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Ziprasidone: A New Atypical Antipsychotic
Diane B. Crutchfiled, Pharm. D., C.G.P.
Geriatric Times September/October 2001 Vol. II Issue 5
In February, the U.S. Food and Drug Administration approved a fifth atypical antipsychotic for the treatment of schizophrenia. Ziprasidone (Geodon) is made by Pfizer Inc. and joins clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel) and risperidone (Risperdal) as an alternative to conventional antipsychotics.
The undesirable side effects of conventional agents make them second-line agents for geriatric patients as side effects in the elderly are often exaggerated. Atypical agents are not free from side effects, but are generally considered preferable for treating psychotic conditions in the elderly.
Conventional antipsychotics, such as chlorpromazine (Thorazine), thioridazine (Mellaril), thiothixene (Navane) and haloperidol (Haldol), include agents that exert their action primarily by blocking dopamine in the mesolimbic pathway, resulting in their action to block the positive symptoms of psychosis. However, this dopamine-blocking action in the nigrostriatal pathway results in the most serious side effect of conventional agents--extrapyramidal symptoms. Long-term use of conventional agents may also cause irreversible tardive dyskinesia (Stahl, 2000).
The effectiveness of the conventional antipsychotics to treat positive symptoms--hallucinations, delusions, agitation, disorganized speech and behavior--is comparable between agents. Until the introduction of atypical agents, which work on different types of receptors, the negative symptoms of psychosis were not treated and may have worsened with the use of older medications. Negative symptoms include blunted affect, withdrawal, apathy, anhedonia and others. Atypical antipsychotics act as dopamine 2 (D2) antagonists as well as serotonin 2A (5HT2A) antagonists, resulting in improvements in both the positive and negative symptoms of the disease.
Ziprasidone is unique to the atypical armamentarium because it is the only one that is a serotonin 1D (5HT1D) antagonist, a serotonin 1A (5HT1A) agonist, and a reducer of the synaptic reuptake of both serotonin and norepinephrine. In brief, it is an antagonist at D2, 5HT2A and 5HT1D and an agonist at 5HT1A receptors. It is a less potent dopamine blocker than serotonin blocker. A six-week, placebo-controlled trial (Daniel et al., 1999) showed that ziprasidone was effective in treating depressive symptoms associated with schizophrenia, likely related to its effects on serotonin and norepinephrine. The authors pointed out, however, that confounding factors interfered with drawing a conclusion at this point about the antidepressant properties of the drug.
Ziprasidone has negligible affinity for muscarinic receptors and modest affinity for
1-adrenergic receptors (Daniel et al., 1999). Somnolence caused by ziprasidone may be a result of histamine H1 receptor antagonism. Blocking of the
A serious concern with the use of ziprasidone, which caused the FDA to delay its approval, is the drug's prolongation of the QTC interval of the electrocardiogram. The package insert contains warnings about the possibility of the dose-related prolongation, avoiding use with other drugs that are known to prolong the QT interval, and avoiding use in patients with congenital long QT syndrome or those with a history of cardiac arrhythmias.
Drugs that prolong the QT interval include, but are not limited to, quinidine (Cardioquin), amiodarone (Cordarone), clarithromycin (Biaxin), erythromycin (E.E.S., Erythrocin), tricyclic antidepressants, thioridazine and certain fluoroquinolones (Pharmacist's Letter, 2001). An extensive list of these drugs can be found at <www.torsades.org>.
Some drugs that prolong the QT/QTC interval have been associated with torsades de pointes and sudden death. This was not observed with the use of ziprasidone at recommended doses in premarketing studies, but the limited experience with the drug does not rule out this possibility. The risk of torsades de pointes is greater with increases in the prolongation of 20 msec or greater or in susceptible patients at longer intervals who have electrolyte imbalances of potassium or magnesium (Pfizer Inc., 2001b). A clinical support study comparing the prolonging effect of ziprasidone with other drugs (risperidone, olanzapine, quetiapine and haloperidol) showed that ziprasidone increased the QTC interval 9 msec to 14 msec greater than the other drugs did. Ziprasidone's effect was 14 msec less than the prolongation by thioridazine, however, and the effect of ziprasidone on the interval was not increased by the presence of a metabolic inhibitor, ketoconazole (Nizoral).
