strategies for successful clinical management of schizophrenia with ziprasidone

1. Introduction

2. Aim

3. Dosing, administration and

uptitration of ziprasidone

4. Management of agitation and

insomnia

5. Beneficial effect on

cardiometabolic risk factors

6. Cardiac safety

7. Transition from intramuscular

to oral ziprasidone

8. Conclusions

9. Expert opinion

Drug Evaluation

Strategies for successful clinicalmanagement of schizophreniawith ziprasidoneAndrea Fagiolini†, Fernando Canas, Bernd Gallhofer, Ilkka Larmo,Pedro Levy, Jose Manuel Montes, Georgios Papageorgiou, Mathias Zink &Alessandro Rossi†University of Siena School of Medicine, Department of Neuroscience, Siena, Italy

Importance of the field: This review addresses practical clinical issues related

to the use of ziprasidone in the treatment of schizophrenia using information

from clinical trials, unpublished data, manufacturer’s information, and

input from an expert faculty of European psychiatrists with extensive

experience of the use of ziprasidone, both in clinical trials and in everyday

clinical practice.

Areas covered in this review: A Medline search of published data

(1998 -- 2010) was carried out, together with a review of unpublished data

and manufacturer’s information. In addition, expert opinion was sought

from psychiatrists with extensive experience of ziprasidone in the treatment

of schizophrenia in clinical settings across Europe.

What the reader will gain: This review has been undertaken to determine

how the information from clinical trials can be optimally translated into

‘real-life’ practice and to establish how a decade of experience with

ziprasidone in clinical practice can inform its optimal use to maximize

effectiveness and minimize side effects.

Take home message: Effective use of ziprasidone in everyday clinical practice

usually requires rapid titration to doses in the range of 120 -- 160 mg/day

and administration with proper meals, thereby achieving the high levels

of schizophrenia symptom control reported in clinical trials. Additional

guidance is provided about effective management of side effects, and appro-

priate coadministration of benzodiazepines and other agents, to achieve

desired outcomes.

Keywords: activation, benzodiazepines, co-medication, dosing, effect of food,

efficacy, insomnia, rapid uptitration, schizophrenia, tolerability, ziprasidone

Expert Opin. Pharmacother. (2010) 11(13):2199-2220

1. Introduction

Ziprasidone (Box 1) is a second-generation antipsychotic (SGA) agent with a uniquereceptor-binding profile that includes high-affinity antagonist activity at dopamineD2 receptors and serotonin 5-HT2A and 5-HT2c receptors, agonist activity at5-HT1A receptors, and a relatively high affinity for serotonin and norepinephrinetransporters (Table 1) [1-4].

Like other SGAs, ziprasidone acts to achieve a balance of dopamine and serotoninneurotransmitter activity in the brain which is predictive for a decrease of both thepositive and negative symptoms of schizophrenia, without causing the motor sideeffects seen with first-generation, conventional antipsychotic drugs. Ziprasidone tar-gets the excessive dopamine neurotransmission at dopamine D2 receptors in themesolimbic pathway of the brain which is understood to be responsible for thepositive symptoms of schizophrenia [1]. It is also antagonistic at the serotonin

10.1517/14656566.2010.507630 © 2010 Informa UK, Ltd. ISSN 1465-6566 2199All rights reserved: reproduction in whole or in part not permitted

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5-HT2A receptors in the nigrostriatal pathway -- an effect thatreverses D2 blockade in the striatum sufficiently to preventmotor side effects [1].Differential affinity for subtypes of serotonin receptors in

relation to D2 affinity has been linked to a variety of clinicaleffects, including reduced negative symptoms of schizophre-nia. A high 5-HT2A/D2 receptor affinity ratio is correlatedwith reduced likelihood of extrapyramidal side effects (EPS)and negative symptoms of schizophrenia [1]. Blockade of5-HT2C receptors in the cortex may lead to improved cogni-tive and affective symptoms as a result of enhanced dopamineand norepinephrine release [1]. Activity at 5-HT1A receptorshas been linked to cognitive improvements and reduction ofnonpsychotic features of schizophrenia such as anxiety,depression, hostility and inadequate social interactions [1].Antagonism of 5-HT1D receptors also has potential forbeneficial effects on mood and affective symptoms, including

anxiety and depression [1]. A summary of ziprasidone’sreceptor-binding profile is presented in Figure 1.

Ziprasidone is among the antipsychotics with the highest5-HT2A/D2, 5-HT2C/D2 and 5-HT1A/D2 receptor affinityratios of all the SGAs and has unique and potent antagonismat the 5-HT1D receptor [1]. In addition to its other effects,ziprasidone interferes with the reuptake of monoaminergicneurotransmitters -- exhibiting affinities for the norepineph-rine transporter (NET) in the same range as the tricyclicantidepressant desipramine. Ziprasidone’s low affinity fora1-adrenoceptors, histamine H1 and muscarinic M1 recep-tors, relative to D2 receptor affinity, is likely to be responsiblefor its low risk of orthostatic hypotension, sedation, cognitivedisturbance, weight gain and dysregulation of prolactin lev-els [1]. However, it should be kept in mind that receptor-binding affinities are not entirely predictive of an agent’sclinical profile, and clinical trials are therefore necessary totest these potential effects.

Ziprasidone is well absorbed after oral administration,reaching peak plasma concentrations in 6 -- 8 h [5]. The initialdata on bioavailability were obtained in a study performed inhealthy volunteers, demonstrating that absolute bioavailabilityof a low, 20-mg dose of ziprasidone under fed conditionsis ~ 60% [5]. Pharmacokinetic studies have shown that thebioavailability of ziprasidone is increased by up to 100% inthe presence of food, and it is therefore required that ziprasi-done should be taken with food [5]. The effectiveness of oralziprasidone is enhanced by ensuring that it is administeredwith a ‡ 500-kcal meal. If this does not occur, absorption oforal ziprasidone is substantially reduced and cannot be over-come by increasing the prescribed dose [6]. When ziprasidoneis not taken with food, bioavailability is reduced by at least50% [5]. Doubling an oral dose of 40 -- 80 mg without foodwill not double the serum drug concentration becauseincreases in AUC and maximum serum drug concentrationsare dose proportional under fed conditions, and this is notthe case in the absence of food [6].

After intramuscular (i.m.) administration, peak serum con-centrations occur ~ 60 min post-dose or earlier, and the meanhalf-life (T½) ranges from 2 to 5 h [5]. A summary ofziprasidone oral and i.m. pharmacokinetic parameters ispresented in Figure 1.

Ziprasidone is extensively metabolized after oral administra-tion with only a small amount excreted in the urine (< 1%) orfeces (< 4%) as unchanged drug. Ziprasidone is primarilycleared via three metabolic routes to yield four major circulat-ing metabolites, benzisothiazole (BITP) sulfoxide, BITP sul-fone, ziprasidone sulfoxide, and S-methyl-dihydroziprasidone.In vitro studies indicate that CYP3A4 is the major cytochromeP450 oxidase contributing to the oxidative metabolism ofziprasidone. CYP1A2 may contribute to a much lesser extent.Based on in vivo abundance of excretory metabolites, lessthan one-third of ziprasidone metabolic clearance is mediatedby cytochrome P450-catalyzed oxidation and approximatelytwo-thirds via reduction by aldehyde oxidase. There are no

Article highlights.

. The beneficial effects of ziprasidone on positive andnegative symptoms of schizophrenia have beendemonstrated in the RCTs and in naturalistic studies.

. In the treatment of agitation in the acute setting,intramuscular (i.m.) ziprasidone has demonstratedsuperior control of psychotic symptoms to that achievedwith i.m. haloperidol and a stronger therapeutic effectmeasured by numbers needed to treat (NNT) versus i.m.aripiprazole.

. Smooth transition from i.m. ziprasidone to the oralformulation can be achieved without difficulty, isassociated with sustained improvement in symptomsand is well tolerated.

. In a comparative study of ziprasidone and haloperidol,dose-related prolongation of QTc interval was reportedwith both treatments, but did not result in any patientexperiencing a QTc interval of ‡ 450 ms.

. Evidence from clinical trials has shown that dosing ofziprasidone in the optimal dose range (60 -- 80 mgtwice daily), administration with food and rapiduptitration are important factors for optimizing efficacyand minimizing treatment discontinuation.

. It is recommended that schizophrenia patients arestarted on a dose of ziprasidone 40 mg twice dailytaken with food and the daily dosage adjustedaccording to patient need to a maximum of 80 mgtwice daily, reached as early as day 3 of treatmentif appropriate.

. Coadministration of benzodiazepines with ziprasidone inclinical trials may explain why agitation and insomniawere less of a problem than sometimes reported inclinical practice, especially when switching patients froma more sedating antipsychotic agent.

. In clinical trials, ziprasidone was consistently associatedwith lower risk for weight gain and cardiometabolicdisturbances than comparator SGAs, and this may haveimportant implications for reducing cardiovascular risk inschizophrenia patients.

This box summarizes key points contained in the article.

Ziprasidone

2200 Expert Opin. Pharmacother. (2010) 11(13)

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known clinically relevant inhibitors or inducers of aldehydeoxidase. It is thought this metabolic profile underlies the lowpropensity for drug--drug interactions seen with ziprasidone.

There are no clinically significant pharmacokineticdrug--drug interactions between ziprasidone and a variety ofmedications, such as antacids, benztropine, cimetidine,

dextromethorphan, lithium, lorazepam, oral contraceptivesor propranolol, all of which are commonly used inschizophrenia patients [5].

In the EU, ziprasidone is licensed for the treatment ofschizophrenia in adults, as well as for the treatment ofmanic or mixed episodes of moderate severity in bipolar

Box 1. Drug summary.

Drug name ZiprasidonePhase LaunchedIndication Ziprasidone oral:

Schizophrenia (USA, EU)Bipolar disorder (manic or mixed episodes) in adult patients (USA, EU) and pediatric patients (EU)Ziprasidone i.m.:Acute treatment of agitation associated with schizophrenia (USA, EU)

Pharmacology description 5 hydroxytryptamine 1A receptor agonist5 hydroxytryptamine 2A receptor antagonist5 hydroxytryptamine 1D receptor antagonistDopamine D2 receptor antagonistSerotonin and norepinephrine reuptake inhibitor

Route of administration Alimentary, p.o.Parenteral, i.m.

