ziprasidone, a new atypical antipsychotic drug

Ziprasidone, a New Atypical Antipsychotic Drug

Ryan M. Carnahan, Pharm.D., Brian C. Lund, Pharm.D., and Paul J. Perry, Ph.D.

Although the introduction of antipsychotic drugs in 1954 was a breakthroughin the treatment of patients with schizophrenia, these agents have a number ofadverse effects that limit effectiveness and compliance. The atypicalantipsychotic drugs provide an improved tolerability profile, particularly inminimizing extrapyramidal side effects; however, they are associated withsignificant weight gain, which may be related to growing evidence linking theatypical agents with diabetes and hyperlipidemia. Ziprasidone, a new atypicalantipsychotic drug, was demonstrated in clinical trials to be more efficaciousthan placebo and similar in efficacy to haloperidol in the treatment ofschizophrenia. Like the existing atypical agents, ziprasidone has a rate ofextrapyramidal side effects similar to that of placebo and does not causesignificant elevations in prolactin levels. In contrast, ziprasidone has a lowpropensity for causing weight gain. For patients requiring an antipsychoticdrug, ziprasidone represents a new treatment option with a limited adverseeffect profile.(Pharmacotherapy 2001;21(6):717–730)

OUTLINE

Clinical PharmacologyPharmacokinetics

Absorption and DistributionMetabolism and EliminationDrug Interactions

Clinical TrialsSchizophrenia and Schizoaffective DisorderAcute ManiaAcute AgitationTourette’s Syndrome

Adverse EffectsOverviewExtrapyramidal Side EffectsCardiovascular Side EffectsWeight GainParenteral FormulationLaboratory Test AbnormalitiesRash

Dosage and AdministrationSummary

Schizophrenia is a chronic and debilitatingillness affecting an estimated 0.5–1.0% of thepopulation in the United States.1 Adverse effectsand ineffectiveness of treatment in refractory2

patients often limit pharmacotherapeutic options.Schizophrenic symptoms are classified into twoprimary categories: positive symptoms andnegative symptoms. Positive symptoms includehallucinations, delusions, disorganized speech,and disorganized or catatonic behavior. Negativesymptoms include affective flattening, alogia(poverty of speech), anhedonia (lack of pleasurefrom normally pleasurable activities), andavolition (lack of goal-directed behavior). Inaddition to the more traditional dichotomy ofpositive and negative symptoms, the role ofimpaired cognition as a primary feature ofschizophrenia is gaining recognition.3

It is proposed that conventional antipsychoticdrugs exert their effect predominantly byblocking dopamine D2 receptors in the brain.These agents have similar efficacy but differ intheir adverse effect profiles. They are separatedinto two categories: low potency (e.g.,chlorpromazine, thioridazine) versus highpotency (e.g., haloperidol, fluphenazine).Although conventional antipsychotics generally

From the Clinical and Administrative Pharmacy Division,College of Pharmacy (Drs. Carnahan, Lund, and Perry), andthe Department of Psychiatry, College of Medicine (Dr.Perry), University of Iowa, Iowa City, Iowa.

Address reprint requests to Paul J. Perry, Ph.D., Universityof Iowa, College of Pharmacy, S415 Pharmacy Building,Iowa City, IA 52242-1112.

PHARMACOTHERAPY Volume 21, Number 6, 2001

produce a dramatic improvement in positivesymptoms, they have limited benefit for, or mayactually worsen, negative symptoms.4 Theatypical agents differ in pharmacology with theaddition of serotonin 5-HT2 antagonism to thetraditional dopamine D2 antagonist effects andtherefore are classified pharmacologically asserotonin-dopamine antagonists. These agentsare associated with lower rates of extrapyramidalside effects and perhaps better efficacy fornegative symptoms.2, 5 The model atypicalantipsychotic, clozapine, also has proven efficacyin treatment-refractory patients with schizo-phrenia (i.e., patients with treatment failures forat least three different chemical classes ofantipsychotics).

Adverse effects of antipsychotic treatment canhave a substantial impact on the lives of patients.Extrapyramidal side effects include akathisia,dystonia, parkinsonism, and tardive dyskinesia.Sedation, sexual dysfunction, postural hypo-tension, electrocardiographic changes, andweight gain are other problematic adverse effects.Furthermore, adverse effects have beenimplicated as a major factor leading tononcompliance, resulting in poor therapeuticresponse.6, 7 Other concerns arising from adverseeffects include the need for secondarypharmacotherapy, such as anticholinergic drugsand b-blockers, to treat extrapyramidal sideeffects. Anticholinergic drugs are associated witha worsening of the cognitive impairmentassociated with schizophrenia, in addition toblurred vision, urinary retention, constipation,and dry mouth.8 Tolerability of treatment is acritically important consideration whendetermining pharmacotherapy for schizophreniaand other psychotic disorders.

Clinical Pharmacology

Ziprasidone (Geodon; Pfizer, New York, NY) ischemically characterized as a benzothia-zolylpiperazine (Figure 1).9 Its receptor-bindingprofile is similar to that of other atypicalantipsychotic drugs in that it includes both D2and 5-HT2A antagonism. Of the numerousdopamine receptors, the D2 receptor is mostclearly associated with psychosis, and allantipsychotics are potent antagonists of thisreceptor.10 Serotonergic neurotransmission isthought to inhibit dopaminergic neurotransmissionin the midbrain and forebrain, and it appears thatserotonin receptor antagonists disinhibitdopamine neurotransmission in the striatum and

neurocortex.11 Importantly, 5-HT2A blockadeseems to moderate the reduction in dopaminergicfunction caused by the D2 antagonism ofantipsychotics. The 5-HT2A affinity of ziprasidoneis about eight times that of the D2 affinity. Thismoderation seems to help create a balance thatpromotes antipsychotic effects and limitsextrapyramidal side effects.12

In addition to 5-HT2A antagonism, ziprasidoneis a potent 5-HT1D and 5-HT2C antagonist, 5-HT1A agonist, and a moderate inhibitor ofserotonin and norepinephrine reuptake.13 Theinhibition of serotonin and norepinephrinereuptake may increase the efficacy of ziprasidonefor depressive symptoms and negative symptoms;however, to our knowledge such claims are notfirmly substantiated with clinical trials.Ziprasidone has a modest affinity for a1-adrenergic and H1-histaminic receptors, whichare associated with postural hypotension andsedation, respectively. Affinity for M1-muscarinicreceptors is negligible; therefore, ziprasidone isnot associated with anticholinergic adverseeffects.14, 15

Pharmacokinetics

Absorption and Distribution

Linear increases in maximum concentration(Cmax) and area under the curve (AUC) are seenwith ziprasidone in the recommended dosagerange of 80–160 mg/day. The administration ofziprasidone with food approximately doubles itsabsolute bioavailability, increasing it to about60%. Administration with food also reducesvariability of absorption. After many oral doses,Cmax occurs at approximately 6 hours after doseadministration with food. Ziprasidone has amean apparent volume of distribution of 1.5L/kg. One to 3 days are required to reach steady-state serum concentrations after two times/dayadministration with food.15, 16

Ziprasidone is greater than 99% protein boundin a concentration-independent manner. Neither

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Figure 1. Chemical structure of ziprasidone.