The efficacy of ziprasidone was studied in five clinical trials. The trials consisted of four short-term, randomized, double-blind, fixed-dose, placebo-controlled studies and a one-year, randomized, double-blind, placebo-controlled study at doses of 40 mg/day, 80 mg/day and 160 mg/day. All trials were conducted on inpatients. Four of the five trials showed ziprasidone efficacy over placebo; one short-term trial did not. The extended one-year trial showed ziprasidone to be superior to placebo in preventing relapse and rate of relapse. No significant difference between doses was noted (Pfizer Inc., 2001b).
Ziprasidone should not be used with other drugs that prolong the QT interval and should be used cautiously with drugs causing hypotension due to the potential for additive effects. As with other antipsychotics, it may reduce the effectiveness of levodopa and dopamine agonists. As an inhibitor of cytochrome P450 3A4, ketoconazole can lead to increased serum levels of ziprasidone.
Cimetidine (Tagamet), antacids, benztropine (Cogentin), propranolol (Inderal), lorazepam (Ativan), lithium or warfarin (Coumadin) did not produce clinically significant drug interactions with ziprasidone.
There is not a special precaution for the use of the drug in the elderly, but it should be noted that only 2.4% (109) of the patients in the clinical studies were 65 years of age or over. It is not necessary to dose-adjust based on renal or hepatic function. It is prudent, however, to monitor for orthostasis, start at a lower dose and titrate more slowly in the elderly. Because many geriatric patients receive diuretic therapy, monitoring electrolytes at baseline and throughout treatment would avoid the increased risk of the interval prolongation resulting from hypokalemia. Potassium and magnesium levels, in particular, should be checked at baseline and corrected before starting treatment.
The recommended starting dose of ziprasidone is 20 mg twice daily with food, this can be increased up to 80 mg twice daily with titration occurring at no less than two days. Steady-state is achieved within three days. Ziprasidone is available in 20 mg, 40 mg, 60 mg and 80 mg capsules. An increase to greater than 80 mg twice daily is generally not recommended. No additional benefits have been noted at a maintenance dose above 20 mg twice daily.
The intramuscular dosage form has been recommended for approval by the FDA Advisory Committee for control of agitated behavior in patients with schizophrenia and schizoaffective disorder (Pfizer Inc., 2001a).
The most common adverse reactions noted in the clinical trials, compared to placebo, included somnolence (14% versus 7%), respiratory disorders (8% versus 3%) and extrapyramidal syndrome (5% versus 1%). The most common reason for dropping out of the studies was rash (1% compared to zero for placebo). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight changes in placebo patients.Ziprasidone is generally not considered the first drug of choice in geriatric patients for the treatment of schizophrenia due to cardiovascular concerns and multiple medication use in older patients. It does, however, provide another option for patients who have not responded to previous atypical therapy.
Dr. Crutchfield is president of Pharmacy Consulting Care, an independent consultant pharmacy practice located in Knoxville, Tenn.
References
Daniel DG, Zimbroff DL, Potkin SG et al. (1999), Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsycho-pharmacology 20(5):491-505.
Pfizer Inc. (2001a), FDA advisory committee recommends approval of Pfizer's injectable schizophrenia medicine ziprasidone. PRNewswire. Feb 15.
Pfizer Inc. (2001b), Geodon package literature. Available at: www.pfizer.com/hml/pi's/geodonpi.pdf. Accessed Aug. 14.
Pharmacist's Letter, (2001), New drug: ziprasidone (Geodon). Detail document No. 70302. March.
Stahl SM (2000), Essential Psychopharmacology, 2nd ed. New York: Cambridge University Press.
