- Email: [email protected]
9-OH risperidone response in risperidone poor responders: An open study of drug response concordance
N E U R O L O G Y, P S Y C H I A T R Y A N D B R A I N R E S E A R C H
1 8 ( 2 0 1 2 ) 1 0 9 –1 1 3
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/npbr
9-OH risperidone response in risperidone poor responders: An open study of drug response concordance Roberto Cavallaro a b c
a,b
, Marta Bosia
a,* ,
Carmelo Guglielmino
a,c
, Enrico Smeraldi
a,b
San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy University of Catania, Catania, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
A major topic about the pharmacotherapy of schizophrenia is the wide variability of anti-
Received 10 April 2011
psychotic effects among patients when treated with each drug, leading to the clinical
Received in revised form 30
judgement of a limited ‘class effect’, also for similar molecules. Paliperidone is the major
December 2011
metabolite of risperidone and pharmacodynamic activities are highly comparable, even
Accepted 2 January 2012
though some differences have been reported. Paliperidone showed to be effective in the
Available online 21 January 2012
treatment of schizophrenia in a number of short and long term studies, however only two short term studies evaluated the differences in clinical response among patients
Keywords:
switched from risperidone to paliperidone. The aim of this study is to evaluate, by means
Schizophrenia
of a naturalistic observational follow-up, the possible concordance of clinical response to
Risperidone
risperidone and paliperidone. Thirty-one patients affected by schizophrenia treated with
Paliperidone
risperidone and showing poor clinical response were enrolled in the study. Patients were
Psychopharmacology
switched to paliperidone and assessed for psychopathology, cognition, general functioning, extrapyramidal tolerability and attitude towards treatment at baseline and after 2, 6 and 12 weeks of treatment. The repeated measures analysis showed an overall significant improvement on several domains after 12 weeks of treatment (Table 1). Remarkably over 40% of patients showed a non-concordant clinical response to paliperidone and risperidone. In conclusion, this naturalistic observation suggests that paliperidone and his mother drug, risperidone may show significant differences both in efficacy and tolerability at individual level. Reasons for this should be looked for at biological levels not necessarily involving the receptor affinity and pharmacological activity profile. Ó 2012 Elsevier GmbH. All rights reserved.
1.
Introduction
A major topic about the pharmacotherapy of schizophrenia is the wide variability of antipsychotic effects among patients when treated with each antipsychotic drug, but also the usual concordance of clinical response/non-response in the same patient during different trials with the same drug. This observation led to the clinical judgement of a limited ‘class effect’ at the individual level1,2 also for atypical antipsychotics.
In the literature concordance/discordance of the effects of drugs have been experimented and described mainly in ‘extreme’ response profiles like resistant schizophrenia. A couple of studies with a sequential design showed individual responses to clozapine in comparison to risperidone and olanzapine using repeated measurement of efficacy of the different drugs in the same patients.3,4 This strategy was also used in antidepressant research with similar results.5 Nevertheless the genetic point of view suggested that response to
* Corresponding author. Address: San Raffaele Scientific Institute, Department of Clinical Neurosciences, Via Stamira d’Ancona 20, 20127 Milan, Italy. Tel.: +39 0226433218; fax: +39 0226433265. E-mail address: [email protected] (M. Bosia). 0941-9500/$ - see front matter Ó 2012 Elsevier GmbH. All rights reserved. doi:10.1016/j.npbr.2012.01.001
110
N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
antipsychotic and antidepressant medication is a heritable trait for both efficacy and tolerability.6–9 The atypical antipsychotic 9-hydroxy-risperidone (paliperidone), is the major metabolite of risperidone, that showed to be effective in the treatment of schizophrenia in a number of double blind short and long term studies.10,11 Doubts were raised about paliperidone as patients taking risperidone have actually variable plasma levels of paliperidone (as a metabolite of risperidone), sharing with the mother compound most of pharmacodynamic activities.12 Pharmacodynamic activities are truly similar to those of risperidone with the exception of times for 50% dissociation from D2 receptors, being of 27 min for risperidone and 60 s for paliperidone.13 The major difference between the two drugs stands in pharmacokinetics, with paliperidone ER formulation leading to minimal peak-to-trough fluctuations at steady state. Paliperidone and risperidone also differ significantly in the EC50 for inhibition of multidrug resistance transporter P-glycoprotein with potential differences in blood-brain barrier transport.14 Preclinical animal model (rats) showed also differences in behavioral paradigms of efficacy and motor tolerability.15 Moreover risperidone and paliperidone differentially altered the firing of 5-HT and NE neurons ‘in vivo’ among rats.16 Only two short term studies evaluating the differences in clinical response among patients switched from risperidone to paliperidone have been published. Canuso et al.17 performed a post-hoc analysis of three 6-weeks, double-blind, placebo-controlled trials in acute patients treated with paliperidone ER 3–12 mg/day or placebo. Among patients who had received previously risperidone, paliperidone ER was significantly more effective than placebo in reducing symptoms. In a 6 weeks prospective study, performed to assess medication satisfaction, patients with suboptimal response to oral risperidone were randomized, under double blind condition, to paliperidone ER immediate or delayed (after 2 weeks, during which risperidone was continued) initiation. At the 2week time point, significantly more participants in the immediate initiation group reported satisfaction, moreover a PANSS scores decrease of about 13 points below the average basal score of 83.5 was observed after 4–6 weeks of treatment with paliperidone.18 Aim of this study was to evaluate, by means of a naturalistic observational follow-up in everyday clinical practice, the possible concordance of clinical response to risperidone and paliperidone in a sample of patients affected by schizophrenia, poor/non-responders to risperidone treatment, who had been switched to paliperidone and followed up for at least 12 weeks.
