Zeldox

1
Zeldox

• First Line in Schizophreniaand Bipolar Mania

2
Contents

• General considerations
• Ziprasidone Receptor profile
• Zeldox in Schizophrenia
• Zeldox in Bipolar Mania
• Pharmacokinetics and Dosing
• Switching to Zeldox

3
General considerations
4
Aetiology neuropathology of schizophrenia
current understanding

• Multiple genetic loci may be involved1
• Life events may be associated with onset2
• Biochemical theories dopamine and glutamate
  hypotheses3,4
• Aberrations in cerebral structure identified5
• Neurodevelopmental hypothesis genetic and
  environmental factors interact to affect brain
  development with psychosis emerging in early
  adulthood6
• Recent neuroimaging studies demonstrate a
  progressive component6
• Effective treatment at first onset may improve
  outcomes7

• McDonald C, Murphy KC. Psychiatr Clin North Am.
  200326(1)41-63.
• Castine MR. et al. J Psychiatr Res.
  199832(5)283-8.
• Seeman P. Synapse. 19871(2)133-52.
• Goff DC, Coyle JT. Am J Psych. 2001158(9)1367-77
  .
• Lawrie SM, Abukmei SS. Br J Psych.
  1998172110-20.
• Jarskog LF. et al. Ann Rev Med. 20075849-61.
• Lieberman JA. J Clin Psych. 199960 Suppl129-12.

5
Schizophrenia opportunities for earlier
intervention
Timeline of Patient Presentations
Progression of symptoms
Functional decline begins
Behavioural changes and incipient delusions
0 months
44 months
12 months
25 months
7 months
Onset of experiential changes
First wave of presentation
Second wave of presentation
Schizophrenia diagnosis
Schizotaxia period
Adapted from Bota RG, et al. CNS Spectr.
200510(12)937-42.
6
Neurophysiology of schizophrenia dopamine
pathways
a) Nigrostriatal system gt movement
control b) Mesolimbic system gt positive
symptoms of psychosis c) Mesocortical system
gt negative/cognitive symptoms of
psychosis d) Tuberoinfundibular system
gt prolactin secretion
Basal Ganglia
a
c
Nucl. accumbens
b
Substantia nigra
Hypothalamus
d
Tegmentum
Adapted from Stahl SM. Essential
psychopharmacology. Cambridge University Press
20002nd edn375.
7
Major serotonergic pathways
Neocortex Anxiolytic andantidepressant effects
Basal ganglia Control movements (akathisia,
agitation) and relief obsessive-compulsive
behavior
Raphe Nucleus
Hypothalamus Regulates/dampen appetiteand eating
behavior
Limbic system Involved in agitation, anxiety and
panic reactions
Brainstem Regulates sleep and dampen sexual
response
Adapted from Stahl SM. Essential
psychopharmacology neuroscientific basis and
practical application. Cambridge University Press
20002nd edn182.
8
Actions of antipsychotic agents
Stahl SM. Essential Psychopharmacology.
2000402-406, 414-24.
9
Factors that influence patient compliance to
medication
Treatment-Related Factors
Patient-Related Factors
Side effects Route of administration Pattern of
dosing Length of treatment Costs of
treatment Polypharmacy
Psychopathology Cognitive impairment Age Co-morbid
ity Gender
COMPLIANCE
Physician-Related Factors
Environment-Related Factors
Following accepted treatment guidelines Belief in
treatment Doctor-patient relationship Aftercare
management Provision of information
Social support Financial support Attitude toward
treatment Supervision of treatment Social rank of
illness Location of treatment provision
Adapted from Fleischhacker WW, et al. J Clin
Psychiatry. 200364 Suppl 1610-3.
10
Zeldox Receptor profile
11
Ziprasidone a distinct receptor profile Relative
receptor binding affinities of atypical
antipsychotics
Clozapine
Risperidone
Ziprasidone
H1
D1
D2
D1
D2
5-HT1A
H1
?1
D2
?1
5-HT1A
5-HT1D
5-HT2C
5-HT1D
H1
5-HT2C
5-HT1D
5-HT2A
5-HT2C
5-HT2A
5-HT2A
?1
Olanzapine
Quetiapine
Aripiprazole
?1
D1
D2
5-HT2C
D1
5-HT1A
D2
H1
5-HT1A
5-HT2A
H1
5-HT1D
5-HT2A
5-HT1A
5-HT2A
?1
?1
H1
5-HT2C
D2
Farah A. Primary Care Companion J Clin
Psychiatry. 20057268-74.
12
Ziprasidone potential clinical implications of
receptor profile
Treatment of Positive and Negative Symptoms1
with the Highest 5HT2A/D2 Receptor Affinity
Ratio in Class2