S N

N N

NClO

ZIPRASIDONE, A NEW ATYPICAL ANTIPSYCHOTIC Carnahan et al

propranolol nor warfarin, two highly protein-bound drugs, interferes with the in vitro proteinbinding of ziprasidone. In addition, ziprasidonedoes not affect the protein binding of propranololor warfarin, suggesting that drug interactions ofthis type are unlikely.15

Metabolism and Elimination

Ziprasidone is extensively metabolized inhumans, with a mean terminal elimination half-life of 6.6 hours after multiple oral dosing. Lessthan 1% and 4% are excreted in the urine andfeces, respectively. In vitro data suggest thataldehyde oxidase-mediated reduction andcytochrome P450 (CYP)-mediated oxidation arethe major metabolic pathways leading to theclearance of ziprasidone.15 According to theresults of in vitro studies, CYP3A4 appears to bethe major CYP pathway involved in themetabolism of ziprasidone. Although CYP1A2may be involved, it does not appear that CYP2D6plays a metabolic role. Only one of ziprasidone’smetabolites, S-methyl-dihydroziprasidone (M9),has a steady-state serum concentration that fallswithin its binding potential for D2 and 5-HT2receptors, suggesting that it may contribute tothe drug’s therapeutic activity. S-methyl-dihydroziprasidone is one of the byproducts ofthe aldehyde oxidase pathway. None of the otherziprasidone metabolites appear to play a role intherapeutic activity.17

Hepatic impairment increased the AUC0–12 ofziprasidone by 19% in patients with Child-Pughclass A cirrhosis and 34% in patients with Child-Pugh class B cirrhosis.18, 19 Renal impairmentdoes not significantly change ziprasidonepharmacokinetics, reflecting its extensive hepaticmetabolism.20 In the elderly, serum concen-trations are, on average, 20% higher than they arein younger individuals.21

Drug Interactions

Administration of ziprasidone with ketoconazole(400 mg/day), a potent CYP3A4 inhibitor,increased the AUC of ziprasidone by only 33%,with a 39% increase in steady-state mean serumconcentrations. Mean serum concentrations ofthe M9 metabolite were increased by 59%.22 Therelatively small increases in steady-state level areattributed to the nonsaturable nature of thealternative aldehyde oxidase metabolic pathway.Administration of ziprasidone with cimetidine(800 mg/day), a weaker CYP3A4 inhibitor, didnot substantially change the metabolism ofziprasidone.23 When ziprasidone was given withcarbamazepine, a CYP3A4 inducer, AUC0–12 andCmax were reduced by 36% and 27%, respectively.24

The results of these pharmacokinetic studiessuggest that dose adjustments are generally notnecessary when ziprasidone is administered withCYP3A4 inducers or inhibitors.

Results of in vitro studies with CYP1A2,

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Table 1. Summary of Ziprasidone Clinical Trials

Duration No. ofStudy No. (wks) Treatment Patients Summary of Results

104 4 Ziprasidone 10 mg 47 No significant differences between groups.Ziprasidone 40 mg 55Ziprasidone 80 mg 48Placebo 50

106 4 Ziprasidone 40 mg 44 Ziprasidone 120 mg better than placebo on CGI-severity andZiprasidone 120 mg 47 BPRS scales.Placebo 48

114 6 Ziprasidone 80 mg 106 Both ziprasidone doses better than placebo on PANSS-total,Ziprasidone 160 mg 104 BPRSd, CGI-severity, and PANSS-negative.Placebo

115 4 Ziprasidone 40 mg 87 All groups better than placebo on PANSS-total, BPRSd-total,Ziprasidone 120 mg 78 and CGI-severity.Ziprasidone 200 mg 86 Haloperidol and ziprasidone 200 mg better than placebo onHaloperidol 15 mg 85 PANSS-negative.Placebo 83

303 52 Ziprasidone 40 mg 75 Relapse (worsening of symptoms) decreased versus placebo inZiprasidone 80 mg 72 all ziprasidone groups.Ziprasidone 160 mg 71Placebo 75

CGI = Clinical Global Impression; BPRS = Brief Psychiatric Rating Scale; PANSS = Positive and Negative Syndrome Scale.


CYP2C9, CYP2C19, CYP2D6, and CYP3A4showed that the concentration of ziprasidoneneeded to inhibit these enzymes was at least 6500times the concentration achievable with clinicaldoses.17 The lack of CYP3A4 inhibition wassupported by a lack of an AUC increase followingexposure to ethinylestradiol, a CYP3A4 substrate,on coadministration with ziprasidone.25 Theeffect of ziprasidone on CYP2D6 activity wasassessed by administering ziprasidone 80 mg,placebo, or paroxetine 20 mg (a potent CYP2D6inhibitor) 2 hours before administeringdextromethorphan (a model CYP2D6 substrate).Ziprasidone did not change the urinary ratio ofdextromethorphan to dextrophan (dextro-methorphan’s CYP2D6 primary metabolite)compared with placebo, whereas it was increased10-fold after paroxetine administration. Theseresults confirm a lack of CYP2D6 inhibition byziprasidone.26 In addition, the pharmacokineticparameters of ziprasidone were unchanged bycoadministration of propranolol, lithium, oraluminum hydroxide-magnesium hydroxideantacid.15, 23 Coadministration of ziprasidone andlithium did not alter lithium clearance.27

Clinical Trials

The safety and efficacy of ziprasidone wereevaluated in several double-blind, randomized,parallel-group clinical trials. Four trials of 4 to 6weeks’ duration evaluated efficacy in treatment ofpatients with acute psychoses (Table 1).15 Theefficacy of ziprasidone in preventing relapse inpatients with chronic schizophrenia wasdemonstrated in a 52-week trial. Anotherflexible-dose, 28-week trial was conducted tocompare ziprasidone with haloperidol in thetreatment of stable schizophrenia.15 Ziprasidonealso was studied in the treatment of Tourette’ssyndrome28 and mania,29 and the intramuscularformulation was studied for acute agitation andpsychosis.30–32

