- Email: [email protected]
Long-acting injectable risperidone in treatment refractory patients: A 14-week open-label pilot study
Schizophrenia Research 123 (2010) 273–275
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editors Long-acting injectable risperidone in treatment refractory patients: A 14-week open-label pilot study
Dear Editors,
A paucity of studies exists in evaluating long acting risperidone injectable (LAR) in treatment refractory patients. The objective of this pilot study (NCT00272597 http://www. clinicaltrials.gov) was to determine if LAR is effective and well tolerated in this patient group. Thirteen treatment refractory inpatients diagnosed with schizophrenia or schizoaffective disorder were recruited. Treatment refractory status was defined as having persistent illness for at least 5 years and: 1) treated previously with clozapine or 2) failed at least two adequate trials with antipsychotics along with a history of multiple hospitalizations in the previous year. Consenting patients entered a two-week run-in phase, in which they received oral risperidone, as monotherapy (maximum 6 mg/day), for at least 5 days before entering the open-label treatment phase. If the patient was treated with an antipsychotic other than risperidone, the dosage was tapered gradually while simultaneously starting oral risperidone. LAR was administered intramuscularly (IM) every 2 weeks. For the first three doses, all patients received 25 mg. At the time of the fourth injection, the dosage could be increased to 37.5 mg. A further increase to 50 mg was allowed if the patient had been on 37.5 mg for at least 4 weeks (2 injection intervals). To accommodate the latency period (time for risperidone to be released from the microspheres of the long-acting formulation), patients took oral risperidone for a three-week period beginning with the first IM dose of LAR. Oral risperidone supplementation was also permitted anytime to treat worsening or exacerbation of psychosis. Apart from adding a second antipsychotic, physicians were not restricted from using other medications for patient management. The primary outcome was severity of symptoms as measured using the total Positive and Negative Syndrome Scale (PANSS) scores (Kay et al., 1987). Secondary measures of effectiveness included the PANSS subscales, and the Clinical Global Impressions-Severity (CGI-S) scale (1976). Adverse events were evaluated using the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980) and the Barnes Akathisia Scale (Barnes, 1989). Metabolic monitoring was also performed. 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.07.016
On average, the patients were 42.3 ± 14.6 years of age and treated with 3.0 ± 1.6 antipsychotics within a 10-month period prior to entering the study. Three patients were excluded from the analysis due to withdrawal of consent (n = 2) and a protocol violation (n = 1). At the end of the study the dosages of LAR for completers were 25 mg (n = 3), 37.5 mg (n = 4), and 50 mg (n = 1). Our data did not find LAR to improve overall illness severity as measured by PANSS and CGI rating scales (Table 1). On the other hand, LAR was well tolerated and did not increase the risk for extrapyramidal symptoms. Apart from a trend towards significance for change in total cholesterol, no significant differences were noted for metabolic indices. Girardi et al. (2010) reported findings contrary to ours in a cohort of outpatients who are surprisingly more severely symptomatic than our group (mean baseline BPRS score was 93.4 ± 4.7). The mean dosage of LAR at the end of their 6month study was 47.4 ± 10.1 mg and coincided with a mean improvement in BPRS scores of 49.7 ± 2.0%. Furthermore, only 9% of their patients received supplementary antipsychotics during this time. By comparison, the mean dose for completers in our study was only 34.4 ± 8.8 mg and 75% of them required supplemental oral risperidone. These data