• Agonist of 5-HT1A receptors for relief of
  anxiety and depression2,4

D2
5-HT1A

• Antagonist of 5-HT2C receptors for predicted
  cognitive improvements2

5-HT2C

• Low affinity for H1 receptors for low sedation
  and weight gain3,4

Relative Receptor Affinity6

• 5-HT/noradrenaline (NA) reuptake inhibition -
  unique amongst atypical antipsychotics - for
  possible antidepressive action2,5

5-HT2A
5-HT1D
?1

• Negligible affinity for M1 muscarinic receptors
  - low propensity for cognitive impairment3

H1
Measured in vitro
1. Daniel DG, et al. Neuropsychopharmacology.
199920491-505. 2. Stahl SM, Shayegan DK. J Clin
Psychiatry. 200364 Suppl 19S6-12. 3. Finkel S.
J Am Geriatr Soc. 2004 Dec52 Suppl 12S258-65.
4. Shayegan DK, Stahl SM. CNS Spectr. 2004
Oct96-14. 5. Schmidt AW, et al. Eur J
Pharmacol. 2001 Aug 17425(3)197-201. 6. Farah
A. Primary Care Companion J Clin Psychiatry.
20057268-74.
13
Zeldox in Schizophrenia
14
Ziprasidone vs placebo (6-week study)

• Objective

• Evaluate efficacy, safety, and tolerability of
  ziprasidone in schizophrenia and schizoaffective
  disorder

• Design

• Double-blind, short-term (6-week), fixed-dose,
  placebo-controlled, multicentre study
• Patients were hospitalised with acute
  exacerbation of chronic or subchronic
  schizophrenia or schizoaffective disorder
• All patients had a minimum duration of disease of
  6 months and had been hospitalised within the
  previous 4 weeks

• Patients were randomised to receive

• Placebo (N92)
• Ziprasidone 80mg/day (given as 40mg BID) (N106)
• Ziprasidone 160mg/day (given as 80mg BID) (N104)

• 80mg/day for Days 1 and 2, then 160mg/day for
  remainder of study

• Efficacy measures

• PANSS total score, PANSS negative subscale score,
  BPRSd total score, BPRSd core items score,
  CGI-S, and CGI-I

Daniel DG, et al. Neuropsychopharmacology.
199920491-505.
15
Efficacy in overall psychopathologysignificant
improvement as early as week 1 Ziprasidone vs
placebo (6-week study)
PANSS Total Score
0
-5



Improvement
Mean Change from Baseline (LOCF)

-10



-15




-20
0
1
2
3
4
5
6
Weeks
PANSS Positive and Negative Syndrome Scale.
LOCF Last Observation Carried Forward.
Plt0.05, Plt0.001 vs placebo
Daniel DG, et al. Neuropsychopharmacology.
199920491-505.
16
Significant symptom improvement as early as week
1 Ziprasidone vs placebo (6-week study)
BPRSd Core Items Score
Ziprasidone 80mg/day (N104)




Improvement
Mean Change from Baseline (LOCF)