Chemical structure

N

S

N

N

NHCI

O

Pivotal trial(s) Ziprasidone oralPivotal registration trials in schizophrenia: [60,72]Pivotal registration trials in adult bipolar disorder: [8,73]Pivotal registration trial in pediatric bipolar disorder (EU only): [10]Ziprasidone i.m.Pivotal registration trials: [28,31]

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

Table 1. Comparative receptor-binding affinities of antipsychotics.

Drug K1 (nM)

5-HT2C 5-HT2A D2 H1 M3 a1A a2A a2B a2C 5-HT1A 5-HT6 5-HT7

Aripiprazole 22.4 8.7 0.66 29.7 4677 26 74 102 37 5.57 783.2 9.6Clozapine 17 5.4 256 1.2 25 1.64 142 26 34 104.8 17 17.9Haloperidol 10000 53 4 1800 10000 12 1130 480 550 1202 3666 377.2Olanzapine 6.8 2 34 2 105 115 314.1 81.6 28.8 2063 6.28 105.4Quetiapine 2502 101 245 11 10000 22 3630 746.6 28.7 431.6 1865 307.2Risperidone 35 0.17 6.5 15 10000 5 150.8 107.6 1.3 427.5 1188 6.6Ziprasidone 13 0.3 9.7 43 10000 18 160 48 59 76 60.9 6.62

Reprinted by permission from Macmillan Publishers Ltd: Neuropsychopharmacology [4], Copyright 2003. All binding essays were done using cloned human

receptor preparations.

Fagiolini, Canas, Gallhofer, et al.

Expert Opin. Pharmacother. (2010) 11(13) 2201

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disorder in adults and children and adolescents aged10 -- 17 years [7]. The efficacy of ziprasidone in the acutetreatment of adults with bipolar disorder was established intwo 3-week placebo-controlled studies [8,9], and ofpediatric patients aged 10 -- 17 years in one 4-weekplacebo-controlled study [10].

2. Aim

This review addresses clinical issues related to the use ofziprasidone in the treatment of schizophrenia using informa-tion from clinical trials identified during a Medline search(up to 19 April 2010), unpublished data, manufacturer’s infor-mation and input from an expert faculty of European psychia-trists with extensive experience of the use of ziprasidone, bothin clinical trials and in everyday clinical practice. These issueswere discussed during an Advisory Board meeting held in Paris,on 12 April 2010, supported by Pfizer, Inc.These issues relate to the perception of ziprasidone’s effi-

cacy, administration and dosage (i.e., uptitration, optimaldosing and relevance of intake with food), management ofside effects, transition from intramuscular to oral ziprasidone,and the practicalities of switching to ziprasidone from otherantipsychotic agents.

This review aims to provide evidence to fill the gaps in cur-rent knowledge and experience for each of the above issues. Italso provides expert opinion on how to apply this informationin everyday clinical practice.

2.1 Efficacy and tolerability of ziprasidoneThe efficacy and tolerability of ziprasidone in schizophreniahave been investigated in extensive head-to-head randomized,controlled trials (RCTs) and comparative analyses with SGAs,including olanzapine, risperidone, aripiprazole, quetiapineand clozapine, and with older first-generation agents (FGAs),such as chlorpromazine and haloperidol. These studies havebeen carried out in a variety of patient populations and clinicalsettings, and attention is drawn to the dosing regimens andcoadministration of benzodiazepines and psychotropic agentsthat have been used in all of the studies with oral ziprasidone,and nearly all of the studies with i.m. ziprasidone. The resultsdemonstrate that ziprasidone is highly effective, providing thestrategies discussed in further sections are followed (e.g., rapidtitration to doses in the range 120 -- 160 mg/day, administra-tion with proper meals, and administration of benzodiazepineswhen clinically required).

Recent meta-analyses [11-13], which have foundziprasidone to be less efficacious than some of the SGAs,

H1

α2

5-HT1D

5-HT2A

D2

5-HT1A

5-HT2C

Positive symptomsD2 – antagonism Efficacy in positive symptomsHigh 5-HT2A/D2 – affinity ratioAntipsychotic efficacy, reduced EPS(compared to D2 antagonism alone)

Negative symptoms5-HT2A– antagonism Efficacy in negative symptoms

Overall symptoms5-HT2C – antagonismAntipsychotic activity

Cognitive and depressive symptoms andsymptoms of social impairment5-HT1A – agonismAntidepressant activity and anxiolyticactivity and improved cognition5-HT1D – antagonismEfficacy in depressive symptoms

i.m. OralMean half-life (t1/2) 2.8 h 6.6 h

Time to maximum serumconcentration

0.6 h 6.8 h

NA 1 – 3 days

Bioavailability afteradministration

100% 60%*

Time to steady state

Figure 1. Receptor binding profile and summary of pharmacokinetic properties of ziprasidone [7].*20-mg dose under fed conditions.

Ziprasidone


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are not discussed in detail in this paper. Generally, results ofmeta-analyses are not informative for the objectives ofthis review since they do not provide any information onissues critical for the clinical efficacy of ziprasidone, suchas effective dose range and rapid uptitration, and areaddressed elsewhere. Also, a number of authors havepointed out that results from meta-analyses should beinterpreted with caution and that their extrapolation tocomplex clinical problems is sometimes difficult [14-16].

This section reviews the trials in which ziprasidone iscompared with the most frequently used SGAs, performedacross different patient populations and treatment settings. Asummary of trials included in this review is presented in Table 2.

2.1.1 Acute schizophreniaComparable efficacy for key measures of positive and negativesymptom control in acute schizophrenia were seen for ziprasi-done and olanzapine in a 6-week, multicenter, double-blind,parallel-design, flexible-dose trial [17]. Two hundred and sixty-nine acutely ill inpatients with schizophrenia or schizoaffectivedisorder were randomized to escalating doses of ziprasidone(40 mg b.i.d. on days 1 and 2; 80 mg b.i.d. on days 3 -- 7; and40, 60 or 80mgb.i.d. inweeks 2 -- 6) or olanzapine (5mg/day ondays 1 and 2; 10mg/day on days 3 -- 7; and 5, 10 or 15mg/day inweeks 2 -- 6). The overall mean daily dose of ziprasidone was129.9 mg and of olanzapine was 11.3 mg (median 138.6 and12.4 mg, respectively). The dose of ziprasidone was within theoptimal dose range of 120 -- 160 mg/day, while the olanzapinedose, although within the US labeling, could be consideredlow. This potential limitation of the study renders the resultsmore difficult to interpret.

During the comparative study of ziprasidone andolanzapine [17], 83% of the ziprasidone group and 75% ofolanzapine group took benzodiazepines for control of agita-tion or insomnia, and 25 and 15% respectively tookanticholinergic agents for control of EPS.

Both antipsychotics were equally effective in improvingsymptoms and global illness severity according to the primaryefficacy measures of Brief Psychiatric Rating Scale (BPRS) [18]

and Clinical Global Impression Severity (CGI-S) [19] scalescores and secondary measures on the CGI improvement(CGI-I) scale, Positive and Negative Syndrome Scale(PANSS) [20] and Calgary Depression Scale for Schizophrenia(CDSS) [21]. Significantly greater improvements in BPRS andCGI-S compared with baseline were seen for ziprasidone atday 7 last observation carried forward (LOCF) (p < 0.05 forboth parameters). BPRS responder rates (20, 30 and 40%change from baseline) were similar for the two treatments [17].

Both agents were well tolerated. The olanzapine group hadsignificantly greater increases in body weight (3.5 vs 1 kg,p < 0.05), total cholesterol, triglycerides and low-densitylipoprotein cholesterol (LDL-C; p < 0.05) and fastinginsulin [17].

Ziprasidone has also been shown to be as effective asrisperidone in the acute treatment of schizophrenia or

schizoaffective disorders [22]. In an 8-week double-blind trialin 296 patients with acute exacerbations, equivalence wasdemonstrated in PANSS total score and CGI-S withziprasidone (40 mg/day b.i.d. during the first week, increasingin weekly increments of 20 mg/day b.i.d. to 80 -- 160 mg/day)or risperidone (1 mg on day 1, 3 mg on days 3 -- 7, increas-ing in weekly increments of 1 mg to a maximum of 5 mg).Equivalence was also demonstrated for the two drugs forresponder rates (20 -- 50% decrease from baseline in PANSStotal), and change from baseline for PANSS negative, andBPRSd (BPRS score derived from PANSS) core item. Risper-idone exhibited a significantly higher Movement DisorderBurden (MDB) score (p < 0.05) and higher incidences ofprolactin elevation and clinically relevant weight gain.However, the authors pointed out that, compared with cur-rent recommendations, study dosing may have been high forsome risperidone-treated patients (mean dose = 7.4 mg/day)and low for some ziprasidone-treated patients (mean dose =114.2 mg/day). Patients could take temazepam during thestudy, but the proportion taking benzodiazepines was notreported. Twenty eight per cent of the ziprasidone groupand 37% of the risperidone group took medication for move-ment disorders during the study; 22 and 33% respectivelytook anticholinergic agents.

Ziprasidone has also been compared with aripiprazole inacutely ill patients with schizophrenia or schizoaffective disor-der [23]. In a double-blind, 4-week study, 253 patients were ran-domized to ziprasidone (40 mg twice daily on day 1, 60 mgtwice daily on day 2, and 80 mg twice daily on days 3 -- 14,and flexible dosing on days 15 -- 28 with 40, 60 or 80 mg twicedaily) or aripiprazole (15 mg every day on days 1 -- 14, flexibledosing on days 15 -- 28 with 10, 15 or 30 mg daily). Themean doses were ziprasidone 149 mg/day and aripiprazole20.9 mg/day. Patients were overweight/obese in both treat-ment groups; body mass index (BMI) in ziprasidone-treatedpatients was 29 for men and 33 for women, and inaripiprazole-treated patients 28 and 32, respectively.

