Continuing Education Activity

Ziprasidone is an atypical antipsychotic used to treat schizophrenia, bipolar mania, and acute agitation in schizophrenic patients. Because it antagonizes H1 receptors, it can cause somnolence. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, monitoring, and toxicity ziprasidone, so providers can direct patient therapy successfully in instances where ziprasidone provides a benefit to patient care.


  • Identify the various indications for initiating therapy with ziprasidone.
  • Summarize the therapeutic mechanism of action of ziprasidone.
  • Explain the contraindications and adverse event profile of ziprasidone.
  • Review the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with ziprasidone.


Ziprasidone is an atypical antipsychotic used to treat schizophrenia, bipolar mania, and acute agitation in schizophrenic patients.[1][2][3]

For schizophrenia, studies have shown that ziprasidone was significantly superior to placebo in rate and time of relapse. The research established the efficacy of ziprasidone in bipolar disorder, and it also indicated improvement on the manic syndrome subscale that measures symptoms of mania such as mood, insomnia, excessive energy and activity, and overall behavior and ideation. Patients with acute agitation in schizophrenia were measured as well, indicating effectiveness short term. Those with long-term risks require a reevaluation on a patient-by-patient basis.

Mechanism of Action

Ziprasidone is an atypical antipsychotic that has a binding affinity for dopaminergic (DA), serotonergic (5HT), adrenergic (a1), and histaminergic (HA) receptors. Regarding treatment for schizophrenia, antagonism of the dopamine (D2) receptor in the mesolimbic pathway has proven efficacious in diminishing positive symptoms, whereas the antagonism of the 5HT2A receptor in the mesocortical pathway has demonstrated reduction of negative symptoms of psychosis. Its efficacy and mechanism of action for treating bipolar disorder is unknown. The antagonization of both histaminergic and adrenergic (a1) receptors can induce somnolence and orthostatic hypotension.[4][5]


Ziprasidone administration can occur through multiple routes. It comes in capsule form and can be supplied orally in 20 mg, 40 mg, 60, and 80 mg capsules. Ziprasidone can also be administered as an intramuscular injection.

For the treatment of schizophrenia, if given orally, it should be initially given at 20 mg twice per day with meals. That maximum dosage is 160 mg daily, given 80 mg twice per day if indicated. Medication adjustments should occur at no less than two-day intervals as it takes several days to reach steady-state concentration.

For the treatment of bipolar mania, ziprasidone should be given initially at a dose of 40 to 80 mg twice per day with meals. On the second day of treatment, the dose should be adjusted from 60 mg to 80 mg twice a day. Dose adjustments should take place every two days as needed.

Ziprasidone can be administered intramuscularly for acute agitation in schizophrenia. The recommendation is to administer the drug at 10 mg to 20 mg dosing with a maximum dose of 40 mg per day. Dosing is performed as 10 mg every two hours or 20 mg every four hours for a maximum of 40 mg per day.

The injection should only be administered muscularly and should not intravenously. First, add 1.2 mL of sterile water into the vial and shake until the drug fully dissolves. To give a 20 mg dose, draw 1.0 ml of reconstituted solution. For 10 mg of ziprasidone, pull 0.5 ml of reconstituted solution. Whatever remains in the vial should be discarded, as there are no bacteriostatic or preservative agents in the solution.[6]

Adverse Effects

Patients treated with antipsychotic drugs may develop tardive dyskinesia. This condition is characterized by repetitive, involuntary movements such as grimacing of the face with protrusion or twisting of the tongue. This condition occurs more commonly in senior women; however, the clinician should not rely on prevalence rates to detect which patients are most likely to develop this adverse effect. High dosage and more prolonged treatment increase the risk and likelihood that tardive dyskinesia becomes irreversible. If you suspect tardive dyskinesia in a patient, discontinue the drug as there is no treatment currently available to treat this movement disorder.[3][7][8]

Patients undergoing therapy with ziprasidone are also at risk for neuroleptic malignant syndrome. In this syndrome, patients present with muscle rigidity, high fever, autonomic instability (high blood pressure, diaphoresis), and altered mental status. If you suspect patients with neuroleptic malignant syndrome, supportive care is the most important in management. Treatment with bromocriptine, dantrolene, and amantadine, with discontinuation of ziprasidone, may help.

