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. Ziprasidone mesylate is used IM for acute agitation in schizophrenic patients.
When deciding among the alternative treatments 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. QTc-interval prolongation has been associated in some other drugs with the ability to cause torsades de pointes and sudden death. In many cases, this would lead clinicians to the conclusion that other drugs should be tried first. The manufacturer states that it is not yet known whether ziprasidone will cause torsades de pointes or increase the rate of sudden death. In one large observational study (Ziprasidone Observational Study of Cardiac Outcomes [ZODIAC]), the incidence of nonsuicide mortality was not found to be higher in ziprasidone-treated patients compared with olanzapine-treated patients; however, the study design did not allow for evaluation of possible differences in the incidence of more uncommon outcomes, such as torsades de pointes and sudden death.
Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.
Ziprasidone hydrochloride is used orally in the acute and maintenance management of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.
Efficacy of oral ziprasidone 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]), principally in patients who met DSM-IIIR criteria for schizophrenia in hospital settings. Ziprasidone appears to be superior to placebo in improving both positive and negative manifestations in acute exacerbations of schizophrenia and in reducing the rate of relapse for up to 52 weeks.
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). 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.
If oral ziprasidone is used for extended periods for the management of schizophrenia, the need for continued therapy should be reassessed periodically.
(See Dosage and Administration: Dosage.)
The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, 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. Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration.
Ziprasidone mesylate is used IM for the management of acute agitation in adults with schizophrenia for whom treatment with ziprasidone is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). The efficacy of IM ziprasidone for the management of acute agitation in schizophrenia was established in single-day controlled trials in hospital settings. 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.
For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program,
Ziprasidone hydrochloride is used orally as monotherapy for the acute treatment of manic and mixed episodes (with or without psychotic features) associated with bipolar I disorder in adults. The drug is also used orally as adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults. According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).
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). 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 Clinical Global Impression-Severity of Illness Scale (CGI-S), which was used to assess the clinical significance of treatment response.
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. The mean dosage of ziprasidone hydrochloride in this study was 132 mg daily. 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. The mean dosage of ziprasidone hydrochloride in this study was 112 mg daily. Ziprasidone was superior to placebo in the reduction of the MRS total score and the CGI-S score in both of these studies.
The manufacturer states that the efficacy of ziprasidone as monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled studies.
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). 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. The primary outcome measure was time to recurrence of a mood episode (manic, mixed, or depressed) requiring intervention. 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.
If ziprasidone is used for extended periods as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder, the need for continued therapy should be reassessed periodically.
(See Dosage and Administration: Dosage.)
For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.