suggest that the dosage of LAR used in our study was likely too low for this patient population. Our pilot study was also limited by its small sample size and open-label design. Further studies using LAR in treatment refractory patients are needed. Role of funding source The current research was supported by the British Columbia Mental Health and Addictions Services, an agency of the Provincial Health Services Authority. The agency had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors RM Procyshyn, S Flynn, C Schenk, S Ganesan, and WG Honer designed the study and wrote the protocol. Author AM Barr undertook the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of Interest Dr. Procyshyn reports receiving consulting or advisory board fees from AstraZeneca, Janssen, and Pfizer; and lecture fees from AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKLine, Janssen, and Pfizer. Dr. Barr has acted as a consultant for Eli Lilly Canada. Dr. Ganesan has received consulting fees from AstraZeneca and Janssen; and lecture fees from AstraZeneca. Dr. Flynn has received consulting and lecture fees from Novartis. Dr. Honer has received consulting fees from sitting on paid advisory boards for In-silico, Wyeth, Janssen, Novartis and AstraZeneca;
274
Letter to the Editors
Table 1 Primary and secondary outcome measures at baseline (Day 0) and at the endpoint (Day 98). Outcome Measure
LOCF
Completers
(5 Males: 5 Females)
Effectiveness PANSS score Total Positive Negative General CGI-S a CGI-I b Tolerability ESRS c Total Parkinsonism Dystonia Dyskinesia Barnes Akathisia Rating Scale
(5 Males: 3 Females)
Day 0
Day 98
P value
Day 0
Day 98
P value
89.2 ± 7.7 22.1 ± 2.4 22.3 ± 2.4 44.8 ± 5.8 4.70 ± 0.68 3.89 ± 1.05
84.8 ± 17.1 21.0 ± 4.7 19.5 ± 4.7 44.3 ± 9.4 4.50 ± 0.71 3.67 ± 1.22
0.51 0.55 0.10 0.90 0.56 0.84
87.1 ± 6.9 22.0 ± 2.5 21.9 ± 2.6 43.3 ± 5.4 4.50 ± 0.54 3.75 ± 1.04
81.7 ± 11.3 19.3 ± 3.3 19.9 ± 4.3 42.6 ± 5.4 4.25 ± 0.46 3.38 ± 0.92
0.34 0.13 0.21 0.83 0.38 0.63
9.8 ± 10.1 8.1 ± 7.8 0.0 ± 0.0 1.8 ± 3.5 0.9 ± 1.4
11.3 ± 11.6 8.0 ± 7.6 0.0 ± 0.0 3.3 ± 4.3 0.4 ± 0.9
0.20 0.84 1.00 0.31 0.25
11.1 ± 10.2 9.0 ± 7.9 0.0 ± 0.0 2.0 ± 3.7 1.0 ± 1.4
12.2 ± 12.0 8.5 ± 8.0 0.0 ± 0.00 3.8 ± 4.4 0.5 ± 0.9
0.25 0.69 1.00 0.31 0.25
88.0 ± 29.8 99.3 ± 20.5 29.4 ± 7.8 4.80 ± 0.44 4.24 ± 0.64 3.34 ± 1.71 1.07 ± 0.38 1.21 ± 0.41
87.7 ± 30.9 102 ± 22.7 29.3 ± 7.9 4.83 ± 0.36 4.81 ± 0.68 3.05 ± 0.71 1.15 ± 0.35 1.32 ± 0.48
0.92 0.27 0.89 0.86 0.07 0.65 0.24 0.18
Metabolics d Weight (kg) Waist circumference (cm) Body-mass index e Fasting glucose (mmol/L) Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L)
Abbreviations: LOCF = Last observation carried forward; PANSS = the Positive and Negative Syndrome Scale; CGI-S = Clinical Global Impressions-Severity of Illness; CGI-I = Clinical Global Impressions-Global Improvement; ESRS = Extrapyramidal Symptom Rating Scale; LDL = Low Density Lipoproteins; HDL = High Density Lipoproteins. Analysis: Paired t-tests were performed for PANSS and metabolic indices. Nonparametric analyses were performed on CGI, ESRS, and BARS using the Wilcoxon's Signed-Rank test. Averages are means ± S.D. and all statistical tests were interpreted at the 5% significance level (two tailed). a CGI-S scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). b CGI-I scores range from 1 (very much improved) to 7 (very much worse). Baseline for CGI-I was on Day 14. c ESRS ranges from 1 to 246, with subscales for parkinsonism (range, 0 to 108), dystonia (range, 0 to 96), and dyskinesia (range, 0 to 42). d All post-baseline measurements were done at the completion of the study (Day 98) and thus reported only under the completer's analysis. e The body-mass index is the weight in kilograms divided by the square of the height in meters.
lecture fees from Janssen and AstraZeneca; and educational grant support from Janssen, Eli Lilly and AstraZeneca. Dr. Schenk has no conflict of interest to declare.
