CLINICAL THERAPEUTICS‘NOL. 24, NO. I. 2002
`
`New Drugs
`
`Ziprasidone: An Atypical Antipsychotic Drug
`for the Treatment of Schizophrenia
`
`Glen L. Stimmel, PharmD, BCPR 1'2 Mary A. Gutierrez, PharmD, BCPIZ’
`and Vivian Lee, PharmD3
`
`Schools of ’ Pharmacy and 3Medicine, University of Southern California, Los Angeles.
`California, and 5School of Pharmacy, The Chinese University of Hong Kong, Shatin,
`Hong Kong
`
`ABSTRACT
`
`Background: Over the past decade. use of the atypical antipsychotic drugs clozapine.
`risperidone, olanzapine, and quetiapine has significantly changed the treatment of schizo-
`phrenia in the United States. The ability to make optimal drug choices will depend on de-
`termining whether there are clinically important differences between these drugs.
`Objective: This review describes ziprasidone. the most recently introduced antipsy-
`chotic drug. Its mechanism of action, pharmacokinetics. and adverse-effect profile are dis-
`cussed, and the results of clinical efficacy trials are summarized.
`Methods: This review of ziprasidone is based on data from premarketing clinical effi-
`cacy and safety trials. a briefing document from the US Food and Drug Administration
`Psychopharmacological Drugs Advisory Committee, published studies. and abstracts pre-
`sented at national and international meetings. lntemational Pharmaceutical Abstracts and
`MEDLINE were searched for relevant citations, with no limitation on year.
`Results: Ziprasidone has been reported to be an effective antipsychotic drug for both
`positive and negative symptoms of schizophrenia. and long-term use has been effective in
`preventing relapse. Its 5-hydroxytryptamine (HT)lD-antagonist and 5-HTlA-agonist ac—
`tivity are consistent with a potential for antidepressant and anxiolytic activity beyond its
`antipsychotic effects. Ziprasidone has been associated with a low incidence of sedative
`effects, a low likelihood of extrapyramidal symptoms and postural hypotension. and no
`anticholinergic effect. although it may cause transient hyperprolactinemia. Unlike most
`atypical antipsychotic drugs. ziprasidone is not associated with weight gain, hyperlipi‘
`demia. or elevated plasma glucose levels. It is, however, more likely than other atypical
`
`Accepted forpub/icatrbn October 31, 2001.
`Printed in the USA. Reproduction in whole or part is not permitted
`
`ouezotsmmwoo
`
`2]
`
`Exhibit 2056
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2056
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`CLINICAL THERAPEUTICS"
`
`likelihood of causing extrapyramidal
`symptoms (EPS) and tardive dyskinesia
`compared with the typical antipsychotic
`drugs. More recently, however, the focus
`has shifted to the characterization of clin-
`
`ically important differences between in-
`dividual atypical antipsychotic drugs,
`including their relative likelihood of
`inducing hyperprolactinemia. elevated
`plasma glucose and lipid levels, weight
`gain. and cardiovascular effects.
`It is within this context that ziprasi-
`done became the fifth atypical antipsy-
`chotic drug to be approved for the treat-
`ment of schizophrenia and schizoaffective
`disorder in the United States. This review
`
`describes the drug’s mechanism of ac-
`tion, pharmacoltinetics, and adverse-
`effect profile, and summarizes the results
`of clinical efficacy trials. Relevant data
`were obtained from reports of premarket~
`ing clinical efficacy and safety trials,
`a briefing document from the US Food
`and Drug Administration Psychopharma-
`cological Drugs Advisory Committee,
`published studies. and abstracts pre-
`sented at national and international meet-
`
`ings. International Pharmaceutical Ab-
`stracts and MEDLINE were searched for
`
`relevant citations, with no limitation on
`year.
`
`MECHANISM OF ACTION
`
`Ziprasidone is a benzothiazolylpiperazine,
`unrelated to the phenothiazine and buty-
`rophenone antipsychotic drugs. Like other
`atypical antipsychotic drugs. it is an an-
`tagonist of both the 5-hydroxytryptamine-
`2A 6-HT”) and dopamine-2 (D2) recep-
`tors, with an ~8-fold greater affinity for
`the 5-HT2A receptor than the 02 receptor.
`These effects are consistent with antipsy-
`chotic activity and a decreased risk of
`
`antipsychotic drugs to increase the QTc
`interval (QT interval corrected for heart
`rate). For acute psychotic symptoms in
`patients with schizophrenia, schizoaf—
`fective disorder. or acute mania, ziprasi-
`done is administered twice daily at a usual
`daily dose of 80 to 160 mg, whereas 40
`mg/d may be an effective maintenance
`dose.
`
`Conclusions: Differences in efficacy
`and tolerability between existing atypical
`antipsychotic drugs allow individualiza-
`tion of drug therapy for patients with
`schizophrenia or schizoaffective disorder.
`Ziprasidone differs from other atypical
`antipsychotic drugs in several clinically
`important ways. although further experi-
`ence is necessary to clarify the signifi-
`cance of these differences.
`
`Key words: ziprasidone, atypical an-
`tipsychotic, weight gain, QTc interval.
`(Clin Ther. 2002;24:21—37)
`
`INTRODUCTION
`
`The 19905 saw the introduction of 4 atyp-
`ical antipsychotic drugs that significantly
`changed the treatment of schizophrenia
`and have effectively supplanted the typi-
`cal antipsychotic drugs haloperidol, chlor-
`promazine. and fluphenazine. Clozapine
`was the first atypical antipsychotic drug
`to demonstrate superior efficacy to the
`typical antipsychotic drugs in treatment-
`resistant schizophrenia and for the nega-
`tive symptoms of schizophrenia. Subse-
`quently.
`risperidone. olanzapine. and
`quetiapine demonstrated improved safety
`compared with clozapine while maintain-
`ing improved efficacy and tolerability
`compared with the typical antipsychotic
`drugs. During the 19903, the focus of in-
`terest was on the atypical antipsychotic
`drugs’ improved efficacy and reduced
`
`22
`
`

