CLINICAL THERAPEUTICS*/VOL.24, NO. 1, 2002
`
`Ziprasidone: An Atypical Antipsychotic Drug
`for the Treatment of Schizophrenia
`
`Glen L. Stimmel, PharmD, BCPP!? Mary A. Gutierrez, PharmD, BCPP,'
`and Vivian Lee, PharmD?
`Schools of 'Pharmacy and *Medicine, University of Southern California, Los Angeles,
`California, and *School of Pharmacy, The Chinese University ofHong 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 whetherthere 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 premarketingclinical 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. International Pharmaceutical Abstracts and
`MEDLINEwere 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 symptomsof schizophrenia, and long-term use has been effective in
`preventing relapse. Its S-hydroxytryptamine (HT), ,-antagonist and 5-HT, ,—agonist ac-
`tivity are consistent with a potential for antidepressant and anxiolytic activity beyondits
`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 for publication October 31, 2001.
`Printed in the USA. Reproduction in whole orpart is not permitted.
`
`0149-2918/02/$ 19.00
`
`21
`
`Exhibit 2056
`Slayback v. Sumitomo
`IPR2020-01053
`
`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 ofclin-
`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-
`mentof schizophrenia and schizoaffective
`disorder in the United States. This review
`describes the drug’s mechanism of ac-
`tion, pharmacokinetics, 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
`
`Ziprasidoneis a benzothiazolylpiperazine,
`unrelated to the phenothiazine and buty-
`rophenoneantipsychotic drugs. Like other
`atypical antipsychotic drugs, it is an an-
`tagonist of both the 5-hydroxytryptamine-
`2A (5-HT,,) and dopamine-2 (D,) recep-
`tors, with an ~8-fold greater affinity for
`the 5-HT,, receptor than the D, 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 symptomsin
`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 1990s saw the introductionof 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
`wasthe 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 1990s, the focus of in-
`terest was on the atypical antipsychotic
`drugs’ improved efficacy and reduced
`
`22
`
`

`

`G.L. STIMMELET AL.
`
`EPS. Unlike other atypical antipsychotic
`drugs, however, ziprasidone also has
`potent 5-HT, ,-antagonist and 5-HT, ,—
`agonist activity, and moderate inhibitory
`activity against S-HT and norepinephrine
`reuptake.'~> 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-1 receptor. Its receptor
`affinities are summarized and compared
`with those of the other atypical antipsy-
`chotic drugs in Table I.
`
`PHARMACOKINETICS
`
`Absorption and Distribution
`
`Over a dosing range of 80 to 160 mg/d,
`linear increases have been observed in
`both the maximum concentration (C,,,.)
`and area under the concentration-time
`
`curve (AUC) of ziprasidone. The C_,.
`occurs 6 hours after multiple oral dosing
`with food. The absolute bioavailability
`of a 20-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-!—acid
`glycoprotein.>4
`
`Metabolism and Elimination
`
`Ziprasidone is extensively metabolized
`to 4 major metabolites, Two thirds ofits
`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. Onethird is metabo-
`lized via a CYP3A4 pathway that pro-
`duces inactive metabolites.>>° After mul-
`
`Table |. Relative receptor affinities of atypical antipsychotic drugs, using the scale 5 = very
`high, 4 = high, 3 = moderate/high, 2 = moderate, | = low, and — = negligible.
`
`Receptor Effects
`
`Ziprasidone
`
`Risperidone
`
`Olanzapine
`
`Quetiapine
`
`D,
`5-HT,,
`5S-HT, 4
`5-HT,,
`Alpha-l—adrenergic
`Muscarinic- |
`Histaminic-!
`
`5-HT/NE reuptake inhibition
`
`4
`5
`4
`4
`2
`=
`2
`
`2
`
`4
`5
`1
`l
`4
`-
`2
`
`-
`
`2
`4
`-
`]
`2
`=
`4
`
`-
`
`l
`I
`|
`~
`2
`2
`4
`
`i (NE only)
`
`D = dopamine; HT = hydroxytryptamine; NE = norepinephrine.
`Adapted from the transcript of the US Food and Drug Administration Psychopharmacological Drugs Advisory
`Committee hearing, July 19, 2000.*
`
`23
`
`