Acknowledgements We would like to thank Ms. Niki Schnurr, Ms. Rebecca Ko, and Mr. Tin Au for their technical assistance.
Ric M. Procyshyn British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Corresponding author. British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4. E-mail address: [email protected].
References Barnes, T.R.E., 1989. A rating scale for drug-induced akathisia. Br. J. Psychiatry 154, 672–676. Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B.D., 1980. Extrapyramidal rating scale. Can. J. Neurol. Sci. 7, 233. Clinical Global Impressions, 1976. In: Guy, W. (Ed.), ECDEU Assessment Manual for Psychopharmacology. U.S. Department of Health, Education, and Welfare, Rockville, MD. DHEW Publication No. (ADM) 76-338. Girardi, R., Serafini, G., Pompili, M., Innamorati, M., Tatarelli, R., Baldessarini, R.J., 2010. Prospective, open study of long-acting injected risperidone versus oral antipsychotics in 88 chronically psychotic patients. Pharmacopsychiatry 43, 66–72. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 262–276.
Alasdair M. Barr British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, B.C., Canada, V6T 1Z3 Sean Flynn Chris Schenk Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Refractory Psychosis Unit, Riverview Hospital, Coquitlam, B.C., Canada V3C 4J2
Letter to the Editors
Soma Ganesan Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Cross Cultural Psychiatry Program, Riverview Hospital, Coquitlam, B.C., Canada, V3C 4J2 William G. Honer British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 13 April 2010
275
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editors Long-acting injectable risperidone in treatment refractory patients: A 14-week open-label pilot study
Dear Editors,
A paucity of studies exists in evaluating long acting risperidone injectable (LAR) in treatment refractory patients. The objective of this pilot study (NCT00272597 http://www. clinicaltrials.gov) was to determine if LAR is effective and well tolerated in this patient group. Thirteen treatment refractory inpatients diagnosed with schizophrenia or schizoaffective disorder were recruited. Treatment refractory status was defined as having persistent illness for at least 5 years and: 1) treated previously with clozapine or 2) failed at least two adequate trials with antipsychotics along with a history of multiple hospitalizations in the previous year. Consenting patients entered a two-week run-in phase, in which they received oral risperidone, as monotherapy (maximum 6 mg/day), for at least 5 days before entering the open-label treatment phase. If the patient was treated with an antipsychotic other than risperidone, the dosage was tapered gradually while simultaneously starting oral risperidone. LAR was administered intramuscularly (IM) every 2 weeks. For the first three doses, all patients received 25 mg. At the time of the fourth injection, the dosage could be increased to 37.5 mg. A further increase to 50 mg was allowed if the patient had been on 37.5 mg for at least 4 weeks (2 injection intervals). To accommodate the latency period (time for risperidone to be released from the microspheres of the long-acting formulation), patients took oral risperidone for a three-week period beginning with the first IM dose of LAR. Oral risperidone supplementation was also permitted anytime to treat worsening or exacerbation of psychosis. Apart from adding a second antipsychotic, physicians were not restricted from using other medications for patient management. The primary outcome was severity of symptoms as measured using the total Positive and Negative Syndrome Scale (PANSS) scores (Kay et al., 1987). Secondary measures of effectiveness included the PANSS subscales, and the Clinical Global Impressions-Severity (CGI-S) scale (1976). Adverse events were evaluated using the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980) and the Barnes Akathisia Scale (Barnes, 1989). Metabolic monitoring was also performed. 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.07.016