0
1
2
3
4
5
6
Weeks
BPRSd Brief Psychiatric Rating Scale Core Items
Score. LOCF Last Observation Carried Forward.
Plt0.05, Plt0.001 vs placebo
Daniel DG, et al. Neuropsychopharmacology.
199920491-505.
17
Efficacy in negative symptomssignificant
improvement as early as week 1 Ziprasidone vs
placebo (6-week study)
PANSS Negative Subscale Score
Ziprasidone 80 mg/day (N104)


Improvement
Mean Change from Baseline (LOCF)









0
1
2
3
4
5
6
Weeks
PANSS Positive and Negative Syndrome Scale.
LOCF Last Observation Carried Forward.
Plt0.05, Plt0.001 vs placebo
Daniel DG, et al. Neuropsychopharmacology.
199920491-505.
18
Efficacy in depressive symptomssignificant
improvement at 160mg/day Ziprasidone vs placebo
(6-week study)
Patients with a Baseline MADRS Score 14
0
-1
-2
-3
-2.9
-3.1
-4
Change in MADRS Score from Baseline
-5
Placebo (N54)
-6
-7
-7.5
-8
Week 6

MADRS Montgomery Åsberg Depression Rating
Scale Plt0.05 vs placebo. Associated with
schizophrenia
Daniel DG, et al. Neuropsychopharmacology.
199920491-505.
19
Efficacy in symptoms of cognitive
impairment Significant improvement by week
1 Ziprasidone vs placebo (6-week study)
PANSS Cognition Subscale
0

-1


-2



Improvement
Change from Baseline
-3



Placebo (N91)

-4
-5
0
1
2
3
4
5
6
Weeks
PANSS Positive and Negative Syndrome Scale.
Plt0.05, Plt0.01 vs baseline.
Pfizer Inc., Data on file.
20
Relapse can have serious consequences !
Kane JM. CNS Spectr. 20071210(Suppl 17)21-6.
21
Ziprasidone vs placebo (ZEUS 1-year relapse
prevention study)

• Objective

• Prospective evaluation of

• The efficacy of ziprasidone in the prevention of
  relapse in patients with stable, chronic
  schizophrenia

• Design

• Double-blind, parallel group, placebo controlled,
  randomised
• 294 inpatients with chronic schizophrenia
• Patients were assigned fixed daily doses of
  ziprasidone 40mg, 80mg, or 160mg/day, or placebo
  for 1 year
• Patients were immediately withdrawn if they met
  criteria for impending relapse

• Patients assigned to 160mg/day were given
  80mg/day for 2 days, then 160mg/day for the
  remainder of the study

• Primary efficacy measures

• Time to impending relapse

Arato M, et al. Int Clin Psychopharmacol.
200217207-15.
22
Long-term efficacy in overall psychopathology red
uced rate of relapse ziprasidone vs placebo
(ZEUS 1-year relapse prevention study)
Placebo (N71)Ziprasidone 40mg/day
(N71) Ziprasidone 80mg/day (N68) Ziprasidone
160mg/day (N67)



Proportion Free of Impending Relapse
0
10
20
30
40
50
52
Weeks
Plt0.01, Plt0.001 vs placebo at 1 year.
Overall log-rank P value0.0001.
Arato M, et al. Int Clin Psychopharmacol.
200217207-15.
23
MOZART ziprasidone vs clozapine in
treatment-resistant/intolerant schizophrenia 18-we
ek double-blind study

• Double-blind, multicentre comparison of the
  efficacy and tolerability of ziprasidone vs
  clozapine in schizophrenic patients resistant
  and/or intolerant to antipsychotic therapy

