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John W. Newcomer, Elise M. Fallucco: Chapter 33. Ziprasidone, in The American Psychiatric Publishing Textbook of
Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric
Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.440629. Printed 5/10/2009 from www.psychiatryonline.com
Textbook of Psychopharmacology >
Chapter 33. Ziprasidone
HISTORY AND DISCOVERY
Ziprasidone (CP-88059) is an atypical, or second-generation, antipsychotic agent that has demonstrated
activity for treating positive, negative, cognitive, and affective symptoms of schizophrenia and
schizoaffective disorder and for treating mania and mixed states in bipolar disorder, with limited adverse
extrapyramidal, sedative, anticholinergic, and cardiometabolic effects. Ziprasidone was first synthesized
on the Pfizer Central Research campus in Groton, Connecticut. Both the oral and intramuscular
formulations of this antipsychotic were initially part of a new drug application for the treatment of
psychotic disorders submitted to the U.S. Food and Drug Administration (FDA) under the product name
Zeldox in 1997. Because of concerns regarding an observed increase in the mean duration of the QT
interval, an electrocardiographic measure of the ventricular depolarization and repolarization phases of
cardiac conduction, the application was not initially approved. Further studies, designed in collaboration
with the FDA, quantified the limited extent of this effect seen with ziprasidone compared with the effect
seen with other agents in wide use; these studies established an approvable level of safety for ziprasidone
with respect to cardiac conduction and a benchmark for the approach to evaluating drug effects on the QT
interval that has subsequently been applied to other agents evaluated by the FDA. The FDA approved oral
ziprasidone in February 2001 under the trade name Geodon for the treatment of schizophrenia. The
intramuscular formulation received FDA approval in 2002 for the treatment of acute agitation due to
schizophrenia. In August 2004, oral ziprasidone received FDA approval for the treatment of bipolar mania,
including manic and mixed episodes. At the time of writing, ziprasidone has received regulatory approval
and is available in over 70 countries, usually under the trade name Zeldox, with more than 1.08 million
patient-years of drug exposure.
[Dr. John Newcomer would like to thank Glennon M. Floyd and Amber Spies for editorial assistance on this
chapter.]
PHARMACOLOGICAL PROFILE
Neuropharmacology and Receptor-Binding Profile
Ziprasidone, or
5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2 H-indol-2-one, is a novel
benzisothiazolylpiperazine antipsychotic (Figure 33–1) with a unique structure and combination of
receptor- and transporter-binding properties that distinguish it from other atypical/second-generation
antipsychotics (Table 33–1) (Richelson and Souder 2000; Shapiro et al. 2003; Weiner et al. 2004).
FIGURE 33–1. Chemical structure of ziprasidone.
TABLE 33–1. Binding affinities of atypical antipsychotics (compared with haloperidol) for human
receptors and rat transportersPrint: Chapter 33. Ziprasidone
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Haloperidol Clozapine Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole
Binding affinities associated with potential therapeutic effects (mean pKi, nM)
D2 receptors 1.4 130 20 2.2 180 3.1 0.4
5-HT1A receptors 3,600 140 2,100 210 230 2.5 4.4
5-HT1B/1D receptors >5,000 1,700 530 170 >5,100 2.0 68
5-HT2A receptors 120 8.9 3.3 0.29 220 0.39 3.4
5-HT2C receptors 4,700 17 10 10 1,400 1.72 15
5-HT uptake
transporters
1,800 3,900 >15,000 1,400 >18,000 53 98
NE uptake
transporters
5,500 390 2,000 28,000 680 48 2,090
Binding affinities associated with potential adverse effects (mean pKi, nM)
H1 receptors 440 1.8 2.8 19 8.7 47 61
M1 receptors 1,600 1.8 4.7 2,800 100 5,100 >10,000
1-adrenoceptors 4.7 4.0 54 1.4 15 13 57
2-adrenoceptors 1,200 33 170 5.1 1,000 310 74
Note. D2 = dopamine2 receptor; H1 = histamine1 receptor; 5-HT = 5-hydroxytryptamine (serotonin); M1 =
muscarinic1 receptor; NE = norepinephrine.
Source. DeLeon et al. 2004; Kroeze et al. 2003; Richelson and Souder 2000; Schmidt et al. 2001; Shapiro et al.
2003; Stahl and Shayegan 2003; Weiner et al. 2004.
Ziprasidone is a potent antagonist at dopamine type 2 (D2) receptors but possesses inverse agonist
activity at 5-hydroxytryptamine (serotonin) type 2A receptors (5-HT 2A receptors). D2 receptor antagonism
is thought to be a key mechanism underlying efficacy for the treatment of psychotic symptoms (Kapur and
Remington 2001); positron emission tomography (PET) studies have shown that clinical antipsychotic
response to ziprasidone is predicted by occupancy of at least 60% of striatal D2 receptors. D2 antagonism
is also associated with potential liability for extrapyramidal side effects (EPS). However, ziprasidone’s
inverse agonist activity at 5-HT2A receptors disinhibits dopamine neurotransmission in the nigrostriatal,
mesocortical, and tuberoinfundibular pathways (Kapur and Remington 1996; Schmidt et al. 2001); this
reduces liability for EPS compared with antipsychotics with unopposed D2 antagonism and potentially
contributes to therapeutic effects. Increased dopamine activity in the prefrontal cortex is putatively linked
to efficacy in improving the negative and cognitive symptoms of schizophrenia (Stahl and Shayegan
2003). Enhanced dopaminergic transmission in the tuberoinfundibular pathway minimizes the potential
effect of D2 receptor antagonism on prolactin secretion. Ziprasidone’s relatively high in vitro 5-HT2A/D2
receptor affinity ratio, compared with that of other second-generation antipsychotics, predicts both a low
liability for EPS and potential therapeutic benefits for negative symptoms (Altar et al. 1986).
Ziprasidone exhibits antagonist activity at 5-HT1D and 5-HT2C receptors, and unique (among
second-generation antipsychotics) agonist activity at 5-HT1A receptors (see Table 33–1) (DeLeon et al.
2004; Schmidt et al. 2001). The 5-HT1A affinity is comparable to that of buspirone, an agent with
antidepressant and anxiolytic properties (Mazei et al. 2002), suggesting a mechanism that may contribute
to observed beneficial effects on affective, cognitive, and negative symptoms in schizophrenia and
schizoaffective disorder (Diaz-Mataix et al. 2005; Ichikawa et al. 2001; Millan 2000; Rollema et al. 2000;
Sumiyoshi et al. 2003; Tauscher et al. 2002). Blockade of 5-HT2C receptors disinhibits both dopamine and
norepinephrine neurons in the cortex, an effect that could contribute to improvements in cognitive and
affective abnormalities (Bremner et al. 2003; Bymaster et al. 2002; Mazei et al. 2002; Stahl 2003).
Although 5-HT2C antagonist activity is potentially predictive of weight gain liability, based, for example, on
a 5-HT2C knockout mouse model of obesity (Tecott et al. 1995), clinically significant predictive effects of
5-HT2C antagonist activity on the weight gain risk associated with antipsychotic drugs have not been
reliably detected (Kroeze et al. 2003), and the weight gain risk associated with ziprasidone is among the
lowest of any currently available antipsychotic (Allison et al. 1999b). Potent antagonism at 5-HT 1D
receptors has been proposed to potentially mediate antidepressant and anxiolytic effects (Briley andPrint: Chapter 33. Ziprasidone
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Moret 1993; Zorn et al. 1998).
Another unique feature of ziprasidone is its relatively high affinity for serotonin and norepinephrine
transporters (Seeger et al. 1995; Tatsumi et al. 1999). In vitro, ziprasidone demonstrates dose-dependent
reuptake inhibition of serotonin and norepinephrine transport, with effects ranging up to those of
imipramine and amitriptyline (Schmidt et al. 2001), suggesting potential antidepressant activity. In vivo,
the clinical significance of ziprasidone’s monoaminergic reuptake inhibition may be limited by plasma
protein binding or be clinically relevant only at higher than currently recommended daily dosages.
Monoaminergic reuptake inhibition is associated with hippocampal neurogenesis, suggesting potential
value in countering the neuronal cell loss observed in both affective illness and schizophrenia (Arango et
- 2001; Duman 2004; Thome et al. 1998). Relevant to this activity, treatment with ziprasidone and
risperidone has been associated with an increase in cortical gray matter volume (Garver et al. 2005).
Ziprasidone has a low affinity for histaminergic1 (H1), muscarinic1 (M1), and 1-noradrenergic receptors.
Among the biogenic amine receptors, H1 antagonist activity is the largest predictor of weight gain liability
(Figure 33–2) (Kroeze et al. 2003). H1 antagonist activity is also predictive of sedative effects, which are
potentially undesirable for patients aiming to maximize cognitive performance and social, occupational,
and community engagement. Low affinity for 1-adrenergic receptors predicts a lower likelihood of
orthostatic hypotension and sedation with ziprasidone than with commonly used antipsychotics with
potent 1-adrenergic antagonist activity. Low affinity for M1 receptors predicts a low risk for
anticholinergic side effects such as dry mouth, blurry vision, urinary retention, constipation, confusion,
and memory impairment.
FIGURE 33–2. Histamine1 (H1) receptor affinity predicts antipsychotic-induced weight gain.
ARI = aripiprazole; CLO = clozapine; HAL = haloperidol; K1 = binding affinity; OLA = olanzapine; QTP = quetiapine;
RIS = risperidone; ZIP = ziprasidone.
Source. Adapted from Kroeze et al. 2003.
Ziprasidone’s complex neuropharmacology provides explanatory support for observed treatment effects
on psychotic and affective symptoms of schizophrenia, schizoaffective disorder, and bipolar disorder and
for its favorable tolerability profile including minimal extrapyramidal and metabolic side effects (Stahl and
Shayegan 2003).
Positron Emission Tomography Studies
An in vivo PET study (Mamo et al. 2004) examining the affinity of ziprasidone for dopamine (D 2) and
serotonin (5-HT2) receptors observed that optimal D2 receptor occupancy occurs at the high end of the
initially recommended dosage range. In this study, the ziprasidone plasma concentration associated with
50% of maximal D2 receptor occupancy was more than twice the plasma concentration associated with
50% of maximal 5-HT2 receptor occupancy. Using an imaging protocol where 60% or greater D2 dopamine
receptor occupancy is generally predictive of antipsychotic activity, approximately 60% D2 occupancy was
observed in relation to plasma concentrations equivalent to those attained with a dosage at or above 120
mg/day. These results, consistent with clinical trial results discussed later in this chapter (see
“Indications and Efficacy”), strongly suggest that antipsychotic activity with ziprasidone is most
commonly associated with dosages of 120 mg/day or greater (Figure 33–3).Print: Chapter 33. Ziprasidone
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FIGURE 33–3. Relationship between dopamine2 (D2) and serotonin2 (5-HT2) receptor occupancy and
ziprasidone plasma levels in 16 patients with schizophrenia or schizoaffective disorder receiving
therapeutic dosages of ziprasidone.
