informed consent, were recruited from the long-term, psychiatric wards of Camarillo State Hospital. All subjects met DSM-III-R criteria for schizophrenia, based on administration of the Structured Clinical Interview for DSM-III-R, examination of hospital chart notes and past medical records, observation by ward staff, and information from patients’ relatives. All subjects met the criteria for “treatment refractoriness” in schizophrenia, as operationalized by Kane et al.13 In addition, all patients must have tried at least three 6-week periods of treatment with neuroleptic medication from at least two different classes of neuroleptics (at chlorpromazine From the University of California Los Angeles Center for Research on Treatment and Rehabilitation of Psychosis and Psychiatric Rehabilitation Program, Los Angeles, CA. Address reprint requests to Robert Paul Liberman, M.D., UCLA Psych REHAB Program, 300 UCLA Medical Plaza, Los Angeles, CA 90095. Copyright 2002, Elsevier Science (USA). All rights reserved. 0010-440X/02/4306-0020$35.00/0 doi:10.1053/comp.2002.33499
Comprehensive Psychiatry, Vol. 43, No. 6 (November/December), 2002: pp 469-473
469
470
equivalents of 1,000 mg/d or greater) in the previous 5 years, resulting in either no significant symptom improvement or an intolerence to such doses. Patients were excluded from the study if they met any of the following exclusion criteria: (1) presence of any clinically significant neurological disorder; (2) history of serious head injury; (3) physical, cognitive, or language impairment sufficient to bring the validity of clinical scores into question; (4) history of substance abuse within the previous 6 months; (5) a medication history that included a risperidol trial of sufficient length to determine clinical response; (6) treatment with investigational drugs or clozapine within the 4 weeks before study entry or depot neuroleptics within the 8 weeks before study entry; (7) behavior that posed significant danger to self or others; and (8) significant clinical improvement (i.e., total 18-item Brief Psychiatric Rating Scale [BPRS] score ⱕ35) between screening and study entry. Once subjects gave informed consent, they were transferred to the 11-bed Camarillo-University of California Los Angeles Clinical Research Unit, which provided a standardized token economy (social learning) milieu, highly structured training of activities of daily living (ADLs) using “shaping” procedures, and twice-daily training sessions in social and independent living skills. This specialized behavior therapy milieu has been thoroughly described in another publication.14 Points were awarded to subjects for improvements in their selfcare, participation in skills training, and moving to higher levels of responsibility and autonomy. These points could then be exchanged three times daily for privileges, coffee, refreshments, snacks, and other personal items. Procedure During a stabilization phase of 3 weeks, all subjects received 15 to 30 mg of haloperidol. Upon entering the randomized, double-blind phases of the study, subjects first received either 6 mg of risperidone (n ⫽ 18) or 15 mg of haloperidol (n ⫽ 18) for 4 weeks (fixed-dose phase), followed by a 4-week flexible-dose phase. In this flex-dose phase, the treating psychiatrist, while still blind to each patient’s drug condition, was able to adjust the dose in either direction. Mean doses during the flexible-dose phase were 8 mg risperidone and 20 mg haloperidol. Neurocognitive tests, as listed in Table 1, were
LIBERMAN ET AL
Table 1. Neurocognitive Tests Administered in the Risperidone Versus Haloperidol Study During the Fixed- and Flexible-Dose Phases Neurocognitive Tests
Digit Span Distractibility Test (DSDT) California Verbal Learning Test (CVLT) Continuous Performance Test (ds-CPT) (degraded stimulus version) Wisconsin Card Sorting Test (WCST)
Domain of Neurocognition Assessed
Verbal Working Memory Verbal Learning Sustained Attention
Executive Functioning
administered before the stabilization phase, and again after the fixed- and flexible-dose phases. The tests, their rationale, modes of administration, and scoring are described in another publication.15 Assessments of Dependent Variables Throughout the day, nursing staff, who were given intensive training and periodic feedback on their reliability for quality assurance, made observations of subjects’ performance in ADLs: grooming, dressing, room clean-up, and showering. Each of the ADLs was operationally defined. For example, the criteria for proper grooming included brushing teeth (use toothpaste, brush majority of teeth and gum surfaces, rinse toothbrush, replace lid on toothpaste, no food particles visible on teeth), washing hands and face (use soap, apply soap to entire face, hands and wrists, rinse off soap, no visible dirt, soap or wetness on skin), and combing hair (use comb or brush with at least three repetitions over hair, hair not visibly matted or tangled). Scores of 0 to 2 were given for each day’s category of ADLs. Two points were awarded if the person engaged in all of the criteria without prompting; one point for completing the tasks with the aid of prompting and instructions; and zero points if the individual refused to do the task or did not complete all criteria satisfactorily. The reliability of the observational data within each subject was measured by Cronbach’s alpha test and ranged between ␣⫽ .68 (grooming) and ␣⫽ .87 (showering). Subjects in both the risperidone and haloperidol groups did not differ at study entry or during the baseline phase on any of the demographic or clinical characteristics listed in Table 2.