Both treatments were effective in improving global illnessseverity and overall psychopathology, with robust effect sizes(range 1.0 -- 1.2). Noninferiority for ziprasidone relative toaripiprazole was established for CGI-S score (p = 0.007),but was not confirmed for BPRSd total score (p = 0.248).Changes from baseline for CGI-S, BPRSd, PANSS total andsubscales were comparable for the two treatments. A mixed-model repeated-measures analysis of BPRSd total scorefavored ziprasidone on day 4, with no significant differencesat other visits.

A direct head-to-head comparison of ziprasidone andquetiapine is not available, but analysis of efficacy for thetwo drugs in schizophrenia treatment from a Cochrane reviewof the efficacy of quetiapine versus other antipsychoticdrugs showed comparable efficacy for quetiapine and ziprasi-done for parameters of mental state [24]. Comparedwith ziprasidone, quetiapine induced slightly fewerextrapyramidal adverse effects (1 RCT: n = 522, RR use of



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Table

2.Overview

ofstudiesincludedin

this

review.

Trial

Drugsco

mpared

Primary

efficacy

outcomemeasu

res

Inso

mnia,agitation,

sedation/somnolence

or

anxiety

asadverseevents

(ziprasidonevsco

mparator)

Ziprasidonedosing

schedule

Meandose:

ziprasidone

Benzo

diaze

pine

use

allowed

RCTs

Acute

schizophrenia

Sim

psonetal.,

2004

[17]

ZIP

vsOLZ

BPRS,CGI-S

Fatigue/sedation:

56.4

vs45.8%

40mgb.i.d.days

1and2

80mgb.i.d.days

3--7

Weeks2--6:40,60or

80mgb.i.d.

129.9

mg/day

Yes

Addingtonetal.,

2004

[22]

ZIP

vsRIS

PANSStotal,CGI-S

Insomnia

24.8

vs12.2%

Somnolence

20.8

vs17.7%

Agitation16.1

vs13.6%

40mg/dayb.i.d.1week

Weekly

increments

20mg/day

b.i.d.to

80--160mg/day

114.2

mg/day

Yes

Zim

broff

etal.,

2007

[23]

ZIP

vsARI

CGI-S,BPRSdtotal

Agitation11.2

vs9.4%

Insomnia

6.4

vs7.0%

Somnolence

16.4

vs13.3%

40mgb.i.d.day1

60mgb.i.d.day2

80mgb.i.d.days

3--14

Days

15--28,flexible

-40,

60or80mgb.i.d.

149.0

mg/day

Yes

Recent-onsetschizophrenia

Grootensetal.,

2009

[25]

ZIP

vsOLZ

PANSStotal,CGI-S,

CGI-I,CDSS

Notreported

40mgb.i.d.days

1and2

Day3onward,flexible

-40,

60or80mgb.i.d.

104mg/day

Yes

Treatm

entofagitationwithziprasidonei.m.form

ulationin

theacute

setting

Brook2000

[74]

ZIP

BPRS,CGI-S,CGI-I

Notreported

FixeddosesZIP

i.m.

(10--60mg/day)

days

1--3

ZIP

oralb.i.d.(attotaldaily

dose

oftw

icei.m.dose

from

day3)

day4

ZIP

oral(20--100mgo.d.)

day5

Fixed-dose

pilot

study

Yes

Danieletal.,

2001

[28]

ZIP

vsethicalPBO

BARS

Somnolence

13vs

20%

Insomnia

5vs

0%

Fixeddosesof2or20mg

Upto

4identicali.m.dosesin

24-h

study,

min.4hapart

Fixed-dose

study

Notallowed

duringthestudy

Brooketal.,

2005

[71]

ZIP

vsHAL

BPRS,CGI-S,CGI-I

Insomnia

6.5

vs5.1%

Combinedphase:

Insomnia

21.7

vs15.2%

Somnolence

12.4

vs5.8%

Anxiety

10.5

vs9.4%

ZIP

i.m.10or20mgi.m.

(max.

40mg/day)

days

1--3

ZIP

oral(40--80mgb.i.d.)day

4onwards

Oral:116.0

mg/day

Yes

AMI:Amisulpride;ARI:Aripiprazole;BARS:BehaviouralActivityRatingScale;BPRS:BriefPsychiatric

RatingScale;BPRSd:BPRSscore

derivedfrom

PANSS;CGI-I:ClinicalGlobalIm

pressionIm

provementScale;

CGI-S:ClinicalGlobalIm

pressionSeverity;ChLP:Chlorpromazine;HAL:

Haloperidol;OLZ:Olanzapine;PANSS:Positive

andNegative

SyndromeScale;PBO:Placebo;QUE:Quetiapine;RIS:Risperidone;ZIP:Ziprasidone.

Ziprasidone


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Table

2.Overview

ofstudiesincludedin

this

review

(continued).

Trial

Drugsco

mpared

Primary

efficacy

outcomemeasu

res

Inso

mnia,agitation,

sedation/somnolence

or

anxiety

asadverseevents

(ziprasidonevsco

mparator)

Ziprasidonedosing

schedule

Meandose:

ziprasidone

Benzo

diaze

pine

use

allowed

Long-term

treatm

entofschizophrenia

Sim

psonetal.,

2005

[34]

ZIP

vsOLZ

BPRS,CGI-S

Notreported

Flexible

dosing40--80mg

b.i.d.

135.2

mg/day

Yes

Addingtonetal.,

2009

[35]

ZIP

vsRIS

PANSStotal,CGI-S

Agitation16.1

vs16.9%

Anxiety

16.1

vs11.7%

Insomnia

32.3

vs18.2%

Somnolence

24.2

vs28.6%

Flexible

dosing40--80mg

b.i.d.

114mg/day

Yes

Refractory/treatm

ent-resistantschizophrenia

Kaneetal.,

2006

[40]

ZIP

vsChLP

BPRSd

Somnolence

19.1

vs28.6%

20mgb.i.d.days

1--3

40mgb.i.d.day4--7

60mgb.i.d.day8onwards

Additionalincreasesto

80mg

b.i.d.(noearlierthanday12)or

decreaseswere

allowed

153.8

mg/day

Yes

Sacchettietal.,

2009

[41]

ZIP

vsCLZ

PANSStotal

Somnolence

4.1

vs23.3%

Insomnia

9.6%

2vs.7%

40mgb.i.d.days

1--3

40--80mgb.i.d.day

4onwards(flexible

dosing)

130mg/day,

(completers:

meandose

at

endpoint:137mg/day)

Yes

First-episodeschizophrenia

Kahnetal.,

2008

[27]

HALvs

ZIP

vsOLZ

vsAMIvs

QUE

All-cause

treatm

ent

discontinuation

Notreported

Flexible

dosing20--80mg

b.i.d.

107.2

mg/day

Yes

Naturalistic

Studies

Arangoetal.,2007

[51]

ZIP

PANSStotal,CGI-S

Insomnia

5%

Somnolence

3.7%

Anxiety

2.6%

Flexible

dosing20--80mg

b.i.d.(dose

requirements

and

dose

escalationwere

established

individually

accordingto

the

clinicaljudgmentofeach

investigator)

126.6

mg/day

Yes

Dıaz-Marsaetal.,

2009

[50]

ZIP

BPRS,CGI-S

Somnolence

7.1%

Insomnia

3.1%

Flexible

dosing20--80mg

b.i.d.(dose

requirements

and

dose

escalationwere

established

individually

accordingto

the

clinicaljudgmentofeach

investigator)

136.9

mg/day

Yes

AMI:Amisulpride;ARI:Aripiprazole;BARS:BehaviouralActivityRatingScale;BPRS:BriefPsychiatric

RatingScale;BPRSd:BPRSscore

derivedfrom

PANSS;CGI-I:ClinicalGlobalIm

pressionIm

provementScale;

CGI-S:ClinicalGlobalIm

pressionSeverity;ChLP:Chlorpromazine;HAL:

Haloperidol;OLZ:Olanzapine;PANSS:Positive

andNegative

SyndromeScale;PBO:Placebo;QUE:Quetiapine;RIS:Risperidone;ZIP:Ziprasidone.



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anti-Parkinson medication = 0.43, CI 0.2 -- 0.93, numberneeded to harm [NNH] not estimable) and prolactinincrease. But quetiapine was more sedating and led tomore weight gain (2 RCTs: n = 754, RR = 2.22, CI1.35 -- 3.63, NNH = 13 CI 8 -- 33) and cholesterol increasethan ziprasidone.