Dotted straight lines represent minimal D2 receptor occupancy and plasma concentration that would be expected to
be associated with a clinical antipsychotic response, corresponding to a ziprasidone dosage of approximately 120
mg/day.
Source. Adapted from Mamo et al. 2004.
Dosing Recommendations
In addition to the PET data, accumulating evidence from clinical trials (discussed below) suggests that
ziprasidone dosing targets should be higher than initially recommended. In the United States, it was
initially recommended that ziprasidone treatment in patients with schizophrenia be initiated at a dosage
of 20 mg twice daily and then titrated at no less than 2-day intervals to a maximal dosage of 80 mg twice
daily (Pfizer Inc. 2008). In contrast, more recent FDA approval of ziprasidone for the treatment of bipolar
mania includes a recommendation that treatment be initiated at 40 mg twice daily with a more rapid
titration; on the second day of treatment, the dosage should be increased to 60 or 80 mg twice daily and
should subsequently be adjusted on the basis of toleration and efficacy within the 40- to 80-mg
twice-daily range.
A review of short-term trials of ziprasidone (Kane 2003) concluded that daily dosages of 120–160 mg are
more effective than lower dosages in the treatment of acute schizophrenia and also are associated with
lower rates of medication discontinuation. A more recent 6-month prospective, observational, naturalistic,
uncontrolled study performed in Spain also found that dosages greater than 120 mg/day were associated
with a lower risk of discontinuation for any cause (Arango et al. 2007). As a corollary, another European
observational multicenter trial found that both initial and overall underdosing are associated with high
discontinuation rates (Kudla et al. 2007). In a pooled analysis of both flexible-dose and fixed-dose studies
(N = 2,174), greater efficacy was observed in patients who received an initial dosage of 80 mg/day than
in patients who received an initial dosage of 40 mg/day (Murray et al. 2004). Reported clinical experience
with ziprasidone has also suggested the need for dosages greater than 160 mg/day in selected patients
(Harvey and Bowie 2005; Nemeroff et al. 2005).
Finally, two large observational database analyses support the other lines of evidence suggesting that
higher dosages of ziprasidone are associated with better treatment outcomes than lower dosages (Joyce
et al. 2006; Mullins et al. 2006). Both studies used prescription refills as an indicator of prescriptionPrint: Chapter 33. Ziprasidone
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adherence, a key measure of treatment continuation and overall effectiveness. Joyce et al. (2006)
examined the files of more than 1,000 commercially insured patients with schizophrenia or schizoaffective
disorder and concluded that an initial daily dosage of 120–160 mg was associated with a significantly
lower risk of discontinuation at 6 months than an initial daily dosage of 60–80 mg. Mullins et al. (2006),
evaluating a sample of more than 1,000 Medicaid recipients with schizophrenia, similarly concluded that
patients receiving an initial dosage of 120–160 mg daily had lower rates of medication discontinuation
than patients receiving an initial dosage of 20–60 mg daily. Taken together, results from receptor
occupancy studies, clinical trials, and pharmacoepidemiological analyses provide support for the
conclusion that initiation and treatment with ziprasidone dosages greater than 120 mg/day are more
likely to be effective than lower dosages in the treatment of schizophrenia and schizoaffective disorder.
PHARMACOKINETICS AND DISPOSITION
Absorption and Distribution
Based on evidence of enhanced absorption in the presence of food, it is recommended that ziprasidone be
taken with meals. Administration with food increases absorption by more than 50%, giving ziprasidone an
oral bioavailability of approximately 60% (Pfizer Inc. 2008). Maximal plasma concentration (C max) is
achieved in 3.7–4.7 hours and reaches 45–139 g/L in healthy volunteers receiving 20–60 mg twice daily,
and steady-state serum concentrations occur within 1–3 days of twice-daily dosing (Hamelin et al. 1998;
Miceli et al. 2000c). In contrast to oral administration, intramuscular administration of ziprasidone results
in 100% bioavailability. A therapeutic plasma level is reached within 10 minutes, and Cmax is achieved
within 30 minutes of administration of a 20-mg dose (Pfizer Inc. 2008).
The mean apparent volume of distribution of ziprasidone is 1.5 L/kg (Pfizer Inc. 2008), which is lower
than that of many other antipsychotic drugs. Given the wider potential for unwanted interactions with
various intracellular targets that has been observed with lipophilic drugs having a high volume of
distribution (Dwyer et al. 1999), this may be a favorable attribute for ziprasidone and other similar
compounds. Ziprasidone is more than 99% bound to plasma proteins. However, in vitro binding studies
indicate that it does not alter the protein binding of two highly protein-bound drugs, warfarin and
propranolol, neither do these two drugs interfere with the protein binding of ziprasidone, suggesting that
these types of drug interactions are unlikely.
Metabolism and Elimination
Ziprasidone is extensively metabolized with a mean terminal elimination half-life of approximately 7 hours
after oral administration within the recommended clinical dosage range (Pfizer Inc. 2008). The elimination
half-life of intramuscular ziprasidone is less than 3 hours with a single dose (Brook et al. 2000).
Ziprasidone is cleared primarily via three metabolic pathways to yield four major circulating metabolites
(Figure 33–4). Elimination occurs primarily through hepatic metabolism, with less than one-third of
metabolic clearance mediated via cytochrome P450 (CYP)–catalyzed oxidation and approximately
two-thirds via reduction of the parent compound by aldehyde oxidase to dihydroziprasidone, which then
undergoes S-methylation. The current published literature reports no commonly encountered clinically
significant pharmacological inhibitors of aldehyde oxidase, suggesting limited real-world potential for
drug–drug interactions that would alter the clinical activity of ziprasidone (Obach et al. 2004).
FIGURE 33–4. Major metabolic pathways of ziprasidone.Print: Chapter 33. Ziprasidone
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BITP = benzisothiazole piperazine; CYP = cytochrome P450; M = metabolite; TMT = thiol methyltransferase.
Source. Adapted from U.S. Food and Drug Administration Pharmacological Drugs Advisory Committee: Briefing
Document for Ziprasidone Mesylate for Intramuscular Injection (Figure 2 [Metabolism of Ziprasidone in Humans:
Proposed Metabolic Pathways to Major Circulating Metabolites], p. 5). February 15, 2001. Available at:
http://www.fda.gov/ohrms/dockets/ac/01/briefing/3685b2_01_pfizer.pdf.
Additional secondary metabolic pathways include N-dealkylation (via CYP enzymes 3A4 and 1A2) and
direct S-oxidation (via CYP3A4) (Beedham et al. 2003; Prakash et al. 2000). S-methyl-dihydroziprasidone
is the only active metabolite, with lower D2 receptor affinity and no significant binding to H1, M1, or 1-
and 2-adrenergic receptors. A small amount of the parent compound is excreted unchanged in the urine
(<1%) and feces (<4%).
There are no clinically significant age- or gender-related differences in the pharmacokinetics of oral
ziprasidone (Pfizer Inc. 2008). Hepatic impairment might be expected to increase the area under the
time–concentration curve (AUC). A multiple-dose study (Everson et al. 2000) comparing subjects with
clinically significant (Childs-Pugh Class A and B) cirrhosis versus healthy control subjects indicated that
12 hours after administration of ziprasidone, the AUC was 13% and 34% greater in subjects with
Childs-Pugh Class A and B cirrhosis, respectively, than in matched control subjects, suggesting that dose
adjustments are generally not mandatory for patients with hepatic impairment. Impairment in renal
function is unlikely to significantly alter the pharmacokinetics of oral ziprasidone, suggesting that
ziprasidone would not be removed by hemodialysis (Pfizer Inc. 2008). Intramuscular ziprasidone has not
been systematically evaluated in the elderly or in patients with hepatic or renal impairment.
Intramuscular ziprasidone contains a cyclodextrin excipient that is cleared by renal filtration; thus, it
should be administered with caution to patients with impaired renal function (Pfizer Inc. 2008).
Impact of Food on Pharmacokinetics
Recent pharmacokinetic studies examined ziprasidone bioavailability under fasting conditions and after
eating food with varying caloric and fat composition to better understand effects of food intake on drugPrint: Chapter 33. Ziprasidone
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availability (Lombardo et al. 2007). In an open-label, nonrandomized, six-way crossover study, healthy
adults received single doses of ziprasidone under fasting conditions and then under fed conditions with a
standard meal of 800–1,000 calories. Serum ziprasidone levels were measured immediately prior to drug
administration and at multiple scheduled time points up to 72 hours following drug administration.
Ziprasidone exhibited linear pharmacokinetics in fed subjects, but nonlinear pharmacokinetics in fasting
subjects. Dose-proportional increases in ziprasidone AUC and Cmax were observed under fed but not
fasting conditions. Cmax was significantly higher in fed states than in fasting states at doses of 40 mg
(63% higher) and 80 mg (97% higher). Results from two additional open-label crossover studies further
clarified the factors regulating drug bioavailability (Lombardo et al. 2007). Results indicated that 1)
significantly greater absorption is achieved during administration with a meal of at least 500 calories and
2) absorption is not significantly influenced by the fat content of the meal. These studies suggest that the
administration of ziprasidone with food provides linear pharmacokinetics and optimal absorption,
supporting predictable symptom control. In addition, the results suggest that total meal bulk sufficient to
slow gastric and duodenal transit time (e.g., a bowl of oatmeal), rather than fat content or specific calorie
counts, may be the key factor contributing to reliable dose-dependent drug absorption with meals.
DRUG–DRUG INTERACTIONS
A study of in vitro enzyme inhibition (Pfizer Inc. 2008) indicated that ziprasidone has little inhibitory
effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and is thus unlikely to interfere with the
metabolism of other medications relying on these enzymes for clearance. In vivo studies indicated that
ziprasidone has no effect on the pharmacokinetics of lithium, estrogen, progesterone, or
dextromethorphan (Pfizer Inc. 2008). As noted above (in “Metabolism and Elimination” subsection), less
than one-third of ziprasidone clearance is mediated by CYP-catalyzed oxidation and, based on this, one
would not anticipate a substantial change in ziprasidone AUC during coadministration with CYP3A4
inhibitors or inducers. Aldehyde oxidase–mediated reduction of ziprasidone to its dihydro- metabolite
constitutes the primary metabolic pathway for ziprasidone. As also noted above, currently no clinically
significant pharmacological inhibitors of aldehyde oxidase are commonly encountered, which suggests
that ziprasidone has limited potential for drug–drug interactions that would alter its clinical activity
(Obach et al. 2004).