2.
Material and methods
2.1.
Sample
The study included patients with diagnosis of schizophrenia according to DSM-IV criteria, followed up in different Italian Clinical Services (see Acknowledgments), currently treated with oral or long-acting risperidone since at least 8 weeks and being judged as non-responders or partial responders. Non-response was corresponding to a score not lower than 3 (minimally improved) at the Clinical Global Impression-
1 8 ( 20 1 2) 1 0 9–11 3
Schizophrenia Scale19 improvement total score together with a score not lower than 4 (no change) in at least two subscales of the same instrument. Exclusion criteria were: concomitant drug abuse, mental retardation, brain injury and neurological disorders.
2.2.
Study design
The study was naturalistic, observational and open label, lasting 12 weeks. Patients were directly switched to paliperidone ER by common patient/doctor decision at free variable doses ranging 6–12 mg in the first 2 weeks according to technical specifications. Doses were then adjusted up to the second week of treatment according to medical judgement and then fixed for the remaining 10 weeks. Only benzodiazepines were allowed as concomitant treatment.All subjects provided informed consent.
2.3.
Assessments and statistical analysis
The sample was assessed for changes in psychopathology, cognition, general functioning, extrapyramidal tolerability and attitude towards treatment. All evaluations were performed before switching to paliperidone and repeated after 2, 6 and 12 weeks of treatment, except for general functioning that was repeated only at week 12. Clinical assessments were conducted by means of: the Clinical Global Impression-Schizophrenia19 and the Positive and Negative Syndrome Scale (PANSS)20 to evaluate clinical severity and treatment response; the seven items Quality of Life Scale (QLS)21 to investigate functional symptoms; the Simpson and Angus Scale (SA)22 to assess extrapyramidal side effects and the Drug Attitude Inventory-30 (DAI-30)23 for the attitudes towards medication. Cognition was assessed before and after 12 weeks trough administration of the Brief Assessment of Cognition in Schizophrenia (BACS)24 and the performance-based instrument UPSA-B,25 this last to assess performances related to cognitive functioning. Repeated measures analysis was performed with ANOVA and MANCOVA, except for CGI-Schiz global severity score, analyzed with the non-parametric Friedman ANOVA.
3.
Results
Sample consisted in 31 patients, 19 males and 12 females, with a mean age of 32.8 years (7.4 SD), a mean education of 9.8 years (2.7 SD) and a mean duration of illness of 7.8 years (2.5 SD). Twenty-five patients had been treated with oral risperidone with an average daily dose of 5.7 mg (1.9 SD), while six had been treated with long acting injections of risperidone with a mean dose of 43 mg (last injection). Paliperidone treatment was stabilized since the third week of treatment at an average dose of 9.1 mg (2.4 SD, 9 median). Two patients dropped out at follow-up: one for an early worsening and one for lack of compliance to scheduled evaluations: both dropped within the second week of treatment and then were excluded from analysis. Table 1 shows raw scores of clinical assessments at basal and follow-up observations.
