Ziprasidone (Geodon): Out of the Box and Approved

Introduction
Ziprasidone is now available after an extended review by the Food and Drug Administration. Delay from the originally planned date of release stemmed from concern that ziprasidone might cause cardiac arrythmias, due to electrocardiographic QT prolongations. Pfizer, the manufacturer, submitted additional data, and the drug is licensed for sale in the USA with a package insert alerting physicians to the possibility that this medicine could cause an abnormal cardiac rhythm. This newsletter has already presented the clinical use of ziprasidone in 1998 (1). The following new article, in this current issue, provides an updated review.

Pharmacology
Ziprasidone has a receptor profile that differs somewhat from those of other antipsychotic drugs. Of the available pharmaceuticals with antipsychotic action, it has the highest equilibrium dissociation constant for the serotonin 5-HT2A receptor, while at the same time, it has relatively low dopamine D2 receptor blocking activity (2-4). Using rat brain research, Pfizer reported that ziprasidone has a higher 5-HT2A to D2 receptor binding affinity ratio as compared to that of clozapine (4). Ziprasidone has appreciable D2 activity that is considered integral to its antipsychotic effect, but with high 5-HT2A antagonism it is unlikely to produce extrapyramidal reactions such as dystonias and/or parkinsonian features.

In addition to 5-HT2A, there are at least 12 other serotonin receptor subtypes, most of which are not well understood. Among the antipsychotic drugs, ziprasidone reportedly offers the highest blockade of the 5-HT1D and 5-HT2C receptors and has the highest agonist activity at the 5-HT1A site (3). The manufacturer has proposed that ziprasidone's binding at the first two receptors might give it an antidepressant potential (4). Affinity for 5-HT1A may augment antipsychotic influence. Activity at 5-HT6 receptors has been proposed to play an important role in giving clozapine its spectrum of antipsychotic action (2); yet, affinity for this receptor by ziprasidone has not yet been established. Muscarinic effects appear to be negligible.

Of the new generation antipsychotic drugs, ziprasidone has a low antagonistic effect for the alpha-1 adrenergic receptor. Although it can cause postural hypotension, reflex tachycardia, and dizziness or syncope, such effects are not prominent clinically (2). It has only modest alpha-2 activity, whose effect on brain is less clear, although side effects could include interference with the antihypertensive properties of alpha-adrenergic blocking agents such as clonidine and methyldopa.

Ziprasidone's histamine H1 blockade is modest; affinity for the H1 receptor is reported to be 52 times less than for olanzapine. In the brain H1 blockade is believed to play a role in weight gain and sedation. Among the new generation of antipsychotic pharmaceuticals, ziprasidone may be the least likely to increase weight (2).

Administering ziprasidone with food roughly doubles bioavailability, bringing it to about 60% (5). The liver extensively metabolizes this medicine, so less than 1% is excreted unchanged. However, in patients with moderate hepatic impairment, dose adjustment is said to usually not be required (1). Since the half-life of ziprasidone is about seven hours, twice-a-day administration is needed. Ziprasidone is metabolized to inactive products by the aldehyde oxidase system and by cytochrome P450 3A4. Simultaneous administration of other substances that are metabolized by these same systems are interestingly not reported to induce significant drug interactions (1). A better understanding of the metabolism and interaction profile of this drug awaits more clinical experience.

Clinical Trials
A one-month dose-finding study with ziprasidone was based on positive symptomatology (6). The investigators accessed the question of what quantities of ziprasidone, up to 160 mg/day, would be most effective and how ziprasidone's efficacy at this dose compared to haloperidol at 15 mg/day. Ninety subjects were randomized and evaluated at a daily regimen of ziprasidone 160 mg or haloperidol 15mg. Analysis showed them to be equivalent.

A large 1999 dose-finding investigation compared daily regimens of ziprasidone at 80 or 160 mg with placebo; positive, negative, and depressive symptoms were evaluated (7). Subjects in three arms of about 100 persons each were evaluated for six weeks. The research documented that both doses of ziprasidone were superior to placebo in reducing positive and negative symptomatology. A statistically significant reduction in affective features was also reported.

Ziprasidone is available for oral administration. Intramuscular (IM) preparations are being researched. Three studies have examined the effectiveness of the parenteral version. A recent report assessed acutely administered doses of 2 and 10 mg IM (8); subjects receiving 10 mg were calmed but not sedated, while patients taking 2 mg were not significantly affected. Similar research indicated that 10 mg of IM ziprasidone is at the lower end of the therapeutic dose range, while 20 mg is more effective (9). Another trial compared blinded IM doses of 5-20 mg ziprasidone to 2.5-10 mg of haloperidol and suggested that injected ziprasidone was more effective in diminishing psychosis and agitation than was parenteral haloperidol (10).