Consistent with this prediction, coadministration with ketoconazole, a potent CYP3A4 inhibitor, results in
only a modest increase in ziprasidone AUC (33%) and Cmax (34%) (Miceli et al. 2000b), while
coadministration with carbamazepine, an inducer of 3A4, results in modest reductions in ziprasidone AUC
(44%) and Cmax (39%) (Miceli et al. 2000a). For comparison, a threefold increase in quetiapine Cmax is
observed during coadministration with ketoconazole, and a significant decrease in quetiapine Cmax occurs
during coadministration with CYP3A4 inducers (AstraZeneca 2008). Furthermore, coadministration with
CYP2D6 inhibitors has no effect on ziprasidone plasma levels, whereas antipsychotics such as aripiprazole
and risperidone exhibit a significant increase in plasma concentrations when coadministered with CYP2D6
inhibitors. Coadministration of ziprasidone with lithium results in no significant change, in steady-state
lithium levels (Apseloff et al. 2000) and commonly used antacids and cimetidine do not significantly alter
ziprasidone pharmacokinetics (Pfizer Inc. 2008).
INDICATIONS AND EFFICACY
Schizophrenia and Schizoaffective Disorder
Acute Treatment
Ziprasidone is indicated for the acute treatment of schizophrenia and schizoaffective disorder. Its efficacy
in the treatment of hospitalized patients with acute schizophrenia or schizoaffective disorder has been
demonstrated in a series of double-blind, placebo-controlled trials of 4–6 weeks’ duration (Daniel et al.
1999; Kane 2003; P. Keck et al. 1998; P. E. Keck et al. 2001). Additional randomized, double-blind,
short-term (4- to 8-week) treatment studies using active antipsychotic agent comparators have indicated
that ziprasidone has efficacy comparable to that of haloperidol, risperidone, and olanzapine for the
treatment of positive symptoms and overall psychopathology (Addington et al. 2004; Goff et al. 1998;
Simpson et al. 2004a). In a pooled analysis of four placebo-controlled, short-term trials and three
active-comparator trials, Murray et al. (2004) demonstrated that ziprasidone dosages of at least 120
mg/day, in comparison with lower dosages, are associated with a more rapid and favorable response in
overall psychopathology as well as a lower discontinuation rate due to inadequate clinical response,
suggesting the importance of rapid titration to at least 120 mg/day in patients with acute schizophreniaPrint: Chapter 33. Ziprasidone
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(Kane 2003; McCue et al. 2006).
Suboptimal dosing, titration, and administration of ziprasidone may have negatively impacted its
performance in some clinical trials. Some clinical trials included efficacy data for dosages that would now
be consider suboptimal (i.e., <120 mg/day), while other studies used prolonged titration of ziprasidone,
only reaching a therapeutic dosage 1 week or more into the study. Clinical trials conducted before the
release of the recent pharmacokinetic data by Lombardo et al. (2007) may not have been designed to
ensure that ziprasidone was administered with food for optimal oral absorption. For example, one small
randomized, open-label trial (N = 327) by McCue et al. (2006) compared the effectiveness of haloperidol,
aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for a minimum of 3 weeks as measured
by duration of inpatient hospitalization. Although all six antipsychotics demonstrated comparable changes
in Brief Psychiatric Rating Scale (BPRS) scores, treatment with haloperidol, olanzapine, and risperidone
was associated with shorter hospital stays than treatment with aripiprazole, quetiapine, and ziprasidone.
This study used slow, gradual titration of ziprasidone, so many patients did not obtain an optimal dosage
of ziprasidone (e.g., 80 mg twice daily) until 1 week or more into this short-term study, suggesting an
explanation for the longer duration of hospitalization in ziprasidone recipients despite achieving
comparable improvement in BPRS scores.
Another approach to evaluating the comparative efficacy of first- and second-generation antipsychotics is
the use of meta-analysis. A series of meta-analyses has found no clear or consistent differences among
the atypical antipsychotics, either when comparing agents within the same class or when comparing
second-generation with first-generation antipsychotics (Bagnall et al. 2003; Geddes et al. 2000; Leucht et
- 1999; Srisurapanont and Maneeton 1999; Tandon and Fleischhacker 2005). One meta-analysis of
randomized, controlled trials by Davis et al. (2003) suggested that some atypical antipsychotics (i.e.,
clozapine, risperidone, olanzapine, and amisulpride) were significantly more efficacious than
first-generation antipsychotics, whereas in this analysis the efficacy of ziprasidone was not observed to be
statistically significantly better than that of first-generation antipsychotics. It is important to note that
this meta-analysis excluded data relating to low dosages of other antipsychotics (olanzapine <11 mg/day
and risperidone <4 mg/day), but included data on ziprasidone dosages as low as 80 mg/day. In addition,
the Davis et al. meta-analysis included relatively few studies of ziprasidone (4 studies as compared with
31 studies of clozapine, 22 studies of risperidone, and 14 studies of olanzapine), making it more difficult
to show statistical significance with this agent. In a subsequent analysis of data from four major
meta-analyses plus additional data from head-to-head comparisons of agents in randomized, controlled
clinical trials, Tandon and Fleischhacker (2005) found that all of the second-generation antipsychotics
including ziprasidone were statistically equivalent in terms of efficacy.
It should be noted that meta-analyses involving ziprasidone are challenged by the same limitations
incurred by the original study designs. These early study limitations included problems related to
inadequate dosing and/or dose titration and administration without food. Although meta-analyses provide
useful information, a need remains for head-to-head comparator studies with flexible doses and
appropriate dosage ranges to address whether specific antipsychotic drugs exhibit preferential
benefit–risk ratios in relevant patient populations.
Debate continues about potential explanations for why some studies find differences in acute efficacy
among the second-generation antipsychotics and other studies do not, with limited evidence suggesting
that study sponsorship might occasionally contribute to a biased study design (e.g., sponsors might
design a study using suboptimal dosing or titration of a comparator) (Lexchin et al. 2003). Based on the
totality of available evidence, it is our opinion that there is currently no compelling overall evidence to
support propositions that clinically significant differences (i.e., differences that are not explainable by lack
of equipotent dosing with respect to D2 antagonist activity) exist in the intrinsic efficacy of
second-generation antipsychotics for the treatment of positive psychotic symptoms in patients with
schizophrenia or schizoaffective disorder, with the exception of the superior efficacy for positive
symptoms of clozapine in well-defined populations of patients with treatment-resistant illness.
With respect to drug effects on total psychopathology, beyond specific effects for positive symptoms, it is
important to note that in general, when the less sedating antipsychotics compete in head-to-head
comparisons with more sedating agents, they tend to face challenges in conventionally designed
randomized, double-blind trials. When the acute state under study also involves agitation and insomnia,
less sedating medications (e.g., ziprasidone) may be at a disadvantage with respect to ratings for these
additional symptoms. Although conventional study designs allow “as needed” access to adjunctivePrint: Chapter 33. Ziprasidone
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benzodiazepines, the as-needed approach carries a potential for underutilization that may fail to fully level
the playing field with respect to sedative effects in the competing treatment arms. Conventional study
designs will continue to present challenges for the growing list of novel antipsychotic agents under
development that, like ziprasidone, are at the less sedating end of the spectrum of currently available
agents. The key question is whether it is desirable to continue to rely on study designs that favor more
sedating agents, given that this will tend to favor agents with higher levels of intrinsic antihistaminic,
antimuscarinic, or anti– 1-adrenergic activity, encouraging the development of medications with
predictable short- and longer-term adverse-event liabilities.
Maintenance Therapy
The maintenance efficacy of ziprasidone in treating schizophrenia and schizoaffective disorder has been
studied in a series of double-blind and open-label extension trials (Arato et al. 2002; Hirsch et al. 2002;
Kane et al. 2003; Schooler 2003; Simpson et al. 2002, 2004b). These studies indicate that long-term
therapy with ziprasidone maintains clinical response and is effective in preventing relapse. The majority of
efficacy and effectiveness studies for ziprasidone can be divided into specific categories based on what the
studies were designed to assess:
Maintenance of effect: patients who meet acute response criteria are randomized to stay on the current
medication or switch to a comparator treatment
Relapse prevention: stable patients defined in terms of remission or level of symptom control are randomly
assigned to ziprasidone versus a control condition and are compared by time to achievement of relapse criteria
- Long-term response: symptomatic patients are compared by improvements in clinical symptom response
Clinical effectiveness: so-called effectiveness trials use endpoints such as time to drug discontinuation as a
marker for clinical effectiveness
Maintenance of effect
In two maintenance-of-effect trials, patients with schizophrenia or schizoaffective disorder with a
demonstrated acute response to treatment (defined as a 20% decrease in Positive and Negative
Syndrome Scale [PANSS] for schizophrenia total score and a Clinical Global Impression [CGI] Scale score
of 2) were randomly assigned to receive either ziprasidone or a comparator antipsychotic agent for at
least 26 weeks (Addington et al. 2003; Schooler 2003; Simpson et al. 2002, 2005). The ziprasidone
treatment groups in both studies demonstrated significant improvements from baseline in overall
psychopathology, as measured by mean changes in symptom ratings using PANSS total, PANSS negative
subscale, Brief Psychiatric Rating Scale–Depression Factor (BPRSd), and CGI–Severity (CGI-S) scores.
These improvements were comparable to those seen in the olanzapine (Simpson et al. 2005) and
risperidone (Addington et al. 2003) treatment groups.
Relapse prevention
To evaluate the efficacy of ziprasidone for relapse prevention, the Ziprasidone Extended Use in
Schizophrenia study enrolled stable inpatients with chronic schizophrenia and randomly assigned
participants to 1 year of treatment with ziprasidone 40 mg/day (n = 72), 80 mg/day (n = 68), or 160
mg/day (n = 67) or placebo (n = 71), with a planned primary Kaplan-Meier analysis of time to relapse
(Arato et al. 2002). Stability was defined by symptom level but this was short of strict definitions of
remission. In this study, all three dosages of ziprasidone were superior to placebo in the prevention of
relapse. In addition, a penultimate-observation-carried-forward analysis (in which the last visit prior to
relapse is excluded) was performed to filter out clinical worsening associated with relapse that might
otherwise obscure symptom response trends during the rest of maintenance therapy (O’Connor and
Schooler 2003), which indicated that nonrelapsing patients treated with ziprasidone experienced modest
symptomatic improvement during maintenance treatment. This study, like a number of other studies of
other antipsychotic agents in schizophrenia patients, was limited by the relatively high level of attrition
observed in all groups over the year of treatment.
Long-term response to treatment in symptomatic patients
A number of long-term double-blind trials designed to examine the efficacy of ziprasidone in symptomatic
patients with schizophrenia have been performed (Breier et al. 2005; Hirsch et al. 2002; Kinon et al.