`

`G.Li STIMMEL ET AL.
`
`EPS. Unlike other atypical antipsychotic
`drugs, however. ziprasidone also has
`potent 5-HTlD—antagonist and 5-HT”-
`agonist activity. and moderate inhibitory
`activity against 5-HT and norepinephrine
`reuptake.“3 These receptor effects are
`consistent with the potential for both an-
`tidepressant and anxiolytic activity. Zipra-
`sidone binds with moderate affinity to the
`histamine-1 and alpha-l—adrenergic re-
`ceptors, corresponding to potential seda-
`tion and orthostatic hypotension, respec-
`tively. Ziprasidone has negligible affinity
`for the muscarinic-l receptor. Its receptor
`affinities are summarized and compared
`with those of the other atypical antipsy-
`chotic drugs in Table l.
`
`PHARMACOKINETICS
`
`Absorption and Distribution
`
`Over a dosing range of 80 to 160 mg/d,
`linear increases have been observed in
`
`both the maximum concentration (Cmax)
`and area under the concentration-time
`
`curve (AUC) of ziprasidone. The Cmax
`occurs 6 hours after multiple oral dosing
`with food. The absolute bioavailability
`of a ZO-mg dose under fed conditions is
`60%, Absorption of ziprasidone is in-
`creased up to 2-fold in the presence of
`food. No difference in absorption has been
`found with low- or high-fat meals or with
`administration up to 2 hours after a meal.
`Ziprasidone has a mean apparent vol-
`ume of distribution of 1.5 L/kg. It
`is
`>99% bound to plasma proteins, binding
`primarily to albumin and alpha-l—acid
`glycoprotcinxz“
`
`Metabolism and Elimination
`
`Ziprasidonc is extensively metabolized
`to 4 major metabolites. Two thirds of its
`metabolism is via reduction by alde-
`hyde oxidase. a non—cytochrome P450
`(CYP) pathway, to a metabolite with much
`lower pharmacologic activity than the
`parent compound. One third is metabo-
`lized via a CYP3A4 pathway that pro-
`duces inactive metabolites.3-5-6 After mul-
`
`Table 1. Relative receptor affinities of atypical antipsychotic drugs, using the scale 5 = very
`high, 4 = high. 3 = moderate/high, 2 = moderate, l = low, and — = negligible.
`
`Receptor Effects
`
`Ziprasidone
`
`Rispcridonc
`
`Olanzapine
`
`Quetiapine
`
`I)2
`5-HTm
`5-HT. A
`5-HT”)
`Alpha- | —adrenergic
`Muscarinic-l
`Histaminic—l
`
`5-HT/NE reuplake inhibition
`
`
`
`NNINbdbmh-
`
`4
`5
`l
`l
`4
`-—
`2
`
`—
`
`2
`4
`—
`l
`2
`4
`4
`
`—
`
`l
`l
`l
`—
`2
`2
`4
`
`1 (NE only)
`
`D = dopamine: HT = hydroxytryptamine; NE = norcpinephrinc.
`Adapted from the transcript of the US Food and Drug Administration Psychopharmacological Drugs Advisory
`Committee hearing. July l9. 2000-1
`
`23
`
`

