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Solian® in schizophrenia an overview

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1 Solian® in schizophrenia an overview

2 Mode of action

3 Solian’s D2-D3 selectivity is consistent with atypicality The dopamine cortico-subcortical imbalance in schizophrenia Positive symptoms attributable to • high dopamine release • overstimulated D2-receptors in limbic system Deficit symptoms attributable to • low dopamine release • understimulated D1-receptors in frontal cortex Solian® blocks D2-receptors does not block D1-receptors Weinberger DR. Arch Gen Psychiatry Davis KL, Kahn RS et al. Am J Psychiatry 1991

4 Solian® a pure D2-D3 antagonist alleviates positive symptoms
In limbic region postsynaptic: predominantly D2-D3 receptors blocked by Solian® -> less positive symptoms Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability Kapur S. in: “Dopamine in the pathophysiology of schizophrenia.” 2003

5 Solian® a pure D2-D3 antagonist alleviates negative symptoms also
In prefrontal region presynaptic: predominantly D2-D3 receptors -> feed-back blocked by Solian® -> enhanced dopamine release postsynaptic: predominantly D1 receptors D1 receptors are NOT blocked by Solian® net result: alleviating hypofrontality and negative symptoms Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability Kapur S. in: “Dopamine in the pathophysiology of schizophrenia.” 2003

6 Solian’s pure D2-D3 antagonism minimizes neuroreceptor mediated side-effects Antipsychotics receptors binding profile Receptor Subtype Receptor affinity Possible clinical effect Solian® olanzapine quetiapine risperidone clozapine haloperidol a-adrenergic receptors a1 a2 - ++ +++ + Hypotension, tachycardia, vertigo, sexual dysfunction serotonin 5HT2A 5HT2C Sedation, weight gain mAch M1-M2 Anticholinergic effects, cognitive deficit histamine H1 Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability Adapted from Duncan et al. 1989, Sunhara et al. 1991, Sokoloff et al. 1992, Bymaster et al. 1996, Schotte et al. 1996, Schoemaker et al package inserts

7 Efficacy

8 Few atypicals with proven superiority over conventionals Effect size versus conventional antipsychotics * a 0,25 effect size unit corresponds to 4-6 PANSS points or 3-4 BPRS points change meta-analysis of randomised efficacy trials: 10 atypical versus conventional antipsychotics 124 randomised controlled efficacy trials (n = schizophrenic patients) Davis JM et al. Arch Gen Psychiatry 2003

9 Efficacy: positive symptoms Effect size versus conventional antipsychotics
meta-analysis of 18 randomised controlled trials, schizophrenic patients Leucht S et al. Am J Psychiatry 2002

10 Acute exacerbation: comparable to risperidone Efficacy on PANSS positive items
-52% NS double blind randomised, non-inferiority trial t = 8 weeks, n = 228 acute exacerbations of schizophrenia DSM III R Peuskens J, Bech P, Möller HJ, Bale R et al. Psychiatry Research 1999

11 Responders rate compared to risperidone (in %)
65,3% 71,9% 76,9% responders = improvement ≥ 50% (PANSS, BPRS) or “much” to “very much” improved (GCI) n = 244 patients with chronic schizophrenia and a recent exacerbation Sechter D et al. Neuropsychopharmacol 2002

12 Acute exacerbation: at least as effective as olanzapine Efficacy on BPRS subscales
double blind randomised, non-inferiority trial, BPRS: primary endpoint t = 6 months, n = 377 acute exacerbations of schizophrenia DSM IV Mortimer A et al. Int Clin Psychopharmacol 2004

13 Efficacy: negative symptoms Effect size versus conventional antipsychotics
meta-analysis of 18 randomised controlled trials, schizophrenic patients Leucht S et al. Am J Psychiatry 2002

14 Improving the whole range of negative symptoms SANS subscores
49,5 43,6 39,9 29,0 43,0 40,9 randomised double blind multicenter versus placebo, n = 141 schizophrenic patients (DSM III R), with predominantly negative symptoms (SANS ≥ 60 and SAPS ≤ 50) Lôo H, Poirier MF, Théron M, Rein W, Fleurot O. Br J Psychiatry 1997

