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Solian® in schizophrenia an overview

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1 Solian® in schizophrenia an overview
Scientific expert: Dr Philippe NUSS Saint Antoine Hospital, Paris

2 The information displayed in this program is provided for medical and scientific purposes only
Sanofi-Aventis does not recommend the use of Solian® in any manner inconsistent with that described in the full prescribing information available in your country

3 Content Schizophrenia: both positive & negative symptoms
Pure dopamine antagonism can assure atypicality Efficacy studies global evaluation scales positive and negative symptoms depression / anxiety subscales Respecting cognition quality of life / socialisation Tolerability of antipsychotics EPS weight gain and metabolic concerns sexual / endocrine side-effects Pharmaco-economics of new generation antipsychotics Dose titration and switching Pharmacokinetics and drug-drug interactions

4 Schizophrenia: course of symptoms
Short term 0-2 years Medium term 3-6 years Long term 7-22 years Positive symptoms frequent major clinical issue less fluctuations more stable decreasing Negative symptoms less frequent becoming more frequent predominant Concerns acute episodes affective changes • anxiety • depression quality of life rehabilitation Adapted from McGlashan TH, Fenton WS. Arch Gen Psychiatry 1992

5 Mode of action

6 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

7 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

8 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

9 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

10 Efficacy

11 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

12 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

13 Acute exacerbation: comparable to haloperidol Efficacy on PANSS positive items
-53% NS double blind randomised study t = 6 weeks, n = 191 acute exacerbations of schizophrenia DSM III R Möller HJ, Boyer P, Fleurot et al. Psychopharmacol 1997

14 Early onset responders* rate
Solian® mg/d (n=219) p = 0,003 p = 0,004 analysis of 2 double blind studies Burns T, Bale R. J Int Med Res 2001 (Analysis of 2 double blind studies: Puech et al. Acta Psychiatr Scand 1998 and Möller et al. Psychopharmacol 1997)

15 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

16 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

17 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

18 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

19 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

20 Efficacy: negative symptoms versus haloperidol (mean reduction PANSS negative) After 6 weeks of treatment After 1 year of treatment2 -37% -7,1 p = 0,038 p < 0,0001 double blind randomised study, t = 6 weeks n = 191 schizophrenic patients DSM III R 1. Möller HJ, Boyer P. Psychopharmacol 1997 randomised, open, follow-up study, t = 12 months n = 365 schizophrenic patients DSM III R 2. Colonna L, Saleem P. Psychopharmacol 2000

21 Efficacy: depression/anxiety symptoms 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

22 Cognitive improvement in patients with predominantly negative symptoms
177 105 9 8 Solian® 100 mg/d for 4 weeks, n = 19 (10 disorganised, 9 residual schizophrenia DSM III R), mean age 31,6 years - deficit syndrome (SANS > 65/125; SAPS < 30/125) Vaiva G, Thomas P, Llorca PM et al. Psych Res Neuroimaging 2002

23 Quality of life versus haloperidol Heinrich’s Scale
NS 1,12 4,88 2,77 5,41 open randomised study n = 488 patients with (sub)chronic schizophrenia DSM III R, acute exacerbation Colonna L, Saleem P et al. Int Clin Psychopharmacol 2000

24 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

25 Tolerability

26 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

27 Low risk of akathisia on the longer term Patients (in %) with signs of akathisia (Barnes Akathisia Scale) p < 0,0001 p = NS open randomised study n = 488 patients with (sub)chronic schizophrenia DSM III R, acute exacerbation, t = 12 months Colonna L, Saleem P et al. Int Clin Psychopharmacol 2000

28 High atypicality: effectiveness with minimal EPS Solian’s high limbic over striatal receptor affinity D2-D3 occupancy1 threshold for antipsychotic efficacy2,3 provoking EPS2,3 Tool: single photon emission tomography (SPET) after injection of [123I ] epidepride in 8 Solian-treated patients (mean dose = 406 mg/d) 1. Bressan RA, Erlandsson K et al. Am J Psychiatry Kapur S, Zipursky R et al. Am J Psychiatry 2000 3. Kapur S, Seeman P. Am J Psychiatry 2001

29 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

30 Solian® induces little weight gain Weight gain at 10 weeks (in kg)
0,80 Leucht S, Wagenpfeil S et al. Psychopharmacol 2004, integrating data from Allison DB, Mentore JL, et al. Am J Psychiatry 1999; Rak IW, Jones AM et al. Schizophrenia Res 2000 (for*) and Jody D, Saka AR et al. Int J Neuropsychopharmacol 2003 (for**)

31 Less clinically relevant weight gain versus risperidone and olanzapine Weight gain ≥ 7% from baseline p < 0,0004 p < 0,05 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

