Solian ® in schizophrenia an overview. Mode of action.

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Solian ® in schizophrenia an overview

Transcript of Solian ® in schizophrenia an overview. Mode of action.

Page 1: Solian ® in schizophrenia an overview. Mode of action.

Solian® in schizophreniaan overview

Page 2: Solian ® in schizophrenia an overview. Mode of action.

Mode of action

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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 1987 Davis KL, Kahn RS et al. Am J Psychiatry 1991

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Solian® a pure D2-D3 antagonist alleviates positive symptoms

QuickTime™ and aAnimation decompressor

are needed to see this picture.

Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability

Kapur S. in: “Dopamine in the pathophysiology of schizophrenia.” 2003

In limbic region postsynaptic: predominantly D2-D3 receptors blocked by Solian® -> less positive symptoms

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Solian® a pure D2-D3 antagonist alleviates negative symptoms also

QuickTime™ and aAnimation decompressor

are needed to see this picture.

Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability

Kapur S. in: “Dopamine in the pathophysiology of schizophrenia.” 2003

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

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Solian’s pure D2-D3 antagonismminimizes neuroreceptor mediated side-effects

Antipsychotics receptors binding profile

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

Receptor Subtype Receptor affinity Possible clinical effect

Solian® olanzapine quetiapine risperidone clozapine haloperidol

-adrenergic receptors

1

2

-

-

++

-

+++

+

+++

+++

+++

++

+++

-

Hypotension, tachycardia, vertigo, sexual dysfunction

serotonin 5HT2A

5HT2C

-

-

+++

++

+++

+++

+++

+++

+++

++

++

-

Sedation, weight gain

mAch M1-M2 - ++ - - ++ - Anticholinergic effects, cognitive deficit

histamine H1 - +++ ++ +++ +++ - Sedation, weight gain

Differences in pharmacological activities do not necessarily imply difference in efficacy/tolerability

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Efficacy

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Few atypicals with proven superiority over conventionals

Effect size versus conventional antipsychotics

meta-analysis of randomised efficacy trials: 10 atypical versus conventional antipsychotics124 randomised controlled efficacy trials (n = 18 272 schizophrenic patients)

Davis JM et al. Arch Gen Psychiatry 2003

* a 0,25 effect size unit corresponds to 4-6 PANSS points or 3-4 BPRS points change

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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

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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

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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

65,3%71,9%

76,9%

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Acute exacerbation: at least as effective as olanzapine

Efficacy on BPRS subscales

double blind randomised, non-inferiority trial, BPRS: primary endpointt = 6 months, n = 377 acute exacerbations of schizophrenia DSM IV

Mortimer A et al. Int Clin Psychopharmacol 2004

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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

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Improving the whole range of negative symptoms

SANS subscores

randomised double blind multicenter versus placebo, n = 141 schizophrenicpatients (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

49,5

43,639,9

29,0

43,0 40,9

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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 = 4 - 8 weeksPeuskens J, Möller HJ, Puech A. Eur Neuropsychopharm 2002 Möller H, Boyer P, Fleurot O, Rein W. Psychopharmacol 1997Puech A, Fleurot O, Rein W. Acta Psychiatr Scand 1998 Peuskens J, Bech P, Möller HJ et al. Psychiatry Res 1999

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Quality of lifeversus risperidone

Social and Occupational Functioning Assessment Scale (SOFAS)

double blind randomised, non-inferiority studyn = 309 patients with chronic schizophrenia DSM IV, recent deterioration at entry

Sechter D et al. Neuropsychopharmacol 2002

p = 0,033

49%

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Tolerability

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Low EPS profile (AIMS)

double blind randomised study, n = 310 acute exacerbationsof schizophrenia DSM IV

Sechter D et al. Neuropsychopharmacol 2002

double blind randomised study, n = 377schizophrenic patients DSM IV

Mortimer A et al. Int Clin Psychopharmacol 2004

-0,16NS

-0,9NS

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High atypicality: effectiveness with minimal EPS

Solian’s fast off-rate from the D2-receptor

Time needed for 50% release from cloned D2-receptors1

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

• an effective attenuation of the tonic dopamine transmission -> antipsychotic efficacy

• with less distortion of the bursts of the phasic physiological signalling2 -> minimal EPS

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Solian® induces little weight gain

Weight gain at 10 weeks

Allison DB, Mentore JL. Am J Psychiatry 1999, Taylor DM, McAskill R. Acta Psychiatr Scand 2000Data for amisulpride: Leucht S, Wagenpfeil S et al. Psychopharmacol 2004

0,80

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Clinically relevant weight gain versus risperidone and olanzapine

double blind randomised study, n = 309 chronicschizophrenia DSM IV, t = 6 months

Sechter D et al. Neuropsychopharmacol 2002

double blind randomised study, n = 377schizophrenic patients DSM IV, t = 6 months

Mortimer A et al. Int Clin Psychopharmacol 2004

p < 0,0004p < 0,05

18%20,6%

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Antipsychotic-induced diabetes mellitus

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

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)

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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 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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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

Solian® 400-1000 mg/dTotal = 41,9 daysof hospitalisation

24,7 17,2

risperidone 4-10 mg/d Total = 52,7 days of hospitalisation

10,442,3

full time hospitalisation

part time hospitalisation

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Posology instructions

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Former antipsychotic(conventional or atypical)

Tapering off

Solian®: easy to start…easy to switch to

Start Solian®

Without titration

-> 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-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

Without titration, immediately at therapeutic dose§

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Solian®: easy to useClear dosing1

Acute exacerbationsProductive states

StabilisationUsual maintenance dose

Chronic psychosisPredominantly 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

1. Lecrubier Y et al. Neuropsychobiology 2001 and Peuskens J et al. Psy Res 1999

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.

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Pharmacokinetics Drug/drug interactions

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Solian® is not metabolized via the CYP450 system

Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

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Solian® is not metabolized via the CYP450 system (continued)

Gillet et al. Neuropsychopharm 10/2000,S331-S332 Package Inserts

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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

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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

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סוליאן בסל הבריאות

שנים,ובהתקיים אחד מהתנאים 18.לחולה סכיזופרניה מעל גיל 1האלה :

וכטיפול ראשון. א. החולה מוגדר כבעל קווי התנהגות תוקפניים,

או פיתח תופעות לוואי risperidone ב. החולה לא הגיב לטיפול ב קשות

לטיפול האמור.

שנים הסובל מסכיזופרניה או מפסיכוזה 18. לחולה מתחת לגיל 2אחרת,

וכטיפול ראשון.

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סוליאן בקופות

של המטופל10%קופת חולים כללית – בהשתתפות

של המטופל15%קופת חולים מכבי- בהשתתפות

של המטופל15%קופת חולים לאומית – השתתפות

של המטופל15%קופת חולים מאוחדת- בהשתתפות

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