`

`tuple oral dosing, ziprasidone has a mean
`terminal elimination half-life of 6.6 hours
`(range, 3.2—10.0 hours). Steady-state se-
`rum concentrations are reached within | to
`3 days after twice-daily dosing under fed
`conditions.*
`
`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-
`prasidone.*© In a study in patients with
`Child-Pugh class A or B cirrhosis, the
`AUCofziprasidone wasincreased by 13%
`and 34%, respectively. The elimination
`half-life was 4.8 hours in the control
`group, compared with 7.1 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.>!°
`Although ziprasidone is highly protein
`bound, warfarin and propranolol have not
`been shownto alter its plasma protein
`binding in vitro.’ This suggests that the
`potential for displacement drug interac-
`tions with ziprasidone is minimal.? No
`changesin ziprasidone’s pharmacokinetic
`parameters occurred with coadminis-
`tration of cimetidine or an aluminum
`hydroxide-magnesium hydroxide antacid.®
`Ziprasidone had no effect on steady-
`state lithium levels or renal clearance of
`lithium,'! and caused no change in the
`pharmacokinetics of an ethiny!] estradiol—
`levonorgestrel oral contraceptive agent. '?
`
`DRUG INTERACTIONS
`
`CLINICAL EFFICACY TRIALS
`
`is only partly dependent on
`Because it
`CYP3A4for 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.’ In 11
`subjects who received ziprasidone coad-
`ministered with 800 mg of cimetidine, a
`weak CYP3A4inhibitor, no significant
`changes in ziprasidone pharmacokinetics
`were seen.’ In 14 subjects who received
`ziprasidone coadministered with 400 mg
`of ketoconazole, a potent CYP3A4 in-
`hibitor, the AUC of ziprasidone was in-
`creased by 33% andits C,,,, was increased
`by 34%.° At the maximum dose of 160
`mg, serum concentrations of ziprasidone
`increased 39% when coadministered with
`400 mg of ketoconazole, with no adverse
`effects or changesin electrocardiographic
`(ECG) parameters.* No other CYP-
`
`24
`
`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:'4 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
`symptomsandits ability to prevent acute
`exacerbation.*!5 Double-blind, placebo-
`controlled clinical
`trials of ziprasi-
`done have also been conducted in the
`treatment of acute mania in patients with
`type | bipolar disorder!® and in Tourette’s
`syndrome.'’ Thesetrials are summarized
`in Table II. Head-to-head clinical trials
`comparing ziprasidone with other atypi-
`cal antipsychotic drugs are currently un-
`der way.
`
`

`

`G.L. STIMMELET AL.
`
`Table II. Placebo-controlled clinica) trials of oral ziprasidone.
`
`Duration,
`wk
`
`Dose,
`mg/d
`
`No.of
`Patients
`
`Diagnosis
`
`Study
`
`1043
`
`106!3
`
`114'4
`
`1153
`
`4
`
`4
`
`6
`
`4
`
`Z10
`Z40
`Z 80
`Placebo
`
`Z 40
`Z 120
`Placebo
`
`Z 80
`Z 160
`Placebo
`
`Z 40
`Z 120
`Z 200
`Hal I5
`Placebo
`
`Z 40
`Z 80
`Z 160
`Placebo
`
`47
`55
`48
`50
`
`44
`47
`48
`
`106
`104
`92
`
`87
`78
`86
`85
`83
`
`76
`72
`71
`75
`
`131
`64
`
`16
`12
`
`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 schizoaffective disorder
`
`Inpatient, acute exacerbation of schizo-
`phrenia or schizoaffective disorder
`
`Inpatient, stable chronic schizophrenia
`
`Acute mania
`
`Tourette’s syndrome
`
`10- and 40-mg doses were ineffective in
`these acutely symptomaticpatients. 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
`
`3033-15
`
`52
`
`Keck and Ice'®
`
`Sallee et al!”
`
`3
`
`8
`
`Z, 80-160"
`Placebo
`
`Z 5-40°
`Placebo
`
`Z = ziprasidone; Hal = haloperidol.
`"Flexible dosing.
`
`Acute Therapy
`
`Study 104
`In a fixed-dose comparative clinical
`trial of ziprasidone 10 (n = 47), 40 (n = 55),
`and 80 (n = 48) mg/d,* 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 PANSSresponders 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 ziprasi-
`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 (MADRSscore >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 schizoaffec-
`tive 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)? all
`active-treatment groups demonstrated
`statistically significant improvement in
`PANSStotal (P < 0.03), BPRStotal (P <
`0.05), BPRS core items (P < 0.05), and
`CGI-S scores (P < 0.04). Only ziprasidone
`200 mg/d wasassociated 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 symptomsis lim-
`ited in a 4-week study ofthis type.
`
`tive, the overall lack of efficacy in this
`study may be explained by the high
`dropout rate.
`
`Study 106
`In a comparison of fixed-dose ziprasi-
`done 40 (n = 44) and 120 mg/d (n = 47),8
`only the 120-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 Impression—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 BPRSdepression clus-
`ter scores and BPRSanergia factor scores
`were significantly improved with ziprasi-
`done 120 mg/d compared with placebo
`(both scores, P < 0.05), suggesting some
`benefit for affective symptomsin 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-weektrial,'* 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. STIMMELETAL.
`
`Schizoaffective Disorder
`
`Results from 115 patients with schizoaf-
`fective disorder in 2 studics!*-'4 were com-
`bined to compare the efficacy of ziprasi-
`done doses of 40, 80, 120, and 160 mg/d
`and placebo.'* In this diagnostic subgroup,
`ziprasidone 160 mg/d was significantly
`more effective than placebo in improving
`mean BPRStotal (P < 0.01), BPRS core
`items (P <0.01), BPRS mania (P <0.001),
`and CGI-S scores (P < 0.01). Ziprasidone
`120 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.!?
`Study 303 compared maintenance therapy
`with fixed doses of ziprasidone 40 (n = 76),
`80 (n = 72), and 160 mg/d (n = 71) ver-
`sus placebo (n = 75) over | 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 71%, re-
`spectively). Significant improvements in
`PANSS total and CGI-S scores occurred
`at all ziprasidone doses compared with
`placebo (both scales, P < 0.05). Ziprasi-
`done 40 and 160 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 = 110)
`and haloperidol 5 to 15 mg/d (n = 117).7°
`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.
`
`Switchingfrom Other Antipsychotic
`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.*! 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
`| week followed by discontinua-
`tion, and gradual tapering over | 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
`
`

