Ziprasidone, a benzisothiazolyl piperazine-derivative, is an atypical antipsychotic agent.1
Ziprasidone hydrochloride is used orally for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder.1 Ziprasidone mesylate is used intramuscularly (IM) for acute agitation in schizophrenic patients who need antipsychotic treatment for rapid control.1
When deciding among therapies available for the condition requiring treatment, clinicians should consider ziprasidone's greater capacity to prolong the QT or QTc (QT interval corrected for rate) interval compared with several other antipsychotic agents.1 Clinicians may consider the use of other drugs initially.1
Ziprasidone hydrochloride is used orally for the treatment of schizophrenia in adults.1 Ziprasidone mesylate is used IM for the acute treatment of agitation in schizophrenic adults.1
Because there is no experience regarding the safety of administering ziprasidone IM to schizophrenic patients already receiving oral ziprasidone, concomitant use of oral and IM formulations of ziprasidone is not recommended.1
Efficacy of oral ziprasidone hydrochloride for the management of schizophrenia was evaluated in 5 placebo-controlled studies of variable duration (4 short-term [4-6 weeks] and one long-term [52 weeks]), in adults who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-IIIR criteria for schizophrenia in hospital settings.1, 2, 3, 115 The studies primarily used the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS), as well as the Clinical Global Impression (CGI) scale, to assess the effects of drug treatment in schizophrenia.1, 2, 3, 115 In one of the 4-week studies, patients were randomized to receive ziprasidone 20 or 60 mg orally twice daily or placebo.1, 3 At the end of 4 weeks, only the 60 mg dosage led to substantial improvements in the BPRS total score and the CGI severity score compared to placebo.1, 3 In another 4-week study, ziprasidone (5, 20, and 40 mg orally twice daily) did not lead to substantial improvements in any outcome of interest compared to placebo.1 In one of the 6-week studies, patients were randomized to receive ziprasidone 40 or 80 mg orally twice daily or placebo.1, 2 At the end of 6 weeks, both ziprasidone dosage groups had substantial improvement compared to placebo in the BPRS total score, the CGI severity score, and the PANSS total and negative subscale scores.1, 2 In another 6-week study, ziprasidone, at dosages of 20, 60, and 100 mg orally twice daily, led to substantial improvements in BPRS total score, PANSS total score, and CGI severity score compared with placebo.1 In the 52-week study, patients were randomized to receive ziprasidone 20, 40, or 80 mg orally twice daily or placebo.1, 115 The main efficacy measure in this study was the probability of relapse.1, 115 Ziprasidone, at all dosages, had a substantially lower probability of relapse compared to placebo at the end of 52 weeks.1, 115
Although results of a limited comparative study suggest that oral ziprasidone hydrochloride (160 mg daily) may be as effective as oral haloperidol (15 mg daily) in reducing positive symptoms of schizophrenia, a reliable and valid comparison of ziprasidone and haloperidol cannot be made at this time based solely on this study due to its relatively small sample size (90 patients), high dropout rate (51.1%), and brief duration (4 weeks).1, 6 Data from a short-term controlled study also suggest that oral ziprasidone hydrochloride (mean dosage of 130 mg daily) is as effective as oral olanzapine (mean dosage of 11 mg daily) in the acute treatment of schizophrenia.96
The efficacy of IM ziprasidone mesylate for the management of acute agitation in schizophrenia in adults was established in single-day, double-blind, controlled trials in hospital settings.1, 117, 118 Efficacy was assessed primarily by analysis of the AUC of the Behavioral Activity Rating Scale (BARS) and the CGI severity rating.1 In the first study, patients were randomized to receive IM ziprasidone 20 mg or IM ziprasidone 2 mg.1, 117 After an initial injection, patients could receive up to 3 additional IM injections at the same dosage, at intervals of at least 4 hours apart until the end of the 24-hour study period.117 At 4 hours after the first injection, the mean AUC of the BARS score was substantially smaller in patients who received ziprasidone IM 20 mg versus patients who received ziprasidone IM 2 mg.1, 117 There was also a substantial decrease in CGI severity at 4 hours in patients who received ziprasidone 20 mg compared to patients who received 2 mg.1, 117 In the second study, patients were randomized to receive IM ziprasidone 10 mg or IM ziprasidone 2 mg.1, 118 Patients in this study could also receive up to 3 additional IM injections at the same dosage, at intervals of at least 2 hours apart for a maximum of 4 total doses in the 24-hour study period.118 At up to 4 hours after the first injection, the mean AUC of the BARS score was substantially smaller in patients who received ziprasidone IM 10 mg versus 2 mg.1, 118
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic medication.119 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.119 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).119 Patients whose symptoms improve on an antipsychotic medication should continue treatment with an antipsychotic medication long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another agent for maintenance therapy.119
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.120 Choice of antipsychotic medication should be based on patient-specific factors and the side effect profiles of the different antipsychotic medications.120 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.120