N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
1 8 ( 2 0 1 2 ) 1 0 9 –1 1 3
111
Table 1 – Table shows assessments raw scores at each evaluation and statistics (MANCOVA for repeated measures except for SA:ANOVA and CGI-SCH severity Friedman ANOVA). Basal score (SD)
2 weeks
6 weeks
12 weeks
Statistics
Psychopathology PANSS total score
97.1 (22.4)
89.2 (17.6)
80 (16.6)
73.4 (19.5)
PANSS positive
19.8 (6.9)
19.4 (6.8)
17.1 (5.2)
15.7 (5.4)
PANSS negative
26.2 (7.9)
22.5 (5.7)
19.8 (5.0)
18.2 (5.8)
PANSS general
51.1 (11.5)
47.3 (9.1)
43.2 (9.9)
39.6 (11.1)
QLS CGI SCH – severity global score
58.3 (27.6) 4.2 (.8)
– 3.7 (.6)
– 3.2 (.9)
61.4 (20.2) 3.0 (.9)
f = 21.2 p < .0001 f = 10.0 p < .0001 f = 21.0 p < .0001 f = 16.0 p < .0001 Ns v2 39.4 p < .0001
Extrapyramidal side effects SA*
9 (6.4)
6.9 (5.8)
5.2 (4.7)
4.5 (4.6)
f = 9.7 p < .0000
Drug attitude DAI-30
)1.7 (13.4)
4.4 (13.7)
10.1 (9.8)
13.4 (9.5)
f = 13.7 p < .0001
Neuropsychological performance Verbal Memory
26.9 (9.3)
–
–
30 (7.9)
Letter fluency
29.6 (8)
–
–
32 (7.4)
Semantic Fluency
15 (4.2)
–
–
16.4 (4)
Working Memory
11 (5.5)
–
–
12.3 (4.7)
Selective attention
22 (11)
–
–
25.1 (11.4)
Planning
11.6 (5)
–
–
13.2 (4.6)
UPSA-B total
65 (19.9)
–
–
76.6 (18.3)
f = 14.6 p < .001 f = 5.8 p = .02 f = 5.2 p = .03 f = 6.2 p = .02 f = 13.3 p = 001 f = 9.7 p = .004 f = 19.0 p < .001
* Only patients with at least one SA positive item (n = 25).
3.1. Concordance in clinical judgement of response to risperidone and paliperidone CGI – Schizophrenia severity judgement at basal and final evaluations was significantly decreased over time (Friedman ANOVA v2 39.4 p < .0001) (Table 1). As for CGI – Schizophrenia improvement global score, 13.8% of patients had a non-concordant response to paliperidone, recorded as ‘worsened’ or ‘markedly worsened’ judgement, while 27% of patients had non-concordant response recorded as ‘much improved’ judgement. The remaining patients had a concordant response between risperidone and paliperidone, having ‘unchanged’ or only ‘slightly improved’ judgements.
3.2. Repeated measures analyses of clinical and tolerability variables As a first analysis, due to the possible changes in extrapyramidal side effects deriving from the switching from a relatively high dose of risperidone to an average dose of paliperidone, possibly influencing also the clinical changes, was conducted to assess changes in extrapyramidal symptoms.
ANOVA showed a statistically significant (f = 9.77; p < .0000) improvement of SA scale scores among patients showing at basal time any EPS sign (score >0 at any SA scores). No incident parkinsonism cases were found. As a consequence of results on SA all other parametric analyses were done using repeated measures MANCOVA with basal SA score as a covariate. Repeated measures MANCOVA showed a statistically significant improvement of PANSS total and subtotal scores (PANSS total f = 21.2, p < .0001; PANSS positive f = 10.06 p < .0001; PANSS negative f = 21.04, p < .0001; PANSS general psychopathology f = 16.02 p < .0001). No statistically significant change was observed at QLS scores. DAI-30 scores improved significantly across the 12 weeks evaluation (MANCOVA f = 13.69, p < .0001). All cognitive performances were statistically and significantly improved at the end of the study. In detail: verbal memory (MANCOVA f = 14.6, p < .001), word fluency (f = 5.8, p = .02), semantic fluency (f = 5.2, p = .03), working memory (f = 6.2, p = .02) selective attention (f = 13.3, p = 001) and planning/executive function (f = 9.78, p = .004). Effect size of change ranged from a minimum of .21 for selective attention
112
N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
to a maximum of .31 for semantic fluency. Also cognitivebased performance measured by means of UPSA-B improved significantly (MANCOVA f = 19.04, p = .0002). Table 1 shows in detail scores of each assessment at each evaluation performed.
4.