2.1.1.1 Recent-onset schizophreniaIn recent-onset, acute schizophrenia, ziprasidone proved aseffective as olanzapine for the control of positive and negativesymptoms during an 8-week treatment period [25]. Seventy-three inpatients were randomized to ziprasidone 40 mgb.i.d. or olanzapine 10 mg/day for the first 2 days of treat-ment, followed by appropriate rapid uptitration accordingto flexible dosing with ziprasidone 40, 60 or 80 mg b.i.d.,or olanzapine 10, 15 or 20 mg/day. The mean daily dose ofziprasidone was 104 mg and that of olanzapine was 14 mg.In the ziprasidone group, 28.2% of patients dropped out oftreatment, and 17.7% in the olanzapine group. No patientsdropped out for efficacy reasons.Comparable reductions from baseline were seen for

ziprasidone and olanzapine in the primary outcome variable,PANSS total, and in the secondary outcomes, CGI Scale,CDSS and the Heinrich Quality of Life Scale (HQLS) [26].Responder rates (20% decrease from baseline in PANSS total)were 61% for ziprasidone and 60% for olanzapine. Remissionrates (defined as ‘mild’ or less on items P1, P2, P3, N1, N4,N6, G5, G9) were 40 and 35% respectively. Mean weightgain was significantly higher in the olanzapine group (6.8 vs0.1 kg, p < 0.001), and increased appetite was significantlymore common (14.3 vs 0%, p = 0.02). Ziprasidone was asso-ciated with decreasing levels of triglycerides, cholesterol andtransaminases, while these parameters increased in the olanza-pine group (all p values < 0.05). There were no significant dif-ferences in fasting glucose and prolactin levels or in cardiac orsexual side effects. Forty-one per cent of patients in theziprasidone group used benzodiazepines (temazepam or oxaz-epam up to 20 mg/day p.r.n.) and 43.6% used anticholinergicdrugs. In the olanzapine group, 31.4% used benzodiazepinesand 20% anticholinergics.An open-label, randomized, 1-year clinical trial (EUFEST)

investigated the effectiveness of the SGAs -- ziprasidone(40 -- 160 mg/day), amisulpride (200 -- 800 mg/day), olanza-pine (5 -- 20 mg/day) and quetiapine (200 -- 750 mg/day) --compared with low-dose FGA haloperidol (1 -- 4 mg/day)in 489 patients with first-episode schizophrenia [27]. Compar-isons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio[HR] = 0.37, 95% CI 0.24 -- 0.57), olanzapine (HR = 0.28,CI 0.18 -- 0.43), quetiapine (HR = 0.52, CI 0.35 -- 0.76)and ziprasidone (HR = 0.51, CI 0.32 -- 0.81). Symptomreductions of ~ 60% were virtually the same for all groups,though more patients discontinued haloperidol treatmentthan treatment with the SGAs. Weight change from baselinewas highest in patients treated with olanzapine (13.9 kg;

SD = 1.7), quetiapine (10.5 kg; SD = 1.8), amisulpride(9.7 kg; SD = 1.7) or haloperidol (7.3 kg; SD = 1.8) and low-est with ziprasidone (4.8 kg; SD = 1.9). Similarly, fewerziprasidone-treated patients (37%) had a > 7% weight gainfrom baseline than those on the other treatments (olanzapine,86%; quetiapine, 65%; amisulpride, 63%; haloperidol,53%) [27].

2.1.1.2 Treatment of agitation in the acute settingAcute psychotic states are often accompanied by anxiety, agi-tation and, in some cases, aggressive behavior. In these situa-tions, injections of FGAs are still considered the treatmentof choice in many hospitals. However, several clinical trialshave demonstrated that intramuscular formulations of SGAsprovide comparable efficacy and improved tolerability.

Intramuscular ziprasidone has been shown significantlyto reduce psychomotor agitation and other symptoms ofpsychosis in acutely agitated schizophrenia patients [28].It has also been associated with significantly improvedBPRS scores compared with i.m. haloperidol [29], and alower numbers needed to treat (NNT) (i.e., stronger thera-peutic effect) than i.m. aripiprazole in an indirect com-parison [29]. In contrast to i.m. olanzapine, which is notrecommended to be coadministered with parenteral benzo-diazepines [30], i.m. ziprasidone can be coadministeredwith benzodiazepines [5].

The efficacy and tolerability of the rapid-acting i.m.ziprasidone in the treatment of inpatients with psychosisand acute agitation was investigated in a 24-h, double-blind,fixed-dose clinical trial [31]. Patients were randomly assignedto receive up to four injections (every 2 h as needed) of 2 mg(n = 54) or 10 mg (n = 63) of ziprasidone i.m. The Behav-ioral Activity Rating Scale (BARS) [32] measured behavioralsymptoms at baseline and the response to treatment up to4 h after the first i.m. injection. Ziprasidone i.m. 10 mgrapidly reduced symptoms of acute agitation and was sig-nificantly more effective (p < 0.01) than the 2-mg dose upto 4 h after the first injection. Significantly more patientstreated with ziprasidone i.m. 10 mg versus 2 mg wereBARS responders 2 h after the first dose (57.1% vs 29.6%,p < 0.001). No acute dystonia or behavioral disinhibitionwere reported.

In a prospective, double-blind, 24-h study, 40 patients withschizophrenia, schizoaffective disorder, bipolar disorder withpsychotic features or another psychotic disorder, and ascore ‡ 3 (mild) on at least three PANSS items (anxiety,tension, hostility and excitement) were randomized toziprasidone i.m. 20 mg and 38 patients to ziprasidone i.m.2 mg [28]. Up to three more doses could be given 4 h apartduring the 24 h. A significantly greater reduction in meanBARS [32] score was recorded with ziprasidone i.m. 20 mgfrom 30 min after the first dose, and this was maintained untilat least 4 h post-dose (p < 0.001). Two hours after the firstinjection, 90% of patients receiving ziprasidone 20 mg wereBARS responders compared with 34% of those receiving

Ziprasidone


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2 mg ziprasidone (p < 0.001). Significant reductions were alsoseen with ziprasidone for PANSS agitation items (p < 0.05)and CGI-S at 4 h (p = 0.008). Both ziprasidone doses werewell tolerated, and ziprasidone i.m. 20 mg was not associatedwith EPS, dystonia, akathisia, respiratory depression or withexcessive sedation.

Comparison of the two studies using identical design, com-paring 10 mg i.m. [31] or 20 mg i.m. [28] ziprasidone with2 mg i.m. ziprasidone in patients with similar levels of psy-chopathology indicates that efficacy with 10 or 20 mg ofziprasidone i.m. is significant and dose related.

Another study compared up to 3 days of flexible-dose i.m.ziprasidone (max. daily dose 80 mg) and i.m. haloperidol(max. daily dose 40 mg) and assessed the transition fromintramuscular to oral treatment (80 -- 200 mg/day and10 -- 80 mg/day respectively) in 132 hospitalized patientswith acute psychotic agitation [29]. Mean reductions inBPRS total, BPRS agitation items and CGI-S scale scoreswere statistically significantly greater (p < 0.05, p < 0.01 andp < 0.01, respectively) after i.m. ziprasidone than i.m. halo-peridol. Additional reductions in scores occurred in bothgroups following transition to oral treatment. Fewer patientsin the ziprasidone had movement disorders and requiredanticholinergic medication during both intramuscular andoral treatment. QTc mean prolongation was 2.14 ms withziprasidone and 2.22 ms with haloperidol.

The efficacy and safety of i.m. ziprasidone has also beencompared with that of i.m. olanzapine and i.m. aripiprazolein a post hoc analysis of pivotal registration trials [33]. Strongertherapeutic effects were seen for studies of i.m. ziprasidoneand i.m. olanzapine than i.m. aripiprazole, with a NNT fortreatment of agitation versus placebo of 3 for i.m. ziprasidone10 -- 20 mg (95% CI 2 -- 4), 3 for i.m. olanzapine 10 mg(95% CI 2 -- 3), and 5 for i.m. aripiprazole 9.75 mg(95% CI 4 -- 8). For i.m. aripiprazole, the NNH versusplacebo was 20 for headache (95% CI 11 -- 170) and 17 fornausea (95% CI 11 -- 38), compared with 15 for head-ache with i.m. ziprasidone (95% CI 8 -- 703) and 50for treatment-emergent hypotension with i.m. olanzapine(95% CI 30 -- 154).

2.1.2 Long-term treatment of

schizophrenia -- comparative studiesLong-term studies have confirmed that the comparable effi-cacy of ziprasidone versus other SGAs was maintained forup to 44 weeks of treatment [34,35].

One hundred and twenty-six patients, who completed a6-week double-blind trial of ziprasidone or olanzapine,had a CGI improvement score of £ 2 or a ‡ 20% reductionin PANSS total score at the end of the acute study and wereoutpatients, entered a blinded 6-month continuation studyusing a flexible dosing regimen, based on the investigators’clinical judgment [34]. At the end of the study, meandoses for ziprasidone and olanzapine were 135.2mg/day (range78 -- 162 mg/day) and 12.6 mg/day (range 5 -- 15 mg/day),

respectively. During this continuation study, 69.1% ofziprasidone and 70.4% of olanzapine patients dropped outof treatment (9.1% and 8.5%, respectively, for reasons relatedto the study drug).

The primary outcome variable was maintenance ofresponse at 6 months, and this was achieved with ziprasidonein 85.5% of patients and with olanzapine in 84.5%. Compa-rable improvements were also seen in BPRS total, CGI-S,PANSS total and subscales, and CDSS. Olanzapine continuedto be associated with significant increases in weight (4.97 vs-0.82 kg, p < 0.01) and BMI (1.31 vs -0.59, p < 0.01), totalcholesterol and LDL-C, and fasting insulin compared withbaseline values from the acute study.

In a similar 28-week study [36], the olanzapine-treatedpatients showed significantly more improvement than theziprasidone-treated patients on the PANSS overall scale andall subscales, and on the CGI-S and CGI-I. However,compared with the Simpson et al. study [34], the mean modaldose of ziprasidone was below (115.96 mg/day; SD = 39.91)the optimal dose range of 120 -- 160 mg/day and lowerthan the mean dose used in the earlier acute study bySimpson et al. [17]. By contrast, the mean modal dose ofolanzapine of 15.27 mg/day (SD = 4.52) was higher thanthe mean dose used in the long-term Simpson trial [34]. Inaddition, the dosing schedule in the Breier et al. study [36]

was such that the maximum ziprasidone dose of 160 mg/dayused in this study (as per the US package insert) could havebeen reached after 2 weeks, while the maximum olanzapinedose of 15 mg/day as per US package insert at the time ofthe study was reached after 1 week. It is therefore possiblethat differences in mean daily doses and uptitration regimensmay account for differences in the Simpson et al. [34] andBreier et al. [36] studies.

In a second continuation study, 139 patients who hadresponded to acute treatment with ziprasidone or risperidonetook part in a 44-week, double-blind continuation study [35].Sixty-two patients received ziprasidone 80 -- 160 mg/day and77 patients received risperidone 6 -- 10 mg/day for up to44 additional weeks. Both the ziprasidone and risperidonegroups showed statistical improvement from baseline in PANSSand CGI-S scores at the end of the study, with no significantdifferences between treatment groups. Response was main-tained in 75% of ziprasidone and 74% of risperidone-treatedpatients. More risperidone-treated patients completed thestudy (41.6%) than ziprasidone-treated patients (33.9%), butthe difference was not statistically significant. Ziprasidone-treated patients who completed the study showed greaterimprovement in depressive symptoms assessed by the Mont-gomery and Asberg Depression Rating Scale (MADRS) [37]

than risperidone-treated patients (p < 0.05). Ziprasidone wasassociated with a more favorable effect on EPS measures andprolactin as well as less weight gain than risperidone.