Lastly, hyperglycemia associated with coma, ketoacidosis, or death can occur in rare cases. Patients who have diabetes mellitus should take ziprasidone with caution. These patients should have monitoring daily.


Patients on drugs that prolong QT interval should not receive ziprasidone therapy. Patients taking other drugs that act on the central nervous system (CNS) should also not be administered the drug due to the effects of ziprasidone on the primary CNS. Many antihypertensive agents may have their effects increased by ziprasidone as well, leading to hypotension. Ziprasidone's dopamine D2 receptor antagonism may counter the therapeutic effect of levodopa and dopamine agonists.[9][10]


Ziprasidone's elimination is primarily through the liver. Its half-life is seven hours to ten hours. This drug will reach steady state-concentration within one to three days of dosing. Clearing systemically occurs at 7.5 ml/min/kg.[11][12][13]

A minimal amount of ziprasidone is excreted in the urine. 

It carries a possible risk of causing leukopenia, neutropenia, and agranulocytosis; therefore, patients with a history of low white blood cells (WBC) or drug-induced neutropenia/leukopenia should have their complete blood count monitored in the first two months of therapy. If patients have a neutrophil count of less than 1000/mm^3, the clinician must discontinue the drug until the WBC count has fully recovered.

In the event of an overdose, ensure the patient maintains ventilation, and intubation may be possible. Intravenous (IV) access must be done with gastric lavage after intubation if the patient is unconscious. Charcoal is also an option, along with a laxative for drug clearance.

As ziprasidone may cause QT-prolongation, continuous ECG monitoring should start in case an arrhythmia occurs.


Patients can develop a rash based on exposure time to the drug. It was found that the higher the exposure time, the greater the risk of developing a rash. Patients that experience rash also had signs of systemic illness, which is treatable with antihistamines, steroids, or discontinuation of the drug.

Orthostatic hypertension can also occur in patients. Patients may experience tachycardia, syncope, dizziness during the first dose titration period due to a1-antagonism. Clinicians should exercise caution in giving ziprasidone to patients with cardiovascular disease and cerebrovascular disease.

Research has determined that a small number of patients may experience seizures with ziprasidone. Therefore, caution is necessary when dosing ziprasidone in patients with a history of seizures or conditions that can lower the seizure threshold.

The risk of aspiration pneumonia in the elderly must undergo an assessment before giving this drug, as well as esophageal dysmotility. Antipsychotics, in general, have been associated with both of these conditions, particularly in patients with Alzheimer's disease.

Hyperprolactinemia, leading to galactorrhea, gynecomastia, impotence, and amenorrhea, is also possible, secondary to the D2 receptor antagonism in ziprasidone, leading to an elevation in prolactin levels.

As ziprasidone also has a binding affinity to histamine H1 receptors, the possibility of somnolence can occur. Priapism, body temperature regulation, and suicide can also occur if the appropriate patient and case management are not in place.[14][10]

Enhancing Healthcare Team Outcomes

Ziprasidone is a widely used antipsychotic drug. A psychiatrist usually starts the drug, but the follow-up of patients is usually done by a primary care provider, nurse practitioner, pharmacist, or physician assistant. Ziprasidone is an effective drug for schizophrenia, but it also has several side effects that require monitoring. Healthcare workers should obtain regular ECGs and blood work and assess the patient for any movement disorder. Many of these patients also gain weight rapidly, and thus they should be urged to exercise and eat a healthy diet. If tardive dyskinesia is suspected, the patient should receive a referral to the psychiatrist for other treatment options.[15]

As with any medication, ziprasidone therapy should be under the guidance and care of an interprofessional team. Clinicians (MDs, DOs, NPs, PAs) will be the prescribers and will determine dosing and titration schedules if applicable. Nursing staff should counsel patients on proper medication use and answer any questions the patient may have regarding their therapy. Pharmacists can verify dosing, check for drug-drug interactions, and also counsel the patient. If adverse events manifest, this needs to be communicated to all team members. This interprofessional approach will yield the best therapeutic results with the fewest adverse events. [Level 5]

Article Details

Article Author

Daniel Bouchette

Article Author

Kamron Fariba

Article Editor:

Raman Marwaha


2/17/2021 6:28:56 AM

PubMed Link:




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