On average, the patients were 42.3 ± 14.6 years of age and treated with 3.0 ± 1.6 antipsychotics within a 10-month period prior to entering the study. Three patients were excluded from the analysis due to withdrawal of consent (n = 2) and a protocol violation (n = 1). At the end of the study the dosages of LAR for completers were 25 mg (n = 3), 37.5 mg (n = 4), and 50 mg (n = 1). Our data did not find LAR to improve overall illness severity as measured by PANSS and CGI rating scales (Table 1). On the other hand, LAR was well tolerated and did not increase the risk for extrapyramidal symptoms. Apart from a trend towards significance for change in total cholesterol, no significant differences were noted for metabolic indices. Girardi et al. (2010) reported findings contrary to ours in a cohort of outpatients who are surprisingly more severely symptomatic than our group (mean baseline BPRS score was 93.4 ± 4.7). The mean dosage of LAR at the end of their 6month study was 47.4 ± 10.1 mg and coincided with a mean improvement in BPRS scores of 49.7 ± 2.0%. Furthermore, only 9% of their patients received supplementary antipsychotics during this time. By comparison, the mean dose for completers in our study was only 34.4 ± 8.8 mg and 75% of them required supplemental oral risperidone. These data suggest that the dosage of LAR used in our study was likely too low for this patient population. Our pilot study was also limited by its small sample size and open-label design. Further studies using LAR in treatment refractory patients are needed. Role of funding source The current research was supported by the British Columbia Mental Health and Addictions Services, an agency of the Provincial Health Services Authority. The agency had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Authors RM Procyshyn, S Flynn, C Schenk, S Ganesan, and WG Honer designed the study and wrote the protocol. Author AM Barr undertook the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of Interest Dr. Procyshyn reports receiving consulting or advisory board fees from AstraZeneca, Janssen, and Pfizer; and lecture fees from AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKLine, Janssen, and Pfizer. Dr. Barr has acted as a consultant for Eli Lilly Canada. Dr. Ganesan has received consulting fees from AstraZeneca and Janssen; and lecture fees from AstraZeneca. Dr. Flynn has received consulting and lecture fees from Novartis. Dr. Honer has received consulting fees from sitting on paid advisory boards for In-silico, Wyeth, Janssen, Novartis and AstraZeneca;
274
Letter to the Editors
Table 1 Primary and secondary outcome measures at baseline (Day 0) and at the endpoint (Day 98). Outcome Measure
LOCF
Completers
(5 Males: 5 Females)
Effectiveness PANSS score Total Positive Negative General CGI-S a CGI-I b Tolerability ESRS c Total Parkinsonism Dystonia Dyskinesia Barnes Akathisia Rating Scale
(5 Males: 3 Females)
Day 0
Day 98
P value
Day 0
Day 98
P value
89.2 ± 7.7 22.1 ± 2.4 22.3 ± 2.4 44.8 ± 5.8 4.70 ± 0.68 3.89 ± 1.05
84.8 ± 17.1 21.0 ± 4.7 19.5 ± 4.7 44.3 ± 9.4 4.50 ± 0.71 3.67 ± 1.22
0.51 0.55 0.10 0.90 0.56 0.84
87.1 ± 6.9 22.0 ± 2.5 21.9 ± 2.6 43.3 ± 5.4 4.50 ± 0.54 3.75 ± 1.04
81.7 ± 11.3 19.3 ± 3.3 19.9 ± 4.3 42.6 ± 5.4 4.25 ± 0.46 3.38 ± 0.92
0.34 0.13 0.21 0.83 0.38 0.63