Sacchetti E, et al. Presented at the 159th
American Psychiatric Association Annual Meeting.
2006 May 20-25 Toronto, Canada poster.
24
MOZART overall psychopathology and severity of
illness 18-week double-blind study
Primary Outcome Mean Change in PANSS Total
Score (LOCF)
Primary Outcome Mean Change in CGI-S Score
(LOCF)
120
6
110
5.5
100
Mean Score
Mean Score
5
90
4.5
80
70
4
0
2
4
6
8
10
12
14
16
18
0
2
4
6
8
10
12
14
16
18
Study Week
Study Week
PANSS Positive and Negative Syndrome Scale.
CGI-S Clinical Global Impression of Severity.
LOCF Last Observation Carried Forward.
Sacchetti E, et al. Presented at the 159th
American Psychiatric Association Annual Meeting.
2006 May 20-25 Toronto, Canada poster..
25
Ziprasidone vs clozapine PANSS responder
rates 18-week double-blind study

97.8
100
90
77.8
80
67.6
70
54.8
60
PANSS Responders ()
50
40
30
20
N45
N45
N71
N73
10
0
ITT-Completers (OC)
ITT-LOCF
PANSS Positive and Negative Syndrome Scale. ITT
Intent-to-treat. Baseline-to-end point
reduction in PANSS total score 20. Baseline
values were 108.5 for ziprasidone and 106.6 for
clozapine. Observed cases. Plt0.007. vs
clozapine
Sacchetti E, et al. Presented at the 159th
American Psychiatric Association Annual Meeting.
2006 May 20-25 Toronto, Canada poster..
26
Ziprasidone vs Clozapine comparable or greater
improvements in cognition 18-week randomised,
double-blind study
Trail Making Test Parts A and B
180
160
ziprasidone Trails B
140
clozapine Trails B
120
100
Mean Time to Completion (sec)
80
60
ziprasidone Trails A
clozapine Trails A
40
20
0
Baseline
Week 12
Week 18
Note. Observed cases only unadjusted means
Harvey PD, et al. Schizophrenia Res. 2007.
(doi10.1016/j.schres.2007.11.014).
27
Low discontinuation rates vs placebo Ziprasidone
vs placebo (1-year study)
Discontinued Due to Adverse Event
50
40
30
Patients ()
20
15
10
10
7
10
0
placebo (N71)
ziprasidone 40mg/day (N72)
ziprasidone160mg/day (N67)
ziprasidone80mg/day (N68)
Arato M, et al. Int Clin Psychopharmacol.
200217(5)207-15.
28
Metabolic Effects
29
Metabolic adverse events
Risk factors and monitoring recommendations

• Risk factors for cardiovascular disease are more
  common in people with schizophrenia than in the
  general population and may be compounded by some
  atypicals, including

• weight gain/obesity
• diabetes
• dyslipidaemia

• Patients should be monitored at baseline and
  regularly thereafter for possible metabolic side
  effects of atypical antipsychotics
• Consider switching medication if it is causing
  excessive weight gain, diabetes or other
  metabolic side effects

