Solian Slide Kit

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

4
Schizophrenia course of symptoms
Adapted from McGlashan TH, Fenton WS. Arch Gen
Psychiatry 1992
5
Mode of action
6
Solians D2-D3 selectivity is consistent with
atypicalityThe 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
Weinberger DR. Arch Gen Psychiatry 1987 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 -gt 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 -gt feed-back blocked by
Solian -gt 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
Solians pure D2-D3 antagonismminimizes
neuroreceptor mediated side-effectsAntipsychotic
s receptors binding profile
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. 1997
package inserts
10
Efficacy
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Few atypicals with proven superiority over
conventionalsEffect 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 18 272
schizophrenic patients) Davis JM et al. Arch Gen
Psychiatry 2003
12
Efficacy positive symptomsEffect 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
haloperidolEfficacy on PANSS positive items
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
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Early onset responders rate
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
risperidoneEfficacy on PANSS positive items
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 )
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
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Acute exacerbation at least as effective as
olanzapineEfficacy 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 symptomsEffect 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
symptomsSANS subscores
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
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Efficacy negative symptoms versus
haloperidol(mean reduction PANSS
negative)After 6 weeks of treatment1 After
1 year of treatment2
21
Efficacy depression/anxiety symptomsversus
haloperidol and risperidoneReduction 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 4 - 8 weeks Peuskens
J, Möller HJ, Puech A. Eur Neuropsychopharm 2002
Möller H, Boyer P, Fleurot O, Rein W.
Psychopharmacol 1997 Puech A, Fleurot O, Rein W.
Acta Psychiatr Scand 1998 Peuskens J, Bech P,
Möller HJ et al. Psychiatry Res 1999
22
Cognitive improvement in patients with
predominantly negative symptoms
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
gt 65/125 SAPS lt 30/125) Vaiva G, Thomas P,
Llorca PM et al. Psych Res Neuroimaging 2002
23
Quality of lifeversus haloperidolHeinrichs
Scale
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 lifeversus risperidoneSocial and
Occupational Functioning Assessment Scale (SOFAS)
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)
27
Low risk of akathisia on the longer
termPatients (in ) with signs of akathisia
(Barnes Akathisia Scale)
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
EPSSolians high limbic over striatal receptor
affinityD2-D3 occupancy1
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
2003 2. 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
EPSSolians fast off-rate from the D2
receptorTime needed for 50 release from cloned
D2 receptors1
an effective attenuation of the tonic dopamine
transmission -gt antipsychotic efficacy
with less distortion of the bursts of the
phasic physiological signalling2 -gt minimal EPS
Differences in pharmacological activities do not
necessarily imply difference in
efficacy/tolerability 1. Seeman P. Can J
Psychiatry 2002. 2. Kapur and Seeman 2001 Kapur
S in Dopamine in the pathophysiology of
schizophrenia. Ed Kapur S, Lecrubier Y at
Martin Dunitz Editions, UK 2003 ISBN 1 84184 366 0
30
Solian induces little weight gainWeight gain
at 10 weeks (in kg)
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 olanzapineWeight gain 7 from
baseline
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 studyn
101, initially non-diabetic patients,
hospitalised for antipsychotic treatment
instauration 1. Consensus statement ADA, APA,
AACE, NAASO. Diab Care 2004 2. Koro CE, Fedder
DO et al. BMJ 2002 3. Lindenmayer JP, Czobor P
et al. Am J Psychiatry 2003 4. Mir S,Taylor D.
Int Clin Psychopharmacol 2001
33
Blood glucose evolution
double blind randomised, non-inferiority trialt
6 months, n 377 acute exacerbations of
schizophrenia (DSM IV) Peuskens J et al. Int J
Psychopharmacol 2004
34
Endocrine/sexual side effectsComparison with
risperidone1
pooled data from 11 randomised clinical
studiesexposure 125 days Solian, 47 days
risperidone 1. Coulouvrat C, Dondey-Nouvel L. Int
Clin Psychopharmacol 1999 2. Schlösser R,
Gründer G et al. Neuropsychobiology 2002
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Pharmaco-economics
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Low withdrawal rate
premature treatment stop leads to
relapsere-hospitalisation after relapse is the
most important direct cost factor4 1. Colonna L
et al. Int Clin Psychopharmacol 2000 2. Sechter
D et al. Neuropsychopharmacol 2002 3. Mortimer
A et al. Int Clin Psychopharmacol 2004 4. Smith
K et al. Br J Psy 1995
37
Re-hospitalisations and hospital staysversus
haloperidol
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Shift to ambulatory careSolian versus
risperidone
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
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Posology instructions
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Solian easy to start
easy to switch to
Without titration, immediately at therapeutic
dose

• -gt start Solian
• at the therapeutic dose required
• - without titration

• -gt 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-S19 2. Solian Product Information,
June 2001 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 useClear dosing1
Acute exacerbations Positive symptoms Stabilisati
on 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 strategyDose equivalence
in predominantly negative symptoms 300 - 50
mg/d doses gt 10 mg/day generally have not been
shown to provide additional efficacy
Scottish National Health Service Boards
Therapeutics Committees. The Lothian Joint
Formulary 2003. Chapter 4.2 Drugs used in
psychoses and related disorders.
43
Solian acute agitationAssociation 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

1. Allen MH et al. Postgrad Med 2001 2. Bridler
R et al. Swiss Med Wkly 2003
44
BZD association with SolianHigh therapeutic
effect Low interaction profile
Effect of single doses Solian and/or lorazepam
on alertness
Solian did not potentiate or antagonise the
effects of lorazepamn 18 healthy volunteers,
highly significant (p lt 0,001) decrease for
lorazepam at 2, 4 and 8 hours Perault MC,
Bergougnan L et al. Hum Psychopharmacol Clin Exp
1998
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Pharmacokinetics Drug/drug interactions
46
Pharmacokinetics of Solianin healthy young
volunteers
No interaction at CYT P4501, no interactions with
lorazepam2 or lithium3
1. Gillet G et al. Eur Neuropsychopharmacol 2000
2. Perault MC et al. Hum Psychopharmacol Clin
Exp 1998 3. 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

50
Solian a pure D2-D3 antagonist alleviates
positive symptoms
In limbic region postsynaptic predominantly
D2-D3 receptors blocked by Solian -gt 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 -gt feed-back blocked by
Solian -gt 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