Discussion
The main result of our study is that paliperidone treatment of poor responders to risperidone led to discordant response in a clinically significant proportion of patients. In fact, after 12 weeks of treatment with paliperidone 13.8% of patients had a ‘worsened’ judgement and 27% of patients received a ‘much improved’ judgement at CGI-Schizophrenia total score. Moreover, in average, all clinical parameters measured, except QLS score, were statistically improved over 12 weeks after switching from risperidone to paliperidone. Data presented correspond to a observational naturalistic follow-up of patients treated ‘as usual’ in everyday clinical practice, and this is a clear limit, in fact most open switch studies show significant improvement after treatment with drug number 2. This may partially depend on the fact that, being ‘‘naturalistic’’, the switch is indicated because of a poor response to drug number 1, therefore allowing a greater percentage of improvements with drug number 2. However, in our study, the strength of the comparison of a same patient response after the treatment with the two drugs, rated by the same rater/clinician who gave the judgement of non-response to the first drug may compensate the open design limit and make the results more near to the naturalistic clinical results of everyday practice. The proportion of patients with a clearly (improved) discordant response to risperidone and paliperidone is of about one-fourth of the sample. This might be judged to have limited epidemiological relevance, being at the lower end of the range of ‘much improved’ CGI clinical judgements in medium term open design trials in recent literature, but points at a difference in clinical effects of the mother drug and its metabolite at individual level in a clinically relevant proportion of patients. Rather than showing a greater efficacy of paliperidone compared to risperidone, our results suggest different individual response profiles, thus pointing out possible different and specific clinical indication for the two drugs, that need to be better and further defined. Data analyzed with repeated measures support previous data of the two studies available17,18 with a average change at PANSS total score of about 23 points. This change describes, in average, a change from a PANSS score attributable to a markedly ill (acute) patient, to a moderately ill score of stabilized patients.26 It was also interesting to appreciate the clear, statistically significant improvement of extrapyramidal tolerability in patients who showed parkinsonian signs after risperidone, another sign of non-concordance between effects of the mother drug and of the metabolite at individual level. Nevertheless average doses of risperidone, before the switch to paliperidone were rather high, while the median daily dose of paliperidone was of 9 mg, considered a target medium daily dosage. All neuropsychological performances were statistically improved with size effects similar to those (limited) found
1 8 ( 20 1 2) 1 0 9–11 3
in literature,27,28 but the UPSA-B performance-based measurement of cognitive abilities showed a significant improvement in cognitive-based performances. No changes was observed at the QLS evaluation, but open observation, limited time lasting from the acute state and items of the abbreviated version of the QLS used (core items of deficit syndrome and functionality) might have been less sensitive to change, in comparison to literature using the full QLS. DAI 30 average scores were significantly improved through the study, a result somewhat confirming the results of the study of Canuso et al.,18 which had as primary outcome measure medication satisfaction measured by means of the Medication Satisfaction Questionnaire. DAI 30 and MSQ share the construct of the subjective judgement of effectiveness presented in different ways, and as previously reported18 both better tolerability and effectiveness might have converged in the subjective evaluation of the treatment satisfaction and then attitude to.
5.
Conclusions
In conclusion, this naturalistic observation suggests that paliperidone and his mother drug, risperidone may show differences in efficacy and tolerability at individual level. Reasons for this should be looked for at biological levels not necessarily involving the receptor affinity and pharmacological activity profile. Nevertheless these preliminary observations should be tested in a prospective double blind study with the same main objectives.
Acknowledgments This study was made possible by the clinical work of doctors Massimiliano Aleffi (Therapeutic Community ‘‘Centro Ippocrate’’, Cagliari, Italy), Paola Clemente (Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy), Valeria Magnolfi (Department of Psychiatry, S. Carlo Borromeo Hospital, Milano, Italy), Claudio Montresor (Department of Psychiatry, Luigi Sacco Hospital, Milano, Italy), Simona Palmieri (Department of Public Health, Section of Psychiatry, Avellino, Italy), Federica Pinna (Department of Psychiatry, University of Cagliari, Cagliari, Italy) and Mario Sammartano (Department of Public Health, Section of Psychiatry, Marsala, Italy), participating to the Master in Clinical Psychopharmacology of Vita-Salute San Raffaele University.
R E F E R E N C E S
1. Tandon R, Belmaker RH, Gattaz WF, et al. World Psychiatric Association, Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008;100:20–38. 2. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother 2009;10:1917–28.
N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
3. Cavallaro R, Brambilla P, Smeraldi E. The sequential treatment approach to resistant schizophrenia with risperidone and clozapine: results of an open study with follow-up. Hum Psychopharmacol Clin Exp 1998;13:91–7. 4. Conley RR, Tamminga CA, Kelly DL, et al. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry 1999;46:73–7. 5. Sacchetti E, Conte G, Guarneri L. Are SSRI antidepressants a clinically homogeneous class of compounds? Lancet 1994;344:126–7. 6. Vojvoda D, Grimmell K, Sernyak M. Monozygotic twins concordant for response to clozapine. Lancet 1996; 347:61. 7. Wehmeier PM, Gebhardt S, Schmidtke J, et al. Clozapine: weight gain in a pair of monozygotic twins concordant for schizophrenia and mild mental retardation. Psychiatry Res 2005;133:273–6. 8. Muller DJ, Schulze TG, Knapp M, et al. Familial occurrence of tardive dyskinesia. Acta Psychiatr Scand 2001;104:375–9. 9. Franchini L, Serretti A, Gasperini M, et al. Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res 1998;32:255–9. 10. Spina E, Cavallaro R. The safety of paliperidone extendedrelease in the treatment of schizophrenia. Expert Opin Drug Saf 2007;6:651–62. 11. Emsley R, Berwaerts J, Eerdekens M, et al. Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies. Int Clin Psychopharmacol 2008;23: 343–56. 12. Citrome L. Paliperidone: quo vadis? Int J Clin Pract 2007;61:653–62. 13. Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 1998;3:23–34. 14. Pani L, Marchese G. Expected clinical benefits of paliperidone extended-release formulation when compared with risperidone immediate-release. Expert Opin Drug Deliv 2009;6:319–31. 15. Marchese G, Pittau B, Casu G, et al. A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats. Eur Psychiatry 2010;25:92–100.