De Hert M.et al. Int Clin Psychopharmacol 200621
Suppl2S11-5. American Diabetes Association.
Diabetes Care. 200427596-601. Tschoner A, et
al. Int J Clin Pract. 2007611356-70.
30
Estimated weight gain after 10 weeks of
antipsychotic therapy Meta-analysis of published
data
Placebo
6
Conventional antipsychotics
Novel antipsychotics
5
Non-pharmacologic control
4
3
2
95 Confidence Interval for Weight Change (kg)
1
0
-1
-2
-3
Placebo
Clozapine
Molindone
Ziprasidone
Haloperidol
Thioridazine/Mezoridazine
Olanzapine
Fluphenazine
Risperidone
Polypharmacy
Sertindole
Chlorpromazine
Non-pharmacologic control
Allison DB, et al. Am J Psychiatry.
19991561686-96.
31
One-year weight gain while on antipsychotic
treatment Review of long-term clinical trials
Mean Change from Baseline Weight
14
14
olanzapine (12.517.5mg) olanzapine (all
doses) quetiapine risperidone ziprasidone aripipra
zole
12
12
10
10
8
8
Change from baseline weight (kg)
6
6
4
4
2
2
0
0
52
48
44
40
36
32
28
24
20
16
12
8
4
0
0
Weeks
Casey DE. Am J Med. 2005118(suppl 2)S15-22.
32
Ziprasidone the only atypical associated with
improvement in 4 metabolic parameters in the
CATIE study CATIE Phase I
Change in Metabolic Parameters in Phase I of CATIE
Glycosylated haemoglobin levels
Weight change
9.4
10
10
7.5
7.5
5
5
0.41
2.5
IMPROVEMENT
2.5
IMPROVEMENT
0.10
Mean change in glycosylated hemoglobin () from
baseline
0.08
Mean change in weight (lb) from baseline
0.8
1.1
0.05
0
0
-2.5
-2.5
-0.10
-1.6
-2.0
-5
-5
-7.5
-7.5
Cholesterol levels
Triglycerides
12
48
9.7
42.9
9
36
5.3
6
24
19.2
3
IMPROVEMENT
8.3
Mean change in cholesterol (mg/dL) from baseline
12
IMPROVEMENT
0.5
Mean change in triglyceride (mg/dL) from baseline
0
0
-3
-2.6
-12
-2.1
-6
-24
-18.1
-9
-36
-9.2
ziprasidone
risperidone
quetiapine
olanzapine
perphenazine
At baseline, gt40 of patients met the criteria
for metabolic syndrome, an important risk factor
for cardiovascular disease.
Lieberman JA, et al. N Engl J Med.
2005353(12)1209-23.
33
Favorable metabolic profile of ziprasidone
ADA/APA consensus statement
The Risk of Obesity, Diabetes, and Dyslipidaemia
Differs Among Second-Generation Antipsychotics
(SGAs)

• Consideration of metabolic risk when starting
  SGA
• If a patient gains 5 of his or her initial
  weight during therapy, one should consider
  switching the SGA
• If a patient develops worsening glycaemia or
  dyslipidaemia while on antipsychotic therapy,
  consider switching to an SGA that is not
  associated with weight gain or diabetes

Increased effect - No effect D
Discrepant results.
American Diabetes Association. Diabetes Care.
200427(2)596-601.
34
ADA/APA consensus statement on atypical therapy
monitoring protocol
More frequent assessments may be warranted based
on clinical status.
American Diabetes Association. Diabetes Care.
200427596-601.
35
Zeldox in Bipolar Mania
36
Response rates in acute bipolar mania Ziprasidone
in acute mania 3-week studies
Keck et al. 20031
Potkin et al. 20052
ziprasidone
placebo
60


50
50
46
40
35
Patients ()
Patients ()
29
30
20
10
N125
N137
N65
N64
0
Response defined as 50 improvement in Manie
Rating Scale (MRS) score at endpoint. Plt0.05 vs
placebo.
1. Keck PE, et al. Am J Psychiatry.
2003160(4)741-8. 2. Potkin S, et al. J Clin
Psychopharmacol. 200525(4)301-10.
37
Improvement in acute bipolar mania Study I Keck
et al 2003
Change in MRS Score
ziprasidone (N131)
placebo (N66)
Mean Change in MRS Scores from Baseline





0
2
4
7
14
21
Day
MRS Mania Rating Scale. LOCF Last Observation
Carried Forward. Baseline scores placebo, 26.7
ziprasidone, 27.0. Plt0.003 Plt0.001 vs placebo.
Keck PE, et al. Am J Psychiatry.
2003160(4)741-8.
38
Improvements in acute bipolar mania Study II
Potkin et al 2005 - replication study
Change in MRS Score From Baseline
0
ziprasidone (N135)
-2
placebo (N62)
-4
-6
Mean Change in MRS Scores from Baseline

-8
-10

-12


-14
0
2
4
7
14
21
Day
MRS Mania rating scale. Baseline values mania
rating scale Placebo, 26.42 ziprasidone,
26.19 or early discontinuation Mean dose
ziprasidone day 15-21 126.5mg/day Plt0.05 vs
placebo P0.01 vs placebo.
Potkin S, et al. J Clin Psychopharmacol.
200525(4)301-10.
39
Improvement in severity in acute bipolar
mania Study II Potkin et al 2005 - replication
study
Change in CGI-S Scores
ziprasidone (N137)
placebo (N65)