Schizophrenia and Schizoaffective Disorder

Ziprasidone versus Placebo

The four trials of 4–6-weeks’ duration includedpatients with schizophrenia or schizoaffectivedisorder, per the Diagnostic and Statistical Manualof Mental Disorders, Revised Third Edition (DSM-III-R), in an acute exacerbation of the illness.Studies 104 and 106 required a minimumduration of illness of 1 year, and studies 114 and115 required a 6-month minimum duration.15

Study 104 was a randomized, double-blindevaluation of the efficacy of ziprasidone 10, 40,or 80 mg/day compared with placebo in 200patients.15 No significant differences were foundin primary or secondary efficacy measuresbetween any of the groups during the 4-weekstudy. However, the 80-mg/day group, whichbegan with 48 patients, had a 44% dropout rate.Of 21 patients who dropped out within the first 2weeks, 10 were for insufficient response and 9 forprotocol violation or withdrawn consent. Thishigh percentage of dropouts may help provide anexplanation for the lack of efficacy since this dosewas effective in other trials.

Study 106 was a 4-week, randomized, double-blind trial comparing the efficacy of ziprasidone40 or 120 mg/day with placebo in 139 patients.33

In an intent-to-treat, last observation carriedforward (LOCF) analysis, the percentageimprovement on the Brief Psychiatric RatingScale (BPRS) was 11% for placebo, 14% forziprasidone 40 mg/day, and 28% for ziprasidone120 mg/day. The improvements in BPRS-totaland Clinical Global Impression (CGI)-severityscores were significantly greater for theziprasidone 120-mg/day group than for theplacebo group (p<0.05). The 40-mg/daytreatment group did not demonstrate significantimprovement over the placebo group. Aresponse analysis was also performed. Responsewas defined as a 30% decrease in BPRS or a CGI-improvement rating of 1 (very much improved)or 2 (much improved). The ziprasidone 120-mg/day group had a higher rate of response thandid the placebo group as measured by CGIratings (33.3% vs 12.8%, p<0.05) and BPRSscores (48.8% vs 25.5%, p<0.05). The rate ofresponse for the 40-mg/day group did not differfrom that of the placebo group.

Study 114 was a randomized, double-blind, 6-week trial that compared the efficacy ofziprasidone 80 or 160 mg/day with placebo.34

With use of an intent-to-treat analysis, bothdosages were more effective than placebo on theprimary efficacy measures. These included thePositive and Negative Syndrome Scale (PANSS)-total (80 mg/day, p=0.048; 160 mg/day, p<0.001),BPRS-derived (BPRSd)-total score (80 mg/day,p=0.047; 160 mg/day, p<0.001), CGI-severity (80mg/day, p=0.030; 160 mg/day, p<0.001), and thePANSS-negative subscale (80 mg/day, p=0.024;160 mg/day, p=0.001). The BPRSd scale consistsof the same items as the BPRS, but the ratingswere extracted from the PANSS. Response in thisstudy was defined as a 30% decrease in PANSS-

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total score or a CGI-improvement score of 1 or 2.Response rates in the ziprasidone 160-mg/daygroup were greater than those in the placebogroup as measured by PANSS-total scores (31.1%vs 17.6%, p<0.05) and CGI ratings (42.7% vs26.1%, p<0.05). Discontinuation due to adverseeffects occurred at a higher frequency in theziprasidone 160-mg/day group (7.7%) than in theziprasidone 80-mg/day (1.8%) and placebo(1.1%) groups. The CGI-improvement rate didnot differ between the 80 mg/day and placebogroups. Response rates in the ziprasidone 80-mg/day group were 28.8% by PANSS-total scoresand 32.7% by CGI ratings. The lack of asignificant response effect raises question as towhether 80 mg/day is a sufficient dosage in theshort-term treatment of schizophrenia. Theeffect of ziprasidone on depressive symptoms wasanalyzed in a subgroup of patients with clinicallyimportant baseline depressive symptoms, definedas a Montgomery-Asberg Depression Rating Scale(MADRS) score of 14 or greater. In thissubgroup, ziprasidone 160 mg/day produced astatistically significant reduction in MADRSscores compared with that in the placebo group(31.3% vs 12.6%, p<0.05). While reductions inMADRS scores were greater in the ziprasidone-treated group, the mean end-point score was stillabove 14. This suggests that even thoughdepressive symptom scores were reduced,patients still had clinically important depressivesymptoms at end point.

Ziprasidone versus Haloperidol

Study 115 was a randomized, double-blind, 6-week trial that used an intent-to-treat LOCFanalysis to assess the efficacy of three fixeddosages of ziprasidone 40, 120, or 200 mg/dayversus haloperidol 15 mg/day and placebo in 419patients with schizophrenia or schizoaffectivedisorder.15 Each of the ziprasidone groupsshowed statistically significant improvement inPANSS-total, BPRSd-total, and CGI-severityscores compared with the placebo group. Onlythe 200-mg/day group showed greaterimprovement (p<0.02) in PANSS-negativesubscale scores than that of the placebo group.The haloperidol 15-mg/day group improved onall of these primary efficacy variables, includingeffect on negative symptoms (p<0.008).Although it did not appear that there were anysignificant differences between the ziprasidoneand haloperidol groups, p values were notpresented. Overall, this study suggests that inrecommended dosages, ziprasidone has similar

efficacy to haloperidol in the treatment ofschizophrenia and schizoaffective disorder.However, ziprasidone did not demonstrate anadvantage over the conventional antipsychotic,haloperidol, in treating negative symptoms.

Efficacy in Maintenance Treatment

Study 303 was a 52-week, randomized, double-blind, controlled trial that used an intent-to-treatLOCF analysis to assess the efficacy ofziprasidone 40, 80, or 160 mg/day and placebo in293 inpatients with chronic schizophrenia.15, 35

Patients had been hospitalized for at least 2months and had CGI-severity scores of 5(markedly ill) or less. They entered the studyreceiving treatment with other antipsychoticdrugs and were switched to ziprasidone orplacebo after a 3-day washout period. Relapsewas defined as a score of 6 (much worse) orgreater on the CGI-improvement scale or a scoreof 6 (severe) or greater in either PANSS item P7(hostility) or G8 (uncooperativeness) on 2successive days. The mean number ofpsychiatric hospitalizations in the patients beforethe start of the study was 9.9. This populationhad moderate to severe negative symptoms(PANSS-negative subscale, mean 25.1) and lowGlobal Assessment of Functioning (GAF) scores(mean 47.9) at baseline.

