Continuing Education Activity

Ziprasidone is an atypical antipsychotic drug 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.

Objectives:

• Identify the various indications for initiating therapy with ziprasidone.
• Summarize the therapeutic mechanism of action of ziprasidone.
• Explain the 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.

Indications

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

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. 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, indicating effectiveness short term. Those with long-term risks require a reevaluation on a patient-by-patient basis.

Ziprasidone intramuscular injection formulation is used for the following FDA-approved indications.[2][3]

• Severe or acute agitation/aggression associated with psychiatric disorders like schizophrenia and bipolar disorder
• Agitation or aggression due to substance intoxication or other natural causes

Ziprasidone oral capsule formulation is used for the following FDA-approved indications.[1][4]

• It is indicated to treat schizophrenia in adults.
• Bipolar I disorder: As monotherapy, ziprasidone hydrochloride capsules are indicated for adult patients with bipolar I disorder. As an adjunct to lithium or valproate, ziprasidone hydrochloride capsules are used as maintenance therapy for adult patients with bipolar I disorder.
• Ziprasidone is also used as off-labeled for monotherapy in acute hypomania, monotherapy as maintenance treatment for adult patients with bipolar I disorder, hyperactivity treatment, and for the treatment of delirium in the ICU.

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 are unknown. The antagonization of both histaminergic and adrenergic (a1) receptors can induce somnolence and orthostatic hypotension.[5][6]

Administration

Ziprasidone administration can occur through multiple routes. It is available as oral capsules in 20 mg, 40 mg, 60, and 80 mg strength. Ziprasidone can also be administered as an intramuscular injection. It is also supplied as a single vial containing 20 mg ziprasidone per mL when reconstituted according to label instructions.

• 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 dose 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. DAfter that, dose adjustments should take place every two days as needed.
• Ziprasidone can be administered intramuscularly for acute agitation in schizophrenia. Ziprasidone is available as mesylate salt for intramuscular injection. The recommendation is to administer the drug at 10 mg to 20 mg dosing with a maximum 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.[7]
• Co-administration of IM and oral ziprasidone is not recommended. Oral capsules should be taken with high-calorie meals to absorb the medicine better.[8]
• Ziprasidone may have a greater capacity to prolong the QT/QTc interval compared to other antipsychotic drugs. This type of QT prolongation in some other drugs may lead to torsade de pointes-type arrhythmia, fatal ventricular tachycardia, and sudden death. Due to this prior knowledge, the healthcare team should consider other alternatives before starting Ziprasidone therapy. Due to its rapid actions, IM formulation is appropriate for patients with only severe or acute agitation.

Pharmacokinetics[9][10][11]

• Ziprasidone has a half-life of seven hours to ten hours.
• This drug will reach a steady-state concentration within one to three days of dosing. 
• The average systemic clearance is 7.5 ml/min/kg.
• A minimal amount of ziprasidone is excreted in the urine. Its elimination is primarily through the liver.

Specific Population

Pregnant Women: Pregnant women using ziprasidone to be evaluated induvial case by case basis. ACOG recommends the treatment should be continued with the same psychotropic medicine if the benefit outweighs the risk. Antipsychotic medicine use in the third trimester can result in extrapyramidal symptoms and withdrawal symptoms (hypotonia, hypertonia,  agitation, somnolence, respiratory distress) in neonates and infants. If treatment is initiated when a woman is pregnant, alternative agents with a better safety profile than ziprasidone are preferred. Clinicians should enroll pregnant women using ziprasidone in the Atypical Antipsychotics Pregnancy Registry.[12]

Breastfeeding Women: According to safety scoring system recommendations, ziprasidone should be used cautiously during breastfeeding. Infants exposed to ziprasidone via breastmilk should be monitored for irritability, excess sedation, poor feeding, and extrapyramidal symptoms (tremors or abnormal muscle movements).[13]

Hepatic Impairment: The product label has no data for patients using ziprasidone with hepatic impairment. Since ziprasidone is significantly metabolized via liver, use caution when given to patients with hepatic impairment.