2006a; Simpson et al. 2004a, 2005). Investigators (Hirsch et al. 2002) have compared the efficacy of
ziprasidone (n = 148) and haloperidol (n = 153) in a 28-week double-blind trial of stable outpatients withPrint: Chapter 33. Ziprasidone
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schizophrenia with prominent negative symptoms. In this study, ziprasidone and haloperidol were
similarly efficacious in reducing overall psychopathology, with an advantage for ziprasidone in the
percentage of patients classified as negative symptom responders. Breier et al. (2005) conducted a
28-week study of ziprasidone and olanzapine in outpatients as well as inpatients ( N = 548) with active
symptoms. In this study, olanzapine treatment was associated with greater improvement from baseline in
total psychopathology scores (PANSS total, the primary efficacy measure) than ziprasidone and a higher
rate of criterion-level response to treatment. Simpson et al. (2004a) conducted a 6-week double-blind,
parallel-design flexible-dose comparison (N = 269) of ziprasidone (n = 136) and olanzapine (n = 133)
where at least minimal responders (CGI-I score 2 or 20% reduction in PANSS total score) were enrolled
in a 6-month double-blind continuation trial (Simpson et al. 2005). In both the 6-week and the 6-month
analyses, no differences between the treatment groups were detected on any primary (e.g., BPRS total,
CGI severity) or secondary (e.g., PANSS total, CGI-I) measures.
Factors contributing to the apparent differences in study results may include differences in study design.
Breier et al. (2005) randomly assigned symptomatic inpatients and outpatients, whereas Simpson et al.
(2004a) enrolled symptomatic inpatients at baseline for the 6-week trial and patients with at least
minimal response into the subsequent 6-month trial. Breier et al. (2005) used a higher mean daily dosage
of olanzapine (15.3 mg) and a lower mean daily dosage of ziprasidone (116.0 mg) in comparison with the
Simpson et al. (2004a, 2005) studies, which used relatively lower mean daily dosages of olanzapine (11.3
mg and 12.6 mg, respectively) and relatively higher mean daily dosages of ziprasidone (129.9 mg and
135.2 mg, respectively). Breier et al. (2005) also employed a prolonged titration of ziprasidone, along
with the lower dosage, increasing the likelihood of initial and sustained underdosing of ziprasidone.
In another comparison study of ziprasidone and olanzapine, Kinon et al. (2006a) evaluated their efficacy
in schizophrenia and schizoaffective disorder patients with prominent depressive symptoms ( N = 394).
They detected greater improvement in PANSS total scores in the olanzapine group, using a
last-observation-carried-forward analysis. However, no significant difference in PANSS total scores
between olanzapine and ziprasidone treatment was detected using an alternative mixed-effects model for
repeated measures (MMRM) analysis. The MMRM analysis notably uses all observed data to adjust for
changes related to dropouts and may offer a more robust approach to the analysis of treatment effects in
clinical trials when missing data occur (Mallinckrodt et al. 2003).
Effectiveness trials
There have been a number of ziprasidone effectiveness trials, with use of various definitions for
effectiveness. The Clinical Antipsychotic Trials of Intervention Effectiveness (the CATIE studies, funded by
the National Institute of Mental Health [NIMH]) included a long-term, double-blind, randomized study of
patients with schizophrenia (N = 1,493; Lieberman et al. 2005). Phase I of the CATIE schizophrenia study
compared ziprasidone, olanzapine, quetiapine, risperidone, and perphenazine on the primary endpoint of
time to discontinuation for lack of efficacy or for any cause. Because of the timing of its FDA approval,
ziprasidone was added to the study after enrollment had begun for all other treatment arms; this resulted
in a smaller sample size for the ziprasidone treatment arm.
The primary analysis for the phase I study detected significant differences in time to discontinuation
across the treatment groups overall. The longest time to discontinuation was in the olanzapine group. In
the total study sample, no significant differences were seen in the time to discontinuation between the
ziprasidone and olanzapine treatment groups, nor between the ziprasidone group and other antipsychotic
treatment groups. Although a subanalysis that was restricted to the overall study cohort of patients who
enrolled after ziprasidone became available indicated a higher rate of discontinuation with ziprasidone
treatment than with olanzapine, this was not significant after a planned adjustment for multiple
comparisons. After adjusting the data for multiple comparisons, the investigators found no significant
differences between ziprasidone and olanzapine or the other antipsychotics in the analyses of all-cause
discontinuations and discontinuations due to lack of efficacy.
Several considerations in this complex study are worth mentioning. Relatively few patients who entered
the CATIE schizophrenia study were currently (i.e., prior to study entry) taking the relatively newly
available medication, ziprasidone, compared with the number of patients taking the other antipsychotic
medications in the trial. This resulted in a larger proportion of patients assigned to the ziprasidone
treatment arm who were just starting to take a new medication and discontinuing their prior treatment,
compared with patients in other treatment arms. For example, 23% of subjects randomly assigned toPrint: Chapter 33. Ziprasidone
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olanzapine treatment were already receiving olanzapine monotherapy as their ongoing treatment,
requiring no medication discontinuation or new drug initiation as a result of their random assignment to
the study arm. Supplemental analysis of phase I CATIE data by Essock et al. (2006) indicated the overall
importance, in terms of subsequent discontinuation rates, of whether randomized subjects were switching
medications or whether the study design allowed them to continue receiving their prior treatment. A
significantly higher rate of subsequent discontinuation was observed in patients who actually made a
medication switch compared with those who were randomly assigned to stay with the same medication
they had been taking prior to the trial. This effect of switching medications may therefore favor treatment
arms with a larger percentage of “nonswitchers” (i.e., olanzapine and risperidone recipients in the CATIE
phase I study, in which nonswitching was allowed). In a reanalysis of phase I CATIE data that excluded
those patients randomly assigned to continue taking the antipsychotic that they were already taking at
baseline, Essock et al. (2006) found that differences between rates of discontinuation in the ziprasidone
group and rates in the other antipsychotic groups were attenuated, and no statistically significant
differences were observed.
Further evidence regarding the effectiveness of ziprasidone was anticipated from the phase II CATIE
study. Subjects enrolled in the phase I study consisted of a population that included some patients with
unremitted illness and some patients with treatment-refractory illness (Meltzer and Bobo 2006), not
undesirably increasing the likelihood that subjects would discontinue treatment in phase I and move on to
phase II of the CATIE study. However, the CATIE study hypothesized that patients who discontinued
phase I due to lack of efficacy would tend to enter the phase IIE efficacy arm, which included clozapine,
while those who discontinued phase I due to intolerability would tend to enter the phase IIT tolerability
arm, which included ziprasidone (Stroup et al. 2006). Instead, a substantial percentage of patients who
discontinued phase I due to lack of efficacy chose not to enter the IIE arm of the study, possibly due to
reluctance to receive treatment with clozapine, and instead entered the IIT arm. From this
larger-than-expected sample of phase IIT subjects, those randomly assigned to the ziprasidone group
received a mean modal dosage of 116 mg/day, with only about one-third of those treated receiving the
maximal allowed dosage of 160 mg/day and about 60% receiving 120 mg/day or less, and there were no
study-specified requirements or instructions regarding administration of the drug with food. In this
setting, ziprasidone, like quetiapine, was associated with a shorter time to all-cause discontinuation of
treatment than risperidone or olanzapine. In the subset of the sample that entered phase II due to lack of
tolerability in phase I (rather than lack of efficacy), no differences in all-cause discontinuation rates were
observed between the treatment arms.
The ZEISIG study (Ziprasidone Experience in Schizophrenia in Germany/Austria) investigated the
effectiveness of ziprasidone as measured by discontinuation rates and mean changes of the BPRS total in
moderately ill and reasonably stable patients (N = 276) with schizophrenia or schizoaffective disorder
(Kudla et al. 2007). Approximately 60% of subjects discontinued ziprasidone prematurely, most within
the first 4 weeks of study treatment. In study completers, ziprasidone was associated with significant
improvements in BPRS total score. The relatively high rate of discontinuation may be explained in part by
the planned dosing strategy. In this study, ziprasidone use was initiated at a low dosage of 40 mg/day,
which is now known to be associated with higher discontinuation rates and shorter durations of therapy
compared with higher dosages (Joyce et al. 2006; Mullins et al. 2006). As in other studies, the maximal
dosage allowed was 160 mg/day, which may be insufficient for some patients (Harvey and Bowie 2005;
Nemeroff et al. 2005).
Arango et al. (2007), of the Ziprasidone in Spain Study Group, examined the effectiveness of ziprasidone
(n = 1,022 in the primary analysis sample) as measured by response rate (defined as a 30% reduction in
the PANSS total score). Nearly half of the patients experienced the defined level of clinical response, and
patients overall had significant and clinically relevant mean reductions in both the PANSS total score and
the positive, negative, and general psychopathology subscale scores (effect sizes were 1.60, 1.83, 0.62,
and 1.40, respectively). Ziprasidone dosages of greater than 120 mg/day were associated with a lower
risk of discontinuation for any cause.
Kinon et al. (2006b) published a post hoc pooled analysis of clinical trials from the Eli Lilly database using
treatment discontinuation rates as a measure of effectiveness. An additional long-term effectiveness
study (Ascher-Svanum et al. 2006) using time to all-cause discontinuation as a measure of effectiveness,
and a naturalistic treatment setting, is available. In both cases, small numbers of subjects in the
ziprasidone arms (e.g., 25 subjects), compared with hundreds or more subjects in comparative arms, limitPrint: Chapter 33. Ziprasidone
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the interpretation of results and conclusions with respect to ziprasidone.
Efficacy by Symptom Type
Efficacy for cognitive symptoms of schizophrenia
The effect of ziprasidone on cognitive function in schizophrenia patients has been evaluated by a battery
of cognitive tests that were included in a double-blind olanzapine comparator study that evaluated
changes at 6 weeks and 6 months (Harvey et al. 2004, 2006a). Antipsychotic treatment with ziprasidone
and with olanzapine both resulted in significant cognitive improvements from baseline in attention
memory, working memory, motor speed, and executive functions, with olanzapine also associated with
improvement in verbal fluency. Further improvements in both treatment groups were observed from the
end of 6 weeks to the 6-month assessment time point on verbal learning, executive functioning, and
verbal fluency, with no differences between treatment groups. A similar magnitude of improvement was
seen with each agent, with the exception of verbal fluency. It should be noted that despite improvements,
a substantial proportion of patients studied continued to experience clinically significant cognitive
impairment posttreatment. Neuropsychological improvements in general are not related to clinical
changes (Harvey et al. 2006b).