The relapse rates by week 52 were as follows:41% for the 40-mg/day group, 35% for the 80-mg/day group, 36% for the 160-mg/day group,and 71% for the placebo group. The relapse ratein each ziprasidone group was significantly lowerthan that in the placebo group (p=0.002,p=0.001, and p<0.001 for the 40-, 80-, and 160-mg/day groups, respectively). Each ziprasidonegroup was superior to the placebo group forchange scores on the PANSS-total (40 mg/day,p=0.001; 80 mg/day, p=0.002; 160 mg/day,p<0.001), CGI-severity (40 mg/day, p=0.001; 80mg/day, p<0.001; 160 mg/day, p<0.001), and GAF(40 mg/day, p=0.003; 80 mg/day, p=0.001; 160mg/day, p<0.001). PANSS-negative subscalescores were reduced in each ziprasidonetreatment group versus the placebo group (40mg/day, p<0.001; 80 mg/day, p=0.012; 160mg/day, p<0.001).

A subgroup of patients with predominantlynegative symptoms was assessed. These werepatients with baseline PANSS-negative subscalescores of at least 21 and a PANSS-positivesubscale score of at least six points lower thanthe PANSS-negative subscale score. The PANSS-negative subscale scores were decreased in the

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ziprasidone 40- and 160-mg/day groups (p=0.009and p=0.002, respectively), but the improvementin the 80-mg/day ziprasidone group did not reachsignificance (p=0.073).

One group of investigators conducted a 28-week, randomized, double-blind, controlled trialcomparing the negative symptom efficacy andtolerability of flexible dosing of ziprasidone80–160 mg/day (148 patients) with those ofhaloperidol 5–15 mg/day (153 patients) in thetreatment of stable outpatients with chronicschizophrenia.36 As treatment of negativesymptoms was the primary focus, inclusioncriteria required a baseline score of 10 or greateron the PANSS-negative subscale. Other efficacymeasures included PANSS-total, BPRSd coreitems (conceptual disorganization, suspicious-ness, hallucinatory behavior, and unusualthought content), CGI-severity, and MADRSscores. Efficacy was assessed by using LOCFanalysis in patients who had received at least 2weeks of treatment: 110 patients in theziprasidone group and 117 receiving haloperidol.Safety was evaluated in all patients who receivedat least one dose. Mean dosages at weeks 6 and28 were 109.5 and 116.5 mg/day of ziprasidoneand 8.5 and 8.6 mg/day of haloperidol,respectively. Patients in both treatment groupsshowed similar improvement in overallpsychopathology. Negative symptom responseswere defined as 20% or greater decrease inPANSS-negative subscale scores. Of theziprasidone patients, 48% were considered tohave negative symptom responses versus 33% inthe haloperidol group (p<0.05). Overall, therewas a 16% decrease in the mean PANSS-negativescores in the ziprasidone group versus a mean14% decrease in the haloperidol group. This wasthe only assessment from the available studiesthat suggests ziprasidone may have an advantageover haloperidol in the treatment of negativesymptoms of schizophrenia.

Antipsychotic Switch Studies

Three 6-week, multicenter, randomized, open-label, parallel-group trials involved switchingpatients from either olanzapine (90 patients),risperidone (42), or conventional antipsychoticdrugs (97) to ziprasidone (40–160 mg/day). Theresults of these studies were pooled into oneanalysis.37 Patients had a diagnosis ofschizophrenia or schizoaffective disorder, hadbeen outpatients for 3 months or more, had atleast a partial response (CGI-improvement score< 4) to their current drug at a dose within 25% of

the recommended range, and required a changein their drug due to inadequate efficacy ortolerability. Patients in each study wererandomized to one of three switch strategies.The first was an abrupt discontinuation of theprevious antipsychotic on initiation ofziprasidone. The second was for patients toreceive 50% of their previous antipsychoticdosage for a week on initiation of ziprasidone,then discontinue the previous drug thereafter.The last used a tapering strategy in whichpatients received 100% of the previousantipsychotic dose for the first 2 days ofziprasidone treatment, 50% for the next 5 days,and none thereafter. Ziprasidone was alwaysinitiated at 80 mg/day for the first 2 days, thenswitched to open-label dosages of 40–160 mg/dayfor the remainder of the study.

For the switch from conventional anti-psychotics, the mean change scores from baselineto end point in PANSS-total, -positive, and-negative scores, as well as the BPRSd scores,were significant for all scales (p<0.001). Meanimprovements for patients switched fromolanzapine to ziprasidone were also significantfor each of these measures (p<0.01, p<0.001,p<0.001, and p<0.01, respectively). Patientsswitched from risperidone had meanimprovements that were significant for PANSS-total (p<0.01), PANSS-negative (p<0.001), andBPRSd scores (p<0.05), but mean improvementson PANSS-positive scores did not reach statisticalsignificance.

Acute Mania

A 3-week, randomized, double-blind study wasconducted that compared flexible-doseziprasidone (80–160 mg/day, 140 patients) withplacebo (70 patients) in the treatment of bipolar Imanic type or mixed type.29 About two-thirds ofthe patients in each group had an acute manicepisode of which the mean duration was 2.4months for the placebo group and 1.4 months forthe ziprasidone group. The remaining patientswith mixed episode type were ill 1.5 months inthe ziprasidone group and 6.3 months in theplacebo group before treatment. Efficacyvariables for this study included changes frombaseline to end point on the Mania Rating Scale(MRS), the CGI-severity, PANSS-total and -positivesubscale, and GAF scores. According to resultsof LOCF analysis, the changes in all the efficacyvariables were significantly different between thetwo groups, and differences were generally

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apparent within the first few days to a week oftreatment. The mean MRS score decreased by12.4 from a baseline of 27.5 in the ziprasidonegroup and by 7.8 from a baseline of 26.7 in theplacebo group (p=0.003). The MRS–manicsyndrome subscale scores for the ziprasidonegroup decreased by 6.5 from a baseline of 13.7,whereas scores for the placebo group decreasedby 4.8 from a baseline of 13.5 (p=0.016). TheMRS–behavior and ideation subscale scoresdecreased by 5.1 from a baseline of 11.5 in theziprasidone group and by 2.7 from a baseline of11.0 in the placebo group (p=0.001). Mean CGI-severity scores decreased by 1.3 from a baselineof 4.9 in the ziprasidone group and by 0.9 from abaseline of 4.9 in the placebo group (p=0.008).Mean PANSS-total scores decreased by 11.4 froma baseline of 67.0 in the ziprasidone group andby 2.7 from a baseline of 64.4 in the placebogroup (p<0.001). The PANSS-positive subscalescores decreased by 4.82 from a baseline of 19.5in the ziprasidone group and by 2.0 from abaseline of 19.0 with placebo (p<0.001). MeanGAF scores were 38.2 and 38.1 at baseline andimproved by 15.3 and 8.3 for the ziprasidone andplacebo groups, respectively (p=0.002).