`

`tiple oral dosing, ziprasidone has a mean
`terminal elimination half-life of 6.6 hours
`
`(range. 3.2-l0.0 hours). Steady-state se-
`rum concentrations are reached within l to
`
`3 days after twicealaily dosing under fed
`conditions.1
`
`Special Populations
`
`Neither age, sex. nor mild to moderate
`renal impairment has been observed to
`have any clinically significant influence
`on the pharmacokinetic behavior of zi—
`prasidonefl‘6 In a study in patients with
`Child-Pugh class A or B cirrh0sis, the
`AUC of ziprasidone was increased by l3%
`and 34%, respectively. The elimination
`half-life was 4.8 hours in the control
`
`group, compared with 7.l hours in the pa-
`tients with cirrhosis.”
`
`CLINICAL THERAPEUTICS”
`
`isozyme inhibitors have been reported to
`affect the metabolism of ziprasidone, and
`ziprasidone has not been reported to af-
`fect
`the metabolizing activity of CYP
`isozymes.3-‘°
`Although ziprasidone is highly protein
`bound, warfarin and propranolol have not
`been shown to alter its plasma protein
`binding in vitro.3 This suggests that the
`potential for displacement drug interac-
`tions with ziprasidone is minimal.3 No
`changes in ziprasidone’s pharmacokinetic
`parameters occurred with coadminis-
`tration of cimetidine or an aluminum
`
`hydroxide —magnesium hydroxide antacid.8
`Ziprasidone had no effect on steady-
`state lithium levels or renal clearance of
`
`lithium.” and caused no change in the
`pharmacokinetics of an ethinyl estradiol—
`levonorgestrel oral contraceptive agent.l2
`
`DRUG INTERACTIONS
`
`CLINICAL EFFICACY TRIALS
`
`is only partly dependent on
`Because it
`CYP3A4 for its metabolism, ziprasidone
`is unlikely to interact with other drugs
`metabolized by this isozyme. Its principal
`metabolic pathway, aldehyde oxidase. has
`no known inhibitors or inducers.3 In ll
`
`subjects who received ziprasidone coad-
`ministered with 800 mg of cimetidine. a
`weak CYP3A4 inhibitor. no significant
`changes in ziprasidone pharmacokinetics
`were seen.8 ln [4 subjects who received
`ziprasidone coadministered with 400 mg
`of ketoconazole. a potent CYP3A4 in-
`hibitor. the AUC of ziprasidone was in-
`creased by 33% and its Cm“ was increased
`by 34%.9 At the maximum dose of 160
`mg, serum concentrations of ziprasidone
`increased 39% when coadministered with
`
`Four short-term double-blind, placebo-
`controlled. fixed-dose clinical trials of
`
`ziprasidone have been conducted in hos-
`pitalized patients with an acute exacer-
`bation of schizophrenia or schizoaffec-
`tive disorder.3“3'H In addition. a 52-week
`randomized. double-blind. controlled.
`fixed—dose trial has been conducted in
`
`inpatients with chronic schizophrenia to
`assess its efficacy in treating negative
`symptoms and its ability to prevent acute
`exacerbation-”5 Double-blind, placebo-
`controllcd clinical
`trials of ziprasi-
`done have also been conducted in the
`
`treatment of acute mania in patients with
`type I bipolar disorder‘6 and in Tourette‘s
`syndrome.'7 These trials are summarized
`in Table II. Head-to-head clinical trials
`
`400 mg of ketoconazole, with no adverse
`effects or changes in electrocardiographic
`(ECG) parameters.3 No other CYP—
`
`comparing ziprasidone with other atypi-
`cal antipsychotic drugs are currently un-
`der way.
`
`24
`
`

`

`CLL STIMMEL ET AL.
`
`Table II. Placebo-controlled clinical trials of oral ziprasidone.
`
`Duration.
`wk
`
`Dose,
`mg/d
`
`No. of
`
`Patients
`
`Diagnosis
`
`Study
`
`lO4-‘
`
`I06'3
`
`114”
`
`”53
`
`4
`
`4
`
`6
`
`4
`
`Z 10
`Z 40
`Z 80
`Placebo
`
`z 40
`Z 120
`Placebo
`
`Z 80
`Z I60
`Placebo
`
`240
`Z l20
`Z 200
`Hal [5
`Placebo
`
`Z 40
`Z 80
`Z I60
`Placebo
`
`47
`55
`48
`50
`
`44
`47
`48
`
`l06
`|O4
`92
`
`87
`78
`86
`85
`83
`
`76
`72
`7 l
`75
`
`l3]
`64
`
`I6
`12
`
`Inpatient. acute exacerbation of schizm
`phrenia or schizoaffective disorder
`
`Inpatient. acute exacerbation of schizo-
`phrenia or schizoaffective disorder
`
`Inpatient, acute exacerbation of schizo-
`phrenia or schizoaffective disorder
`
`Inpatient. acute exacerbation of schizo-
`phrenia or schizoal’fective disorder
`
`Inpatient, stable chronic schizophrenia
`
`Acute mania
`
`Tourette's syndrome
`
`lO~ and 40—mg doses were ineffective in
`these acutely symptomatic patients. Forty-
`four percent of the 80-mg group dropped
`out of the study within 2 weeks, approxi-
`mately half for protocol violations or
`withdrawal of consent and the other half
`
`for inadequate response. Given that later
`clinical trials found this dose to be effec—
`
`25
`
`3033'”
`
`52
`
`Keck and lce'6
`
`Sallee et al'7
`
`3
`
`8
`
`Z 80—]60'
`Placebo
`
`Z 5—40‘
`Placebo
`
`Z = ziprasidone; Hal = haloperidol.
`'Flexible dosing.
`
`Acute Therapy
`
`Study 104
`In a fixed-dose comparative clinical
`trial of ziprasidone IO (n = 47), 40 (n = 55).
`and 80 (n = 48) mg/d,3 no differences in
`efficacy were found between any treat-
`ment group and placebo (n = 50). The
`
`