RISPERIDONE v HALOPERIDOL FOR DAILY LIVING
Table 2. Subject Demographic Characteristics for the Risperidone and Haloperidol Conditions Combined Age Gender Age at onset of illness Summary score of 24-item BPRS at baseline Mean points for all ADLs (0-8 pts possible)
37.4 years (7.5) 67% male, 33% female 17.8 years (4.0) 68.2 (14.4) 6.74 (1.0)
NOTE. Data are presented as means and (SD).
Data Analysis Within-subject changes in performance of ADLs were measured by subtracting each subject’s mean score on each of the four ADLs (grooming, dressing, room clean-up, showering) at study completion from his/her score at study entry. One-way analyses of variance were then conducted to test differences between drug conditions on changes in performance of ADLs from study entry to study conclusion. Spearman correlations were computed to examine the relation between neurocognitive functioning and an overall composite measure that integrated all ADLs. In addition, general linear mixed-model regression analyses (SAS Proc MIXED) were conducted to evaluate possible interactions between neurocognitive performance and ADLs across the two time periods (fixed dose/flexible dose) in the study. RESULTS
Activities of Daily Living There were no statistically significant differences between drug conditions for any of the categories of daily living skills, nor for the sum of activities across all domains (dressing ⫹ grooming ⫹ room clean-up ⫹ showering). However, subjects in both drug conditions showed statistically significant improvements from the start to the finish of the study in showering (t ⫽ 2.24, df ⫽ 27, P ⫽ .034) and grooming (t ⫽ 2.77, df ⫽ 27, P ⫽ .01). Modest improvements (though not statistically significant) from the baseline phase to the end of the study were also found in the other two activities of daily living (dressing and room cleanup). Thus, there was evidence from this evaluation that ADLs improved during subjects’ stay on the Clinical Research Unit, suggesting that the Unit’s token economy and skills training program may
471
have had a salutary effect on these behavioral dimensions, regardless of the drug treatment condition. Relationship Between Neurocognitive and Functional Measures No significant differences were found between drug conditions for any of the ADLs and neurocognitive performance. Spearman correlations between neurocognitive performance and ADLs are shown in Table 3 across both drug conditions. A summary score was derived from the Digit Span Distractibility Test (DSDT) by summing the distraction and nondistraction conditions because these two conditions correlated highly in both dosage phases (fixed: r ⫽ .87, df ⫽ 33, P ⫽ .0001; flexible: r ⫽ .76, df ⫽ 32, P ⫽ .0001). During the fixed-dose phase of the study, the following neurocognitive measures had statistically significant relationships with the functional behaviors comprising ADLs: DSDT with overall ADLs; California Verbal Learning Test (CVLT) with overall ADLs. During the flexible-dose phase of the study, the following statistically significant relationships emerged: DSDT with overall ADLs; CVLT with overall ADLs. It should be emphasized that these relationships were found for the fixed and flexible phases of the medication trial when subjects in both the risperidone and haloperidol conditions were combined. In addition to these simple analyses within each medication phase, a general linear, mixed-model, regression analysis with repeated measures (fixed and flexible phases) was done to obtain maximal statistical power across the two time periods and evaluate possible interactions between medication
Table 3. Spearman Correlations Between Neurocognitive Tests and Overall Score on Activities of Daily Living ADLs
Neurocognitive Measure
Fixed
Flexible
WCST ds-CPT CVLT DSDT
0.12 0.19 0.58* 0.48*
0.36 0.23 0.66† 0.62†
NOTE. The specific number of subjects for whom test data were available during fixed and flexible dose phases of medication varied between 25 and 33. Data are pooled for both risperidone and haloperidol groups. *P ⬍ .01. † P ⬍ .001.