Recent data from the CATIE schizophrenia study indicate that treatment with all of the antipsychotics
tested (i.e., ziprasidone, perphenazine, olanzapine, risperidone, and quetiapine) was associated with a
small but significant improvement in neurocognition after 2 months of treatment (Keefe et al. 2007).
There was no significant difference between ziprasidone and the other antipsychotics. Neurocognitive
improvement predicted a longer time to treatment discontinuation, independent of symptom
improvement, in patients treated with quetiapine or ziprasidone.
Efficacy for affective symptoms
Ziprasidone has been hypothesized to be a promising treatment for affective disorders, based on its
unique in vitro potency as a serotonin and norepinephrine reuptake inhibitor comparable to that of known
antidepressants (see “Neuropharmacology and Receptor-Binding Profile” section above). If this effect
translates to antidepressant activity in vivo, it could be useful in reducing the likelihood of
treatment-emergent depression, an outcome in approximately 10%–20% of patients with bipolar or
schizoaffective disorder treated with first-generation antipsychotics or olanzapine (Kohler and Lallart
2002; Tohen et al. 2000, 2001, 2003). Addressing the question of ziprasidone’s potential antidepressant
efficacy in schizophrenia patients with comorbid affective symptoms, data can be examined from
randomized, double-blind, placebo-controlled clinical trials (Daniel et al. 1999; P. Keck et al. 1998; P. E.
Keck et al. 2001) and from double-blind, head-to-head trials comparing ziprasidone to risperidone or
olanzapine (Kane 2003). The results of placebo-controlled studies (Daniel et al. 1999; P. Keck et al. 1998)
suggest that treatment of schizophrenia and schizoaffective disorder with ziprasidone is associated with
significant improvement in comorbid depressive symptoms, based on intent-to-treat analyses, but
sometimes only in the subset of patients with higher levels of baseline depression. The baseline severity
of depressive symptoms in these studies tends to be relatively mild, so subgroups of patients with more
pronounced comorbid depressive symptoms at baseline were also analyzed; the antidepressant effect of
ziprasidone is larger than that of placebo in these analyses. In the two active-comparator studies,
improvement in depression and anxiety symptoms in patients receiving ziprasidone was comparable to
the improvement in olanzapine recipients but greater than the improvement in risperidone recipients. A
smaller study (Kinon et al. 2006a) compared the efficacy of olanzapine and ziprasidone over 24 weeks in
the treatment of schizophrenia or schizoaffective disorder patients with prominent depressive symptoms.
Both treatment groups had significant improvements in depressive symptoms for the first 8 weeks, with
olanzapine-treated patients showing significantly greater improvements in depressive symptoms at study
endpoint. However, the interpretation of this study is limited by that fact that a substantial number of
patients (52.8% of N = 394 at study entry) received concurrent treatment with nonstandardized
antidepressants. These overall results provide preliminary evidence suggesting that ziprasidone, like some
other antipsychotic agents, may be effective in treating comorbid depressive symptoms in patients with
schizophrenia and schizoaffective disorder.
Efficacy for social deficits and improvement in quality of life
To date, the NIMH CATIE study is the largest trial examining the effect of ziprasidone and other
antipsychotics on psychosocial functioning in patients with schizophrenia (Swartz et al. 2007). This studyPrint: Chapter 33. Ziprasidone
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used the Quality of Life Scale, a widely used clinician-rated measurement (Heinrichs et al. 1984), to
assess changes in social functioning, interpersonal relationships, vocational functioning, and psychological
well-being. One-third of the patients in the phase I study antipsychotic treatment groups made modest
improvements on the Quality of Life Scale from baseline to the 12-month endpoint (average effect size,
0.19 standard deviation units), with no significant differences between the agents.
The effect of ziprasidone on social functioning has also been evaluated using the prosocial subscale of the
PANSS, including items related to active and passive social avoidance, emotional withdrawal, stereotypical
thinking, and suspiciousness (Purnine et al. 2000). In three separate but related studies from one group,
stable patients taking either conventional antipsychotics, olanzapine, or risperidone were switched to
ziprasidone and followed for 6 weeks with ratings of safety, efficacy, and effectiveness (Weiden et al.
2003b). Six weeks of treatment with ziprasidone in all three prior-treatment groups resulted in significant
improvement on the PANSS prosocial subscale (Loebel et al. 2004). The interpretation of results as being
specific to ziprasidone use, rather than being simply an effect of extended, closely monitored treatment, is
complicated by the absence of a control condition other than the prior-treatment baseline ratings.
Treatment-Resistant Schizophrenia
The efficacy of ziprasidone for treatment-resistant schizophrenia was evaluated in a 12-week double-blind
chlorpromazine comparator study (N = 306 patients), with treatment-resistant status defined by failure to
achieve criterion-level response after 6 weeks of prospective treatment with haloperidol (Kane et al.
2005). The mean daily dosage of ziprasidone at study endpoint was approximately 154 mg, compared
with a mean daily chlorpromazine dosage of approximately 744 mg. Treatment with ziprasidone produced
significantly greater improvement at endpoint in PANSS negative subscale scores compared with
chlorpromazine. In addition, ziprasidone treatment was associated with a 1.3-fold higher likelihood of
achieving a 50% reduction in BPRS total score compared with chlorpromazine treatment.
Switching From Other Antipsychotics
As discussed above, evidence suggests that the efficacy of ziprasidone is comparable to that of other
atypical and conventional antipsychotics during both acute and maintenance treatment of schizophrenia
and schizoaffective disorder. Subsequent sections provide evidence to support the safety, particularly the
cardiometabolic safety, of ziprasidone compared with other antipsychotics (see “Side Effects and
Toxicology” section). These results support interest in the clinical outcomes associated with switching
from antipsychotic treatment with other agents to treatment with ziprasidone.
Three open-label, medication-switching studies evaluated the effect of switching to ziprasidone on
measures of efficacy, safety, and tolerability, as well as the effect of different titration schedules on the
outcome (Weiden et al. 2003b). In each study, patients were randomly assigned to one of three switching
strategies to be completed in 1 week:
- Immediate discontinuation of the previous antipsychotic and immediate starting of ziprasidone the next day
- Lowering the dose of the previous antipsychotic by half while simultaneously starting ziprasidone
Overlapping the start of ziprasidone with the full dosage of the prior antipsychotic and then gradually reducing
the prior antipsychotic dosage after 4 days of ziprasidone therapy.
For all switching strategies, the starting dosage of ziprasidone was 80 mg/day (40 mg twice daily), with
subsequent dosage adjustments based on clinical judgment. In one study, patients taking high-potency
conventional antipsychotics (N = 108) were switched to ziprasidone. In the second study, patients (N =
58) were switched from risperidone to ziprasidone. In the third study, patients (N = 104) were switched
from olanzapine to ziprasidone. Discontinuation rates were low in all three studies, ranging from 2%–6%
for lack of efficacy to 6%–9% for adverse events. In study completers, statistically significant
improvements were observed on PANSS total, PANSS positive subscale, PANSS negative subscale, and
BPRSd total scores. Different switching strategies were not associated with a different likelihood of trial
completion or different magnitude of clinical response. The absence of active or placebo control subjects
in this set of studies, in combination with the similarly favorable response profile, limits the interpretation
of results with respect to changes in psychiatric symptoms associated with the change in medications.
Bipolar Disorder
Acute ManiaPrint: Chapter 33. Ziprasidone
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Ziprasidone has received regulatory approval (e.g., by the FDA) for the acute treatment of bipolar mania,
with efficacy for acute mania demonstrated in two double-blind, placebo-controlled trials, each 3 weeks in
duration, in patients with bipolar I disorder (P. E. Keck et al. 2003b; Potkin et al. 2005). In both studies,
onset of action was rapid (within 48 hours) and sustained through 3 weeks of treatment in patients with
bipolar mania or bipolar mixed states, with or without psychotic symptoms (results of P. E. Keck et al.
[2003b] are shown in Figure 33–5). At endpoint, approximately half of the treated patients from both
studies met response criteria for mania ( 50% reduction in Mania Rating Scale [MRS] scores).
FIGURE 33–5. Effect of ziprasidone on mania: rating scale scores in patients with bipolar disorder
receiving 21-day randomized treatment with ziprasidone or placebo.
*P <0.003 (F test), placebo-treated patients versus ziprasidone-treated patients.
**P <0.001 (F test), placebo-treated patients and ziprasidone-treated patients ( P <0.001, F test).
Source. Adapted from P. E. Keck et al. 2003b.
A growing number of placebo-controlled trials evaluating the efficacy of short-term monotherapy with
various atypical antipsychotics, including ziprasidone, olanzapine, risperidone, quetiapine, and
aripiprazole, have demonstrated comparable improvement in symptoms of mania (Bowden et al. 2005;
Hirschfeld et al. 2004; P. E. Keck et al. 2003a, 2003b; Khanna et al. 2005; McIntyre et al. 2005; McQuade
et al. 2003; Potkin et al. 2005; Sachs et al. 2006; Smulevich et al. 2005; Tohen et al. 1999, 2000); Weisler
et al. 2003). Two recent large meta-analyses of randomized, placebo-controlled trials have examined the
relative efficacy of various atypical antipsychotics for the adjunctive treatment of mania (Perlis et al.
2006; Scherk et al. 2007). Although the statistical results of the two meta-analyses are similar, the
authors of each study interpreted the results somewhat differently. Perlis et al. (2006) concluded that
add-on therapy with atypical antipsychotics (ziprasidone, olanzapine, quetiapine, and risperidone)
conferred an additional benefit over monotherapy with a traditional mood stabilizer in reducing manic
symptoms, with no difference in efficacy among the drugs. Scherk et al. (2007) also concluded that
atypical antipsychotics as a group were significantly superior to placebo as adjunctive treatment for
mania, but that ziprasidone and other individual agents may not be significantly superior to placebo in the
adjunctive treatment of manic symptoms. Although regulatory approvals for the individual agents have
supported the efficacy and safety of a number of individual antipsychotics for the acute treatment of
mania, including ziprasidone (which is also approved for the acute treatment of mixed states),
prospective, head-to-head comparator trials may be required to clarify whether differences suggested by
some meta-analyses are clinically meaningful or are related to differences in study design or
methodology.
Maintenance Treatment
Two 52-week open-label extension studies support the safety, tolerability, and sustained efficacy ofPrint: Chapter 33. Ziprasidone
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ziprasidone as maintenance treatment for bipolar disorder (P. E. Keck et al. 2004; Weisler et al. 2004). P.