`

`CLINICAL THERAPEUTICS‘
`
`allowed were lorazepam (for insomnia or
`agitation) and benztropine or beta-blockers
`(for EPS). The percentages of patients
`classified as PANSS responders and CGI—
`Improvement responders were signifi—
`cantly greater in the group that received
`ziprasidone 160 mg/d compared with
`placebo (both, P < 0.001 ). Significant im-
`provement
`in negative symptoms was
`demonstrated with both doses of ziprasiv
`done compared with placebo (80 mg/d,
`P < 0.05; 160 mg/d, P < 0.001).
`An evaluation of depressive symptoms
`found that ziprasidone had no significant
`effect on overall Montgomery-Asberg
`Depression Rating Scale
`(MADRS)
`scores. In patients with more severe de—
`pressive symptoms (MADRS score >13).
`ziprasidone 160 mg/d significantly reduced
`scores compared with placebo (P < 0.05).
`suggesting that ziprasidone may reduce
`but not completely resolve depressive
`symptoms in patients with an acute exac-
`erbation of schizophrenia or schizoal‘fec»
`the disorder.
`
`Study 115
`In a trial that compared fixed doses
`of ziprasidone 40 (n = 87), 120 (n = 78),
`and 200 mg/d (n = 86) and haloperidol 15
`mg/d (n = 85) with placebo (n = 83)3 all
`active-treatment groups demonstrated
`statistically significant improvement in
`PANSS total (P < 0.03), BPRS total (P <
`0.05), BPRS core items (P < 0.05), and
`
`CGI—S scores (P < 0.04). Only ziprasidone
`200 mg/d was associated with statistically
`significant improvement in the PANSS
`negative subscale score (P < 0.012). There
`was no difference in improvement in neg-
`ative symptoms between ziprasidone and
`haloperidol. although the ability to assess
`the response of negative symptoms is lim-
`ited in a 4-week study of this type.
`
`tivc, the overall lack of efficacy in this
`study may be explained by the high
`dropout rate.
`
`Study 106
`[n a comparison of fixed-dose ziprasi-
`done 40 (n = 44) and 120 mg/d (n = 47).'3
`only the lZO-mg/d dose demonstrated sig—
`nificant efficacy compared with placebo
`(n = 48) (P < 0.05). The only concomitant
`medications allowed were lorazepam (for
`insomnia or agitation) and benztropine or
`beta-blockers (for EPS). Ziprasidone 120
`mg/d was more effective than placebo in
`improving mean Brief Psychiatric Rating
`Scale (BPRS) total scores and Clini-
`
`cal Global lmpression~Severity (CGI-S)
`scores. Mean improvements in primary
`efficacy variables were no different with
`ziprasidone 40 mg/d than with placebo.
`At 4 weeks. mean BPRS depression clus-
`ter scores and BPRS anergia factor scores
`were significantly improved with ziprasi-
`done 120 mg/d compared with placebo
`(both scores. P < 0.05). suggesting some
`benefit for affective symptoms in this pa-
`tient population. After 1 week of treat-
`ment, improvement was noted in all 3
`treatment groups. No further improvement
`was seen in the placebo group after the
`first week, but patients receiving ziprasi—
`done 120 mg/d improved progressively
`over the 4 weeks, with maximal improve-
`ment at 4 weeks.
`
`Study 114
`In a 6-week trial.” both ziprasidone 80
`(n = 106) and 160 mg/d (n = 104) were
`more effective than placebo (n = 92) on
`the primary efficacy measures (Positive
`and Negative Syndrome Scale [PANSS]
`total. BPRS total. BPRS core items. CGI-S,
`
`and PANSS negative subscale scores).
`Again, the only concomitant medications
`
`26
`
`