472
LIBERMAN ET AL
condition and activities of daily living. The model included the DSDT, CVLT, drug condition, and drug treatment phase as independent measures with interactions. These analyses confirmed the association of the DSDT and CVLT with ADLs, only when subjects in both drug conditions were combined. The main effects for the DSDT and CVLT with the composite score for activities of daily living were F ⫽ 7.4, P ⫽ .01, and F ⫽ 6.4, P ⫽ .02, respectively. The other two neurocognitive assessments (degraded stimulus Continuous Performance Test [ds-CPT] and the Wisconsin Card Sorting Test [WCST]) did not bear significant relationships with the changes in functional behaviors of subjects on the ward. DISCUSSION
Why did risperidone, found by others8,9,12 to differentially improve several neurocognitive functions when compared with haloperidol, not differentially improve activities of daily living in our analysis? A possible explanation for the lack of differences may be that the Unit’s system of behavioral shaping and contingencies of reinforcement had a prepotent effect on the subjects’ adherence to performing their own ADLs regardless of drug condition. This explanation was supported by the improvements in ADLs as subjects increased the duration of their residency on the Unit, possibly reflecting the learning that took place over time. In a “triple blind” study of antipsychotic medications and functional ward behaviors conducted in a social learning program16 that resembled the Clinical Research Unit, the point or token system was more powerful than medications in producing behavioral improvements in regressed, chronic mental patients. An alternative, but not mutually exclusive explanation may be that ADLs are more habitual and are not so dependent on the higher level neurocognitive functions such as working memory and verbal learning which are differentially affected by atypical antipsychotics. “Implicit“ or ”procedural“
learning that takes place largely outside of conscious awareness and has been shown to operate relatively normally in schizophrenia17 may be more responsible for determining ADLs but less differentially influenced by risperidone and haloperidol. Recently reported findings suggest that atypical antipsychotic drugs, despite their favorable effects on neurocognition, have not been associated with better vocational outcomes.18,19 In one of these studies, 82 schizophrenia-spectrum patients receiving either risperidone or olanzapine versus conventional antipsychotics were followed for up to 2 years. Patients from both medication conditions worked for an average of 4 weeks, with 13% of both groups attaining competitive employment.18 There is a growing body of evidence to suggest that improvements in neurocognitive functioning are stronger predictors of functional outcome than are improvements in psychotic symptomatology.2,6 Recall memory has been specifically associated with behavioral skill acquisition.4 As clinical psychopharmacology extends its reach to the study of neurocognitive processes and functional activities of life, the relationships among antipsychotic drugs, information processing, and instrumental and social role behavior will become clearer. At this time, we are simply “opening doors” for this much needed progression in research to take place. Recently published studies of neurocognition in schizophrenia may generate more promising hypotheses that can identify the specific neurocognitive variables or functions that have specific ratelimiting control over specific instrumental and social behaviors of persons with schizophrenia.20-22 As research on neurocognitive pharmacology proceeds, it will be important for investigators to comprehend that medications are never administered, ingested, metabolized or have their effects in a socioenvironmental vacuum. The interactions of drug and psychosocial treatment effects must be considered in the design and interpretation of the outcomes of treatment.23
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