- Keck et al. (2004) reported that treatment with ziprasidone (n = 127; mean daily dosage, 123 mg) was
associated with significantly lower MRS and CGI-S scores compared with baseline, beginning as early as
the first week. Overall, improvements in manic symptoms achieved during acute treatment continued to
consolidate during maintenance treatment with ziprasidone. During 52 weeks of treatment, only 6% of
patients discontinued ziprasidone use due to relapse of mania. Similarly, only 4% of patients discontinued
due to a clinical switch into depression. An important caveat regarding these results is the high rate of
attrition observed by the end of 1 year, which is consistent with long-term studies involving other atypical
antipsychotics but which limits the full interpretation of results. Similar results were observed in a
separate extension study of adjunctive ziprasidone therapy (mean daily dosage, 92.6 mg) by Weisler et al.
(2004); this study reported a mean improvement from baseline in MRS scores at all points throughout the
study (Patel and Keck 2006).
Treatment-Resistant Depression
Although there have been no randomized studies, small uncontrolled studies have prompted interest in
the efficacy of ziprasidone for treatment-resistant depression (Barbee et al. 2004; Jarema 2007;
Papakostas et al. 2004). Papakostas et al. (2004) reported the results of a small study of 20 patients with
major depression resistant to treatment with selective serotonin reuptake inhibitors (SSRIs). Open-label
treatment with ziprasidone for 6 weeks, adjunctive to ongoing SSRI treatment, was evaluated with an
intent-to-treat analysis that identified 10 treatment responders (defined as having a 50% decrease in
depressive symptoms as measured by the Ham-D-17). In a smaller retrospective chart review (Barbee et
- 2004), in which only 5 of 10 patients were exposed to ziprasidone for at least 6 weeks, 1 patient met
criteria for being a treatment responder (requiring ratings of “very much improved”). Randomized studies
are needed to evaluate the efficacy and safety of ziprasidone for patients with treatment-resistant
depression.
Agitation
The efficacy of intramuscular ziprasidone for the treatment of agitated psychosis has been demonstrated
in two randomized, double-blind trials (2 mg im vs. 20 mg or 10 mg im, respectively, with up to three
more doses allowed as needed at 4-hour or 2-hour intervals, respectively), leading to regulatory approval
by the FDA (Daniel et al. 2001; Lesem et al. 2001). Treatment with single 10- or 20-mg doses leads to
rapid reductions in symptom severity, with most patients having remission of agitation within 1 hour of
dosing. Treatment with intramuscular ziprasidone is associated with a relatively low rate of concomitant
benzodiazepine use (<20%). Sequential use of intramuscular ziprasidone followed by oral ziprasidone for
the treatment of acute psychotic agitation has demonstrated superior efficacy, compared with sequential
use of intramuscular and oral haloperidol, in two 7-day randomized, open-label trials (Brook et al. 2000;
Swift et al. 1998) as well as in a 6-week randomized, single-blind, flexible-dose study (Brook et al. 2005).
Clinical improvement occurred more rapidly than with haloperidol in one study, and as quickly as 30
minutes after the first intramuscular administration of ziprasidone (Swift et al. 1998). Cumulative data
from these studies indicate that intramuscular ziprasidone can rapidly control agitation and psychotic
symptoms and provide greater mean improvements in acute agitation than seen with intramuscular
haloperidol (e.g., greater mean improvements in BPRS total score, agitation, and CGI-S score) (Brook
2003).
One uncontrolled prospective study of 21 patients (Barak et al. 2006) and a retrospective chart review of
35 cases (Kohen et al. 2005) evaluated the safety and efficacy of intramuscular ziprasidone for treatment
of acute psychotic agitation in the elderly; both suggested that ziprasidone is effective and well tolerated
in the elderly. Larger controlled studies are necessary to confirm these results and the safety of
ziprasidone in this patient population.
Pediatric Patients
Ziprasidone has not to date been approved by the FDA for use in children or adolescents, and published
data concerning the safety and efficacy of ziprasidone use in children and adolescents remain limited. To
date, there has been one randomized, controlled trial of ziprasidone in children and adolescents (ages
10–17 years) with bipolar disorder (Versavel et al. 2005). In this study, treatment with ziprasidone was
associated with improvement in mania and overall psychopathology. Two retrospective chart reviews of
hospitalized children and adolescents reported that intramuscular ziprasidone demonstrated efficacy in
the treatment of acute agitation and aggression (Staller 2004) and that intramuscular ziprasidone was asPrint: Chapter 33. Ziprasidone
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effective as intramuscular olanzapine in pediatric patients (Khan and Mican 2006). Two additional small
studies suggested that ziprasidone may reduce tic severity in children and adolescents with Tourette’s
syndrome (Sallee et al. 2006) and may improve symptoms of aggression, agitation, and irritability in
children and adolescents with autism (McDougle et al. 2002).
SIDE EFFECTS AND TOXICOLOGY
Ziprasidone has a favorable tolerability profile based on both short- and long-term clinical trials (Daniel
2003; Pfizer Inc. 2004). The four most common treatment-related adverse events associated with oral
ziprasidone in short-term premarketing, placebo-controlled trials for schizophrenia were somnolence
(14%), EPS (14%), nausea (10%), and constipation (9%) (Pfizer Inc. 2008). In subsequent clinical trials,
treatment with ziprasidone was associated with a low occurrence of adverse events, most of which were
considered mild to moderate in severity (Arango et al. 2007; Arato et al. 2002; Lieberman 2007; Nemeroff
et al. 2005; Weiden et al. 2002, 2003b). In addition to the comprehensive listing of potential adverse
events available in the full U.S. prescribing information (USPI) (Pfizer Inc. 2008), published case reports
offer accounts of various rare adverse events that may be associated with the use of ziprasidone (Akkaya
et al. 2006; Kaufman et al. 2006; Miodownik et al. 2005; Murty et al. 2002; Villanueva et al. 2006).
Intramuscular ziprasidone shows a favorable tolerability profile similar to that of oral ziprasidone. In
premarketing trials, the most common side effects of intramuscular ziprasidone (those with an incidence
of >5% and an incidence greater than that seen in placebo recipients) were somnolence (20%), headache
(13%), and nausea (12%) (Pfizer Inc. 2008). Pooled data from more recent clinical trials of intramuscular
ziprasidone indicate that most treatment-related adverse events were mild to moderate in severity, with
the most common side effects being headache, nausea, dizziness, insomnia, anxiety, and pain at the
injection site (Daniel 2003; Zimbroff et al. 2002). Ziprasidone is considered a Category C drug in
pregnancy. Although some specific developmental effects have been noted in animal studies at dosages
ranging from 0.5 to 8.0 times the maximal recommended human dosage (Pfizer Inc. 2008), there are as
yet no similar reports of such effects in humans. The reader is advised to consult the current USPI for a
detailed listing of potential adverse drug effects identified in the regulatory approval process and
postmarketing surveillance.
The FDA recently required the addition of black box warnings in the USPI regarding an increased risk of
mortality associated with the use of both atypical and conventional antipsychotics used in elderly patients
with dementia-related psychosis. Observed causes of death have been varied, and the mechanism of any
drug effect in schizophrenia remains uncertain (Pfizer Inc. 2008). In particular, it remains unclear to what
extent these uncontrolled observations of increased mortality are due to specific drug effects or to the
advanced medical risk characteristics of patients with dementia or delirium who tend to receive these
medications (Farber et al. 2000; Rochon et al. 2008). Regulatory interest in drug effects on
cerebrovascular risk (i.e., risk of stroke) in the elderly, in contrast to generalized considerations of
cardiovascular risk factors (e.g., myocardial infarction and stroke) discussed below (see “Metabolic
Adverse Events” and “Cardiac Conduction, Including Ventricular Depolarization and Repolarization”), has
also been focused on some atypical antipsychotics. Studies including those by Street et al. (2000),
Wooltorton (2002), and De Deyn et al. (2004) have suggested that olanzapine and risperidone treatment
may be associated with an increase in the risk of cerebrovascular adverse events and mortality. Again,
possible mechanisms underlying hypothesized effects remain unclear, with some evidence suggesting that
patient characteristics other than the specific antipsychotic used may be more significant predictors of
cerebrovascular event risk than any drug-specific effects (Finkel et al. 2005).
Clinical experience with ziprasidone in the years following initial U.S. approval has suggested that a small
subgroup of patients may experience insomnia or what has been characterized as activation or akathisia
soon after initiation of treatment (Nemeroff et al. 2005). These presentations have been described as
transient manifestations of anxiety, restlessness, insomnia, increased energy, or hypomania-like
symptoms, occurring most commonly at what is now considered the lower end of the dosage range.
Anecdotal reports suggest that starting dosages of 120 mg/day or greater and more rapid dose titration
can substantially reduce the incidence of these clinical presentations (Weiden et al. 2002). These
anecdotal clinical observations are consistent with controlled experimental evidence indicating that a
significantly lower rate of discontinuation occurs in patients who begin ziprasidone therapy at higher
dosages (120–160 mg/day) than in patients who receive initial dosages of 80 mg/day or less (Joyce et al.
2006). Several mechanisms may explain these observations:
First, ziprasidone, like some of the other newer antipsychotics and many under development, is lessPrint: Chapter 33. Ziprasidone
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intrinsically sedating than many other antipsychotics in current widespread use (e.g., due to less H1 receptor
antagonism), so that patients initiating ziprasidone treatment after months or years of receiving a different,
more sedating therapy may experience initial difficulties adjusting to the new level of dosing time–specific
(e.g., at bedtime) or around-the-clock sedation.
Second, as discussed above (see “Pharmacological Profile” and “Indications and Efficacy” sections earlier in
chapter) many patients have been treated with ziprasidone at doses that were insufficient to achieve optimal
D2 receptor blocking, leading to undertreatment of the underlying illness compared with what might have been
achieved with an appropriately dosed prior therapy.
Furthermore, ziprasidone underdosing with respect to D2 receptor binding can produce a well-understood but
unwanted pharmacodynamic situation with respect to the differential balance of 5-HT2C receptor antagonism
relative to D2 receptor antagonism. As illustrated in Figure 33–3, using ziprasidone doses at the lower end of
the clinical dosage range can allow 5-HT2 receptors to reach 50% of maximal receptor occupancy or more, well
before clinically significant levels of D2 occupancy are achieved (Mamo et al. 2004). 5-HT2C antagonist activity
at this level disinhibits cortical monoaminergic neurotransmission (e.g., dopamine release), which, in the
absence of sufficient D2 blockade, may lead to clinically relevant excess monoaminergic neurotransmission
(Bonaccorso et al. 2002; Pozzi et al. 2002).
Clinicians commonly address these potential issues through appropriate dosing and through the transient,
targeted use of concomitant medication strategies (e.g., adjunctive benzodiazepine treatment) for
relevant patients starting new treatment in the acute inpatient setting or for stable outpatients needing a
smooth transition to new therapy.
Two other areas of potential adverse drug effects deserve further discussion: drug effects on risk for EPS
and drug effects on cardiometabolic risk factors (e.g., changes in weight, plasma lipids, and glucose).