Discontinuations due to lack of clinicalresponse occurred in 25 patients (35.7%) in theplacebo group and 27 patients (19.3%) in theziprasidone group. Discontinuations due toadverse effects occurred in 3 patients (4.3%)receiving placebo and 10 patients (7.1%)receiving ziprasidone. None of the adverseeffects was considered severe by the investigators.Thus, unsurprisingly, ziprasidone was similar toclozapine, risperidone, and olanzapine in thetreatment of acute mania. Its role may beenhanced with the eventual availability of aninjectable formulation.

Acute Agitation

A randomized, double-blind, 24-hour trialcompared ziprasidone 2 mg (38 patients) withziprasidone 20 mg (41) in patients withpsychosis and acute agitation.30–32 Theintramuscular doses were administered every 4–6hours as needed. Efficacy variables included theseven-point Behavioral Activity Rating Scale(BARS; 1 = difficult or unable to arouse, 7 =violent and need for restraints), PANSS-agitationscores (sum of anxiety, tension, hostility andexcitement items), and the CGI-severity and -improvement scales. Response was defined as atwo-point or greater decrease on the BARS within

90 minutes of the first injection. The 20-mggroup had a significantly larger number ofpatients with response (65%) than that of the 2-mg group (26%; p<0.001). From 1 hour past thefirst injection until study end point, the 20-mggroup had significantly lower BARS scores thanthat of the 2-mg group (p<0.001). Mean AUC forBARS scores over 0–2 and 0–4 hours weresignificantly less in the 20-mg group than in the2-mg group (p<0.001 for both). The meanimprovement in PANSS-agitation scores at 4hours after the initial dose was greater in the 20-mg group than in the 2-mg group (p<0.05). Thisdifference was not significant at 24 hours.Compared with the 2-mg group, the 20-mg grouphad significantly greater improvements in CGI-severity (p<0.01) and CGI-improvement(p<0.001) scores at 4 and 24 hours after theinitial dose. The modal number of injections forthe 20-mg group (41.5%) was one, whereas itwas two for the 2-mg group (42.1%).

A second controlled trial of the parenteralformulation of ziprasidone was conducted with anearly identical design. It only differed in thatpatients received either 2 mg (54 patients) or 10mg (63) of intramuscular ziprasidone.31, 32

Approximately 45% of the 10-mg group and 21%of the 2-mg group responded (p<0.05). TheAUC of BARS scores for 0–2 and 0–4 hours afterthe first injection were significantly less in the10-mg than the 2-mg group (p<0.001). Finally,improvements in CGI-severity (p<0.05) and -improvement (p<0.05) scores both favored the10-mg dose. The PANSS-agitation scores did notdiffer between doses. When the BARS responserates and treatment effects for the 10-mg and 2-mg groups were compared, they were found to bedose related.31 The studies suggest that the 10-mg and 20-mg doses of intramuscularziprasidone can be effective in treating patientswith psychosis and acute agitation.

Tourette’s Syndrome

An 8-week, double-blind, randomized, parallel-group trial compared ziprasidone with placebo inthe treatment of Tourette’s syndrome.28 Patientswere 28 boys and girls, aged 7–17 years, with ticsymptoms serious enough to need treatment asjudged by the investigator. All patients had adiagnosis of Tourette’s syndrome except for onein the ziprasidone group who had chronic ticdisorder. The ziprasidone group received a 5-mgdose that was titrated as tolerated to a maximumdose of 40 mg over the first 28 days of the trial.

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The dose was kept constant for the rest of thetrial if clinically possible. Primary efficacymeasurements included the Yale Global Severityand Total Tic Severity Scale (YGTSS) and theCGI-severity scale for Tourette’s syndrome (CGI-TS). Secondary efficacy measurements were theGoetz Videotape Rating Scale (GVRS), whichincludes a total score and 5-minute videotape ticcounts, and the Children’s Yale-Brown ObsessiveCompulsive Scale (CY-BOCS). The meanimprovement in YGTSS–global severity scorefrom baseline to last visit was greater in theziprasidone group than in the placebo group(39.0% vs 16.2%, p=0.016). The meanimprovement in YGTSS–total tic score alsofavored ziprasidone versus placebo (34.8 vs 6.9%,p=0.008). The mean improvement in CGI-TSscores were 30.4% for the ziprasidone group and15.6% for the placebo group, but the differencewas not significant (p=0.107). The meanimprovement on the total score of the GVRS wassignificantly greater in the ziprasidone groupthan in the placebo group (54.0% vs 0.92%,p=0.043). The mean improvement in the totalnumber of motor and phonic tics counted whenassessing the videotapes was also greater in theziprasidone group than in the placebo group(49.8% vs 3.5%, p=0.039). Five patients in eachgroup were considered to have significantobsessive compulsive disorder symptoms.Patients receiving ziprasidone had a meanimprovement of 26.5% on the CY-BOCScompared with a 4.5% worsening for thosereceiving placebo. Although this series was notlarge enough to fully evaluate ziprasidone inTourette’s syndrome and chronic tic disorder,these results suggest that ziprasidone may play arole as a treatment option for patients with thesedisorders.

Adverse Effects

Overview

Arguably the most intriguing characteristic ofziprasidone is its adverse effect profile. Table 2contrasts qualitatively the adverse effect profile ofthe atypical antipsychotic drugs and theconventional antipsychotic, haloperidol. Theseassessments were based on the in vivo receptorbinding affinities of the atypical antipsychoticsand haloperidol and adverse effect rates reportedin the package inserts.14 Other than sedation thatoccurs at a rate similar to that of olanzapine,effects of ziprasidone on the cholinergic system,extrapyramidal system, weight, blood pressure,and prolactin level are minimal in contrast to theother atypical antipsychotics and the conventionalantipsychotic.