Ziprasidone was also evaluated as a potential treatment for children and adolescents with Tourette's Syndrome (11). Ziprasidone was found to have an "anti-tic" potential, as indicated by a mean decrease of 35 % in a tic rating score, but was slightly less effective than haloperidol (12).

Side Effects
QT Interval Prolongation: The QT interval of the electrocardiogram is reflective of activity in the heart from the start of ventricular depolarization through repolarization (13). The depolarization/repolarization process has to occur more rapidly as the heart rate increases, and the corrected QT interval (QTc) accounts for this difference. QTc prolongations may be associated with ventricular tachycardia, Torsades de Pointes, and sudden death. Concerns about ziprasidone causing dangerous QT prolongations resulted in a delay in its marketing release. To avoid cardiac arrhythmias, physicians should carefully monitor patients taking ziprasidone, especially those with heart disease or who are also prescribed other pharmaceuticals that may be associated with QT interval prolongations.

A variety of other factors influence the QT interval. Hypokalemia, hypocalcemia, hypomagnesemia, decreased heart rate, food consumption, and obesity can lead to QT prolongation. Athletes and women tend to have a longer QT interval than most men (14). There is great variability in the QTc duration of healthy individuals, with a mean interval of 66 to 95 msec (13). The upper limit of normal is not well established, but is commonly considered to be 440 msec. The risk of Torsades de Pointes is greatly increased when the QTc interval is over 500 msec. Underlying conditions including myocarditis, bradycardia, and certain pharmaceuticals may also cause Torsades de Pointes. Altered sensitivity to catecholamines and autoimmune instability can predispose to QT lengthening (15).

Pharmaceuticals exert their effect on the QT by influencing potassium channels. Thioridazine and to a much lesser degree ziprasidone have been shown to cause the greatest mean QTc prolongation, as compared to haloperidol, olanzapine, and risperidone. Reportedly, 29% and 21% of subjects taking thioridazine and ziprasidone respectively, had a QT prolongation of 60 msec or more; only 11% of patients taking quetipine and 4% of those on risperidone, olanzapine, or haloperidol experienced such changes. QT prolongation of 60 to 75 msec may not be clinically relevant to a healthy person whose baseline QTc is within the mean of 66-95 msec; however, for people with baseline value of 425-440 msec, it would be possible for this interval to increase above the 500 msec danger zone for arrhythmias (13). The actual incidence of a prolonged QTc may not be very high, but clinical experience will provide greater clarity. Ziprasidone use seems, at this time, to be an unlikely cause for significant abnormalities of the QT interval or heart rhythm in most people.

Ziprasidone has a dose-response relationship to the QTc; there is a correlation between dose and the QT prolongation. It may be more dangerous to prescribe ziprasidone to patients with heart disease, especially those prone to arrythmias due to a long QT interval (13). Obtaining an electrocardiogram (EKG) before and during treatment may not always identify the patient-at-risk (13). The absence of a long QTc in a single EKG tracing does not rule out the propensity to develop Torsades de Pointes. T-wave morphology should be assessed, as well as checking electrolyte blood levels. Syncope can be a harbinger of Torsades de Pointes and must be monitored carefully as an important sign of grave risk; drug discontinuation may be required.
Postural Hypotension: Because of some antagonism of alpha 1 receptors, ziprasidone has some risk for causing postural hypotension and tachycardia. However, clinically significant changes in sitting and standing blood pressure and heart rate are rare (16).

Weight Gain: Current evidence suggests that ziprasidone has a low propensity to induce weight gain, which may reflect serotonergic properties along with relatively low histamine antagonism (17). The median increase from baseline in body weight was 0.5 kg. The percentage of individuals treated with ziprasidone who had more than a 7% increase in weight was nevertheless higher than for placebo (9.8% vs. 4%).

Glucose Dysregulation: An increased incidence of diabetes mellitus has long been noted in patients with schizophrenia (18). There is also evidence that antipsychotic drugs may contribute to glucose intolerance, possibly because of increased weight and obesity, suppression of insulin release, insulin resistance, or by impairment of glucose utilization (19).

For ziprasidone, only premarketing trials are known to be available. There is little evidence that ziprasidone is associated with significant alterations in glycemic control or insulin levels; however, there have been infrequent reports of hyperglycemia and glycosuria with decreased glucose tolerance (20). One study evidenced no change in blood sugar concentrations (15).