These adverse-event domains are notable as areas of considerable clinical and research interest. For
example, drug effects on EPS and cardiometabolic risk factors such as weight and plasma lipid level
changes were the only side effect categories observed to contribute to differential rates of treatment
discontinuation in the primary analysis of the NIMH-funded phase I CATIE study (Lieberman et al. 2005).
Extrapyramidal Side Effects
Short-term trials indicate that treatment with ziprasidone is associated a measurably larger incidence of
EPS than treatment with placebo (Pfizer Inc. 2008; Potkin et al. 2005). In contrast, data from a 52-week
trial (Arato et al. 2002) indicate that the incidence of abnormal movement disorders during treatment
with ziprasidone is comparable to the incidence during placebo treatment. Other long-term studies
suggest a low (<6%) incidence of treatment-related EPS (Arango et al. 2007; Kudla et al. 2007). Both
active-comparator studies and medication-switching studies suggest that ziprasidone is associated with
fewer EPS than risperidone (Addington et al. 2003; Weiden et al. 2003a, 2003b) or conventional
antipsychotics (Hirsch et al. 2002; Weiden et al. 2003a, 2003b). Comparing ziprasidone and olanzapine, a
drug with intrinsic antimuscarinic activity as well as 5-HT 2 receptor antagonist activity, one direct
comparison study indicates that treatment with olanzapine is associated with fewer EPS (Kinon et al.
2006a), whereas two other direct comparison studies (Breier et al. 2005; Simpson et al. 2002) and one
medication-switching study (Weiden et al. 2003b) have reported that both drugs exhibit a similar liability
for EPS. With respect to akathisia, one comparison study indicates that less akathisia occurs with
olanzapine use (Breier et al. 2005), whereas another study suggests no difference in akathisia rates with
olanzapine versus ziprasidone (Kinon et al. 2006a). Results from phase I and phase II of the large-scale
CATIE trial suggest no significant differences between ziprasidone, perphenazine, olanzapine, quetiapine,
and risperidone in the incidence of EPS and akathisia (Lieberman 2007; Lieberman et al. 2005; Stroup et
- 2006). However, the perphenazine arm in the CATIE study was restricted to patients who did not
already have tardive dyskinesia, suggesting a possible selection bias toward patients less likely to
experience EPS. Despite this advantage, the perphenazine group still had the highest rate of dropouts due
to EPS, suggesting along with other lines of evidence that clinically meaningful EPS are more common in
patients treated with conventional agents like perphenazine.
Intramuscular ziprasidone has been tolerated at dosages of up to 80 mg/day with a low liability for EPS
(Daniel 2003; Daniel et al. 2001; Lesem et al. 2001). Both intramuscular ziprasidone use and sequential
intramuscular/oral ziprasidone use are associated with a lower incidence of treatment-related movement
disorders than intramuscular haloperidol use (Swift et al. 1998; Zimbroff et al. 2002) and sequential
intramuscular/oral haloperidol use (Brook et al. 2000, 2005). Although the results of controlled
experimental studies indicate a generally low risk of EPS with ziprasidone, there have been severalPrint: Chapter 33. Ziprasidone
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uncontrolled observational reports of EPS-related adverse events co-occurring with ziprasidone treatment
and, in many cases, concomitant treatment with other agents (Dew and Hughes 2004; Duggal 2007; M. E.
Keck et al. 2004; Mason et al. 2005; Papapetropoulos et al. 2005; Ramos et al. 2003; Rosenfield et al.
2007; Weinstein et al. 2006; Yumru et al. 2006; Ziegenbein et al. 2003).
Metabolic Adverse Events
Adverse medication effects on modifiable risk factors for cardiovascular disease and type 2 diabetes
mellitus have become an important topic of clinical, research, and regulatory concern, based in part on the
increased prevalence of these disease states and associated premature mortality observed in patients
with major mental disorders like schizophrenia and bipolar disorder (Brown 1997; Brown et al. 2000;
Colton and Manderscheid 2006; Harris and Barraclough 1998; Hennekens et al. 2005; Joukamaa et al.
2001; Osby et al. 2000, 2001). Modifiable cardiometabolic risk factors include obesity, hyperglycemia,
dyslipidemia, hypertension, and smoking, all prevalent conditions in patients with major mental disorders,
with substantial evidence that primary and secondary prevention approaches are underutilized in these
patients (Allison et al. 1999a; Brown et al. 2000; Druss and Rosenheck 1998; Druss et al. 2000, 2001;
Frayne et al. 2005; Hippisley-Cox et al. 2007; McEvoy et al. 2005; Nasrallah et al. 2006; Newcomer and
Hennekens 2007). In particular, use of recommended monitoring of changes in weight and in plasma
glucose and lipid levels during antipsychotic treatment has heightened interest in cardiometabolic risk
effects that may go undetected during the course of treatment (American Diabetes Association 2004;
Morrato et al. 2008). All currently available antipsychotic medications are associated with a risk of weight
gain, as well as potential adverse effects on plasma glucose and lipid levels, although there is substantial
variability in the magnitude of these effects across individual agents (Casey et al. 2004; Eli Lilly 2008; “Eli
Lilly updates label warning for Zyprexa” 2007; Newcomer 2005). Potential adverse treatment effects on
body weight can be predicted to increase the risk for cardiovascular disease as well as for conditions like
type 2 diabetes, commonly involving corresponding, measurable increases in insulin resistance,
dyslipidemia, and hyperglycemia (Fontaine et al. 2001; Haupt et al. 2007; Koro et al. 2002a, 2002b).
Treatment with ziprasidone is associated with a relatively small risk of clinically significant increases in
body weight. An analysis of available studies with this agent and other antipsychotics, both first- and
second-generation antipsychotics (Allison et al. 1999b), estimated a 0.04-kg weight gain over a 10-week
treatment period with ziprasidone, identifying ziprasidone as having one of the lowest estimated effects
on body weight of those analyzed. In a 6-week randomized, controlled trial in patients with acute
exacerbations of schizophrenia or schizoaffective disorder, treatment with ziprasidone 80 mg/day
produced a median increase in body weight of 1 kg, compared with no change in median weight with
ziprasidone 160 mg/day or placebo (Daniel et al. 1999). In a 28-week study of outpatients with
schizophrenia, mean changes in body weight from baseline to endpoint were similar during treatment
with ziprasidone (+0.31 kg) and haloperidol (+0.22 kg) (Hirsch et al. 2002). In a 28-week study
comparing the effects of ziprasidone and olanzapine, ziprasidone-treated patients experienced a small
decrease in mean body weight (–1.12 kg) compared with a statistically and clinically different 3.06-kg
mean increase in body weight observed with olanzapine treatment (Hardy et al. 2003; Kinon et al. 2006a).
Reductions in body weight were also associated with ziprasidone treatment in the 1-year Ziprasidone
Extended Use in Schizophrenia study of patients with chronic, stable schizophrenia (Arato et al. 2002);
this study reported mean decreases from baseline of 2.7 kg, 3.2 kg, and 2.9 kg reported with 40 mg/day,
80 mg/day, and 160 mg/day dosages of ziprasidone, respectively, compared with a 3.6-kg decrease
observed with placebo treatment. Results from the phase I and phase IIT CATIE studies provide further
confirmation that treatment with ziprasidone has a low intrinsic risk for producing clinically significant
weight gain, with 6%–7% of ziprasidone recipients demonstrating a 7% or greater increase from baseline
body weight compared with, for example, 27%–30% of olanzapine recipients (Lieberman 2007; Stroup et
- 2006). In the phase I CATIE study, ziprasidone treatment was associated with a mean reduction in
body weight of 0.14 kg (0.3 lb) per month of treatment, compared with a mean increase of 0.91, 0.23, and
0.18 kg/month (2.0, 0.5, and 0.4 lb/month) during treatment with olanzapine, quetiapine, and
risperidone, respectfully, the other atypical antipsychotics tested (Lieberman et al. 2005).
It is important to note that the ranking of weight gain liability for individual medications appears to apply
in patients being treated for their first psychotic episode or during early drug exposure but perhaps not
during chronic treatment, although there have been fewer studies in this area and initial courses of
treatment can clearly be associated with greater weight gain than subsequent courses of treatment
(McEvoy et al. 2007). In addition, chronically treated patients switching treatment from a medication withPrint: Chapter 33. Ziprasidone
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greater weight gain liability to a medication with less weight gain liability are likely to lose body weight in
relation to that medication change, an effect that likely underlies the mean reductions in weight noted in
some of the trials with ziprasidone discussed above. The magnitude of change in body weight during
treatment with ziprasidone varies as a function of the weight gain liability of the prior treatment: the
greatest potential for weight loss is associated with switching from previous treatments with the greatest
weight gain liability (Weiden et al. 2008). For example, 6 weeks of ziprasidone therapy was associated
with statistically significant decreases in mean body weight from baseline in patients switched from
olanzapine (–1.8 kg) and from risperidone (–0.9 kg), whereas patients switched from high-potency
conventional antipsychotics such as haloperidol experienced a small increase in weight (+0.3 kg) (Weiden
et al. 2008). The 1-year extension of this medication-switching study indicated that weight loss was
progressive and persistent throughout the 1-year period for patients who switched from olanzapine (–9.8
kg, or 10.3% of baseline body weight) and from risperidone (–6.9 kg, or 7.8% of baseline) (Figure 33–6;
Weiden et al. 2008). Another study found similar significant decreases in weight in patients treated for 6
months with ziprasidone who were switched from olanzapine (–7.0 kg) and from risperidone (–2.2 kg)
(Montes et al. 2006).
FIGURE 33–6. Time course of weight change over 58 weeks after switching to ziprasidone.
Previous treatments were conventional antipsychotics (line with circles; n = 71), risperidone (line with squares; n =
43), or olanzapine (line with triangles; n = 71). Individual observed cases within each treatment group are also
shown (circle = conventional agent: baseline weight, 198 lb [90 kg]; square = risperidone: baseline weight, 194.9 lb
[88.6 kg]; triangle = olanzapine: baseline weight, 210.3 lb [95.6 kg]).
LS = least-squares analysis; MMRM = mixed-model repeated measures analysis; OC = observed case analysis.
*P <0.01 versus baseline (MMRM and OC).
Source. Adapted from Weiden PJ, Newcomer JW, Loebel AD, et al.: “Long-Term Changes in Weight and Plasma Lipids
During Maintenance Treatment With Ziprasidone.” Neuropsychopharmacology 33:985–994, 2008 (Figure 1, p. 988).