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16. Dremencov E, ElMansari M, Blier P. Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons. Psychopharmacology 2007;194:63–72. 17. Canuso C, Youssef EA, Bossie CA, et al. Paliperidone extended-release tablets in schizophrenia patients previously treated with risperidone. Int Clin Psychopharmacol 2008;23:209–15. 18. Canuso CM, Grinspan A, Kalali A, et al. Medication satisfaction in schizophrenia: a blinded-initiation study of paliperidone extended release in patients suboptimally responsive to risperidone. Int Clin Psychopharmacol 2010;25:155–64. 19. Haro JM, Kamath SA, Ochoa S, et al. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl 2003;416:16–23. 20. Kay SR, Opler LA, Lindermayer JP. The positive negative syndrome scale (PANSS): rationale and standardization. Br J Psychol 1989;158:59–67. 21. Bilker WB, Brensinger C, Kurtz MM, et al. Development of an abbreviated schizophrenia quality of life scale using a new method. Neuropsychopharmacology 2003;28:773–7. 22. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9. 23. Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983;13:177–83. 24. Keefe RS, Goldberg TE, Harvey PD, et al. The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 2004;68:283–97. 25. Mausbach BT, Harvey PD, Goldman SR, et al. Development of a brief scale of everyday functioning in persons with serious mental illness. Schizophr Bull 2007;33:1364–72. 26. Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res 2005;79:231–8. 27. Harvey PD, Keefe RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 2001;58:176–84. 28. Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007;64:633–47.
1 8 ( 2 0 1 2 ) 1 0 9 –1 1 3
Available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/npbr
9-OH risperidone response in risperidone poor responders: An open study of drug response concordance Roberto Cavallaro a b c
a,b
, Marta Bosia
a,* ,
Carmelo Guglielmino
a,c
, Enrico Smeraldi
a,b
San Raffaele Scientific Institute, Department of Clinical Neurosciences, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy University of Catania, Catania, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
A major topic about the pharmacotherapy of schizophrenia is the wide variability of anti-
Received 10 April 2011
psychotic effects among patients when treated with each drug, leading to the clinical
Received in revised form 30
judgement of a limited ‘class effect’, also for similar molecules. Paliperidone is the major
December 2011
metabolite of risperidone and pharmacodynamic activities are highly comparable, even
Accepted 2 January 2012
though some differences have been reported. Paliperidone showed to be effective in the
Available online 21 January 2012
treatment of schizophrenia in a number of short and long term studies, however only two short term studies evaluated the differences in clinical response among patients
Keywords:
switched from risperidone to paliperidone. The aim of this study is to evaluate, by means
Schizophrenia
of a naturalistic observational follow-up, the possible concordance of clinical response to
Risperidone
risperidone and paliperidone. Thirty-one patients affected by schizophrenia treated with
Paliperidone
risperidone and showing poor clinical response were enrolled in the study. Patients were
Psychopharmacology
switched to paliperidone and assessed for psychopathology, cognition, general functioning, extrapyramidal tolerability and attitude towards treatment at baseline and after 2, 6 and 12 weeks of treatment. The repeated measures analysis showed an overall significant improvement on several domains after 12 weeks of treatment (Table 1). Remarkably over 40% of patients showed a non-concordant clinical response to paliperidone and risperidone. In conclusion, this naturalistic observation suggests that paliperidone and his mother drug, risperidone may show significant differences both in efficacy and tolerability at individual level. Reasons for this should be looked for at biological levels not necessarily involving the receptor affinity and pharmacological activity profile. Ó 2012 Elsevier GmbH. All rights reserved.
1.
Introduction
A major topic about the pharmacotherapy of schizophrenia is the wide variability of antipsychotic effects among patients when treated with each antipsychotic drug, but also the usual concordance of clinical response/non-response in the same patient during different trials with the same drug. This observation led to the clinical judgement of a limited ‘class effect’ at the individual level1,2 also for atypical antipsychotics.