Ziprasidone hydrochloride is used orally as monotherapy for the acute treatment of manic and mixed episodes associated with bipolar I disorder in adults.1 The drug is also used orally as adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults.1
Efficacy of ziprasidone monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 2 short-term (i.e., 3 weeks' duration), double-blind, placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features).1, 73, 74 The principal rating instruments used for assessing manic symptoms in these trials were the Mania Rating Scale (MRS), which is derived from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C) with items grouped as the Manic Syndrome subscale (e.g., elevated mood, less need for sleep, excessive energy, excessive activity, grandiosity), the Behavior and Ideation Subscale (irritability, motor hyperactivity, accelerated speech, racing thoughts, poor judgment), and impaired insight, and the CGI-Severity of Illness Scale, which was used to assess the clinical significance of treatment response.1, 73, 74
In the first 3-week, placebo-controlled monotherapy trial, ziprasidone hydrochloride was given at an initial dosage of 40 mg twice daily on the first day and 80 mg twice daily on the second day; dosage adjustment in 20-mg twice daily increments within a dosage range of 40-80 mg twice daily was then permitted for the remainder of the study.1, 73 The mean dosage of ziprasidone hydrochloride in this study was 132 mg daily.1, 73 In the second 3-week, placebo-controlled monotherapy trial, patients also were given an initial dosage of ziprasidone hydrochloride 40 mg twice daily on the first day; subsequent dosage titration in 20 mg twice daily increments within a dosage range of 40-80 mg twice daily was permitted.1, 74 The mean dosage of ziprasidone hydrochloride in this study was 112 mg daily.1, 74 Ziprasidone was superior to placebo in the reduction of the MRS total score and the CGI-S score in both of these studies.1, 73, 74
Efficacy of ziprasidone as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder has been demonstrated in a double-blind, placebo-controlled study of 6 months' duration in adult outpatients who met DSM-IV criteria for bipolar I disorder with a recent or current manic or mixed episode (with or without psychotic features).1, 103 In the open-label phase, patients were stabilized on ziprasidone combined with either lithium or valproate for at least 8 weeks; patients were then randomized into the double-blind phase where they continued to receive lithium or valproate in addition to either ziprasidone (40-80 mg twice daily) or placebo.1, 103 The primary outcome measure was time to recurrence of a mood episode (manic, mixed, or depressed) requiring intervention.1, 103 Ziprasidone given in conjunction with lithium or valproate was superior to placebo in increasing the time to recurrence of a mood episode in this study.1, 103
Legacy practice guidelines from APA recommend lithium plus an antipsychotic or valproate plus an antipsychotic for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.75 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to side effect profiles.75 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic.75 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign side effect profile.75 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.75 The guideline states that, for patients treated with an antipsychotic medication during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotics should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.75
Guidelines from the Department of Veterans Affairs and Department of Defense suggest lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.121 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, and risperidone are recommended as alternative treatments.121 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.121 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.121 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.121 Aripiprazole, olanzapine, quetiapine, or ziprasidone may also be used in combination with lithium or valproate for prevention of mania recurrence.121
Ziprasidone has been used orally for the management of Tourette's syndrome in pediatric patients 7-17 years of age† .122, 123
The American Academy of Child and Adolescent Psychiatry (AACAP) has developed a practice parameter for children and adolescents with tic disorders, including Tourette's disorder.123 According to AACAP, behavioral interventions for chronic tic disorders should be considered when tics cause impairment, are moderate in severity, or if behavioral-responsive psychiatric comorbidities are present.123 Medications should be considered for patients with chronic tic disorders if they have moderate to severe tics causing severe impairment in quality of life or medication-responsive psychiatric comorbidities.123 Atypical antipsychotics such as aripiprazole and risperidone are listed as options to treat tic disorders.123 There is evidence that ziprasidone decreases the severity and frequency of tics based on a randomized controlled trial of 28 pediatric patients 7 to 17 years of age.122, 123 However, due to concerns with electrocardiographic changes with use of ziprasidone, pediatric patients should be screened by experienced cardiologists if considering use.123
Ziprasidone hydrochloride is available as capsules and is administered orally twice daily with food for optimal absorption.1 Absorption of ziprasidone is increased up to 2-fold in the presence of food.1 Swallow ziprasidone capsules whole; do not open, crush, or chew the capsules.1
Store ziprasidone hydrochloride capsules at 25°C (excursions permitted between 15-30°C).1