The effectiveness of two dose regimens of ziprasidone(40 -- 80 mg/day twice daily, n = 72; or 80 -- 120 mg/day asa single dose, n = 67) was compared with that of haloperidol



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(5 -- 20 mg/day; n = 47), in a double-blind, randomized,3-year (156 weeks) continuation study in schizophrenia,following a 40-week core phase [38]. Efficacy evaluation wasbased on remission criteria for schizophrenia proposed byAndreassen et al. [39] which require maintenance, over a6-month period, of ratings of mild or less (£ 3) on eight PANSSitems. Compared with haloperidol, ziprasidone treatmentresulted in significantly higher proportions of patients meetingfull remission criteria (p < 0.05) in the final 6 months of thestudy. Ziprasidone showed a numerically faster onset of remis-sion (68 and 71 days for twice-daily and single-daily doseadministration, respectively) than haloperidol (153 days), butthe difference was not significant. Both ziprasidone groupsshowed significantly greater improvement in Quality of LifeScale (QLS) scores and increase in symptom-severity remissionthan haloperidol over the 3-year extension phase.These findings support the efficacy of both ziprasidone

dose regimens in the long-term treatment of patientswith schizophrenia.

2.1.3 Ziprasidone in patients refractory or intolerant

to other treatmentsThe efficacy of ziprasidone has also been shown to be compa-rable to that of other antipsychotic agents in schizophreniapatients who were refractory or intolerant to other treat-ments [40,41], though switching treatment-refractory patientsfrom clozapine to ziprasidone cannot be recommended as ithas not been evaluated in clinical trials.A total of 306 patients with treatment-resistant schizo-

phrenia were randomized to ziprasidone up to 160 mg/dayor chlorpromazine up to 1200 mg/day [40]. Treatmentresistance was defined as at least three treatment periods ofat least 6 weeks each with two or more antipsychotic agentsduring the past 5 years without significant response thatwas unresponsive to 6 weeks of open-label haloperidol(£ 30 mg/day). Ziprasidone was initiated at 20 mg b.i.d.,increased to 40 mg b.i.d. on day 4. An increase to 60 mgb.i.d. on day 8 was permitted, and additional increases to80 mg (no earlier than day 12) or decreases were allowed inaccordance with the investigator’s judgment. Chlorpromazinewas initiated at 50 mg b.i.d. and increased to 100 mg b.i.d. onday 4, 150 mg b.i.d. on day 8 and 200 mg b.i.d. on day 11.Further increases, to 400 mg b.i.d. (on or after day 15)and 600 mg b.i.d. (on or after day 21), or decreases werepermitted at the investigator’s discretion.The primary efficacy measures were BPRSd, PANSS total

score, BPRSd core psychotic symptoms and CGI-S, whilesecondary efficacy variables included PANSS total score,PANSS negative subscale, and the MADRS. Improvementsin efficacy variables were greater with ziprasidone at weeks 3and 6, reaching statistical significance versus chlorpromazine(p < 0.05) at week 6 for CGI-S and week 12 for PANSS neg-ative subscale. Improvements in BPRSd total and core itemsand PANSS total scores were comparable at weeks 9 and 12.Ziprasidone was associated with a greater decrease in median

prolactin levels and a lower incidence of clinically significantweight change.

In a study in treatment-refractory schizophrenia,147 patients with a history of resistance and/or intoleranceto at least three acute cycles with different antipsychoticagents given at therapeutic doses, and a greater illness severitythan typically reported in trials of treatment-refractorypatients, were randomized to ziprasidone 80 mg/day b.i.d.for the first 3 days and flexibly dosed (80 -- 160 mg/day)thereafter, or clozapine 25mg/day, titrated to 300mg/day over10 days, maintained at this dose for 1 week, and dosed flexibly(250 -- 600 mg/day) thereafter [41].

Comparable and significant decreases from baseline wereseen with both treatments for PANSS total scores, CGI-S,CGI-I, CDSS and Global Assessment of Functioning(GAF) [42]. On the primary Intention to Treat (ITT)-LOCF analysis, baseline-to-endpoint decreases in PANSStotal scores were similar in the ziprasidone (-25.0 ± 22.0,95% CI -30.2 to -19.8) and clozapine (-24.5 ± 22.5, 95%CI -29.7 to -19.2) groups. A progressive and significantreduction from baseline in PANSS total score was observedfrom day 11 in both study arms.

Similar rates of early discontinuation due to adverse eventswere reported for the two treatments and adverse events weremostly of similar mild to moderate severity in the two groups.There were no unwanted effects on prolactin, renal and liverfunction, hematology and cardiovascular parameters. Ziprasi-done, but not clozapine, showed a significant reduction ofSimpson Angus Scale (SAS) [43] and Abnormal InvoluntaryMovement Scale (AIMS) [44] scores of EPS. Ziprasidone alsohad a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol,LDL-C and triglycerides.

2.1.4 Ziprasidone as add-on in treatment refractory

schizophreniaPromising results have been reported when ziprasidone iscoadministered with clozapine in patients with treatmentrefractory schizophrenia [45-47].

In a 6-week, randomized open-label head-to-head trial ofziprasidone or risperidone added to clozapine in treatment-refractory schizophrenic psychosis, marked and statisticallysignificant reductions in PANSS and the Scale for theAssessment of Negative Symptoms (SANS) were seen withboth treatments, together with nonsignificant improve-ments in CGI, Hamilton Rating Scale for Depression(HAMD) and GAF [48]. Both approaches were well tolerated,though the clozapine--ziprasidone group experienced a sig-nificant increase in QTc-interval from 387.7 to 403.2 ms(F = 4.0, df = 1.77, p = 0.043) as evaluated by the for-mula of Fridericia. The maximal value QTc interval in theclozapine--ziprasidone group was 423.5 ms, compared with417.7 ms in the clozapine--risperidone group. Clozapine--ziprasidone was associated with a rise in serum prolactinfrom 15.6 to 48.7 µg/liter (F = 3.47, df = 16.5, p = 0.003).

Ziprasidone


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Over a long-term observation period of 12 months,significant favorable effects of both strategies weremaintained [49].

2.1.5 Naturalistic studies of ziprasidone

in schizophreniaA recent naturalistic study has investigated the effectiveness oforal ziprasidone in 196 patients with acute exacerbations ofschizophrenia or schizoaffective disorder treated as hospitalinpatients [50]. Patients spent a mean 23.4 days in hospital.The mean overall dose of ziprasidone was 136.9 mg/day,and the mean dose at discharge was 186.3 mg/day, with45% of patients taking doses > 160 mg/day at this time.The results of the study showed a rapid and progressiveimprovement in psychopathologic symptoms from the firstweek through to discharge, with response rates according toBPRS and CGI criteria of 74 and 67% respectively. Allchanges from baseline to the study end point for BPRS andCGI scores were clinically relevant, with effect sizes > 0.80.

Results of a 6-month naturalistic study of the effectivenessand tolerability of ziprasidone in 1266 patients with schizo-phrenia were also consistent with those seen in clinical tri-als [51]. Of 1022 patients who were included in the primaryeffectiveness analysis, 47.3% were responders at the end ofthe study (at least 30% reduction in PANSS total score).There were significant and clinically relevant reductions inPANSS total, positive, negative and general psychopathologysubscales scores (effect size of 1.60, 1.83, 0.62 and 1.40 respec-tively). Overall, 35.8% of patients withdrew from the study,9.3% owing to adverse events. Patients who took ziprasidonein doses > 120 mg/day had a lower risk of discontinuation forany cause (OR = 0.46, 95% CI 0.33 -- 0.65).

3. Dosing, administration and uptitration ofziprasidone

There is evidence to show that dosing of ziprasidone in theoptimal dose range (120 -- 160 mg/day), administration withfood and fast uptitration are important factors influencingtherapeutic efficacy as well as treatment discontinuation.

3.1 Ziprasidone dosingIn the EU, recommendations for ziprasidone dosing inschizophrenia, based on pivotal trials, proposed a startingdose of 40 mg twice daily, adjusted on the basis of individualclinical status up to 80 mg twice daily.

However, accumulated evidence about ziprasidone in theyears since introduction indicates that optimal dosing is inthe range of 120 -- 160 mg/day. For example, positron emis-sion tomography (PET) imaging of D2 and 5-HT2 receptoroccupancy in schizophrenia patients showed that a plasmaziprasidone concentration of at least 120 mg/day was requiredto achieve the 60% D2 receptor occupancy required forantipsychotic effects (Figure 2) [52].

Observational data from the USA have shown that meandaily doses of ziprasidone in schizophrenia patients rosefrom 112 mg/day soon after the drug became available in2001 to 138 mg/day in December 2005 [53]. But even this isat the lower end of the optimal range.

Yet there is good evidence [51,54-57] to indicate that discon-tinuation rates are significantly higher in schizophreniapatients taking ziprasidone in doses < 120 mg/day than inpatients taking higher doses [6].

In an analysis of data for maximum ziprasidonedoses achieved in 33,340 patients with schizophrenia/schizoaffective disorder or bipolar disorder, 16.6% receivedlow-dose (20 -- 60 mg/day) ziprasidone, 22.0% medium-dose (61 -- 119 mg/day) and 61.4% high-dose (120 -- 160mg/day) [54]. Mean time to discontinuation for low, medium,and high doses in schizophrenia patients was 90.5,117.2 and 201.6 days, and the hazard ratios for discontinuingtherapy were significantly lower for the medium- (0.84) andhigh-dose (0.57) groups relative to the low-dose group [54].