In the literature concordance/discordance of the effects of drugs have been experimented and described mainly in ‘extreme’ response profiles like resistant schizophrenia. A couple of studies with a sequential design showed individual responses to clozapine in comparison to risperidone and olanzapine using repeated measurement of efficacy of the different drugs in the same patients.3,4 This strategy was also used in antidepressant research with similar results.5 Nevertheless the genetic point of view suggested that response to
* Corresponding author. Address: San Raffaele Scientific Institute, Department of Clinical Neurosciences, Via Stamira d’Ancona 20, 20127 Milan, Italy. Tel.: +39 0226433218; fax: +39 0226433265. E-mail address: [email protected] (M. Bosia). 0941-9500/$ - see front matter Ó 2012 Elsevier GmbH. All rights reserved. doi:10.1016/j.npbr.2012.01.001
110
N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
antipsychotic and antidepressant medication is a heritable trait for both efficacy and tolerability.6–9 The atypical antipsychotic 9-hydroxy-risperidone (paliperidone), is the major metabolite of risperidone, that showed to be effective in the treatment of schizophrenia in a number of double blind short and long term studies.10,11 Doubts were raised about paliperidone as patients taking risperidone have actually variable plasma levels of paliperidone (as a metabolite of risperidone), sharing with the mother compound most of pharmacodynamic activities.12 Pharmacodynamic activities are truly similar to those of risperidone with the exception of times for 50% dissociation from D2 receptors, being of 27 min for risperidone and 60 s for paliperidone.13 The major difference between the two drugs stands in pharmacokinetics, with paliperidone ER formulation leading to minimal peak-to-trough fluctuations at steady state. Paliperidone and risperidone also differ significantly in the EC50 for inhibition of multidrug resistance transporter P-glycoprotein with potential differences in blood-brain barrier transport.14 Preclinical animal model (rats) showed also differences in behavioral paradigms of efficacy and motor tolerability.15 Moreover risperidone and paliperidone differentially altered the firing of 5-HT and NE neurons ‘in vivo’ among rats.16 Only two short term studies evaluating the differences in clinical response among patients switched from risperidone to paliperidone have been published. Canuso et al.17 performed a post-hoc analysis of three 6-weeks, double-blind, placebo-controlled trials in acute patients treated with paliperidone ER 3–12 mg/day or placebo. Among patients who had received previously risperidone, paliperidone ER was significantly more effective than placebo in reducing symptoms. In a 6 weeks prospective study, performed to assess medication satisfaction, patients with suboptimal response to oral risperidone were randomized, under double blind condition, to paliperidone ER immediate or delayed (after 2 weeks, during which risperidone was continued) initiation. At the 2week time point, significantly more participants in the immediate initiation group reported satisfaction, moreover a PANSS scores decrease of about 13 points below the average basal score of 83.5 was observed after 4–6 weeks of treatment with paliperidone.18 Aim of this study was to evaluate, by means of a naturalistic observational follow-up in everyday clinical practice, the possible concordance of clinical response to risperidone and paliperidone in a sample of patients affected by schizophrenia, poor/non-responders to risperidone treatment, who had been switched to paliperidone and followed up for at least 12 weeks.
2.
Material and methods
2.1.
Sample
The study included patients with diagnosis of schizophrenia according to DSM-IV criteria, followed up in different Italian Clinical Services (see Acknowledgments), currently treated with oral or long-acting risperidone since at least 8 weeks and being judged as non-responders or partial responders. Non-response was corresponding to a score not lower than 3 (minimally improved) at the Clinical Global Impression-
1 8 ( 20 1 2) 1 0 9–11 3
Schizophrenia Scale19 improvement total score together with a score not lower than 4 (no change) in at least two subscales of the same instrument. Exclusion criteria were: concomitant drug abuse, mental retardation, brain injury and neurological disorders.
2.2.
Study design
The study was naturalistic, observational and open label, lasting 12 weeks. Patients were directly switched to paliperidone ER by common patient/doctor decision at free variable doses ranging 6–12 mg in the first 2 weeks according to technical specifications. Doses were then adjusted up to the second week of treatment according to medical judgement and then fixed for the remaining 10 weeks. Only benzodiazepines were allowed as concomitant treatment.All subjects provided informed consent.
2.3.
Assessments and statistical analysis
The sample was assessed for changes in psychopathology, cognition, general functioning, extrapyramidal tolerability and attitude towards treatment. All evaluations were performed before switching to paliperidone and repeated after 2, 6 and 12 weeks of treatment, except for general functioning that was repeated only at week 12. Clinical assessments were conducted by means of: the Clinical Global Impression-Schizophrenia19 and the Positive and Negative Syndrome Scale (PANSS)20 to evaluate clinical severity and treatment response; the seven items Quality of Life Scale (QLS)21 to investigate functional symptoms; the Simpson and Angus Scale (SA)22 to assess extrapyramidal side effects and the Drug Attitude Inventory-30 (DAI-30)23 for the attitudes towards medication. Cognition was assessed before and after 12 weeks trough administration of the Brief Assessment of Cognition in Schizophrenia (BACS)24 and the performance-based instrument UPSA-B,25 this last to assess performances related to cognitive functioning. Repeated measures analysis was performed with ANOVA and MANCOVA, except for CGI-Schiz global severity score, analyzed with the non-parametric Friedman ANOVA.
3.