Ziprasidone mesylate is available in a single-dose vial as lyophilized powder for IM injection.1 Ziprasidone mesylate is administered only by IM injection and should not be administered IV.1
The lyophilized powder for injection must be reconstituted prior to administration by adding 1.2 mL of sterile water for injection to single-dose vials of ziprasidone to provide a solution containing 20 mg/mL.1 Other solutions should not be used to reconstitute ziprasidone mesylate injection, and the drug should not be admixed with other drugs.1 The vials should be shaken vigorously to ensure complete dissolution.1 Strict aseptic technique must be observed since the drug contains no preservative or bacteriostatic agent.1 Ziprasidone mesylate injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1
To administer a 10 mg dose, draw up 0.5 mL of the reconstituted solution.1 To administer a 20 mg dose, draw up 1 mL of the reconstituted solution.1 Discard any unused portion.1 Refer to the full prescribing information for additional details on preparation and administration.1
Store ziprasidone mesylate for injection at 25°C (excursions permitted between 15-30°C) in dry form; protect from light.1 Following reconstitution, ziprasidone mesylate for injection is stable, when protected from light, for 24 hours at 15-30°C or for up to 7 days when refrigerated at 2-8°C.1
Dosage of ziprasidone hydrochloride is expressed in terms of the hydrochloride monohydrate.1 Dosage of ziprasidone mesylate is expressed in terms of ziprasidone.1
Oral Dosage : For the symptomatic management of schizophrenia, the recommended initial adult dosage of ziprasidone hydrochloride is 20 mg orally twice daily.1 In some patients, dosage may be increased based on clinical status up to 80 mg twice daily.1 Dosage adjustments, if indicated, generally should occur at intervals of not less than 2 days, since steady-state concentrations of the drug are achieved within 1-3 days.1 To ensure use of the lowest effective dosage, however, it is recommended that patients be observed for several weeks prior to upward titration of ziprasidone dosage.1 The effective dosage of ziprasidone hydrochloride in short-term clinical studies generally ranged from 20-100 mg twice daily.1 Although there were trends toward a dose response within a dosage range of 20-80 mg twice daily, results were not consistent.1 The manufacturer states that no additional benefit has been demonstrated for ziprasidone hydrochloride dosages beyond 20 mg twice daily.1 The manufacturer additionally states that dosages exceeding 80 mg twice daily generally are not recommended, and safety of dosages exceeding 100 mg twice daily has not been established.1
The optimum duration of ziprasidone therapy currently is not known.1 A maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo showed a delay in time to relapse for patients receiving ziprasidone.1 Patients responding to ziprasidone therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage, and the need for continued therapy with the drug should be reassessed periodically.1
IM Dosage : For the prompt control of acute agitation in patients with schizophrenia, the recommended initial adult IM dose of ziprasidone mesylate is 10-20 mg given as a single dose.1 Depending on patient response, doses of 10 or 20 mg may be repeated every 2 or 4 hours, respectively, up to a maximum cumulative dose of 40 mg daily.1
Oral therapy should replace IM therapy as soon as possible if long-term therapy is indicated.1 Safety and efficacy of administering ziprasidone mesylate IM injection for longer than 3 consecutive days have not been evaluated.1 Because there is no experience regarding the safety of administering ziprasidone mesylate IM injection to patients with schizophrenia who already are receiving oral ziprasidone hydrochloride, the concomitant use of oral and IM formulations of ziprasidone is not recommended by the manufacturer.1
Oral Dosage : For the acute treatment of manic or mixed episodes associated with bipolar disorder (with or without psychotic features), the recommended initial adult dosage of ziprasidone hydrochloride is 40 mg orally twice daily on the first day of therapy.1 Dosage may then be increased to 60 or 80 mg twice daily on the second day of therapy.1 Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40-80 mg twice daily.1 In the flexible-dosage clinical trials, the mean dosage of ziprasidone hydrochloride was approximately 120 mg daily.1
For the maintenance treatment of bipolar I disorder (as adjunctive therapy to either lithium or valproate) in adults, ziprasidone should be continued at the same dosage on which the patient was initially stabilized within the dosage range of 40-80 mg orally twice daily.1 The manufacturer of ziprasidone states that the need for continued maintenance therapy should be reassessed periodically.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
IM ziprasidone has not been systematically evaluated in patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
IM ziprasidone has not been systematically evaluated in patients with renal impairment.1 Because the cyclodextrin excipient present in ziprasidone for IM injection is cleared by renal filtration, IM ziprasidone should be administered with caution in patients with renal impairment.1
Although dosage adjustment of oral ziprasidone is generally not necessary in geriatric patients, the manufacturer states that use of lower initial dosages, slower titration, and careful monitoring during the initial dosing period may be considered in some geriatric patients.1
IM ziprasidone has not been systematically evaluated in geriatric patients (≥65 years of age).1