15 Efficacy: depression/anxiety subscore versus haloperidol and risperidone Reduction BPRS depression/anxiety subscore pooled results of 3 previously published randomised studies, n = 612 chronic or subchronic schizophrenia (DSM III R and IV), acute exacerbation, (disorganised, paranoid of undifferentiated type), t = weeks Peuskens J, Möller HJ, Puech A. Eur Neuropsychopharm Möller H, Boyer P, Fleurot O, Rein W. Psychopharmacol 1997 Puech A, Fleurot O, Rein W. Acta Psychiatr Scand Peuskens J, Bech P, Möller HJ et al. Psychiatry Res 1999

16 Quality of life versus risperidone Social and Occupational Functioning Assessment Scale (SOFAS)
49% double blind randomised, non-inferiority study n = 309 patients with chronic schizophrenia DSM IV, recent deterioration at entry Sechter D et al. Neuropsychopharmacol 2002

17 Tolerability

18 Low EPS profile (AIMS) -0,16 -0,9 NS
double blind randomised study, n = 310 acute exacerbations of schizophrenia DSM IV Sechter D et al. Neuropsychopharmacol 2002 double blind randomised study, n = 377 schizophrenic patients DSM IV Mortimer A et al. Int Clin Psychopharmacol 2004

19 High atypicality: effectiveness with minimal EPS Solian’s fast off-rate from the D2-receptor Time needed for 50% release from cloned D2-receptors1 • an effective attenuation of the tonic dopamine transmission -> antipsychotic efficacy • with less distortion of the bursts of the phasic physiological signalling2 -> minimal EPS Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability 1. Seeman P. Can J Psychiatry Kapur and Seeman Kapur S in “Dopamine in the pathophysiology of schizophrenia”. Ed: Kapur S, Lecrubier Y at Martin Dunitz Editions, UK 2003 ISBN

20 Solian® induces little weight gain Weight gain at 10 weeks
0,80 Allison DB, Mentore JL. Am J Psychiatry 1999, Taylor DM, McAskill R. Acta Psychiatr Scand 2000 Data for amisulpride: Leucht S, Wagenpfeil S et al. Psychopharmacol 2004

21 Clinically relevant weight gain versus risperidone and olanzapine
18% 20,6% double blind randomised study, n = 309 chronic schizophrenia DSM IV, t = 6 months Sechter D et al. Neuropsychopharmacol 2002 double blind randomised study, n = 377 schizophrenic patients DSM IV, t = 6 months Mortimer A et al. Int Clin Psychopharmacol 2004

22 Antipsychotic-induced diabetes mellitus
Emergence of new onset diabetes attributable to antipsychotic use multiple case reports1 - confirmed in a case control study2 Different antipsychotics unequally involved - confirmed in a prospective randomised double blind study3 No published report about a potential relation between Solian® and hyperglycemia or ketoacidosis4 as of May 2003, 650 million treatment days worldwide (IMS figures) prospective randomised double blind study n = 101, initially non-diabetic patients, hospitalised for antipsychotic treatment instauration 1. Consensus statement ADA, APA, AACE, NAASO. Diab Care Koro CE, Fedder DO et al. BMJ Lindenmayer JP, Czobor P et al. Am J Psychiatry Mir S,Taylor D. Int Clin Psychopharmacol 2001

23 Endocrine/sexual side effects Comparison with risperidone1
Prolactin elevation with Solian®2 • not dose dependent • decreases as treatment continues • returns to pretreatment levels within 3 months after treatment stop pooled data from 11 randomised clinical studies exposure: 125 days Solian®, 47 days risperidone 1. Coulouvrat C, Dondey-Nouvel L. Int Clin Psychopharmacol Schlösser R, Gründer G et al. Neuropsychobiology 2002

