The mechanism of action of ziprasidone in the treatment of the listed indications could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Ziprasidone binds with relatively high affinity to the dopamine D2 and D3, serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and α1-adrenergic receptors (Ki s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and with moderate affinity to the histamine H1 receptor (Ki=47 nM). Ziprasidone is an antagonist at the D2, 5HT2A, and 5HT1D receptors, and an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 >1 µM).

Ziprasidone is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of Ziprasidone to prolong the QT interval and may consider the use of other drugs first. Ziprasidone capsules are indicated for the:

• treatment of schizophrenia in adults.
• acute treatment of adults as monotherapy of manic or mixed episodes associated with bipolar I disorder.
• maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate in adults.

Administer capsules orally with food. Do not open, crush, or chew. 

Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted up to 80 mg twice daily. Dose adjustments should occur at intervals of not less than 2 days. Safety and efficacy has been demonstrated in doses up to 100 mg twice daily. The lowest effective dose should be used.

Acute treatment of manic/mixed episodes of bipolar I disorders: Initiate at 40 mg twice daily. Increase to 60 mg or 80 mg twice daily on day 2 of treatment. Subsequent dose adjustments should be based on tolerability and efficacy within the range of 40–80 mg twice daily.

Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate: Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40–80 mg twice daily.

Acute treatment of agitation associated with schizophrenia (intramuscular administration): 10 mg 20 mg up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every 2 hours. Doses of 20 mg may be administered every 4 hours.

• Do not use in patients with a known history of QT prolongation
• Do not use in patients with recent acute myocardial infarction
• Do not use in patients with uncompensated heart failure
• Do not use in combination with other drugs that have demonstrated QT prolongation
• Do not use in patients with known hypersensitivity to ziprasidone

Commonly observed adverse reactions (incidence ≥5% and at least twice the incidence for placebo) were:

• Schizophrenia: Somnolence, respiratory tract infection.
• Manic and Mixed Episodes Associated with Bipolar Disorder: Somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting.
• Intramuscular administration (≥5% and at least twice the lowest intramuscular ziprasidone group): Headache, nausea, somnolence.

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack).

QT Interval Prolongation: ziprasidone use should be avoided in patients with bradycardia, hypokalemia or hypomagnesemia, congenital prolongation of the QT interval, or in combination with other drugs that have demonstrated QT prolongation.

Neuroleptic Malignant Syndrome (NMS): Potentially fatal symptom complex has been reported with antipsychotic drugs. Manage with immediate discontinuation of drug and close monitoring.

Severe Cutaneous Adverse Reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome has been reported with ziprasidone exposure. DRESS and other Severe Cutaneous Adverse Reactions (SCAR) are sometimes fatal. Discontinue ziprasidone if DRESS or SCAR are suspected.

Tardive Dyskinesia: May develop acutely or chronically.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain.

Hyperglycemia and Diabetes Mellitus (DM): Monitor all patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients with DM risk factors should undergo blood glucose testing before and during treatment.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been reported. Monitor weight gain.

Rash: Discontinue in patients who develop a rash without an identified cause.

Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease.

Leukopenia, Neutropenia, and Agranulocytosis has been reported with antipsychotics. Patients with a pre existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue ziprasidone at the first sign of a decline in WBC in the absence of other causative factors.

Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold.

Potential for Cognitive and Motor impairment: Patients should use caution when operating machinery.

Suicide: Closely supervise high-risk patients.