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death.1 The prescribing information for ziprasidone contains a boxed warning regarding this risk.1 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs compared with that observed in patients receiving placebo.1 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1 Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.1
Other Warnings and Precautions
Cerebrovascular Adverse Reactions, Including Stroke, in Geriatric Patients with Dementia-related Psychosis
In placebo-controlled trials in geriatric patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke.1
Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.1
Prolongation of QT Interval and Risk of Sudden Death
Prolongation of the QT interval can result in an occurrence of ventricular arrhythmias (e.g., torsades de pointes) and/or sudden death.1 In one study, oral ziprasidone prolonged the QTc interval (QT interval corrected for rate) from baseline on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine.1 In a study evaluating the QT/QTc prolongation effect of IM ziprasidone, the mean increase in QTc interval from baseline following 2 IM injections of ziprasidone (20 mg, then 30 mg, which is 50% higher than the recommended therapeutic dose) or haloperidol (7.5 mg, then 10 mg), given 4 hours apart, was 12.8 or 14.7 msec, respectively.1 Ziprasidone's larger prolongation of the QTc interval compared with several other antipsychotic agents raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs used in the treatment of schizophrenia.1 Although torsades de pointes was not associated with ziprasidone therapy when the drug was administered at recommended dosages in premarketing clinical studies, and experience with the drug is too limited to rule out an increased risk, rare postmarketing cases of torsades de pointes (in the presence of multiple confounding factors) have been reported.1
Sudden unexplained deaths have been reported in patients receiving ziprasidone or other antipsychotic agents at recommended dosages.1 Although premarketing experience with ziprasidone did not demonstrate an excess risk of mortality compared with that of other antipsychotic agents, the extent of exposure was limited.1 The greater risk of QT-interval prolongation compared with several other antipsychotic agents raises the possibility that the risk of sudden death may be greater with ziprasidone.1 This possibility should be considered when deciding among alternative antipsychotic agents.1
Patients at particular risk of torsades de pointes and/or sudden death include those with bradycardia, hypokalemia, or hypomagnesemia; those receiving concomitant therapy with other drugs that prolong the QTc interval; and those with congenital prolongation of the QT interval.1 The manufacturer states that ziprasidone should be avoided in patients with a history of clinically important cardiovascular disease (e.g., QT-interval prolongation [including congenital long QT syndrome], recent acute myocardial infarction, uncompensated heart failure, history of cardiac arrhythmias) and in those receiving concomitant therapy with other drugs that prolong the QTc interval.1
Baseline serum potassium and magnesium concentrations should be determined in patients at risk for substantial electrolyte disturbances, particularly hypokalemia, and hypokalemia or hypomagnesemia should be corrected prior to initiating ziprasidone therapy.1 In addition, serum electrolytes (potassium and magnesium) should be monitored periodically in patients who initiate diuretic therapy while receiving ziprasidone.1 Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during therapy in patients with symptoms that could indicate torsades de pointes (e.g., dizziness, palpitations, syncope).1 Ziprasidone therapy should be discontinued in patients who have persistent QTc interval measurements exceeding 500 msec.1
Ziprasidone can precipitate serotonin syndrome.1 The risk of serotonin syndrome is increased with concomitant use of other serotonergic drugs, including selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John's Wort, and with drugs that impair metabolism of serotonin, such as MAOIs.1
Signs and symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and GI symptoms (e.g., nausea, vomiting, diarrhea).1
The concomitant use of ziprasidone with MAOIs is contraindicated.1 Do not initiate ziprasidone in a patient being treated with MAOIs including linezolid or IV methylene blue.1 If it is necessary to initiate an MAOI in a patient taking ziprasidone, discontinue ziprasidone before initiating the MAOI.1
Monitor all patients for the emergence of serotonin syndrome during ziprasidone therapy.1 Discontinue ziprasidone and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment.1 If concomitant use of ziprasidone with other serotonergic drugs is clinically warranted, inform patients of the increased risk of serotonin syndrome and monitor for symptoms.1
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving antipsychotic agents.1
Clinical manifestations of NMS may include hyperpyrexia, muscle rigidity, altered mental status, autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia), elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1
The management of NMS consists of immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious conditions for which specific treatments are available.1
If a patient requires antipsychotic therapy after recovery from NMS, carefully consider the potential reintroduction of the drug.1 Carefully monitor the patient since recurrence of NMS may occur.1
Severe Cutaneous Adverse Reactions
Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients receiving ziprasidone.1 DRESS, which is fatal in some cases, consists of a combination of 3 or more of the following manifestations: cutaneous reaction (e.g., rash, exfoliative dermatitis), eosinophilia, fever, lymphadenopathy, and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis.1
Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported in patients treated with ziprasidone.1 Severe cutaneous adverse reactions are sometimes fatal.1
Ziprasidone therapy should be immediately discontinued if DRESS or other severe cutaneous adverse reactions are suspected.1
Because use of antipsychotic agents, including ziprasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients with a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1
If signs and symptoms of tardive dyskinesia appear in a ziprasidone-treated patient, ziprasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite presence of the syndrome.1
Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1
Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents.1 Confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities.1
Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available.1
Patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.1 Any patient treated with atypical antipsychotics should be monitored for manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment, and patients who develop these manifestations should undergo fasting blood glucose testing.1 In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1
Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotics.1
Weight gain has been observed with atypical antipsychotic therapy.1 The manufacturer recommends clinical monitoring of weight in patients receiving ziprasidone.1
Rash and/or urticaria, possibly related to dosage and/or duration of therapy, occurred in about 5% of patients in premarketing clinical studies and necessitated discontinuance of the drug in about 17% of these cases.1 Although the occurrence of rash was related to the dosage of ziprasidone, the finding may also be explained by the longer exposure time in patients receiving higher dosages of the drug.1 Several ziprasidone-treated patients with rash had signs and symptoms of associated systemic illness (e.g., elevated leukocyte count).1 Adjunctive treatment with antihistamines or corticosteroids and/or drug discontinuance may be required.1 Ziprasidone should be discontinued if an alternative etiology of rash cannot be identified.1
Orthostatic hypotension and associated adverse effects (e.g., dizziness, tachycardia, syncope) may occur during ziprasidone therapy in some patients, particularly during the initial dosage titration period, because of the drug's α1-adrenergic blocking activity.1 Syncope was reported in 0.6% of ziprasidone-treated patients in clinical studies.1
Ziprasidone should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1
Antipsychotic agents, including ziprasidone, may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries.1
Complete fall risk assessments when initiating ziprasidone and during long-term antipsychotic therapy in patients with concomitant diseases, conditions, or medications that could exacerbate the risk of falls.1
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents.1 Agranulocytosis (including fatalities) also has been reported with other antipsychotic agents.1
Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their CBC monitored frequently during the first few months of therapy.1 Ziprasidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.1
Patients with neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), ziprasidone should be discontinued and the leukocyte count monitored until recovery occurs.1
Seizures occurred in 0.4% of patients receiving ziprasidone in clinical trials.1 In many cases, confounding factors may have contributed to the occurrence of seizures.1
Ziprasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.1
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.1 Ziprasidone should be used with caution in patients at risk for aspiration pneumonia.1
Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, ziprasidone can cause elevated serum prolactin concentrations.1 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs; however, the clinical significance of elevated serum prolactin levels is unknown for most patients.1 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.1
If ziprasidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.1 Published epidemiologic studies have shown inconsistent findings when investigating the potential association between hyperprolactinemia and breast cancer.1
Cognitive and Motor Impairment
Like other antipsychotic agents, ziprasidone potentially may impair judgment, thinking, or motor skills.1 Somnolence was reported in 14% of ziprasidone-treated patients compared with 7% of placebo recipients in short-term clinical trials in adults.1
Caution patients about performing activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are reasonably certain that ziprasidone does not affect them adversely.1
Priapism has been reported with ziprasidone.1 Although a causal relationship to ziprasidone has not been established, other drugs with α-adrenergic blocking activity have been reported to cause priapism, and ziprasidone may share this pharmacologic effect.1 Severe priapism may require surgical intervention.1
Although not reported in premarketing clinical studies with ziprasidone, disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1
The manufacturer recommends appropriate caution when ziprasidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1
Suicide is an attendant risk with psychotic illness or bipolar disorder; high-risk patients should be closely supervised.1 Ziprasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1
Experience with ziprasidone in patients with certain concomitant diseases is limited.1