The starting dose of ziprasidone may also affect the likeli-hood of patients continuing their treatment. In a large sampleof more than 1000 Medicaid patients with schizophrenia orschizoaffective disorder, those started on a high dose of zipra-sidone (120 -- 160 mg/day) were 20% less likely to discon-tinue treatment up to 12 months after starting treatmentthan those who started with a low dose (40 -- 80 mg/day) [55].

Another study of a similar number of patients identifiedthrough medical and pharmacy claims data showed similarfindings [56]. The 6-month risk of discontinuation wassignificantly lower in patients started on ziprasidone120 -- 160 mg/day than those on an initial starting dose of40 mg up to < 80 mg/day (HR = 0.737 for high-dose vslow-dose, 95% CI 0.581, 0.935; p = 0.012) with a trendtowards lower risk of discontinuation with ziprasidone120 -- 160 mg/day compared with ziprasidone 80 mg/day toup to < 120 mg/day.

A post hoc analysis of pooled data for the first 28 daysfrom four prospective double-blind, fixed-dose RCTs of zipra-sidone reached the same conclusions as the ‘real-world’observational studies: that higher doses of ziprasidone(120 -- 160 mg/day) were associated with significantly lowerall-cause discontinuation rates (Figure 3) [57]. All-cause discon-tinuation was defined as when an enrolled subject ceased toparticipate in the study, regardless of the circumstances, beforecompletion of the protocol. All-cause discontinuation forziprasidone ranged from 26.9% for the 160-mg/day doseto 40.9% for the 40-mg/day dose and 45.5% for the80-mg/day dose. This compared to an all-cause discontinua-tion rate of 49.5% for placebo. p values for a Cox proportionalhazard analysis for ziprasidone 40, 120 and 160 mg/day versusplacebo were p = 0.0468, p = 0.031 and p < 1.0001 respec-tively. The NNTs for avoiding one additional all-cause discon-tinuation compared with placebo were 12 (40 mg/day),25 (80 mg/day), 9 (120 mg/day) and 4 (160 mg/day). The120 mg/day and 160 mg/day groups were the only ziprasidone



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regimens associated with significantly lower all-cause discon-tinuation rates versus placebo in both the survival analysisand in examination of the NNT (p = 0.031 and p < 0.0001,respectively). The 160-mg/day group was associated withlower all-cause discontinuation rates versus lower-doseziprasidone regimens (p = 0.0158 for versus 40 mg/day,

p = 0.002 for versus 80 mg/day; Figure 3). Efficacy accountedfor 51% of all medication discontinuations across ziprasidonegroups, compared with 62% for placebo.

To address possible concerns about the potential for pro-longed QTc interval with higher doses of ziprasidone, a studyto compare the effects of oral ziprasidone and oral haloperidol

Greater than 80% D2 occupancy increases risk of extrapyramidal symptoms

80

100

60

40

20

00 20 40 60 80 100

5-HT2 receptor

60% D2 occupancy = 120 mg/d

Ant

ipsy

chot

ic e

ffica

cy

D2 receptors

120 140 160

Ziprasidone plasma level (ng/ml)

Rec

epto

r o

ccu

pan

cy (

%)

Figure 2. Positron emission tomography (PET) imaging data: plasma level versus D2 occupancy at 12 h post ziprasidone dose.Clinical response to atypical antipsychotics occurs at approximately 60 to 80% D2 receptor occupancy.

Estimated oral dose of ziprasidone associated with 60% D2 occupancy is 120 mg/d.

Reprinted with permission from the American Journal of Psychiatry, (Copyright 2004). American Psychiatric Association [52].

Study duration (days)

Pro

bab

ility

of

rem

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ing

on

stu

dy

trea

tmen

t

Placebo (n = 273)

80 mg/day (n = 154)

40 mg/day (n = 186)120 mg/day (n = 125)

160 mg/day (n = 104

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0 7 14 21 28

Figure 3. All-cause discontinuation Kaplan--Meier Survival Curve by treatment and ziprasidone dose.Adapted from [57] with permission from Elsevier.

Ziprasidone


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on QTc interval was carried out in 59 patients with schizo-phrenia or schizoaffective disorder who had no clinicallysignificant abnormality on electrocardiogram (ECG) atscreening [58]. Escalating oral doses of ziprasidone 40,160 and 320 mg/day or haloperidol 2.5, 15 and 30 mg/daywere administered. Mean changes from baseline in the QTcinterval (ms) for ziprasidone were 4.5, 19.5 and 22.5 forsteady-state doses of 40, 160 and 320 mg/day, respectively.Comparative figures for haloperidol 2.5, 15 and 30 mg/daywere -1.2, 6.6 and 7.2 respectively. No patient in eithertreatment group experienced a QTc interval of ‡ 450 ms.

3.2 Ziprasidone and foodThe effectiveness of oral ziprasidone is enhanced by ensuringthat it is administered with a ‡ 500-kcal meal. If this doesnot occur, absorption of oral ziprasidone is substantiallyreduced and cannot be overcome by increasing the prescribeddose [6]. When ziprasidone is not taken with food, bioavail-ability is reduced by at least 50% [5]. Doubling an oral doseof 40 -- 80 mg without food will not double the serumdrug concentration because increases in AUC and maximumserum drug concentrations are dose proportional under fedconditions, and this is not the case in the absence of food [6].

Additional evidence of the effects of food was obtained in asmall study in 15 patients with schizophrenia, schizoaffectivedisorder, bipolar disorder or psychotic disorder who tookziprasidone under six meal conditions in randomized sequen-ces (fasted, low calorie/low fat, low calorie/high fat, highcalorie/low fat, and high calorie/high fat) [59]. Maximum zipra-sidone exposures were observed with high-calorie (1000 kcal)and medium-calorie (500 kcal) meals, which were nearly twicethose seen under fasting conditions. Low-calorie meals(250 kcal) were associated with exposures ~ 60 -- 90% lowerthan those of medium- and high-calorie meals. The fat con-tent of meals had no significant impact on outcomes. Therewas less variability in ziprasidone exposure when the drugwas taken with medium- and high-calorie meals than withlow-calorie meals and under fasting conditions.

3.3 The importance of fast titrationRapid uptitration of ziprasidone to the optimal daily doseof 120 -- 160 mg/day by day 3 of treatment was success-fully achieved in many of the clinical trials demonstratingcomparable efficacy of the drug with other SGAs [5,23,25].

For example, in a placebo-controlled, 6-week study of302 patients with an acute exacerbation of subchronicschizophrenia, patients were randomized to ziprasidone80 or 160 mg/day [60]. Those who received the higher dosewere started on ziprasidone 80 mg/day for 2 days and thentransferred to the full dose of 160 mg/day. Improvements inPANSS total, BPRS total, BPRS core items, CGI-S andPANSS negative subscale scores were significantly greaterwith both doses of ziprasidone than placebo (p < 0.05), andresponder rates (‡ 30% reduction) were significantly higherwith ziprasidone 160 mg/day than with placebo (p < 0.05).

In patients with clinically significant depressive symptoms,there was a significantly greater improvement in MADRSscore with ziprasidone 160 mg/day than placebo (p < 0.05).The percentage of patients experiencing adverse events wassimilar in each treatment group, and resultant discontinuationwas rare, demonstrating that fast uptitration was well tolerated.

4. Management of agitation and insomnia

Ziprasidone has a good safety profile, and is associated with fewdrug interactions [5]. Rapid uptitration of ziprasidone is usuallywell tolerated [60-62]. However, concerns have been raised aboutthe potential for agitation and insomnia with higher doses ofthe drug, and when patients are switched from sedating anti-psychotic agents -- though use of a nonsedating antipsychoticagent may have advantages for cognition [63].

Reports of agitation and insomnia with ziprasidone areoften associated with a lack of sedation [64], especially whenswitching from a more sedating antipsychotic agent, such asolanzapine, to a less sedating agent, such as ziprasidone. Ben-zodiazepines were permitted across all the clinical trialsreviewed previously, and this may explain why activationand insomnia have presented less of a problem in clinical trialsthan in clinical practice.

Bearing in mind the effects of ziprasidone on dopamine,serotonin and noradrenaline transmission, and the role ofthese neurotransmitters on sleep, a double-blind, placebo-controlled, randomized, crossover study was carried out toinvestigate the effects of ziprasidone on polysomnographicsleep structure and subjective sleep quality [65].

Administration of ziprasidone 40 mg orally 2 h beforebedtime was shown significantly to increase total sleep time,sleep efficiency, percentage of sleep stage 2, and slow-wave sleep [65]. The number of awakenings, proportion ofrapid eye movement (REM) and REM density were decreasedand REM latency increased. These REM sleep-suppressingproperties were similar to those of many antidepressant drugs.

In addition, i.m. ziprasidone has been shown to signifi-cantly reduce psychomotor agitation and other symptoms ofpsychosis in acutely agitated schizophrenia patients [28]. Ithas also been associated with significantly improved BPRSscores compared with i.m. haloperidol [29] and therapeuticeffects compared with i.m. aripiprazole [29].

5. Beneficial effect on cardiometabolic riskfactors

Patients with schizophrenia are approximately twice as likely todie as a result of cardiovascular disease as the rest of the popu-lation [66], and have an increased prevalence of cardiovascularrisk factors, such as obesity, smoking, diabetes, hypertension,dyslipidemia and metabolic syndrome [67].