Renal Impairment: The manufacturer recommends using intramuscular ziprasidone with caution in patients with renal dysfunction as cyclodextrin is eliminated via renal filtration.[14]

Geriatric Population: Ziprasidone is listed as potentially inappropriate medication by Beers Criteria, and use should be discouraged in patients 65 and above due to a higher rate of cognitive decline, an increased risk of stroke, and death in patients with dementia.

Adverse Effects

Patients treated with antipsychotic drugs may develop tardive dyskinesia. This condition is characterized by repetitive, involuntary movements such as facial grimacing 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 prolonged treatment increase the risk of tardive dyskinesia becoming 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][15][16]

Patients undergoing therapy with ziprasidone are also at risk for the 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.[17][18]

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.[19][20]

Rare but fatal Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with Ziprasidone exposure.

Antipsychotic drugs, including ziprasidone, may cause motor and sensory instability and postural hypotension, leading to falls, fractures, or other injuries. 

Hyperprolactinemia, priapism, and dyslipidemia are reported in a few patients taking ziprasidone. Chronic hyperprolactinemia with hypogonadism may lead to decreased bone density. 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.

Common adverse effects found in more than 10 % of patients enrolled in the clinical trial were drowsiness, headache, dizziness, nausea, and lightheadedness. More than 5% of patients experienced orthostatic hypotension, akathisia, anxiety, skin rash, weight gain, constipation, dyspepsia, xerostomia, vomiting, diarrhea, visual disturbances, and pain at the injection site.[21]

When co-administered, carbamazepine (CYP3A4 inducer) can reduce ziprasidone levels, resulting in subtherapeutic levels of ziprasidone and ketoconazole (CYP3A4 inhibitor) increase ziprasidone levels.

Contraindications

Besides hypersensitivity reactions to ziprasidone or any formulation excipients, there are several contraindications listed below.[22][23]

• Patients with a known history of QT prolongation (including congenital long QT syndrome) 
• Patients with uncompensated heart failure
• Patients with recent acute myocardial infarction 
• Patients taking medicines that have demonstrated QT prolongation including Class Ia and III antiarrhythmics, dofetilide, sotalol, quinidine, thioridazine, mesoridazine, chlorpromazine,  pimozide, droperidol, sparfloxacin, moxifloxacin, gatifloxacin, halofantrine, pentamidine, mefloquine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, or tacrolimus.

Warning/Precautions [23]

• Patients taking other drugs that act on the central nervous system (CNS) should also not be administered the drug due to additive adverse reaction potential.
• Many antihypertensive agents increase their effects when used with ziprasidone, leading to hypotension.
• ziprasidone dopamine D2 receptor antagonism may counter the therapeutic effect of levodopa and dopamine agonists.

Monitoring

Patient therapeutic response, worsening of depressive symptoms, and risk of suicidal ideation should be monitored initially and at follow-up visits.

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 been fully recovered.

As ziprasidone may cause QT-prolongation, baseline ECG is recommended, especially in patients with preexisting cardiac conditions, and monitored periodically. Continuous ECG monitoring should start in case an arrhythmia occurs.[24]

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. Monitor blood pressure at baseline and periodically thereafter.

Monitor patient weight, lipid profile, blood glucose levels at baseline and three months after starting the medicine. Additionally, electrolyte levels (potassium, magnesium) could be monitored annually and as clinically indicated.

Toxicity

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.

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.

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.[25][23]

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

In 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.

Enhancing Healthcare Team Outcomes

Ziprasidone is a widely used antipsychotic drug. A psychiatrist usually starts the drug, but the follow-up of patients is generally 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 movement disorder. Many of these patients also gain weight rapidly, and thus patients 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.[26]

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 determine dosing and titration schedules as applicable. Nursing staff should counsel patients on proper medication use and answer any questions the patient may have regarding their therapy. To reduce the risk of overdose and suicide in patients with psychotic illness, clinicians should write prescriptions for ziprasidone for the smallest quantity of capsules, along with a management plan to monitor and address possible adverse effects. Therapeutic drug monitoring can be used if adherence is suspected. Pharmacists can verify dosing, check for drug-drug interactions, and 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]