Change in CGI-S Score (LOCF)




Day
CGI-S Clinical Global Impression of Severity
LOCF Last Observation Carried Forward. Mean
dose ziprasidone day 15-21 126.5mg/day. Plt0.05
P0.01 P0.001 vs placebo.
Potkin S, et al. J Clin Psychopharmacol.
200525(4)301-10.
40
Pooled studies PANSS positive subscale items
PANSS Positive Subscale
Conceptual disorganisation
Hallucinatorybehaviour
Suspiciousness/persecution
Delusions
Excitement
Grandiosity
Hostility
Mean Change from Baseline to Endpoint (LOCF)
Consistent withimprovement in coremanic symptoms
-1
-1


ziprasidone placebo
PANSS Positive and Negative Syndrome Scale
LOCF Last Observation Carried Forward. Plt0.01
Plt0.001 N247 (ziprasidone) N120 (placebo).
Pfizer Inc., Data on file.
41
Pooled studies improvement in manic and mixed
episodes
Change in MRS Score From Baseline
Mixed episode
Manic episode
0
0
ziprasidone (N101 BL 23.64) placebo (N50 BL
23.16)
ziprasidone (N167 BL 28.74) placebo (N81 BL
28.62)
-2
-2
-4
-4


-6
-6
Change in MRS Score (LOCF)
-8

-8


-10
-10


-12

-12

-14
-14
Day
Day
MRS Mania Rating Scale LOCF Last Observation
Carried Forward. BL Baseline. Plt0.05 Plt0.01.
Keck PE, et al. Presented at the American
Psychiatric Association 56th Institute on
Psychiatric Services October 6-10, 2004
Atlanta, Ga poster.
42
Pooled studies improvement in manic and mixed
episodes
Change in MRS Score
Psychotic symptoms
No psychotic symptoms
ziprasidone (N167 BL 25.28) placebo (N79 BL
24.73)
ziprasidone (N101 BL 29.37) placebo (N50 BL
29.12)
0
0
-2
-2
-4
-4
-6

Change in MRS Score (LOCF)
-8
-6

-10

-8
-12



-10
-14


-16
-12
Day
Day
MRS Mania Rating Scale LOCF Last Observation
Carried Forward. BL Baseline. Plt0.05 Plt0.01.
Keck PE, et al. Presented at the American
Psychiatric Association 56th Institute on
Psychiatric Services October 6-10, 2004
Atlanta, Ga poster.
43
Pharmacokinetics and Dosing
44
For optimal efficacy, oral ziprasidone requires
administration with food

• Food doubles the bioavailability of ziprasidone
• Ziprasidone must be administered with food to
  achieve the necessary plasma concentration for
  effective symptom control

AUC Fed
AUC Fasted
AUC (ng-h/mL)
Dose (mg)
Ziprasidone was administered with a standard FDA
meal.
Lombardo I, et al. Presented at American
Psychiatric Association 58th Institute of
Psychiatric Services October 5-8, 2006 New
York.
45
For optimal efficacy, oral ziprasidone requires
administration with food

• Food doubles the bioavailability of ziprasidone
• Ziprasidone must be administered with food to
  achieve the necessary plasma concentration for
  effective symptom control

Fed
Fasting
Ziprasidone trough plasma level (ng/ml)
60 D2 occupancy
ziprasidone dose (mg)
Pfizer Inc., Data on file.
46
Effective D2 receptor occupancy is dependent on
ziprasidone plasma levels Pharmacokinetics

• Clinical response occurs at approximately 60 D2
  receptor occupancy1
• 60 D2 receptor occupancy corresponds to a plasma
  level of approximately 50ng/ml
• A plasma level of 50ng/ml corresponds to about
  120mg/day of ziprasidone1,2