In a number of the studies reviewed previously,ziprasidone was associated with lower weight gain and less



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adverse effect on metabolic risk factors than comparatorSGAs [17,24,25,34,41].An analysis of short- and long-term weight effects seen in

patients taking part in 21 randomized, placebo-controlled,parallel-group studies from an integrated clinical trial databasesupported the favorable weight effects seen with ziprasidonecompared with olanzapine and risperidone (Figure 4) [68].During 1 year of treatment, the incidence of weight gain

for patients treated with ziprasidone (17%) was not signifi-cantly different from the placebo (13%) or haloperidol(41%) groups based on 95% confidence interval. By contrast,weight gain for the olanzapine (57%) and risperidone (39%)groups was significantly greater than for placebo. Medianweight change with ziprasidone (-0.082 kg/month) was com-parable to placebo (-0.145 kg/month) and less than with hal-operidol (+0.223 kg/month), olanzapine (+0.680 kg/month)and risperidone (+0.249 kg/month).In the 1-year, open-label EUFEST study of first-episode

schizophrenia, weight change from baseline was highest inpatients treated with olanzapine, quetiapine or amisulprideand lowest with ziprasidone and haloperidol. Similarly, fewerziprasidone-treated patients had a > 7% weight gain frombaseline than those on the other treatments [27].In the Clinical Antipsychotic Trials of Intervention Effective-

ness (CATIE) study, the time to the discontinuation of treat-ment for any cause was significantly longer in the olanzapinegroup than in the quetiapine (p < 0.001) or risperidone(p = 0.002) groups, but not in the perphenazine (p = 0.021)or ziprasidone (p = 0.028) groups [69]. However, the

comparison of secondary outcome variables (i.e., weightchange, cholesterol, triglyceride and hemoglobin A1C levels),showed that ziprasidone was the only drug associated withimprovement in metabolic parameters in this trial (Figure 5) [69].

6. Cardiac safety

Modest prolongation of QTc interval was observed during thedevelopment of ziprasidone [5]. In placebo-controlled trials,oral ziprasidone increased the QTc interval compared withplacebo by ~ 10 ms at the highest recommended daily doseof 160 mg [5]. In clinical trials with oral ziprasidone, theECGs of 2/2988 (0.06%) patients who received ziprasidoneand 1/440 (0.23%) patients who received placebo revealedQTc intervals exceeding the potentially clinically relevantthreshold of 500 ms. In the ziprasidone-treated patients,neither case suggested a role of ziprasidone.

To investigate further the possible effects of ziprasidone onQTc interval, a comparative study directly comparing theQT/QTc-prolonging effect of oral ziprasidone with severalantipsychotics was conducted in patient volunteers [70]. MeanQTc intervals did not exceed 500 ms in any patient takingany of the antipsychotics studied, in the absence or presenceof metabolic inhibition. The mean QTc interval change wasgreatest in the thioridazine group, both in the presence andabsence of metabolic inhibition. The presence of metabolicinhibition did not significantly augment QTc prolongationassociated with any agent. Each of the antipsychotics studiedwas associated with measurable QTc prolongation at

Perc

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%)

Shortterm

studies

Patientsexposedfor 1 year

60

40

> 7% weight loss > 7% weight gain

20

0

Perc

enta

ge (

%) 60

40

20

0

Placebon = 187

-0.3Mean change (kg)

Mean change (kg)

Ziprasidonen = 1067

0.6

Risperidonen = 112

1.9

Olanzapinen = 92

5.1

Haloperidoln = 230-0.009

Placebon = 301

-4.3

Ziprasidonen = 322

-1.9

Risperidonen = 85

3.4

Olanzapinen = 15

4.3

Haloperidoln = 18

1.5

> 7% weight loss > 7% weight gain

*

*

*

*

Figure 4. Ziprasidone: weight-neutral profile in short- and long-term studies in schizophrenia.*p < 0.001 (vs placebo for distribution of weight change from base line).

Short time: up to 12 weeks; Long term: 1-year exposure.

Adapted from [68] with permission from Elsevier.

Ziprasidone


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steady-state peak plasma concentrations, which was notaugmented by the metabolic inhibitor, ketoconazole.

Changes in QTc interval with ziprasidone in the trialsreviewed previously [17,22,25,34,36,40,41,63] were comparablewith those seen in earlier placebo-controlled and comparativetrials [5,71].

In a previously described prospective, randomized, open-label, parallel-group study [58], 59 patients with schizophreniaor schizoaffective disorder without clinically significant abnor-mality on ECG at screening were treated with escalating dosesof ziprasidone (40, 160 or 320 mg/day) or haloperidol (2.5,15 and 30 mg/day). The QTc interval in ziprasidone- andhaloperidol-treated patients increased with dose, but did notresult in any patient experiencing a QTc interval of ‡ 450 ms.

To elucidate the effects of i.m. ziprasidone on QT/QTcinterval, a study investigating the QT/QTc effect of high-dose i.m. ziprasidone (20 mg, then 30 mg), with high-dose i.m.haloperidol (7.5 mg, then 10 mg) as a control, was done inpatients with schizophrenia or schizoaffective disorder inwhom long-term antipsychotic therapy was indicated. Theresults showed a mean increase in QTc from baseline for zipra-sidone of 4.6 ms following the first injection and 12.8 ms fol-lowing the second injection [5]. This compared with a meanQTc increase from baseline for haloperidol of 6.0 ms followingthe first injection and 14.7 ms following the second injection.No patients had a QTc interval exceeding 500 ms, even though

the second dose of ziprasidone was 50% higher than themaximum recommended dose.

7. Transition from intramuscular to oralziprasidone

Smooth transition from intramuscular ziprasidone to the oralformulation can be achieved without difficulty, is associatedwith sustained improvement in symptoms and is welltolerated [71].

A 6-week intramuscular-to-oral transition study in572 patients with acute schizophrenia or schizoaffective dis-order compared the efficacy and tolerability of ziprasidonei.m. or haloperidol i.m. for up to 3 days, followed by oralziprasidone or oral haloperidol to the study end point [71].At the end of intramuscular treatment, improvements inBPRS total and negative subscale scores were significantlygreater with ziprasidone than with haloperidol (p < 0.0018and p < 0.0001, respectively). At the study end point, therewere no significant differences in BPRS total scores, butthere was a significantly greater improvement in BPRSnegative subscale scores in ziprasidone-treated patients(p < 0.0001). Haloperidol-treated patients exhibited signifi-cantly more EPS at the end of intramuscular treatmentand at the end of the study (p < 0.0001). They also hadsignificantly higher ratings for akathisia (p < 0.0001) and

Mea

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n = 185

n = 143

n = 262 n = 268 n = 286

n = 212 n = 143

n = 262 n = 268 n = 286

n = 212

-9.2

-2.1

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-18.1

-2.6

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8.3

n = 341 n = 337

n = 261 n = 89

n = 139 n = 137

n = 157

n = 107-2.0 -0.10

0.08 0.05

0.41

0.10n = 336

9.4

-1.6

1.1

Weight change Hemoglobin A1C levels

Cholesterol levels Triglycerides

0.8

Ziprasidone Risperidone Quetiapine Olanzapine Perphenazine

Mea

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LO

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Figure 5. Ziprasidone was the only antipsychotic associated with improvement in metabolic variables in the CATIE trial.CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness.

Adapted from [69].



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MDB (p < 0.005), as well as higher incidences of movementdisorder-related adverse events.The dosing regimens used in the study were: 10 mg or

20 mg ziprasidone i.m./injection to a maximum of 40 mgi.m./day; or 2.5 mg or 5 mg haloperidol i.m./injection, to amaximum of 10 mg i.m./day. During oral treatment, patientsreceived ziprasidone 80 -- 100 mg/day or haloperidol10 -- 40 mg/day. The mean daily dose of ziprasidone i.m.was 20.1 mg, and for haloperidol i.m. it was 6.8 mg. Meanoral ziprasidone dose was 116 mg/day, and mean oralhaloperidol dose was 11.5 mg/day during the oral phaseof treatment.In summary, dosing recommendations for intramuscular

ziprasidone and transition to oral ziprasidone are as follows:

. Doses of 10 mg i.m. may be administered every 2 h

. Doses of 20 mg i.m. may be administered every 4 h

. Maximum intramuscular daily dose: 40 mg

. Intramuscular administration for more than 3 consecu-tive days has not been studied

. If longer-term therapy with ziprasidone is indicated,intramuscular administration should be replaced withoral administration

. Coadministration of intramuscular and oral ziprasidoneis not studied.

8. Conclusions

To achieve the level of efficacy reported in the individual clin-ical trials in everyday clinical practice, it is important to upti-trate rapidly the dose of ziprasidone to the optimal dose range(120 -- 160 mg/day) and to ensure that treatment is adminis-tered with food. Ziprasidone has a good safety profile, withfew drug interactions, and the risk of agitation and/or insom-nia associated with rapid uptitration or switching from a moresedating antipsychotic agent can be reduced by short-termcoadministration of a benzodiazepine when clinically needed.

9. Expert opinion

The expert opinion that follows is based on extensive discus-sion of the clinical trial data that have been reviewed andthe authors’ own experiences of optimizing the use of ziprasi-done in everyday practice. It includes suggestions, based onexperience rather than clinical trials, of how to maximizeefficacy further while minimizing adverse effects.

9.1 EfficacyResults from comparative RCTs with other frequently usedSGAs demonstrate comparable efficacy of ziprasidone andcomparator drugs, coupled with a favorable tolerability pro-file, in particular regarding the effects on body weight andmetabolic indices. Results of naturalistic studies with ziprasi-done further confirm its effectiveness in everyday clinicalpractice. Typically, in the RCTs and naturalistic studies, rapid

uptitration of dosing was used, daily doses were pushedtowards the optimal dose range, and ziprasidone was adminis-tered with food. In addition, coadministration of benzodiaze-pines as per clinical need was allowed to manage side effectssuch as activation or insomnia.

9.2 Optimizing dosageThe ability to rapidly uptitrate the dose of ziprasidone has obvi-ous advantages for early control of all symptoms of psychosis inthe acute setting. From clinical trials and practical experience, itis clear that patients can be started on a dose of ziprasidone40 mg twice daily taken with food. Daily dosage may subse-quently be adjusted on the basis of individual clinical statusup to a maximum of 80 mg twice daily. If indicated, the maxi-mum recommended dose may be reached as early as day 3 oftreatment. Higher doses of ziprasidone are related not only toenhanced efficacy but also with lower discontinuation rates.

The importance of ziprasidone dosing with food cannotbe over-stressed, and it is essential to provide patients andcaregivers with practical information about what and whento eat. As demonstrated in clinical trials, a calorie intake of‡ 500 kcal is needed to ensure adequate bioavailability. As canbe seen in Table 3, this cannot be achieved with a small snack.Instead, it requires a balanced meal, and patients/carers needexamples of locally available foods appropriate to differentmealtimes that will provide the necessary calorie intake.