Results
Sample consisted in 31 patients, 19 males and 12 females, with a mean age of 32.8 years (7.4 SD), a mean education of 9.8 years (2.7 SD) and a mean duration of illness of 7.8 years (2.5 SD). Twenty-five patients had been treated with oral risperidone with an average daily dose of 5.7 mg (1.9 SD), while six had been treated with long acting injections of risperidone with a mean dose of 43 mg (last injection). Paliperidone treatment was stabilized since the third week of treatment at an average dose of 9.1 mg (2.4 SD, 9 median). Two patients dropped out at follow-up: one for an early worsening and one for lack of compliance to scheduled evaluations: both dropped within the second week of treatment and then were excluded from analysis. Table 1 shows raw scores of clinical assessments at basal and follow-up observations.
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1 8 ( 2 0 1 2 ) 1 0 9 –1 1 3
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Table 1 – Table shows assessments raw scores at each evaluation and statistics (MANCOVA for repeated measures except for SA:ANOVA and CGI-SCH severity Friedman ANOVA). Basal score (SD)
2 weeks
6 weeks
12 weeks
Statistics
Psychopathology PANSS total score
97.1 (22.4)
89.2 (17.6)
80 (16.6)
73.4 (19.5)
PANSS positive
19.8 (6.9)
19.4 (6.8)
17.1 (5.2)
15.7 (5.4)
PANSS negative
26.2 (7.9)
22.5 (5.7)
19.8 (5.0)
18.2 (5.8)
PANSS general
51.1 (11.5)
47.3 (9.1)
43.2 (9.9)
39.6 (11.1)
QLS CGI SCH – severity global score
58.3 (27.6) 4.2 (.8)
– 3.7 (.6)
– 3.2 (.9)
61.4 (20.2) 3.0 (.9)
f = 21.2 p < .0001 f = 10.0 p < .0001 f = 21.0 p < .0001 f = 16.0 p < .0001 Ns v2 39.4 p < .0001
Extrapyramidal side effects SA*
9 (6.4)
6.9 (5.8)
5.2 (4.7)
4.5 (4.6)
f = 9.7 p < .0000
Drug attitude DAI-30
)1.7 (13.4)
4.4 (13.7)
10.1 (9.8)
13.4 (9.5)
f = 13.7 p < .0001
Neuropsychological performance Verbal Memory
26.9 (9.3)
–
–
30 (7.9)
Letter fluency
29.6 (8)
–
–
32 (7.4)
Semantic Fluency
15 (4.2)
–
–
16.4 (4)
Working Memory
11 (5.5)
–
–
12.3 (4.7)
Selective attention
22 (11)
–
–
25.1 (11.4)
Planning
11.6 (5)
–
–
13.2 (4.6)
UPSA-B total
65 (19.9)
–
–
76.6 (18.3)
f = 14.6 p < .001 f = 5.8 p = .02 f = 5.2 p = .03 f = 6.2 p = .02 f = 13.3 p = 001 f = 9.7 p = .004 f = 19.0 p < .001
* Only patients with at least one SA positive item (n = 25).
3.1. Concordance in clinical judgement of response to risperidone and paliperidone CGI – Schizophrenia severity judgement at basal and final evaluations was significantly decreased over time (Friedman ANOVA v2 39.4 p < .0001) (Table 1). As for CGI – Schizophrenia improvement global score, 13.8% of patients had a non-concordant response to paliperidone, recorded as ‘worsened’ or ‘markedly worsened’ judgement, while 27% of patients had non-concordant response recorded as ‘much improved’ judgement. The remaining patients had a concordant response between risperidone and paliperidone, having ‘unchanged’ or only ‘slightly improved’ judgements.
3.2. Repeated measures analyses of clinical and tolerability variables As a first analysis, due to the possible changes in extrapyramidal side effects deriving from the switching from a relatively high dose of risperidone to an average dose of paliperidone, possibly influencing also the clinical changes, was conducted to assess changes in extrapyramidal symptoms.
ANOVA showed a statistically significant (f = 9.77; p < .0000) improvement of SA scale scores among patients showing at basal time any EPS sign (score >0 at any SA scores). No incident parkinsonism cases were found. As a consequence of results on SA all other parametric analyses were done using repeated measures MANCOVA with basal SA score as a covariate. Repeated measures MANCOVA showed a statistically significant improvement of PANSS total and subtotal scores (PANSS total f = 21.2, p < .0001; PANSS positive f = 10.06 p < .0001; PANSS negative f = 21.04, p < .0001; PANSS general psychopathology f = 16.02 p < .0001). No statistically significant change was observed at QLS scores. DAI-30 scores improved significantly across the 12 weeks evaluation (MANCOVA f = 13.69, p < .0001). All cognitive performances were statistically and significantly improved at the end of the study. In detail: verbal memory (MANCOVA f = 14.6, p < .001), word fluency (f = 5.8, p = .02), semantic fluency (f = 5.2, p = .03), working memory (f = 6.2, p = .02) selective attention (f = 13.3, p = 001) and planning/executive function (f = 9.78, p = .004). Effect size of change ranged from a minimum of .21 for selective attention
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N E U R O L O G Y, P S Y C H I AT R Y A N D B R A I N R E S E A R C H
to a maximum of .31 for semantic fluency. Also cognitivebased performance measured by means of UPSA-B improved significantly (MANCOVA f = 19.04, p = .0002). Table 1 shows in detail scores of each assessment at each evaluation performed.