The commonly occurring adverse events in the4- and 6-week controlled trials in schizophreniaand schizoaffective disorder were somnolence,nausea, constipation, akathisia, dyspepsia,dizziness, and respiratory disorders. Of these,only somnolence (14.4% vs 6.6%) andrespiratory disorder (7.7% vs 3.3%) were morecommon with ziprasidone than with placebo(p<0.05). Somnolence was described as beingmild to moderate and transient in its course.Importantly, it required the discontinuation oftreatment in only two patients.15 The respiratorydisorder was described as generalized rhinitissymptoms that occurred soon after initiation oftreatment but were transient in nature.38 Theseadverse events are summarized in Table 3.15

In study 303, asthenia (muscle weakness) wasthe only adverse event that occurred more oftenin patients treated with ziprasidone. It occurredin 5.5% of patients receiving ziprasidone and didnot occur in patients receiving placebo(p<0.05).15

The switch studies assessed changes in weightand lipid and prolactin levels.39 Patientsswitched from olanzapine had decreases in meanbody weight (1.65 kg for men, 1.63 kg forwomen, p<0.001 for both) and in body massindex (31.40 to 30.76, p<0.001). Median

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Table 2. Adverse Effect Profiles of the Atypical Antipsychotic Drugs and Haloperidol

Adverse Drug Reaction HLP CZP RSP OZP QTP ZPRAnticholinergic side effect 0 +++ 0 ++ 0 0Extrapyramidal side effect +++ +/- ++ + +/- +Sedation + +++ + ++ ++ ++Weight gain +/- +++ ++ +++ ++ +/-Orthostasis +/- +++ + + + +Prolactin elevation +++ 0 ++ + 0 +HLP=haloperidol; CZP=clozapine; RSP=risperidone; OZP=olanzapine; QTP=quetiapine; ZPR=ziprasidone. 0 = none;+/- = minimal; + = mild; ++ = moderate; +++ = severe.


nonfasting triglyceride and total cholesterollevels showed reductions in patients switchedfrom olanzapine (p<0.001) and risperidone(p<0.01). Total cholesterol levels decreased in75% of patients switched from olanzapine and74% of those switched from risperidone. Ofspecial interest, the group switched fromolanzapine had a decrease of approximately 40ng/ml in median nonfasting triglyceride levelsand 25 ng/ml in median nonfasting totalcholesterol levels. Finally, median serumprolactin levels decreased from baseline to endpoint in the groups switched from conventionalagents (p<0.05) and risperidone (p<0.001). Mildto moderate insomnia and somnolence were themost common adverse events in the switchstudies.37 Insomnia occurred in 41% of patientsswitched from olanzapine, about twice as muchas in either of the other groups. Anxiety wasreported in only 2.4% of patients switched fromrisperidone, compared with 17.5% of thoseswitched from conventional agents and 18.9% ofthose switched from olanzapine. About 15% ofthe patients switched from olanzapine orconventional antipsychotics reported dizzinesscompared with 4.8% of those switched fromrisperidone. One can only speculate on thereasons for these differences, but they may beworth noting if a choice is made to switch apatient from one of these agents to ziprasidone.Although the switch studies were uncontrolled,the results tentatively suggest that ziprasidonemay be a reasonable treatment option in patientswho have had an inadequate response orintolerable side effects with risperidone,olanzapine, or conventional agents.

In the Tourette’s syndrome study, the mostcommon adverse event was mild sedation,present on at least one visit for 69% of theziprasidone group but also 45% of the placebo

group.28 Severe adverse effects included one caseof somnolence and one of akathisia, both in theziprasidone group. The akathisia resolved withdose reduction. The somnolence was reduced tomoderate with dose reduction and resolved onstudy completion. Mean weight gain was similarfor each group, 0.7 kg in the ziprasidone groupand 0.8 kg with placebo. This is an importantfinding since the other atypical antipsychoticdrugs at least anecdotally cause clinicallysignificant weight gains in children andadolescents.40

Extrapyramidal Side Effects

Extrapyramidal side effects are hypothesized toresult from extensive D2 receptor blockade in thenigrostriatal pathway.12 Atypical antipsychoticdrugs are associated with a lower prevalence ofextrapyramidal side effects than are conventionalagents, although the risk with risperidoneincreases in daily doses above 6 mg.41 Clinicaltrials with olanzapine and quetiapinedemonstrated rates of extrapyramidal side effectssimilar to that with placebo.42, 43 Clozapine, thefirst antipsychotic to be considered atypical, isassociated with an almost negligible rate ofextrapyramidal side effects.41

The Simpson-Angus Extrapyramidal SideEffects Scale, Abnormal Involuntary MovementScale, and the Barnes Akathisia Scale were usedto assess extrapyramidal side effects in theclinical trials with ziprasidone. The meanchanges in scores from baseline to end point oneach of these scales for ziprasidone-treatedpatients were not significantly different fromthose for placebo-treated patients.15, 35 The needfor benztropine to control movement disorders inziprasidone-treated patients was similar to that inthe placebo group (22.4% vs 18.3%, respectively),as was the need for b-blocker use to control

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Table 3. Prevalence of Common Adverse Events in Short-term ClinicalTrials

Ziprasidone Haloperidol PlaceboAdverse Event (n=702) (n=85) (n=273)Somnolencea 14.4 23.5 6.6Nausea 9.5 9.4 7.0Constipation 9.3 7.1 8.4Akathisia 8.4 28.2 7.0Dyspepsia 8.1 15.3 7.0Dizziness 7.8 9.4 5.9Respiratory disordera 7.7 8.2 3.3Data are percentages.ap<0.05 for ziprasidone versus placebo.


suspected akathisia (7.1% vs 6.2%, respectively).These observations support the conclusion thatziprasidone has a low propensity for producingextrapyramidal side effects.15

Cardiovascular Side Effects

The initial new drug application forziprasidone submitted to the U.S. Food and DrugAdministration was not approved due touncertainty about the effects of ziprasidone onQTc interval. Marked QTc prolongation can leadto syncope, the ventricular arrhythmia torsadesde pointes, and sudden death. Most cases oftorsades de pointes occurred in patients with QTcintervals of 500 msec or greater. The Pfizerziprasidone database suggests that this is anunlikely event. Only 2 of 2988 patients in theziprasidone database had a QTc interval of 500msec or greater. One patient had a baseline QTcinterval of 489 msec and a QTc interval duringtreatment of 503 msec. The other patient had aQTc interval of 391 msec at the end ofziprasidone treatment. However, when thepatient was switched to thioridazine, onconsecutive electrocardiograms, the QTc intervalincreased to 518 and 592 msec.38

Study 054 was conducted to contrast the safetyof ziprasidone 160 mg/day with that ofhaloperidol 10 mg/day, quetiapine 750 mg/day,olanzapine 20 mg/day, risperidone 6–8 mg/dayand 16 mg/day, and thioridazine 300 mg/day.15

The 95% confidence interval for the changesobserved with ziprasidone, risperidone, andquetiapine overlapped, indicating similar effectson QTc interval. In contrast, haloperidol andolanzapine produced significantly less change toQTc interval. The QTc prolongation caused bythioridazine was significantly greater than that ofthe other antipsychotics, including ziprasidone.The thioridazine package insert has a warningindicating that it increases the QTc interval in adose-dependent manner.