24 Pharmaco-economics

25 Shift to ambulatory care Solian® versus risperidone
risperidone 4-10 mg/d Total = 52,7 days of hospitalisation 10,4 42,3 full time hospitalisation part time hospitalisation Solian® mg/d Total = 41,9 days of hospitalisation 24,7 17,2 double blind randomised study n = 198 (at 6 months), patients with chronic schizophrenia DSM IV and a recent exacerbation Knapp M, Spiesser L, Jourdan S. Submitted for publication. Data from Sechter et al. Neuropsychopharmacol 2002

26 Posology instructions

27 Solian®: easy to start…
easy to switch to Without titration, immediately at therapeutic dose§ Start Solian® Without titration Former antipsychotic (conventional or atypical) Tapering off -> start Solian® at the therapeutic dose required - without titration§ -> taper off the old antipsychotic over a 3-4 week period* (by approximately 30-50% every 3-7 days)1 without washout period2 - previous concomitant anticholinergics should also be stopped progressively 1. Peuskens J. J Int Clin Psychopharmacol 2000, 15(4):S15-S Solian® Product Information, June § in patients with renal impairment dose should be adjusted according to Product Information *Slow tapering off the young, the elderly, recently relapsed, patients on clozapine, those previously treated with doses of low potency neuroleptics, patients difficult to stabilise

28 Solian®: easy to use Clear dosing1
Acute exacerbations Productive states Stabilisation Usual maintenance dose Chronic psychosis Predominantly negative symptoms 800 mg/day (BID) (to max 1200 mg/d) 400 mg/day (OD) 300 to 50 mg/day (OD) If positive symptoms reappear: increase dose to previous stabilizing level For acute psychotic episodes, doses should be adjusted according to individual response. For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms. Maintenance treatment should be established individually with the minimally effective dose. For patients characterized by predominant negative symptoms, oral doses between 300 and 50 mg / day are recommended. Doses should be adjusted individually. 1. Lecrubier Y et al. Neuropsychobiology 2001 and Peuskens J et al. Psy Res 1999

29 Pharmacokinetics Drug/drug interactions

30 Solian® is not metabolized via the CYP450 system
Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

31 Solian® is not metabolized via the CYP450 system (continued)
Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

32 Solian® at a glance Pure D2-D3 selectivity: a unique mode of action • restoring the dopamine imbalance in schizophrenia • minimising side-effects mediated by other neuroceptors A high limbic over striatal receptor affinity and a fast off-rate from the D2-receptor • explaining a low EPS level In general a high effect size on schizophrenia symptoms • one of the few atypicals with proven efficacy over conventionals In acute situations • fast onset of antipsychotic action involving the whole range of BPRS subscales • easy and clear posology instructions • easy manageable combination with benzodiazepines whenever necessary

33 Solian® at a glance In predominant negative symptoms
• acting on the whole range of negative symptoms • improving depression/anxiety without affecting cognition On the longer term • low weigth gain - low incidence of metabolic side-effects • low sexual / endocrine side effects in daily practice • respecting quality of life / facilitating socialisation • manageable drug-drug interactions Value for money • less hospitalisation days / shift towards ambulatory care • good therapy adherence

34 סוליאן בסל הבריאות 1.לחולה סכיזופרניה מעל גיל 18 שנים,ובהתקיים אחד מהתנאים האלה : א. החולה מוגדר כבעל קווי התנהגות תוקפניים,וכטיפול ראשון. ב. החולה לא הגיב לטיפול ב risperidone או פיתח תופעות לוואי קשות לטיפול האמור. 2. לחולה מתחת לגיל 18 שנים הסובל מסכיזופרניה או מפסיכוזה אחרת, וכטיפול ראשון.

35 סוליאן בקופות קופת חולים כללית – בהשתתפות 10% של המטופל
קופת חולים מכבי- בהשתתפות 15% של המטופל קופת חולים לאומית – השתתפות 15% של המטופל קופת חולים מאוחדת- בהשתתפות 15% של המטופל

36 תודה על ההקשבה


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