4.
Discussion
The main result of our study is that paliperidone treatment of poor responders to risperidone led to discordant response in a clinically significant proportion of patients. In fact, after 12 weeks of treatment with paliperidone 13.8% of patients had a ‘worsened’ judgement and 27% of patients received a ‘much improved’ judgement at CGI-Schizophrenia total score. Moreover, in average, all clinical parameters measured, except QLS score, were statistically improved over 12 weeks after switching from risperidone to paliperidone. Data presented correspond to a observational naturalistic follow-up of patients treated ‘as usual’ in everyday clinical practice, and this is a clear limit, in fact most open switch studies show significant improvement after treatment with drug number 2. This may partially depend on the fact that, being ‘‘naturalistic’’, the switch is indicated because of a poor response to drug number 1, therefore allowing a greater percentage of improvements with drug number 2. However, in our study, the strength of the comparison of a same patient response after the treatment with the two drugs, rated by the same rater/clinician who gave the judgement of non-response to the first drug may compensate the open design limit and make the results more near to the naturalistic clinical results of everyday practice. The proportion of patients with a clearly (improved) discordant response to risperidone and paliperidone is of about one-fourth of the sample. This might be judged to have limited epidemiological relevance, being at the lower end of the range of ‘much improved’ CGI clinical judgements in medium term open design trials in recent literature, but points at a difference in clinical effects of the mother drug and its metabolite at individual level in a clinically relevant proportion of patients. Rather than showing a greater efficacy of paliperidone compared to risperidone, our results suggest different individual response profiles, thus pointing out possible different and specific clinical indication for the two drugs, that need to be better and further defined. Data analyzed with repeated measures support previous data of the two studies available17,18 with a average change at PANSS total score of about 23 points. This change describes, in average, a change from a PANSS score attributable to a markedly ill (acute) patient, to a moderately ill score of stabilized patients.26 It was also interesting to appreciate the clear, statistically significant improvement of extrapyramidal tolerability in patients who showed parkinsonian signs after risperidone, another sign of non-concordance between effects of the mother drug and of the metabolite at individual level. Nevertheless average doses of risperidone, before the switch to paliperidone were rather high, while the median daily dose of paliperidone was of 9 mg, considered a target medium daily dosage. All neuropsychological performances were statistically improved with size effects similar to those (limited) found
1 8 ( 20 1 2) 1 0 9–11 3
in literature,27,28 but the UPSA-B performance-based measurement of cognitive abilities showed a significant improvement in cognitive-based performances. No changes was observed at the QLS evaluation, but open observation, limited time lasting from the acute state and items of the abbreviated version of the QLS used (core items of deficit syndrome and functionality) might have been less sensitive to change, in comparison to literature using the full QLS. DAI 30 average scores were significantly improved through the study, a result somewhat confirming the results of the study of Canuso et al.,18 which had as primary outcome measure medication satisfaction measured by means of the Medication Satisfaction Questionnaire. DAI 30 and MSQ share the construct of the subjective judgement of effectiveness presented in different ways, and as previously reported18 both better tolerability and effectiveness might have converged in the subjective evaluation of the treatment satisfaction and then attitude to.
5.
Conclusions
In conclusion, this naturalistic observation suggests that paliperidone and his mother drug, risperidone may show differences in efficacy and tolerability at individual level. Reasons for this should be looked for at biological levels not necessarily involving the receptor affinity and pharmacological activity profile. Nevertheless these preliminary observations should be tested in a prospective double blind study with the same main objectives.
Acknowledgments This study was made possible by the clinical work of doctors Massimiliano Aleffi (Therapeutic Community ‘‘Centro Ippocrate’’, Cagliari, Italy), Paola Clemente (Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy), Valeria Magnolfi (Department of Psychiatry, S. Carlo Borromeo Hospital, Milano, Italy), Claudio Montresor (Department of Psychiatry, Luigi Sacco Hospital, Milano, Italy), Simona Palmieri (Department of Public Health, Section of Psychiatry, Avellino, Italy), Federica Pinna (Department of Psychiatry, University of Cagliari, Cagliari, Italy) and Mario Sammartano (Department of Public Health, Section of Psychiatry, Marsala, Italy), participating to the Master in Clinical Psychopharmacology of Vita-Salute San Raffaele University.
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