`

`G.L. STIMMEL ET AL.
`
`Schizoaflective Disorder
`
`Results from 1 l5 patients with schizoaf-
`fcctive disorder in 2 studies”-” were com-
`
`bined to compare the efficacy of ziprasi-
`done doses of 40. 80. 120. and 160 mgld
`and placebo.‘8 In this diagnostic subgroup.
`ziprasidone 160 mg/d was significantly
`more effective than placebo in improving
`mean BPRS total (P < 0.01), BPRS core
`items (P< 0.01). BPRS mania (P <0.001 ).
`and CGl-S scores (P < 0.01). Ziprasidone
`l20 mg/d was significantly more effective
`than placebo in improving mean CGI-S
`scores (P < 0.05). Mean improvements in
`BPRS depression items and MADRS
`scores were not statistically significant
`compared with placebo.
`
`Maintenance Therapy
`
`The standard of practice for chronic
`schizophrenia requires maintenance drug
`therapy for the prevention of relapse.'9
`Study 303 compared maintenance therapy
`with fixed doses of ziprasidone 40 (n = 76).
`80 (n = 72). and 160 mg/d (n = 7]) ver-
`sus placebo (n = 75) over 1 year in inpa-
`tients with stable chronic schizophrenia.”
`This patient population had long—standing
`illness. stable overall psychopathology
`(reflected in relatively modest positive
`symptoms), but moderate to severe nega-
`tive symptoms. with seriously impaired
`social and occupational functioning. All
`ziprasidone doses significantly reduced
`the probability of an acute exacerbation
`of psychotic symptoms compared with
`placebo (41%. 35%. 36%. and 7l%, re-
`spectively). Significant improvements in
`PANSS total and CGl—S scores occurred
`
`at all ziprasidone doses compared with
`placebo (both scales. P < 0.05). Ziprasi—
`done 40 and l60 mg/d were statistically
`
`superior to placebo for the treatment
`of negative symptoms (P < 0.05 and P <
`0.01. respectively), with improvement
`continuing throughout the study. Ziprasi-
`done was associated with significant im-
`provements in Global Assessment of
`Functioning (GAF) scores in all dose
`groups (40 and 80 mg/d. P < 0.05: 160
`mg/d. P < 0.001).
`To more specifically evaluate the
`response of negative symptoms, a 28-
`week study in outpatients with stable
`schizophrenia compared flexible doses
`of ziprasidone 80 to 160 mg/d (n = NO)
`and haloperidol 5 to 15 mg/d (n = 117).20
`Whereas both groups had similar over~
`all improvement. a response in negative
`symptoms occurred in 48% of patients
`receiving ziprasidone compared with 33%
`of patients receiving haloperidol.
`
`Switching from Other Antipsychon'c
`Drugs to Ziprasidone
`
`Several open—label studies have evalu-
`ated the efficacy and tolerability of a
`switch from other antipsychotic drugs to
`ziprasidone. In a study in patients with a
`diagnosis of schizophrenia or schizoaffec-
`tive disorder. those with at least a partial
`response to current antipsychotic drug
`therapy but with inadequate efficacy
`or tolerability were switched to zipra-
`sidone.2| Ninety patients were switched
`from olanzapine, 42 from risperidone. and
`97 from typical antipsychotic drugs. Three
`switching strategies were compared-
`abrupt discontinuation of the origi-
`nal antipsychotic drug. 50% reduction
`for
`1 week followed by discontinua-
`tion. and gradual tapering over 1 week.
`In all groups. ziprasidone was initiated
`at 80 mg/d for 2 days and then given
`at flexible open-label doses of 40 to
`
`27
`
`