Effects on Lipid Profile: Ziprasidone demonstrated a median decrease from baseline in triglyceride and total cholesterol levels (21,22). There has been no known report of an effect on high density lipoproteins.

Movement Disorders: There is a correlation between extraprymidal signs (EPS) and dopamine receptor affinity. Ziprasidone has a high 5-HT2A/DA D2 receptor affinity ratio. It also has activity at a number of serotonin, dopamine, and noradrenaline receptor subtypes, which should minimize neurological dysfunction.

Although ziprasidone rarely causes EPS, there is a higher prevalence among elderly people and women (22). Some movement disorders, such as tardive dyskinesia, may be potentially irreversible. The risk for developing EPS increases with higher dosage and duration of treatment. Thus, in patients who require prolonged pharmacotherapy, use the lowest effective quantity (22).
Neuroleptic Malignant Syndrome (NMS): Due to its dopamine receptor antagonism, ziprasidone can cause NMS (16). The features of this potentially fatal syndrome are hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, etc.). Whenever a ziprasidone-treated patient presents with signs of NMS, immediate discontinuation of the drug along with intensive monitoring and symptomatic management is warranted.

Since recurrence of NMS has been reported to be associated with ziprasidone, reintroduction of the drug should only be deliberately and carefully considered, after a ziprasidone-free period (16). Low dosage titration, careful assessment, and good hydration are recommended.

Other Side Effects: About 14% of subjects receiving ziprasidone reported somnolence, versus 7% on placebo (16). Ziprasidone has some potential to impair judgment, thinking, and motor skills; therefore, patients should be cautioned about performing activities requiring mental alertness. In premarketing trials, cutaneous eruptions developed in a dose-related manner in 5% of those studied. Seizures, hyperprolactinemia, and dysphagia have been reported as well.

Dosage
Ziprasidone is supplied for oral administration in 20 mg (blue/white), 40 mg (blue/blue), 60 mg (white/white), and 80 mg (blue/white) capsules. Pfizer 396, Pfizer 397, Pfizer 398, and Pfizer 399 are imprinted on each capsule respectively, for identification purposes.

The manufacturer recommends that treatment should be initiated at a daily dose of 20 mg BID with food (16). The dosage may subsequently be adjusted up to 80 mg BID on an individualized clinical basis. Steady state is achieved within 1 to 3 days; thus dosage adjustment might occur at 2-day intervals. In psychotic, but physically healthy in-patients, many physicians elect to start therapy with a 40 mg BID oral regimen; however, some doctors initiate ziprasidone at 80 mg BID.

Acknowledgement
We are thankful to medical students, Lisa Johnson, Lisa Lyon, and Geoff Mills, for their productive editorial assistance.

ZIPRASIDONE (GEODON): OUT OF THE BOX AND APPROVED

Yasser Morgan,M.D.
Leonard Drey,M.D.
Anupinder Kaur,M.D.
Fayez Roman,M.D.
Mohammad Safi,M.D.
Abu Siddiqui,M.D.
Firoz Munshi,M.D.
Steven Lippmann,M.D.
University of Louisville School of Medicine
Department of Psychiatry and Behavioral Sciences

Correspondence Author:
Steven Lippmann, M.D.
University of Louisville Hospital,5-East
530, South Jackson Street
Louisville,KY40202
Phone: (502) 852-5859
Fax: (502) 562-4044

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(3) Richelson E, Souder T: Binding of antipsychotic drugs to human brain receptors:
Focus on Newer Generation Compounds. Life Science 2000; 68: 29-39.
(4) Seebger T, et al.: Ziprasidone (CP-88, O59): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. Journal of Pharmacology and Experimental Therapeutics 1995; 275: 101-131.
(5) Tandon R: The pharmacokinetics of ziprasidone: introduction. British Journal of Clinical Pharmacology 2000; 49 (l.1): 1S-3S.
(6) Goff D, et al.: An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospital patients with schizophrenia or schizoaffective disorder. Journal of Clinical psychopharmacology 1998; 18: 296-304.
(7) Daniel D, 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. Neuropsychopharmacology 1999; 20:491-505.
(8) Lesem M, et al.: Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients. Journal of Clinical Psychiatry 2001; 62:12-18.
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(15) Data on file (19)- Pfizer Inc.
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(20) Ziprasidone package insert.
(21) Data on file (20)-Pfizer Inc.
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