The concurrent administration of the potentCYP3A4 inhibitor ketoconazole did not producea QTc interval of 500 msec or greater in anypatients treated with ziprasidone. It has beensuggested that ketoconazole administration hadlittle effect on ziprasidone metabolism due to thealternative nonsaturable aldehyde oxidasemetabolic pathway. This is in contrast toterfenadine, which was removed from the U.S.market due to sudden deaths associated with QTcinterval prolongation when coadministered withCYP3A4-inhibiting drugs such as ketoconazole

and erythromycin. In addition, no problemswere evident in 10 cases of ziprasidone overdose(240–4600 mg). All patients survived withoutsequelae. The QTc interval was not prolonged to500 msec or greater (345–476 msec) in any ofthese patients. The mean QTc prolongation inpatients receiving therapeutic doses of ziprasidonewas 5–10 msec, with a prolongation of about15–20 msec at peak plasma concentrations. Thisis comparable with the effects of terfenadinewhen its metabolism is not inhibited, underwhich conditions the drug was considered safe.15, 38

The ziprasidone package insert contains awarning that ziprasidone should be avoided incombination with other drugs that are known toprolong the QTc interval. Torsades de pointes ismore likely to occur in patients who havemultiple risk factors for QTc prolongation. Theserisk factors are drugs that increase the QTcinterval (e.g., potassium channel blockers),hypokalemia (e.g., from diuretic therapy),hypomagnesemia (e.g., from alcoholism),bradycardia (e.g., from b-blockers, digoxin), QTcintervals of greater than 450 msec, syncopalepisodes, presence of concomitant drugs capableof inhibiting the metabolism of the QTc interval-prolonging drugs, and female gender. If none ofthe risk factors is present, the risk for torsades depointes is relatively low. If several risk factors arepresent, the use of haloperidol or olanzapineversus ziprasidone or the other atypicalantipsychotic drugs is preferable. From amedical-legal standpoint, the package insertwarning would suggest that it is prudent toobtain an electrocardiogram for all patients whoare to receive ziprasidone at least for the first6–12 months of the postmarketing period untilthere is more clinical experience with the drug.However, from an academic standpoint, it isprobably prudent to obtain an electrocardiogramin any patient being treated with a typical or anatypical antipsychotic drug and who has severalrisk factors for QTc prolongation and torsades depointes since all antipsychotic drugs blockpotassium channels to some extent.

Postural hypotension occurred in 1.3% ofziprasidone-treated patients in comparison to0.4% of patients receiving placebo.15 The lowprevalence of this side effect allows ziprasidoneto be rapidly titrated to a therapeutic dosage of160 mg/day.

Weight Gain

The mean weight gain in the 4- and 6-week,

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randomized, double-blind, placebo-controlledtrials was 0.9 kg for patients receivingziprasidone. Patients receiving placebo had amean weight loss of 0.4 kg. Clinically significantweight gain, defined as a 7% or greater increasefrom baseline weight, occurred in 9.8% ofziprasidone-treated patients and 4% of thosereceiving placebo. In the 52-week maintenancetrial, the mean weight changes for ziprasidone40, 80, and 160 mg/day and placebo wereapproximately -1 kg, -2 kg, –3 kg, and –3 kg,respectively.35 In a recent meta-analysis ofantipsychotic drug studies that addressed weightgain, mean weight change at 10 weeks wasestimated as follows: -0.74 kg with placebo,+1.08 kg with haloperidol, +2.1 kg withrisperidone, +4.15 kg with olanzapine, +4.45 kgwith clozapine, and +0.04 kg with ziprasidone.44

The mean weight change seen with quetiapinewas estimated to be +2.18 kg at 6 weeks. Theresults of this meta-analysis suggest that, of theatypical antipsychotics, weight gain is mostnotable with clozapine and olanzapine. This isfollowed by an intermediate degree of weightgain seen with quetiapine and risperidone.Ziprasidone appears to be the least likely of theatypical antipsychotic drugs to cause weight gain.

Parenteral Formulation

In the original intramuscular ziprasidone trial,adverse effects graded as mild to moderateoccurred in 14 (37%) of 38 patients in the 2-mggroup and 18 (44%) of the 41 patients in the 20-mg group.30–32 No patients discontinuedtreatment due to treatment-emergent adverseevents. Mild or moderate somnolence andnausea were the most common adverse events.Somnolence occurred in 13.2% of the 2-mggroup and 19.5% of the 20-mg group. Nauseaoccurred in 7.9% of the 2-mg group and 12.2% ofthe 20-mg group. Postural hypotension occurredin two patients (4.9%) in the 20-mg group, andstanding heart rate increased in four patients(9.8%) in this group. Three patients (7.3%) inthe 20-mg group and one patient (2.6%)receiving 2 mg reported mild to moderateinjection-site pain. One patient (2.6%) receiving2 mg had mild extrapyramidal side effects.Dystonia or akathisia was not reported in eithergroup.

In the second study of intramuscularziprasidone for acute agitation, adverse eventsoccurred in 19 (35%) of the 54 patients in the 2-mg group and 27 (43%) of the 63 patients in the

10-mg group.31, 32 Some adverse events with ahigher prevalence in the 10-mg group than in the2-mg group were nausea (7.9% vs 1.9%,respectively), somnolence (7.9% vs 3.7%,respectively), and headache (12.7% vs 5.6%,respectively). Injection-site pain occurred in13% (7 of 54) and 8% (5 of 63) in the 2- and 10-mg groups, respectively. One patient in the 10-mg group experienced akathisia. Extrapyramidalside effects were reported in one patient in the 2-mg group. No episodes of postural hypotensionor dystonic reactions were reported. None of theadverse events was categorized as severe.