`

`CLINlCAL THERAPEUTICS"
`
`subscale (P < 0.001) scores. GAF scores
`were also significantly improved in
`the ziprasidonc group compared with
`placebo (P < 0.01). Discontinuation of
`treatment due to lack of clinical response
`occurred in 19% of Ziprasidone and 36%
`of placebo recipients.
`
`Tourette ’s Syndrome
`
`Treatment of Tourette’s syndrome has
`traditionally involved use of
`typical
`dopamine—blocking antipsychotic drugs
`such as haloperidol. Preliminary evidence
`suggests that the atypical antipsychotic
`drugs may be as effective as such agents,
`with the potential for fewer adverse ef—
`fects.'7 An 8-week randomized. double-
`blind clinical trial compared Ziprasidone
`5 to 40 mg/d with placebo in 28 patients
`with Tourette’s syndrome.” Ziprasidone
`was initiated at 5 mg/d. with titration to a
`maximum of 40 mg/d: the mean (tSD)
`daily dose in the last 4 weeks of the study
`was 28 4.: 9.6 mg. Ziprasidone was signif~
`icantly more effective than placebo in re-
`ducing global severity (P < 0.016) and
`total tic (P < 0.008) scores on the Yale
`Global Tic Severity Scale. and it signifi-
`cantly reduced tic frequency as deter-
`mined by blind videotape tic counts (P <
`0.039). Although the patient sample was
`small, results of this study support the ef-
`ficacy of atypical antipsychotic drugs in
`the treatment of Tourette’s syndrome.
`
`ADVERSE EFFECTS
`
`Common Adverse Effects
`
`Table 111 compares the relative adverse-
`effect profiles of the atypical antipsychotic
`drugs based on the results of receptor-
`affinity studies and clinical trials.22 in the
`
`160 mg/d for the remainder of the 6—week
`study. Significant improvements were ob—
`served in negative symptoms (P < 0.01)
`and overall psychopathology (P < 0.05)
`with a switch from any of the original
`drugs. Ziprasidone was associated with
`significant
`improvements
`in positive
`symptoms compared with conventional
`antipsychotic drugs and olanzapine (P <
`0.001) but not compared with risperidone.
`Abrupt switching without cross-tapering
`was as well tolerated as the other switch-
`
`ing strategies, suggesting that patients can
`be switched to Ziprasidone over a rela-
`tively short period.
`
`Acute Mania
`
`A randomized, double—blind study com-
`pared ziprasidone at doses ranging from
`80 to 160 mg/d (n = 131) with placebo
`(n = 64) over 21 days in inpatients with
`acute mania.‘6 Patients had a diagnosis of
`type 1 bipolar disorder. manic or mixed.
`with moderate to marked symptom sever—
`ity. Concomitant anxiolytic agents (oral
`or intramuscular lorazepam up to 8 mg/d
`or temazepam up to 30 mg at night) were
`administered to 76% of patients in each
`group in the first 9 days of the study.
`At baseline, patients had high levels of
`manic and positive psychotic symp~
`toms as well as a low GAF score. Based
`
`on scores on the Mania Rating Scale and
`its manic syndrome and behavior/ideation
`subscales, after 2 days of Ziprasidone ther-
`apy there were significant improvements
`in both manic (P < 0.05) and behavior/
`ideation (P < 0.01) symptoms compared
`with placebo. These improvements per—
`sisted throughout the 21-day trial. From
`days 7 through 2|, those receiving zi—
`prasidone had significant improvements
`in CGl-S (P < 0.01) and PANSS positive
`
`28
`
`

`

`G.L. STIMMEL ET AL.
`
`Table lll. Relative adverse effects of atypical antipsychotic drugs. on a scale from I = low
`to 5 = high.
`
`Drug
`
`Sedation EPS
`
`Anticholinergic
`Effect
`
`Postural
`Hypotension
`
`Weight
`Gain Hyperprolactinemia
`
`Haloperidol
`Chlorpromazine
`Clozapine
`Olanzapine
`Quetiapine
`Risperidone
`
`Ziprasidone
`
`I
`4
`4
`2
`2
`I
`1—2
`
`5
`2
`0-I
`I
`0—]
`[—2
`I
`
`Adapted from Stimmel GL.22
`
`0—!
`4
`4
`2
`l
`l
`0
`
`4- to 6-week efficacy studies in hospital-
`ized patients with an acute exacerbation
`of schizophrenia or schizoaffectivc disor-
`der, the most common adverse effects oc-
`
`least twice as often as with
`curring at
`placebo were somnolence (l4%), respira
`tory disorder (8%), and EPS (5%).3 Som-
`nolence was described as mild to moderate
`
`and transient. and rarely required discon—
`tinuation of therapy. Using the Simpson—
`Angus and Barnes Akathisia rating scales,
`no significant difference in the incidence
`of EPS was found between ziprasidone
`and placebo (see following section on BPS).
`Over 90% of events classified as respira-
`tory disorders were initial transient cold
`symptoms or upper respiratory tract in-
`fections. Adverse effects commonly seen
`with some antipsychotic drugs that were
`not observed more often with ziprasidone
`than placebo included orthostatic hy-
`potension( | 3%). weight gain (0.4%). and
`male sexual dysfunction (0.3%).3
`In the 1-year maintenance trial,3 the
`only adverse effect that occurred signifi-
`cantly more often with ziprasidone than
`with placebo was asthenia (5.5%) (P <
`0.05). Although n0t statistically different
`
`l
`5
`5
`I
`2
`3
`l
`
`2
`5
`5
`5
`3
`3
`0~l
`
`5
`5
`O~I
`l
`O—l
`3
`I
`
`from placebo. other treatment-emergent
`adverse events reported with ziprasidone
`in this study included insomnia (35.6%
`ziprasidone vs 32.0% placebo). akathisia
`(9.6% vs 5.3%), headache (6.8% vs 5.3%),
`and rash (5.9% vs 1.3%).
`
`In the acute mania study,” all adverse
`effects were reported as either mild or
`moderate in severity. Seven percent of
`ziprasidone patients and 4% of placebo
`recipients discontinued treatment because
`of adverse effects. The most common ad-
`
`verse effects reported with ziprasidone
`compared with placebo included somno-
`lence (37% vs 13%. respectively), dizzi-
`ness (22% vs I0%), headache (21% vs
`19%), nausea (”‘70 vs l0%), akathisia
`(l I% vs 6%), agitation (9% vs I3%), and
`insomnia (8% vs 10%). No clinically sig-
`nificant changes in blood pressure. heart
`rate, or ECG variables were observed.
`In the study in patients with Tourette‘s
`syndrome.'7 the most common adverse
`effect was mild sedation. Sedation was
`
`present on at least I visit in 69% of ziprasi-
`done patients and 45% of placebo recipi-
`ents. In the ziprasidone group, sedation
`scores (based on a rating scale from 0 =
`
`29
`
`