Ziprasidone has not been adequately evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable cardiovascular disease and patients with these conditions were excluded from premarketing clinical studies.1 Because of the risk of QTc-interval prolongation and orthostatic hypotension associated with ziprasidone, the manufacturer states that the drug should be used with caution in patients with cardiovascular disease.1
A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ziprasidone, during pregnancy.1 Clinicians are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at [Web].1
Currently available data from published epidemiologic studies of pregnant women exposed to ziprasidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse outcomes in the mother or fetus.1 However, there are risks to the mother (e.g., risk of relapse, hospitalization, suicide) associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ziprasidone, during pregnancy.1 Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.1
In animals, administration of ziprasidone to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity at dosages similar to human therapeutic dosages.1 Ziprasidone was teratogenic in rabbits at 3 times the maximum recommended human dose.1 In rats exposed to ziprasidone during gestation and lactation, increased perinatal pup mortality and delayed neurobehavioral and functional development of offspring were observed at doses less than or similar to human therapeutic dosages.1
Neonates exposed to antipsychotic agents, including ziprasidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1 Symptoms reported have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required prolonged hospitalization.1 Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.1
Limited data indicate that ziprasidone distributes into human milk.1 There are no reports of adverse effects on breast-fed infants exposed to ziprasidone through breast milk; however, excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) have been reported in infants exposed to other atypical antipsychotics through breast milk.1 There are no data on the effects of ziprasidone on milk production.1
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ziprasidone and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.1
Monitor infants exposed to ziprasidone for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).1
Females and Males of Reproductive Potential
Based on the D2 antagonistic activity of ziprasidone, treatment with the drug may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.1
Safety and efficacy of ziprasidone have not been established in pediatric patients.1
In clinical studies evaluating oral ziprasidone hydrochloride, 2.4% of patients were 65 years of age and older.1 Although no overall differences in safety or efficacy of oral ziprasidone were observed between geriatric and younger adults and other reported clinical experience has not identified differences in responses between geriatric and younger patients receiving the drug, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1 Because multiple factors may increase the pharmacodynamic response to ziprasidone or cause poorer tolerance or orthostasis, lower initial dosages, slower titration, and careful monitoring during the initial dosing period should be considered in some geriatric patients.1
Ziprasidone mesylate IM injection has not been systematically evaluated in geriatric patients.1
In a multiple-dose study and a population pharmacokinetic evaluation of oral ziprasidone, no clinically important differences in pharmacokinetics were observed between geriatric and younger adults.1
Geriatric patients with dementia-related psychosis treated with ziprasidone are at an increased risk of cerebrovascular adverse reactions (including stroke) and death compared with those treated with placebo.1 The manufacturer states that ziprasidone is not approved for the treatment of patients with dementia-related psychosis.1
In individuals with clinically important cirrhosis given oral ziprasidone hydrochloride (20 mg twice daily for 5 days), ziprasidone AUCs were increased by 13 and 34% in those with Child-Pugh class A and B cirrhosis, respectively, compared with matched controls.1 The elimination half-life of oral ziprasidone was also increased in individuals with cirrhosis compared with matched controls (7.1 versus 4.8 hours, respectively).1 Dosage adjustment of oral ziprasidone in patients with hepatic impairment is not required.1
Ziprasidone mesylate IM injection has not been systematically evaluated in patients with hepatic impairment.1
Pharmacokinetics of oral ziprasidone hydrochloride (20 mg twice daily for 8 days) were similar between individuals with varying degrees of renal impairment and those with normal renal function, suggesting that dosage adjustment based on the degree of renal impairment is generally not necessary.1 Ziprasidone is not removed by hemodialysis.1
Ziprasidone mesylate IM injection has not been systematically evaluated in patients with renal impairment.1 However, commercially available ziprasidone for injection, when reconstituted, contains methanesulfonic acid solubilized to sulfobutylether β-cyclodextrin sodium, an excipient that is cleared by renal filtration.1 Therefore, IM ziprasidone should be used with caution in patients with renal impairment.1
Adverse effects occurring in 5% or more of patients with schizophrenia receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence and respiratory tract infection.1
Adverse effects occurring in 5% or more of patients with bipolar mania receiving oral ziprasidone and at a frequency at least twice that reported with placebo include somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, and vomiting.1