9.8 ± 10.1 8.1 ± 7.8 0.0 ± 0.0 1.8 ± 3.5 0.9 ± 1.4
11.3 ± 11.6 8.0 ± 7.6 0.0 ± 0.0 3.3 ± 4.3 0.4 ± 0.9
0.20 0.84 1.00 0.31 0.25
11.1 ± 10.2 9.0 ± 7.9 0.0 ± 0.0 2.0 ± 3.7 1.0 ± 1.4
12.2 ± 12.0 8.5 ± 8.0 0.0 ± 0.00 3.8 ± 4.4 0.5 ± 0.9
0.25 0.69 1.00 0.31 0.25
88.0 ± 29.8 99.3 ± 20.5 29.4 ± 7.8 4.80 ± 0.44 4.24 ± 0.64 3.34 ± 1.71 1.07 ± 0.38 1.21 ± 0.41
87.7 ± 30.9 102 ± 22.7 29.3 ± 7.9 4.83 ± 0.36 4.81 ± 0.68 3.05 ± 0.71 1.15 ± 0.35 1.32 ± 0.48
0.92 0.27 0.89 0.86 0.07 0.65 0.24 0.18
Metabolics d Weight (kg) Waist circumference (cm) Body-mass index e Fasting glucose (mmol/L) Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L)
Abbreviations: LOCF = Last observation carried forward; PANSS = the Positive and Negative Syndrome Scale; CGI-S = Clinical Global Impressions-Severity of Illness; CGI-I = Clinical Global Impressions-Global Improvement; ESRS = Extrapyramidal Symptom Rating Scale; LDL = Low Density Lipoproteins; HDL = High Density Lipoproteins. Analysis: Paired t-tests were performed for PANSS and metabolic indices. Nonparametric analyses were performed on CGI, ESRS, and BARS using the Wilcoxon's Signed-Rank test. Averages are means ± S.D. and all statistical tests were interpreted at the 5% significance level (two tailed). a CGI-S scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). b CGI-I scores range from 1 (very much improved) to 7 (very much worse). Baseline for CGI-I was on Day 14. c ESRS ranges from 1 to 246, with subscales for parkinsonism (range, 0 to 108), dystonia (range, 0 to 96), and dyskinesia (range, 0 to 42). d All post-baseline measurements were done at the completion of the study (Day 98) and thus reported only under the completer's analysis. e The body-mass index is the weight in kilograms divided by the square of the height in meters.
lecture fees from Janssen and AstraZeneca; and educational grant support from Janssen, Eli Lilly and AstraZeneca. Dr. Schenk has no conflict of interest to declare.
Acknowledgements We would like to thank Ms. Niki Schnurr, Ms. Rebecca Ko, and Mr. Tin Au for their technical assistance.
Ric M. Procyshyn British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Corresponding author. British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4. E-mail address: [email protected].
References Barnes, T.R.E., 1989. A rating scale for drug-induced akathisia. Br. J. Psychiatry 154, 672–676. Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B.D., 1980. Extrapyramidal rating scale. Can. J. Neurol. Sci. 7, 233. Clinical Global Impressions, 1976. In: Guy, W. (Ed.), ECDEU Assessment Manual for Psychopharmacology. U.S. Department of Health, Education, and Welfare, Rockville, MD. DHEW Publication No. (ADM) 76-338. Girardi, R., Serafini, G., Pompili, M., Innamorati, M., Tatarelli, R., Baldessarini, R.J., 2010. Prospective, open study of long-acting injected risperidone versus oral antipsychotics in 88 chronically psychotic patients. Pharmacopsychiatry 43, 66–72. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 262–276.
Alasdair M. Barr British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, B.C., Canada, V6T 1Z3 Sean Flynn Chris Schenk Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Refractory Psychosis Unit, Riverview Hospital, Coquitlam, B.C., Canada V3C 4J2
Letter to the Editors
Soma Ganesan Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 Cross Cultural Psychiatry Program, Riverview Hospital, Coquitlam, B.C., Canada, V3C 4J2 William G. Honer British Columbia Mental Health and Addictions Research Institute, A3-938 W 28th Avenue, Vancouver B.C., Canada V5Z 4H4 Department of Psychiatry, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3 13 April 2010
275