`

`absent to 3 = severe) were |.2 at baseline
`and varied from L] to a high of 1.8 at week
`6. One case of sedation (day 35. ziprasi-
`done 40 mg/d) and l case of akathisia (day
`43, ziprasidone 40 mg/d) were considered
`to be severe. Both cases resolved with
`
`dose reduction, and the patients continued
`in the study. No significant differences
`were noted in movement disorder ratings
`between the ziprasidone and placebo
`groups. nor were there any clinically sig-
`nificant changes in heart rate. standing or
`sitting blood pressure, or ECG parame—
`ters. The mean (18D) change in body
`weight at week 8 was minimal and simi-
`lar between groups (+0.7 i l.5 kg ziprasi-
`done vs 40.8 t 2.3 kg placebo).
`In the short—terrn clinical trials, 5% of
`
`the ziprasidone groups and 4% of the
`placebo groups developed a rash. The
`overall incidence of rash in the Phase ll
`
`and ill trials was 4.5% with ziprasidone
`and 3.4% with placebo. Most of these pa-
`tients continued treatment, with resolu-
`tion of the rash, and no other evidence of
`
`systemic illness or hypereosinophilia was
`reported.3
`Ziprasidone has a pregnancy category
`C ratings No adequate controlled studies
`have been conducted in pregnant women.
`
`Extrapyramidal Symptoms
`
`In the short-term efficacy trials, move-
`ment disorders were assessed using both
`the Simpson-Angus and Barnes Akathisia
`rating scales. There were no statistically
`significant differences in mean decreases
`from baseline to study end point on either
`movement disorder scale between the
`
`ziprasidone and placebo groups.3 Further
`information on the occurrence of EPS can
`
`be inferred from the use of benztropine
`for EPS and beta-blockers for akathisia.
`
`30
`
`CLINICAL THERAPEUTICS"
`
`Pooled data from the short-term, fixed-dose
`
`trials showed similar numbers of ziprasi-
`done and placebo recipients requiring ad-
`junctive benztropine (22% vs 18%, respec-
`tively) or propranolol (7% vs 6%). During
`study ”5, in contrast, 51% of patients re-
`ceiving haloperidol required benztropine.
`and l9% required a beta-blocker.3
`The 1-year data from study 303'5
`showed no difference in the oceurrence of
`
`EPS between the 3 doses of ziprasidone
`and placebo, with scores on both the
`Simpson-Angus and Barnes Akathisia rat-
`ing scales decreasing from baseline. Anti-
`cholinergic and beta-blocker use was
`lower than before the study and similar in
`all groups.
`In an early dose—finding study,23 4 doses
`of ziprasidone were compared with halo—
`peridol l5 mg/d for 4 weeks. At the end of
`the trial. 67% of patients receiving halo-
`peridol required benztropine. compared
`with 30% of patients receiving ziprasi-
`done 40 mg/d and 15% of those receiving
`ziprasidone 160 mg/d. The majority of pa-
`tients in the 4 ziprasidone groups had ei-
`ther no change or a decrease in Simpson-
`Angus rating scale scores at the end of the
`study, and n0 between-group differences
`were seen in the mean change in Simpson-
`Angus. Barnes Akathisia. or Abnormal
`Involuntary Movement Scale scores from
`baseline.
`
`Weight Change
`
`common
`the
`Whereas EPS were
`adverse effects of most concern with
`
`the older typical antipsychotic drugs.
`the common adverse effect of most
`
`concern with the atypical antipsychotic
`drugs is weight gain. Among these agents.
`clozapine and olanzapine cause the
`greatest weight gain. followed by queti-
`
`10
`
`