`

`CLINICAL THERAPEUTICS”
`
`subscale (P < 0.001) scores. GAF scores
`were also significantly improved in
`the ziprasidone 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
`wasinitiated at 5 mg/d, with titration to a
`maximum of 40 mg/d; the mean (+SD)
`daily dose in the last 4 weeksof the study
`was 28 + 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 I1f comparesthe relative adverse-
`effect profiles ofthe atypical antipsychotic
`drugs based on the results of receptor-
`affinity studies andclinicaltrials.** In the
`
`160 mg/d for the remainderof 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 overa 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.'© Patients had a diagnosis of
`type | 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 GAFscore. 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 21, those receiving zi-
`prasidone had significant improvements
`in CGI-S (P < 0.01) and PANSSpositive
`
`28
`
`

`

`G.L. STIMMELET AL.
`
`Table III. Relative adverse effects of atypical antipsychotic drugs, on a scale from 1 = low
`to 5 = high.
`
`Drug
`
`Sedation EPS
`
`Anticholinergic
`Effect
`
`Postural
`Hypotension
`
`Weight
`Gain Hyperprolactinemia
`
`Haloperidol
`Chlorpromazine
`Clozapine
`Olanzapine
`Quetiapine
`Risperidone
`Ziprasidone
`
`
`|
`4
`4
`2
`2
`1
`1-2
`
`5
`2
`0-1
`I
`0-1
`1-2
`I
`
`Adapted from Stimmel GL.2
`
`0-1
`4
`4
`2
`1
`1
`0
`
`4- to 6-week efficacy studies in hospital-
`ized patients with an acute exacerbation
`of schizophrenia or schizoaffective disor-
`der, the most commonadverse effects oc-
`curring at
`least twice as often as with
`placebo were somnolence (14%), respira-
`tory disorder (8%), and EPS (5%). Som-
`nolence was described as mild to moderate
`and transient, and rarely required discon-
`tinuation of therapy. Using the Simpson-
`Angus and Barnes Akathisiarating scales,
`no significant difference in the incidence
`of EPS was found between ziprasidone
`and placebo (see following section on EPS).
`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 (1.3%), weight gain (0.4%), and
`male sexual dysfunction (0.3%).3
`In the l-year maintenancetrial, the
`only adverse effect that occurred signifi-
`cantly more often with ziprasidone than
`with placebo was asthenia (5.5%) (P <
`0.05). Although not statistically different
`
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`5
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`2
`3
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`
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`5
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`
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`
`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 10%), headache (21% vs
`19%), nausea (11% vs 10%), akathisia
`(11% vs 6%), agitation (9% vs 13%), 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,'? the most common adverse
`effect was mild sedation. Sedation was
`presenton at least | 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 =
`
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`