Ziprasidone’s effects on plasma glucose and lipid levels are best understood as a function of
treatment-related changes in adiposity. Whereas some antipsychotics, such as clozapine and olanzapine,
have been reported to produce adiposity-independent effects on insulin sensitivity, and related changes in
glucose and lipid metabolism, ziprasidone has demonstrated no similar adiposity-independent effects in
this same experimental paradigm (Houseknecht et al. 2007). In general, increases in adiposity are
associated with decreases in insulin sensitivity in individuals taking or not taking antipsychotic
medications, with reduced insulin sensitivity leading to increased risk for hyperglycemia, dyslipidemia,
and other adverse changes in cardiometabolic risk indicators (Haupt et al. 2007; Newcomer and HauptPrint: Chapter 33. Ziprasidone
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2006).
Ziprasidone’s relatively low risk for drug-related increases in weight is therefore not surprisingly
associated with a low risk for adverse effects on plasma lipids and other metabolic indices. Both short
and long-term studies have shown little significant adverse effect of ziprasidone on glucose levels, plasma
insulin levels, insulin resistance, or fasting and nonfasting lipid levels (Daniel et al. 1999; Glick et al.
2001; Rettenbacher et al. 2006; Simpson et al. 2004a, 2005) in contrast to the degree of adverse effects
detected with some active comparators. For example, olanzapine treatment can produce statistically
significant increases in fasting glucose and insulin levels (Glick et al. 2001; Hardy et al. 2003; Simpson et
- 2002, 2005) as well as fasting lipids and insulin resistance calculated by homeostasis model
assessment (Simpson et al. 2004a, 2005). In the CATIE Phase I study, olanzapine-treated patients
demonstrated drug exposure–adjusted mean increases in blood glucose (+13.7 ± 2.5 mg/dL) and
glycosylated hemoglobin (hemoglobin A1c [HbA1c]) (+0.4 ± 0.07%), plasma triglycerides (+40.5 ± 8.9
mg/dL), and total cholesterol (+9.4 ± 2.4 mg/dL), whereas ziprasidone treatment was associated with
minimal drug exposure–adjusted mean increases in blood glucose (+2.9 ± 3.4 mg/dL) and HbA1c (+0.11
± 0.09%), and decreases in plasma triglycerides (–16.5 ± 12.2 mg/dL) and total cholesterol (–8.2 ± 3.2
mg/dL) (Lieberman 2007). In the CATIE Phase IIT study, olanzapine-treated patients again had the
greatest drug exposure–adjusted mean increases in HbA1c (+0.97 ± 0.3%), triglycerides (+94.1 ± 21.8
mg/dL), and total cholesterol (+17.5 ± 5.2 mg/dL), with quetiapine treatment associated with drug
exposure–adjusted mean increases in blood glucose (+1.2 ± 6.0 mg/dL) and HbA1c (+0.61 ± 0.3%),
glucose (+13.8 ± 5.9 mg/dL), triglycerides (+39.3 ± 22.1 mg/dL), and total cholesterol (+6.5 ± 5.3
mg/dL). In contrast, ziprasidone-treated patients in CATIE Phase IIT showed minimal drug
exposure–adjusted mean increases in blood glucose (+0.8 ± 5.6 mg/dL) and HbA1c (+0.46 ± 0.3%) and
decreases in triglycerides (–3.5 ± 20.9 mg/dL) and total cholesterol (–10.7 ± 5.1 mg/dL) (Stroup et al.
2006).
Similar to the effect of prior treatment conditions on changes in weight during treatment with ziprasidone,
improvements in plasma lipid levels observed in the CATIE study can best be understood as the effect of
switching from a previous treatment that is associated with larger adverse effects on lipid metabolism to a
treatment with minimal adverse effects. Weiden et al. (2003a) noted that ziprasidone treatment was
associated with significant decreases from baseline in both median nonfasting triglyceride levels and
median nonfasting total cholesterol levels at the end of the 6-week treatment period in patients whose
prior medication was olanzapine or risperidone, with minimal change following prior treatment with
high-potency conventional agents like haloperidol. Notably, the reductions in lipids observed in this study
occurred within the first 6 weeks of initiating treatment with ziprasidone, with substantial reductions in
total cholesterol (>20 mg/dL) and plasma triglycerides (78 mg/dL) in the patients previously treated with
olanzapine. In the 12-month extension of this study, the reductions achieved in the initial weeks following
the switch from prior treatment were sustained during continued treatment with ziprasidone (Weiden et
- 2008).
Cardiac Conduction, Including Ventricular Depolarization and Repolarization
Some medications, including psychotropics, can increase the duration of the QTc interval (the QT interval
corrected for heart rate). Basic research suggests plausible mechanisms by which an increase in the QTc
interval could increase the risk of sudden cardiac death, and clinical investigations suggest that certain
small subgroups of the general population may have an increased risk of sudden cardiac death, for
example, those with a family history of congenital long-QT syndrome (>500 msec) and those who
concomitantly use drugs that markedly increase the QTc interval (e.g., by >60 msec) via either
pharmacokinetic or pharmacodynamic interactions (Montanez et al. 2004). This has understandably led to
regulatory interest in drug effects on the QTc interval. It should be noted that epidemiological studies in
the general population suggest that modest prolongations of the QTc interval are not a risk factor for
cardiovascular mortality or sudden death, so any risk in the general population of modest QTc
prolongations is likely to be small and difficult to detect reliably (Montanez et al. 2004). Compared with
risks like obesity, hypercholesterolemia, diabetes, hypertension, physical inactivity, or cigarette smoking,
each with well-characterized effects in the general population, modest QTc prolongations are not a
comparable risk factor for cardiovascular mortality or sudden death in the general population.
Against this background, thioridazine was recently required to add to its prescribing information a black
box warning related to its QTc interval–prolonging effects, following decades of use. Other conventional
antipsychotics, including haloperidol, are also associated with some risk of QTc prolongation (Gury et al.Print: Chapter 33. Ziprasidone
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2000; O’Brien et al. 1999). Investigators (Glassman and Bigger 2001) have estimated the rate of
occurrence of torsades de pointes with conventional antipsychotics as “10–15 such events in 10,000
person-years of observation” (p. 1774). Ziprasidone, like some other antipsychotic agents, can induce
orthostatic hypotension, particularly early in treatment exposure, which can lead to transient tachycardia,
dizziness, or syncope (Swainston Harrison and Scott 2006). However, tachycardia has been observed to
be infrequent and as common in patients treated with ziprasidone as in those treated with placebo
(Swainston Harrison and Scott 2006). Tachycardia and syncope related to hypotension are to be
distinguished from ventricular arrhythmias that can rarely occur in relation to QTc prolongation.
Ziprasidone treatment has been demonstrated to result in a modestly increased risk of QTc prolongation
(Pfizer Inc. 2008). This QTc prolongation at Cmax (mean increase, >15 msec) is 9–14 msec greater than
that seen with risperidone, olanzapine, quetiapine, or haloperidol but approximately 14 msec less than
that seen with thioridazine. Unlike the case with thioridazine, the modest effect of ziprasidone on the QTc
interval is not worsened by the presence of commonly encountered inhibitors of drug metabolism. In
clinical trials of ziprasidone monotherapy that report QTc changes as well as in case reports of ziprasidone
overdosing (with doses up to 12,800 mg), there has been no evidence of any significant clinical sequelae
such as torsades de pointes or sudden death (Arato et al. 2002; Arbuck 2005; Daniel 2003; Gomez-Criado
et al. 2005; Harrigan et al. 2004; Insa Gómez and Gutiérrez Casares 2005; Levy et al. 2004; Lieberman
2007; Miceli et al. 2004; Montanez et al. 2004; Nemeroff et al. 2005; Taylor 2003; Weiden et al. 2002,
2003a). This is consistent with analyses of large population samples, which have failed to demonstrate
any association between QTc duration and either cardiovascular or all-cause mortality (Goldberg et al.
1991). Rare cases of torsades de pointes have been reported in patients being treated with multiple
medications including ziprasidone, but the incidence of these events appears to be below the known
prevalence of torsades de pointes in community-based population samples (Heinrich et al. 2006). The
USPI suggests that clinicians should nonetheless be cognizant of this potential risk and be aware of
circumstances that may increase risk for the occurrence of torsades de pointes and/or sudden death in
association with the use of any drugs that can prolong the QTc interval. Such circumstances include
bradycardia, hypokalemia, or hypomagnesemia; concomitant use of other medications known to cause
clinically significant QT prolongation (although an additive effect with ziprasidone has not been
established); and presence of congenital long-QT syndrome. The USPI further states that ziprasidone
should not be used in patients with significant cardiovascular conditions, such as uncompensated heart
failure or a cardiac arrhythmia, or in those who have had a recent acute myocardial infarction or
persistent QTc measurements of greater than 500 msec, and the prudent clinician might consider
employing the same caution with many other antipsychotic and psychotropic medications currently in use.
CONCLUSION
Ziprasidone is the fourth atypical antipsychotic following clozapine to become available in the United
States. This agent has a unique pharmacological profile with the highest 5-HT 2A/D2 affinity ratio of
currently available agents, potent serotonin and norepinephrine reuptake inhibition activity, agonist
activity at 5-HT1A receptors, and clinically relevant antagonist activity at various 5-HT2 receptor subtypes.
Ziprasidone has demonstrated rapid-onset and sustained efficacy for the treatment of schizophrenia,
schizoaffective disorder, and bipolar mania, with promising evidence of favorable mood, cognitive, and
prosocial effects. It is now available in an intramuscular formulation for the treatment of acute agitated
psychoses.
Ziprasidone has a highly favorable safety and tolerability profile with limited potential for drug–drug and
drug–disease interactions, critical issues for a patient population that generally has a high burden of
medical comorbidity and is commonly exposed to complex polypharmacy. The adverse-effect profile of
ziprasidone is particularly noteworthy in areas that are key to safety and tolerability in patients with
major mental disorders such as schizophrenia and bipolar disorder, including low drug-related risk for EPS
and minimal effects on cardiometabolic risk factors like obesity and dyslipidemia. As a fuller
understanding of the cumulative risks associated with prolonged antipsychotic treatment develops, along
with the risks and benefits of various commonly used adjunctive medications, it is likely that clinicians will
increasingly appreciate individual medications with a wide spectrum of therapeutic activity and a
favorable safety profile that support long-term use and optimize both medical and psychiatric outcomes.
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Course Content
Introduction to Ziprasidone: Mechanism of Action and Pharmacokinetics
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Understanding Ziprasidone: An Overview
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Mechanism of Action of Ziprasidone
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Pharmacokinetics of Ziprasidone
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Pharmacokinetics Review Quiz
Clinical Indications and Efficacy of Ziprasidone
Dosing Strategies and Administration Guidelines for Ziprasidone
Managing Side Effects and Drug Interactions with Ziprasidone
Advanced Case Studies and Best Practices in Ziprasidone Therapy
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