Adverse effects occurring in 5% or more of patients with schizophrenia receiving IM ziprasidone 10 or 20 mg and at a frequency at least twice that reported among those receiving IM ziprasidone 2 mg include somnolence, headache, and nausea.1
Less than one-third of ziprasidone's metabolic clearance is mediated by cytochrome P-450 (CYP)-catalyzed oxidation, mainly by CYP3A4 and possibly by CYP1A2 to a much lesser extent.1 Ziprasidone did not substantially inhibit CYP 1A2, 2C9, 2C19, 2D6, or 3A4 isoenzymes in vitro.1
Approximately two-thirds of ziprasidone is metabolized via a combination of chemical reduction by glutathione and enzymatic reduction by aldehyde oxidase.1 There are no known clinically important inhibitors or inducers of aldehyde oxidase.1
All interaction studies described below have been conducted with oral ziprasidone.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 inducers (e.g., carbamazepine) and CYP3A4 inhibitors (e.g., ketoconazole) may alter the metabolism of ziprasidone.1
Concomitant administration of carbamazepine (200 mg twice daily for 21 days), an inducer of CYP3A4, with ziprasidone resulted in an approximate 35% decrease in ziprasidone's AUC; this effect may be greater with higher dosages of carbamazepine.1
Concomitant administration of ketoconazole (400 mg daily for 5 days), a strong CYP3A4 inhibitor, with ziprasidone increased the AUC and peak plasma concentrations of ziprasidone by about 35-40%.1 Concomitant administration of cimetidine (800 mg daily for 2 days), a CYP3A4 inhibitor, did not have a clinically important effect on the pharmacokinetics of ziprasidone.1
Inhibitors or inducers of CYP 1A2, 2C9, 2C19, or 2D6 isoenzymes: Pharmacokinetic interactions are unlikely.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4: Pharmacokinetic interactions are unlikely.1
Drugs that Prolong QT Interval
Due to the potential for additive effects on QT-interval prolongation, concomitant use of ziprasidone is contraindicated with drugs that are known or consistently observed to prolong the QT interval (e.g., dofetilide, quinidine, sotalol, other class Ia and III antiarrhythmics, thioridazine, chlorpromazine, droperidol, pimozide, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, dolasetron mesylate, probucol, tacrolimus).1 Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as a pharmacodynamic effect and for which this effect is described in the full prescribing information as a contraindication or a boxed warning.1
Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been conducted.1
There is an increased risk of serotonin syndrome with concomitant use of ziprasidone and other serotonergic drugs, including selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, opioids (e.g., fentanyl, tramadol, meperidine, methadone), lithium, tryptophan, buspirone, amphetamines, and St. John's Wort, and with drugs that impair metabolism of serotonin, such as monoamine oxidase inhibitors (MAOIs).1
Pharmacokinetic interactions due to protein-binding displacement are unlikely.1
Concomitant administration of an antacid containing aluminum hydroxide and magnesium hydroxide (Maalox® 30 mL) did not have a clinically important effect on the pharmacokinetics of ziprasidone.1
Possible disruption of body temperature regulation may occur with concomitant use; ziprasidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.1
Additive hypotensive effects may occur with concomitant use with certain antihypertensive drugs.1 Because of its α1-adrenergic blocking activity and potential to cause orthostatic hypotension, ziprasidone should be used with particular caution in patients receiving other drugs that can cause hypotension.1
Due to potential for additive CNS effects, caution is advised when ziprasidone and other CNS agents are used concomitantly; use of alcohol during ziprasidone therapy should be avoided.1
A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and benztropine.1
Consistent with in vitro results, ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 substrate, or its major metabolite dextrorphan in healthy individuals.1
The manufacturer states that patients initiated on diuretic therapy while receiving ziprasidone require periodic monitoring of serum electrolytes (e.g., potassium and magnesium concentrations).1
Levodopa and Dopamine Agonists
Ziprasidone may antagonize the effects of levodopa and dopamine agonists.1
Concomitant administration of lithium (450 mg twice daily for 7 days) with ziprasidone (40 mg twice daily) did not affect the steady-state serum concentrations or renal clearance of lithium.1 Ziprasidone given adjunctively to lithium in a maintenance clinical trial in patients with bipolar disorder did not affect mean therapeutic lithium concentrations.1
A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and lorazepam.1
In vivo, ziprasidone did not affect the pharmacokinetics of estrogen or progesterone components.1 Ziprasidone (20 mg twice daily) did not affect the pharmacokinetics of concurrently administered ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).1
A population pharmacokinetic analysis in schizophrenic patients has not revealed evidence of a clinically important pharmacokinetic interaction between ziprasidone and propranolol.1
Propranolol did not alter the plasma protein binding of ziprasidone in vitro, and vice versa.1
A pharmacokinetic interaction between ziprasidone and valproate appears unlikely because of the lack of common metabolic pathways for the 2 drugs.1 Ziprasidone given adjunctively to valproate in a maintenance clinical trial in patients with bipolar disorder did not affect mean therapeutic valproate concentrations.1
Warfarin did not alter the plasma protein binding of ziprasidone in vitro, and vice versa.1