`absent to 3 = severe) were 1.2 at baseline
`and varied from 1.1 to a high of 1.8 at week
`6. One case of sedation (day 35, ziprasi-
`done 40 mg/d) and | 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 (+SD) change in body
`weight at week 8 was minimal and simi-
`lar between groups (+0.7 + 1.5 kg ziprasi-
`done vs +0.8 + 2.3 kg placebo).
`In the short-term clinical trials, 5% of
`the ziprasidone groups and 4% of the
`placebo groups developed a rash. The
`overall incidence of rash in the Phase II
`and III 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.>
`Ziprasidone has a pregnancy category
`C rating.> 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
`tating scales. There were nostatistically
`significant differences in mean decreases
`from baseline to study end point on either
`movement disorder scale between the
`ziprasidone and placebo groups.* Further
`information on the occurrence of EPS can
`be inferred from the use of benztropine
`for EPS and beta-blockers for akathisia.
`
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`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 115, in contrast, 51% of patients re-
`ceiving haloperidol required benztropine,
`and 19% required a beta-blocker.
`The 1-year data from study 303'5
`showed no difference in the occurrence of
`EPS between the 3 doses of ziprasidone
`and placebo, with scores on both the
`Simpson-Angusand Barnes Akathisiarat-
`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,” 4 doses
`of ziprasidone were compared with halo-
`peridol 15 mg/d for 4 weeks. At the end of
`the trial, 67% of patients receiving halo-
`perido] 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-
`Angusrating scale scores at the end of the
`study, and no between-group differences
`were seen in the mean change in Simpson-
`Angus, Barnes Akathisia, or Abnormal
`Involuntary MovementScale 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
`drugsis weight gain. Amongthese agents,
`clozapine and olanzapine cause the
`greatest weight gain, followed by queti-
`
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`

`G.L. STIMMELETAL.
`
`apine and risperidone, whereas ziprasi-
`done is weight neutral.
`In |
`study,?4
`mean weight gains after 10 weeksoftreat-
`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 10 weeks of therapy, 7 to 8 kg after 40
`weeks, and 12 kg after | year.*> Within the
`dose range from 5 to 20 mg/d, weight gain
`with olanzapine has not been shown to be
`dose dependent: the amountof weight gain
`appears to increase Over time and plateau
`at ~36 to 40 weeks. In | report,?° 43% of
`olanzapine-treated patients had no weight
`change or had gained <5 kg after 2 years
`of treatment, 23% gained 5 to 10 kg, and
`34% gained >10 kg: 7% gained >20 kg.
`Fewerdata 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 12
`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.”
`Given the growing concern about
`weight gain with the atypical antipsy-
`chotic drugs, ziprasidone has been care-
`fully evaluated forits 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% ofthe placebo
`groups.* In the 1-year clinical trial, the
`mean weight loss was 1, 2, 3, and 3 kg in
`the ziprasidone 40-, 80-, and 160-mg
`
`groups and the placebo group, respec-
`tively.3 In the switching studies,>?! pa-
`tients switched from olanzapineto 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 sameperiod.
`
`Changes in Laboratory Values
`
`Serum Prolactin Levels
`
`Becauseofits D,-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.2’ Ziprasidone in-
`creases serum prolactin levels less fre-
`quently than do haloperidol and risperi-
`done, and the elevations appear to be
`transient.?!
`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% ofrisperidone
`groups. In women, at least
`| serum pro-
`lactin measurement >50 ng/mL occurred
`in 9% ofziprasidone, 27% of haloperidol,
`and 77% of risperidone groups.* In a 4-
`weekclinicaltrial,?> serum prolactin lev-
`els did not differ from baseline during
`treatment with ziprasidone 4, 10, 40, or
`160 mg/d, whereas they increased by a
`factor of 5 with haloperidol. In the clini-
`cal trial in Tourette’s syndrome,"’ 5 of 14
`boys treated with ziprasidone had a tran-
`sient increase in prolactin levels, which
`returned to normal by the endofthe study.
`In the studies of therapeutic switching,?!
`
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`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 glucoselevels with cloza-
`pine and olanzapine, including cases of
`new-onset diabetes mellitus?! and diabetic
`ketoacidosis.*? In 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 14%
`in the haloperidol group. In all Phase II
`and III clinical trials, elevations in ran-
`dom glucose levels occurred in 12% of
`placebo, 15% of ziprasidone, 15% ofris-
`peridone, and 16% of haloperidol groups.*
`There were no cases of treatment-emergent
`diabetes mellitus in the 3834 patients who
`received ziprasidone. In the switching
`studies,?! there were no changesin plasma
`glucose levels over a 6-weektrial of
`ziprasidone.”
`
`Cardiovascular Effects
`
`Orthostatic Hypote