Available data support the effectiveness of twice- or once-daily administration of ziprasidone in long-term patientswith schizophrenia [38]. Clinical usage of ziprasidone in dos-ages greater than 160 mg/day is not systematically investi-gated, and the safety profile above 160 mg/day has not beenconfirmed [6].

9.3 Addressing agitation/insomniaAs demonstrated in clinical trials, transient coadministrationof benzodiazepines, such as lorazepam, can be used effectivelyto reduce agitation/insomnia, especially during uptitrationof ziprasidone or when switching from a more sedatingantipsychotic agent.

When initiating treatment with oral ziprasidone, it shouldbe remembered that it will take 2 -- 3 days to achieve a steadystate with the drug, and the blood level will be relatively lowduring that period of time. In addition, peak blood concen-trations of ziprasidone are reached after 6 -- 8 h, so administer-ing the drug at bed time may not result in the patientfalling immediately to sleep. These pharmacokinetic factorssupport temporary benzodiazepine use at the beginning ofziprasidone treatment.

When a patient switches from sedating medication to anonsedating treatment, it is unsurprising that they experiencesleep difficulties. These can be addressed by attention to sleephygiene, in particular advice to reduce caffeine intake, as wellas possible coadministration of benzodiazepines.

Psychiatrists will be understandably wary of administeringbenzodiazepines over long periods of time, as this conflicts

Ziprasidone


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with extensive guidance about the need to restrict treatment toshort periods for the vast majority of patients. An alternativecould be administration of other sedating agents in low dos-age. In either case, coadministration of benzodiazepines/sedating agents should be guided by clinical need, and theadvisability of continued treatment evaluated regularly.

Long-term benzodiazepine administration may also signifi-cantly impair cognitive functioning. While coadministrationis undoubtedly useful during transition from a sedating antipsy-chotic agent, the period of benzodiazepine coadministrationwith ziprasidone should be limited to a maximum of 2 weeks.

For patients for whom there are concerns about the use ofbenzodiazepines, an alternative option could be a combina-tion of ziprasidone with a low dose of a more sedating SGAsuch as quetiapine, or the antidepressant trazodone.

However, it should be kept in mind that combination ofziprasidone and quetiapine or trazodone has not been testedin randomized, placebo-controlled trials and, therefore, theuse of a benzodiazepine is usually preferred.

9.4 Practicalities of switching to ziprasidoneA growing body of evidence is showing that significantimprovements in schizophrenia symptom control can beachieved when patients are switched from FGAs and SGAsto ziprasidone, with additional benefits for improved cardio-metabolic parameters, such as weight reduction and morefavorable lipid profile.

A number of switching strategies were used in ziprasidoneswitch studies, including immediate-switch and 1-week,dose-tapering approaches [61] (Table 4).

Data from switch studies support the safety, tolerabilityand acceptability of all three strategies. Agitation, anxiety orinsomnia, which may arise when switching from more sedat-ing agents, can be minimized with appropriate use of benzo-diazepines and other sedating agents. The choice ofswitching strategy will depend on the patient and the setting.Clinical issues to be considered when starting or switching toziprasidone are summarized in Box 2.

However, in some clinical situations (e.g., stable outpatientson a very potent anticholinergic and sedating agent or thosepatients in whom medication switch is not a matter of urgency)a longer switch time (up to 4 weeks) could be advisable.

9.5 Use of intramuscular ziprasidonePrevious suboptimal experience with oral ziprasidone makessome psychiatrists reluctant to use intramuscular ziprasidonein emergency situations. However, evidence from clinicaltrials shows that intramuscular ziprasidone offers effectivecontrol of psychomotor agitation and other symptoms ofpsychosis in acutely agitated schizophrenia patients. Safetystudies have confirmed that the risk of prolongation of theQTc interval with intramuscular ziprasidone is lower thaninitially perceived. Additional research has demonstratedthat smooth transition from intramuscular to oral treatmentcan be achieved once patients are stabilized and, for thesereasons, it would appear that intramuscular ziprasidone canplay a useful role in the management of acutely agitatedschizophrenia patients.

Acknowledgements

The authors acknowledge the efforts of J Bryan in providingeditorial support, preparing the first draft of this manuscript,revising the paper based on author feedback and stylingthe paper for journal submission. J Bryan received an hono-rarium from Pfizer in connection with the development ofthis manuscript.

Declaration of interest

Development of this paper was sponsored by Pfizer, Inc.A Fagiolini is/has been a consultant and/or a speaker and/orhas received research grants and/or participated in studiessupported by Boehringer Ingelheim, Bristol-Myers Squibb,Lundbeck, Eli Lilly, Jannssen, Novartis, Pfizer, Sigma Tauand Takeda. B Gallhofer is a chairman of the nationalAstraZeneca Advisory Board in Germany. He lectures forLundbeck International, AstraZeneca Germany, Pfizer Interna-tional, Servier Germany, Bristol-Myers Squibb Germany, andis a former member of the European Zeldox Advisory Board(Pfizer). F Canas has received consultant or speaker feesfrom Bristol-Myers Squibb, Lundbeck, Janssen-Cilag, Pfizer,Schering-Plough and Servier. I Larmo has received honorariaand travel support from Pfizer, Eli Lilly, AstraZeneca,Janssen-Cilag, Bristol-Myers Squibb, Lundbeck, Boehringer

Table 3. Overview of common foods and caloric

counts.

Item Approx. kcal value

1 large bagel 3501 doughnut 1201 cup of cornflakes cereal 100Small fast food French fries 230Ham and cheese sandwich 350Hamburger, with bun, plain 270Hotdog, with bun, plain 240Egg sandwich in English muffin 300Danish fruit pastry 3351 egg, boiled 702 snack cakes with creme filling 2501 slice pizza 35020 potato chips (crisps) 2001 orange 801 banana 901 apple 80

All foods alone have < 500 kcal, and each one alone would not be enough to

ensure optimal absorption of ziprasidone.

With kind permission from Springer Science + Business Media: Adv Ther,

Using oral ziprasidone effectively: the food effect and dose-response,

2009;26:739-48, Citrome L.



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Ingelheim and Orion. P Levy has received consultant fees fromGlaxoSmithKline and Pfizer. JM Montes has received unre-stricted scientific grants from Pfizer, and speaker and travel sup-port from Pfizer, Bristol-Myers Squibb and AstraZeneca. Hehas been a consultant for Boehringer Ingelheim, AstraZenecaand Bristol-Myers Squibb. G Papageorgiou has received hono-raria from Schering-Plough, Janssen-Cilag, Pfizer, BoehringerIngelheim, Sanofi-Aventis, and has been a research consultant

for Janssen-Cilag, Pfizer and Eli Lilly, and a speaker forJanssen-Cilag, Pfizer and Boehringer Ingelheim. M Zink hasreceived unrestricted scientific grants from Pfizer, Bristol-Myers Squibb, and speaker and travel support from Pfizer,Bristol-Myers Squibb, AstraZeneca, Eli Lilly and Janssen-Cilag.A Rossi has received honoraria and travel support from Pfizer,Eli Lilly, AstraZeneca, Janssen-Cilag, Bristol-Myers Squibband Boehringer Ingelheim.

Box 2. Clinical issues related to starting or switching to ziprasidone.

1. Assess and communicate to the patient and caregiver what symptom areas or tolerability issues you want to improve withziprasidone2. Assess the patient and caregiver to determine potential challenges or barriers to correct ziprasidone administration that mayexist and provide clear advice to both on how to use ziprasidone, including relevant local examples of proper meals3. Ensure uptitration to optimal dose range (for most patients 120 -- 160 mg/day within 3 days) and continue b.i.d.administration in the optimal dose range with proper meals4. When clinically indicated, manage possible activation or insomnia with temporary coadministration of benzodiazepines orother appropriate sedative agents as needed (max. 3 -- 4 weeks)5. When switching, understand the drug profiles (switching from and switching to) and select the appropriate switchingmethod to manage possible withdrawal/rebound effects

Table 4. Switch strategies investigated in ziprasidone studies [55,56].

Type of switch strategy Definition in ziprasidone studies

Immediate switch Discontinuation of past antipsychotic on the day before initiating ziprasidone andthe initiation of ziprasidone (80 mg/day) on day 1

50 -- 0% taper A dose of antipsychotic equivalent/closest to 50% of the baseline dose wasadministered on day 1, maintained for the first 7 days, and then discontinued.Ziprasidone (80 mg/day) was initiated on day 1

1-week taper 100% of the original antipsychotic dose was maintained on days 1 -- 3, reducedto 50% on days 4 -- 7, and then discontinued. Ziprasidone (80 mg/day) was initiated on day 1

Ziprasidone


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AffiliationAndrea Fagiolini†1, Fernando Canas2,

Bernd Gallhofer3, Ilkka Larmo4, Pedro Levy5,

Jose Manuel Montes6, Georgios Papageorgiou7,

Mathias Zink8 & Alessandro Rossi9

†Author for correspondence1University of Siena School of Medicine,

Department of Neuroscience,

Viale Bracci 1,

53100 Siena, Italy

Tel: +39 0577 586275; Fax: +39 0577 233451;

E-mail: [email protected] Dr R Lafora,

Department of Psychiatry,

Madrid, Spain3Justus Liebig University School of Medicine,

Centre for Psychiatry and Psychotherapy,

Giessen, Germany4Aurora Psychiatric Hospital,

Helsinki, Finland5Hospital Santa Maria,

Psychiatry Department,

Lisbon, Portugal6Hospital del Sureste,

Psychiatric Section,

Madrid, Spain7Evangelismos General Hospital,

Department of Psychiatry,

Athens, Greece8Central Institute of Mental Health,

Department of Psychiatry and Psychotherapy,

Mannheim, Germany9University of L’Aquila,

Department of Experimental Medicine,

L’Aquila, Italy

Ziprasidone


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strategies for successful clinical management of schizophrenia with ziprasidone

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