`

`G.L. STIMMEL ET AL.
`
`apine and risperidone, whereas ziprasi—
`done is weight neutral.
`In I
`study.24
`mean weight gains after 10 weeks of treat—
`ment were 4.5 kg with clozapine. 4 kg
`with olanzapine, 2 kg with quetiapine
`(after 8 weeks). 2 kg with risperidone,
`1 kg with haloperidol. and 0.04 kg with
`ziprasidone.
`Although the exact numbers vary among
`studies. the mean weight gain with olan-
`zapine has been reported to be 4.5 kg af-
`ter I0 weeks of therapy, 7 to 8 kg after 40
`weeks, and l2 kg after I year.25 Within the
`dose range from 5 to 20 mg/d, weight gain
`with olanzapine has not been shown to be
`dose dependent: the amount of weight gain
`appears to increase over time and plateau
`at ~36 to 40 weeks. In I report.26 43% of
`olanzapine-treated patients had no weight
`change or had gained <5 kg after 2 years
`of treatment. 23% gained 5 to IO kg. and
`34% gained >l0 kg; 7% gained >20 kg.
`Fewer data are available on weight gain
`with risperidone and quetiapine, but both
`commonly cause less weight gain than
`olanzapine. With risperidone, weight gain
`reaches a plateau of 2 to 3 kg at 8 to l2
`weeks. Quetiapine has been associated
`with a weight gain of 3 kg in short-term
`trials and 2 to 5.6 kg with longer-term
`treatment.25
`
`Given the growing concern about
`weight gain with the atypical antipsy-
`chotic drugs, ziprasidone has been care-
`fully evaluated for its effect on weight. In
`the 4 short-term trials. ziprasidone was
`associated with a weight increase of 0.9
`kg, compared with a 0.4-kg weight loss
`with placebo. Weight gain, defined as 27%
`of body weight. occurred in 9.8% of the
`ziprasidone groups and 4% of the placebo
`groups.3 In the l-year clinical trial. the
`mean weight loss was I. 2. 3. and 3 kg in
`the ziprasidone 40-, 80—. and I60-mg
`
`groups and the placebo group. respec-
`tively.3 In the switching studies}21 pa—
`tients switched from olanzapine to ziprasi-
`done had a mean decrease in body weight
`of 1.8 kg after 6 weeks, whereas patients
`switched from risperidone to ziprasidone
`had a mean decrease in body weight of
`0.8 kg over the same period.
`
`Changes in laboratory Values
`
`Serum Prolaclt'n Levels
`
`Because of its Dz-receptor antagonism,
`ziprasidone has the potential to increase
`serum prolactin levels. In men. such in-
`creases may be associated with decreased
`libido. erectile dysfunction. and hypo-
`spermatogenesis. whereas women may
`experience disturbances in the menstrual
`cycle. galactorrhea. vaginal dryness. and
`sexual dysfunction.27 Ziprasidone in-
`creases serum prolactin levels less fre-
`quently than do haloperidol and risperi-
`done, and the elevations appear to be
`transient.21
`In the Phase II and III clinical trials.
`
`prolactin levels >22 ng/mL occurred in
`4% of placebo. 20% of ziprasidone, 46%
`of haloperidol. and 89% of risperidone
`groups. In women, at least
`1 serum pro-
`lactin measurement >50 ng/mL occurred
`in 9% of ziprasidone. 27% of haloperidol.
`and 77% of risperidone groups.3 In a 4-
`week clinical trial,23 serum prolactin lev—
`els did not differ from baseline during
`treatment with ziprasidone 4,
`IO, 40. or
`160 mg/d, whereas they increased by a
`factor of 5 with haloperidol. In the clini—
`cal trial in Tourette’s syndrome,'7 5 of I4
`boys treated with ziprasidone had a tran—
`sient increase in prolactin levels. which
`returned to normal by the end of the study.
`In the studies of therapeutic switching.“
`
`31
`
`11
`
`

`

`CLINICAL THERAPEUTICS“
`
`median triglyceride and total cholesterol
`levels in these patients.“
`
`Plasma Glucose Levels and
`New-Onset Diabetes Mellitus
`
`There have also been reports of eleva—
`tions in plasma glucose levels with cloza-
`pine and olanzapine, including cases of
`new-onset diabetes mellitus“ and diabetic
`ketoacidosis.32 [n the short-term clinical
`
`trials of ziprasidone. the incidence of ab-
`normal elevations in random glucose lev-
`els was the same in the ziprasidone and
`placebo groups (8%). compared with l4%
`in the haloperidol group. In all Phase II
`and ill clinical trials, elevations in ran-
`
`dom glucose levels occurred in 12% of
`placebo. 15% of ziprasidone. 15% of ris—
`peridone. and 16% of haloperidol groups.3
`There were no cases of treatment-emergent
`diabetes mellitus in the 3834 patients who
`received ziprasidone. In the switching
`studies,