Ziprasidone Plasma Level vs. D2 Occupancy 12 hr
Post-Dose
14-16 hours post dose
1. Mamo D, et al. Am J Psychiatry.
2004161(5)818-25. 2. Miceli JJ, et al. Br J
Clin Pharmacol. 200049 Suppl 1S5-13.
47
For optimal efficacy, titrate ziprasidone to
120-160mg/day with food1-4
Day 3 If indicated
Day 1
The recommended starting dose is 80mg/d. If
indicated, the maximum recommended dose may be
reached as early as day 3 of treatment. The full
dose range is 40-160mg/d.1 gt500 kcal
1. Zeldox, Summary of Product Characteristics. 2.
Nemeroff CB, et al. CNS Spectr.
200510(11Suppl17)1-20. 3. Joyce AT, et al.
Schizophr Res. 2006 Apr83(2-3)285-92. 4. Daniel
DG, et al. Neuropsychopharmacology. 1999
May20(5)491-505.
48
Greater antipsychotic efficacy with ziprasidone
120-160mg/day in acute schizophrenia Pooled,
short-term, fixed-dose, placebo-controlled trials
BPRS Total, Mean Change from Baseline
P0.036

Effect Size

N335
N220
40-80mg/day
120-160mg/day
Effect size (Cohens d) (ziprasidone
placebo)/pooled SD. BPRSBrief Psychiatric
Rating Scale. Plt0.01, Plt0.001.
Nemeroff CB, et al. CNS Spectr. 200510(11)S1-20.
49
Greater adherence rates with higher initial
prescribed ziprasidone doses in
schizophrenia Dosing 6-month retrospective
claims database
Patients () Remaining on Therapy at 6 Months
Initial ziprasidone dose
P0.012
Proportion of Patients Remaining on Therapy at
Endpoint
n220
40-79mg/day (N413)
80-119mg/day (N356)
120-160mg/day (N289)
Joyce AT, et al. Schizophr Res 200683285-92.
50
Dosing adjustments of ziprasidone in special
populations

• No dose adjustments are required in patients
  with impaired renal function
• Dose adjustments with ziprasidone may be
  considered in patients over 65 when clinical
  factors warrant
• In patients with hepatic insufficiency lower
  doses should be considered

Zeldox, Summary of Product Characteristics.
51
Ziprasidone metabolism Metabolism
Metabolic Pathways to Major Circulating
Metabolites
N-dealkylation CYP3A4
Reduction Aldehyde oxidase (2/3)
ziprasidone
Oxidation
dihydroziprasidone
benzisothiazole (BITP) sulphoxide
S-oxidation (CYP3A4)
S-oxidation (CYP3A4)
S-methylation (S-methyltransferase)
ziprasdione sulphoxide
BITP sulphoxide
S-methyl-dihydroziprasidone
S-oxidation (CYP3A4)
S-oxidation (CYP3A4)
Faeces
S-methyl-dihydroziprasidone sulphoxide
BITP suphone
ziprasdione sulphone
Major inactive circulating metabolites
Major potentially active circulating metabolite
Adapted from Beedham C, et al. J Clin
Psychopharmacol. 2003 Jun23229-32.
52
Switching to Zeldox
53
Switching to ziprasidone can be effective
irrespective of the switching strategy Ziprasidone
(switch studies)
Stable but Symptomatic Outpatients with
Schizophrenia
conventionals (N108), olanzapine (N104),
risperidone (N58)
Randomly switched to ziprasidone by
Discontinuation abrupt cessation of current
treatment before starting ziprasidone Cross-taperi
ng dose reduction of current treatment when
starting ziprasidone therapy Delayed
withdrawal delayed dose reduction of current
treatment 4 days after ziprasidone initiation

• No significant differences were observed between
  switching strategies in changes from baseline to
  endpoint PANSS total, BPRSd, PANSS negative
  subscale, PANSS positive subscale, CGI-S or CGI-I
  scores

Weiden PJ, et al. J Clin Psychiatry.
200364(5)580-8.
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