Laboratory Test Abnormalities

No pattern of laboratory test abnormalities wasassociated with ziprasidone treatment during theclinical trials.15 In the 4- and 6-week, placebo-controlled trials, 4 (0.6%) of the 702 ziprasidone-treated patients had treatment discontinued dueto unspecified laboratory abnormalities. Nodiscontinuations occurred due to laboratory testabnormalities in the groups receiving haloperidolor placebo. In the 52-week maintenance trial,treatment was discontinued due to unspecifiedlaboratory abnormalities in 3 (1.4%) of the 219ziprasidone-treated patients and in 1 (1.3%) ofthe 75 patients receiving placebo.15

Serum Lipids

The median total serum cholesterol andtriglyceride levels decreased in the ziprasidonegroups in both the short- and long-term trials.15

In addition, patients switched from olanzapine orrisperidone to ziprasidone had significantdecreases in triglyceride and total cholesterollevels.39 These measurements were takenrandomly, not under fasting conditions, so thevalidity of the results is not clear. Elevations(> 1.2 times upper limit of normal [ULN]) inserum cholesterol and triglycerides were seen in16 (2.3%) of 685 and 85 (12.4%) of 684ziprasidone-treated patients, respectively, andzero (0%) and 17 (6.5%), respectively, of 261patients receiving placebo.15

Fasting lipid profiles were obtained in a short-term trial with mean treatment durations from14–24 days.15 The ziprasidone group showeddecreases in median total cholesterol (p<0.001)and median triglyceride (p<0.001) levels. Thehaloperidol group also had decreases in thesemeasurements (p<0.001 and p<0.01, respectively),as well as a decrease in median low-densitylipoprotein cholesterol level (p<0.001). In

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contrast, the thioridazine group had increases inmedian total and low-density lipoproteincholesterol levels, and the olanzapine andquetiapine groups had increases in mediantriglyceride levels (p<0.001). The median high-density lipoprotein level for the haloperidolgroup decreased (p<0.01). No high-densitylipoprotein change was observed with theziprasidone group. No median lipid measure-ments were changed in the risperidone group. Itis difficult to evaluate lipid effects based onmedian measurements, as the variance may belarge in these groups and the duration of thisstudy was short. However, the results of thisstudy suggest that ziprasidone does not have anadverse effect on the lipid profiles of mostpatients. The results of the antipsychotic switchstudies, as discussed previously, also suggest alack of adverse lipid effects.39

Prolactin Elevation

Ziprasidone can elevate serum prolactin levelsdue to D2 receptor antagonism, but for mostpatients this appears to be a transientphenomenon. In all phase II and III trialsevaluating ziprasidone, the rate of prolactinelevation greater than 22 ng/ml (> 1.1 timesULN) was 20% (148 of 741) in ziprasidone-treated patients, 46% (45 of 98) in haloperidol-treated patients, 89% (105 of 118) in risperidone-treated patients, and 4% (3 of 75) in patientsreceiving placebo. Persistent prolactin elevationfrom ziprasidone (defined as > 35 ng/ml for menand > 50 mg for women on more than onepostbaseline measurement) occurred in 7 (1.7%)of 421 men and 5 (3.5%) of 143 women whoreceived more than one postbaseline measure-ment. These rates of persistent prolactinelevation are in comparison with 2 (4.0%) of 50men and 4 (21.1%) of 19 women who receivedhaloperidol, and 16 (32.0%) of 50 men and 19(73.1%) of 26 women who received risperidone.No patients who received placebo experiencedpersistent elevations in serum prolactin levels.15

The consequences of persistent prolactinelevation in women can include menstrual cycleand reproductive disturbances, galactorrhea,hirsutism, vaginal dryness, loss of libido, andpossibly obesity, decreased bone density, andincreased breast cancer risk over the long term.In men, the most common problems associatedwith persistent prolactin elevation are erectiledysfunction, impotence, hypospermatogenesis,and loss of libido.45 In the 52-week ziprasidonetrial, median prolactin levels for each ziprasidone

group and the placebo group actually decreasedfrom baseline, and no dose response was seen.

Of the existing atypical antipsychotic drugs,clozapine, quetiapine, and olanzapine areassociated with little or no clinically significantincreases in prolactin levels. In contrast,risperidone can cause prolactin increase similarto that caused by conventional antipsychotics.41

Ziprasidone appears to be similar in effects toolanzapine, which generally causes only transientprolactin elevation.46

In the Tourette’s syndrome study, 5 of the 14boys receiving ziprasidone experienced transientserum prolactin elevations of greater than 1.1times the upper limit of normal.28 However, inall cases the prolactin concentrations returned tonormal by the end of the 56-day study. At theend of the study, the prolactin concentrations didnot differ between the placebo group (5.7 ± 1.6ng/ml) and the ziprasidone group (5.7 ± 2.8ng/ml).

Rash

Of the 702 patients treated with ziprasidone inshort-term clinical trials, there were 7discontinuations due to rash. Overall, theprevalence of rash in patients in the ziprasidoneclinical trial database was 4.5% in ziprasidone-treated patients, 3.4% in patients receivingplacebo, and 2.3% in haloperidol-treatedpatients.15 The majority of patients continuedtreatment, with resolution of the rash and noreport of life-threatening reactions.15

Dosage and Administration

The recommended dosage for ziprasidone in anacute exacerbation of schizophrenia orschizoaffective disorder is 40–160 mg/day.38 Thisis to be administered as two divided doses withfood to maximize absorption. As wasdemonstrated in the clinical trials, treatment isinitiated at 40 mg/day, and the dosage can beincreased to a maximum of 160 mg/day as soonas the third day, as clinically indicated. Low a1-adrenergic receptor affinity and resultant lowprevalence of orthostatic hypotension allow forthis rapid dose titration.15, 34, 38

The 52-week maintenance trial showed similarefficacy for 40-, 80-, and 160-mg/day dosages ofziprasidone in preventing relapse in patients withchronic and subchronic schizophrenia. Thissuggests that for maintenance treatment somepatients may require as little as 40 mg/day.38

Clinical trials with intramuscular ziprasidone

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showed efficacy for 10- and 20-mg doses intreating acute agitation and psychosis. Thesewere given at least 4 hours apart, up to 4times/day. Currently no atypical antipsychoticdrugs are available in an injectable form. Ifreleased, intramuscular ziprasidone may reducethe need for intramuscular conventionalantipsychotic drugs to control agitation in theacute setting.

Summary

Ziprasidone is a new antipsychotic drug withthe most tolerable adverse effect profile of any ofthe atypical antipsychotic drugs. For patientswith acute psychosis, the recommended dosage is40–160 mg/day in two divided doses with food.The maximum dosage of 160 mg/day can bereached as early as the third day of treatment.Ziprasidone is efficacious in treating acuteexacerbations of schizophrenia and schizo-affective disorder, as well as in preventingrelapses. The efficacy of ziprasidone in treatingpositive symptoms of schizophrenia is similar tothat of haloperidol 15 mg/day. However, therelative benefit for negative symptoms incomparison to that of haloperidol is somewhatunclear. The prevalence of extrapyramidal sideeffects with ziprasidone is less than that withhaloperidol and similar to that with placebo. Inaddition, the intramuscular formulation ofziprasidone appears efficacious and welltolerated. The most promising aspect ofziprasidone is the low rate of weight gain incontrast to that with other atypical antipsychoticdrugs. This is clinically relevant, as anti-psychotic-induced weight gain may lead tononcompliance and medical complications suchas diabetes and hyperlipidemia.

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ziprasidone, a new atypical antipsychotic drug

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