32 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

33 Blood glucose evolution
107 mg/dl double blind randomised, non-inferiority trial t = 6 months, n = 377 acute exacerbations of schizophrenia (DSM IV) Peuskens J et al. Int J Psychopharmacol 2004

34 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

35 Pharmaco-economics

36 Low withdrawal rate 7,2% 8,9% 10,7% 13,8% 8,1% 8,6%
premature treatment stop leads to relapse re-hospitalisation after relapse is the most important direct cost factor4 1. Colonna L et al. Int Clin Psychopharmacol Sechter D et al. Neuropsychopharmacol Mortimer A et al. Int Clin Psychopharmacol Smith K et al. Br J Psy 1995

37 Re-hospitalisations and hospital stays versus haloperidol
13,2 24,8 Solian®: Souêtre E et al. Encephale 1992 • on annual basis 11,4 hospitalisation days avoided (p < 0,04) • less concomitant medications (p < 0,001) • less need for second adjuvant antipsychotic (p < 0,001)

38 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

39 Posology instructions

40 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

41 Solian®: easy to use Clear dosing1
Acute exacerbations Positive symptoms Stabilisation Usual maintenance dose Chronic and predominantly negative psychosis 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

42 Solian®: clear dosing strategy Dose equivalence
usual maintenance dose maximum dose a day chlorpromazine mg/d 1 000 mg/d haloperidol mg/d 30 mg/d Solian® mg/d* 1 200 mg/d olanzapine mg/d 20 mg/d quetiapine mg/d 750 mg/d risperidone 4 - 6 mg/d 16 mg/d** * in predominantly negative symptoms: mg/d ** doses > 10 mg/day generally have not been shown to provide additional efficacy Scottish National Health Service Boards & Therapeutics Committees. The Lothian Joint Formulary Chapter 4.2: Drugs used in psychoses and related disorders.

43 Solian®: acute agitation Association with benzodiazepines
Background: - Agitation should be controlled in hours, full antipsychotic efficacy takes weeks or months. Unnecessary sedation is a barrier for optimal patient function and compliance.1 - Solian® is not a sedative agent Expert consensus guidelines1: 2 distinct needs: immediate sedation AND long-term antipsychotic effect 2 complementary solutions: benzodiazepine AND a non-sedating antipsychotic Conclusion: Sedation should not be achieved by increasing the dose of the antipsychotic, but by initial addition of a sedative agent such as a benzodiazepine.2 1. Allen MH et al. Postgrad Med Bridler R et al. Swiss Med Wkly 2003

44 BZD association with Solian® High therapeutic effect Low interaction profile
Effect of single doses Solian® and/or lorazepam on alertness Solian® did not potentiate or antagonise the effects of lorazepam n = 18 healthy volunteers, highly significant (p < 0,001) decrease for lorazepam at 2, 4 and 8 hours Perault MC, Bergougnan L et al. Hum Psychopharmacol Clin Exp 1998

45 Pharmacokinetics Drug/drug interactions

46 Pharmacokinetics of Solian® in healthy young volunteers
3 hours 54 ng/ml Tmax2 (median) ( mg oral) Cmax2 The two peaks merge to one if administered with food 1 hour 38 ng/ml Tmax1 (median) ( mg oral) Cmax1 Absorption No effect of food on bioavailability, except if a very high carbohydrate meal 43-48 % absolute bioavailability Bioavailability 16 % plasma protein bound fraction A relatively low plasma protein binding fraction -> distribution unlikely to be affected by physiological modifications or by concomitant administered drugs 5,8 l/kg volume of distribution Distribution No active metabolites. Only traces from the oxydation of the pyrolidin rings, N-deethylation and hydrogenation limited Metabolism 50 % excreted unchanged (after i.v. administration) 64 % total in faeces Two routes of excretion. The renal clearance may be reduced by age and by renal impairment • creatinin clearance ml/min: dose should be reduced to half • creatinin clearance ml/min: dose should be reduced to a third • creatinin clearance < 10 ml/min: experience lacking, so particular care is recommended in these patients 35 % total in urine Excretion 19 l/h plasma renal clearance 42 l/h plasma systemic clearance No modification of pharmacokinetic profile following repeated once daily administration reported 12 hours plasma elimination t1/2 (after oral administration) Elimination No interaction at CYT P4501, no interactions with lorazepam2 or lithium3 1. Gillet G et al. Eur Neuropsychopharmacol Perault MC et al. Hum Psychopharmacol Clin Exp Canal M et al. Int J Neuropsychopharmacol 2003

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

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

49 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 • as effective as haloperidol or atypical antipsychotics in acute positive symptoms • easy and clear posology instructions • easy manageable combination with benzodiazepines whenever necessary In predominantly negative symptoms • acting on the whole range of negative symptoms • improving depression/anxiety without affecting cognition On the longer term • low weight 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

50 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

51 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


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