In vitro studies indicate that ziprasidone is not a substrate for CYP1A2, which is induced by smoking.1 In a population pharmacokinetic analysis, no substantial pharmacokinetic differences were reported between smokers and nonsmokers receiving the drug.1
Ziprasidone is a benzisothiazolyl piperazine-derivative antipsychotic agent that is chemically unrelated to phenothiazine and butyrophenone antipsychotic agents and is an atypical antipsychotic agent.1 Ziprasidone is available in the form of ziprasidone hydrochloride salt for oral administration and in the form of ziprasidone mesylate salt for IM administration.1 The mechanism of antipsychotic action of ziprasidone may involve antagonism of both type 2 serotonergic (5-HT2) receptors and dopamine D2 receptors.1
Ziprasidone exhibits relatively high binding affinity for dopamine D2 and D3 receptors; serotonin 5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D receptors; and α1-adrenergic receptors.1 Ziprasidone functions as an antagonist at D2, 5-HT2A, and 5-HT1D receptors and as an agonist at the 5-HT1A receptor.1 The drug exhibits moderate affinity for the histamine H1 receptor.1 Ziprasidone inhibits the synaptic reuptake of serotonin and norepinephrine.1 The drug did not exhibit appreciable affinity for other receptor or binding sites tested, including muscarinic receptors.1
Ziprasidone's activity is primarily due to the parent drug.1 Ziprasidone is well absorbed following oral administration, reaching peak plasma concentrations in 6—8 hours.1 Under fed conditions, the absolute bioavailability of a 20 mg dose is approximately 60%.1 Food increases oral absorption up to 2-fold.1 Steady-state concentrations of ziprasidone are achieved within 1—3 days of dosing.1 The bioavailability of IM ziprasidone is 100%.1 After IM administration of single doses, peak serum concentrations typically occur at about 1 hour post-dose or earlier.1 Exposure increases in a dose-related manner and following 3 days of IM dosing; minimal drug accumulation is observed.1
Ziprasidone is >99% bound to plasma proteins, primarily to albumin and α1-acid glycoprotein.1 Ziprasidone is extensively metabolized in the liver following oral administration, principally via reduction by aldehyde oxidase with minimal excretion of unchanged drug in urine (<1%) or feces (<4%).1 Less than one-third of ziprasidone's metabolic clearance is mediated by cytochrome P-450 (CYP)-catalyzed oxidation, mainly by CYP3A4 and possibly by CYP1A2 to a much lesser extent, and approximately two-thirds via reduction by aldehyde oxidase.1 Although the metabolism and elimination of IM ziprasidone have not been systematically evaluated, the IM route of administration is not expected to alter the drug's metabolic pathways.1
Following administration, approximately 20 and 66% of a dose is excreted in the urine and feces, respectively.1 Unchanged ziprasidone represents approximately 44% of total drug-related material in serum.1 The mean terminal half-life of ziprasidone following oral administration is about 7 hours; following IM administration, the half-life is 2-5 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 20 mg* | Ziprasidone Hydrochloride Capsules | |
Viatris | ||||
40 mg* | Ziprasidone Hydrochloride Capsules | |||
Geodon® | Viatris | |||
60 mg* | Ziprasidone Hydrochloride Capsules | |||
Geodon® | Viatris | |||
80 mg* | Ziprasidone Hydrochloride Capsules | |||
Geodon® | Viatris |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IM use only | 20 mg (of ziprasidone)* | Ziprasidone Mesylate for Injection | |
Geodon® | Viatris |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Viatris Inc. Geodon® (ziprasidone hydrochloride) capsules and Geodon® (ziprasidone mesylate) injection for intramuscular use prescribing information. New York, NY; 2025 Jan.
2. Daniel DG, Zimbroff DL, Potkin SG et al. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology. 1999; 20:491-505.
3. Keck P, Buffenstein A, Ferguson J et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 1998; 140:173-84.
6. Goff DC, Posever T, Herz L et al. An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol . 1998 Aug; 18:296-304.
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74. Potkin SG, Keck PE Jr, Segal S et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005; 25:301-10.
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96. Simpson GM, Glick ID, Weiden PJ et al. Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry . 2004; 161:1837-47. [PubMed 15465981]
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115. Arato M, O'Connor R, Meltzer HY and the ZEUS Study Group. A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80, and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study. Int Clin Psychopharmacol. 2002; 17:207-15. [PubMed 12177583]
117. Daniel DG, Potkin SG, Reeves KR, Swift RH, Harrigan EP. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155(2):128-134.
118. Lesem MD, Zajecka JM, Swift RH, Reeves KR, Harrigan EP. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients. J Clin Psychiatry. 2001;62(1):12-18.
119. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, third edition. 2020. Accessed 2024 Dec 11. [Web]
120. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of First-Episode Psychosis and Schizophrenia, 2023. [Web]
121. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder, 2023. [Web]
122. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette's syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry. 2000;39(3):292-299.
123. Murphy TK, Lewin AB, Storch EA, Stock S; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with tic disorders. J Am Acad Child Adolesc Psychiatry. 2013 Dec;52(12):1341-59.