Ziprasidone chemical structure
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Ziprasidone (Geodon®) was the fifth atypical antipsychotic to gain FDA approval. Ziprasidone is FDA approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients. Clinical trials were conducted in acute cases of mania. Long-term trials have not been conducted for acute bipolar symptoms. Any "hypersensitivity to the product" -- including any of the adverse events noted during clinical trials-- should be grounds for discontinuance. It has been approved for acute episodes indicative of bipolar type I. It has not been studied in adolescents or children (under age 10). more...

Zoledronic acid

Such a trial has been ordered by the FDA as one condition during the approval process. The brand name (Geodon®) has been suggested to bring to mind the phrase 'down (don) to earth (geo)' referring to the goals of medication.


Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone is somewhat unique among the "atypicals" in that it also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it is theorized that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A antagonism is debated among researchers. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.


The systemic bioavailability of ziprasidone administered intramuscularly is 100%, or 60%, administered orally with food. After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. The mean half-life (T 1/2) ranges from two to five hours. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.


Ziprasidone is hepatically metabolized by aldehyde reductase. Minor metabolism occurs via cytochrome P450 3A4. Medication that induce (e.g carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone. There are no known induces or inhibitors of aldehyde reductase.

Adverse Events

Ziprasidone may increase the QTc interval in some patients and may increase the risk of a type of heart arrythmia known as torsades de pointes. Ziprasidone should be used cautiously in patients taking other medications likely to interact with ziprasidone or increase the QTc interval.

Adverse events reported for ziprasidone include sedation, insomnia, orthostasis, akathisia and other permanent extrapyramidal side-effects such as tardive dyskinesia. Rarely, temporary speech disorders may result.

The medication can cause any conceivable side effect. See the FDA label for more information.

Recently, the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics at causing insulin resistance and weight gain. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI>27) actually had a mean weight loss overall. Ziprasidone, though, is not a weight loss drug. The weight loss reflected in this study on ziprsidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.


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E-FALCONS: a mnemonic for monitoring the prescribing of atypical antipsychotics
From Geriatrics, 8/1/04 by Tirath Gill

A typical antipsychotic medications are increasingly being prescribed for the treatment of multiple conditions associated with psychosis in older patients. These conditions include schizophrenia, bipolar disorder, depression with psychotic features, substance-induced psychosis, psychosis due to medical conditions, delusional disorders, and dementia. (1-6)

Atypical antipsychotic medications have a relatively safe adverse effect profile, including low incidence of extrapyramidal side effects, Parkinsonian-like syndromes, and akathisia. (1,6) Recent studies, however, have indicated that patients who receive atypical antipsychotic drugs are at increased risk for developing a host of metabolic disorders, including type 2 diabetes, abnormal lipid profiles, and hyperprolactinemia. (3,4) Other side effects include weight gain, hemodynamic changes, sleep apnea, arthritis, cardiac conduction delays, bone marrow suppression, cardiomyopathy, and seizures. (7,8) Atypical antipsychotics are not free from the risk of the permanent side effect, tardive dyskinesia. In addition, sedation and associated orthostatic hypotension, particularly in older adults, may increase the risk of falls and subsequent central nervous system (eg, subdural hematoma) and musculoskeletal (eg, vertebral or femoral fractures) injuries, which, by themselves, are associated with increased morbidity and mortality. (1,5,7,8)

In response to concerns related to adverse effects of these drugs and the U.S. Food and Drug Administration's recent warning regarding the risks of developing complications while on atypical antipsychotics, we developed an acronym--E-FALCONS--as a clinical tool. This mnemonic can assist clinicians in appropriate monitoring of atypical antipsychotic use.

E-FALCONS recognizes that the following diagnostic evaluations should be monitored as indicated.

E is for ECG (electrocardiogram). At baseline and every 6 months for clozapine and if cardiac risk factors are present for ziprasidone (1,5)

F is for fasting glucose. At baseline and every 3 months if weight gain >7% body weight (1,9,10)

F is for falls risk assessment. Measure blood pressure at baseline, 1 hour after first dose, then every 3 months or at clinician discretion to monitor for orthostatic hypotension. (1,7)

A is for AIMS (abnormal involuntary movement scale) and extrapyramidal symptoms. Monitor at baseline and at every follow-up. (1,3)

L is for lipids (cholesterol/triglycerides). Monitor at baseline and every 3 to 4 months if weight gain >7%, otherwise every year. (1,4,10)

L is for LFT (liver function tests). At baseline and yearly (1,3,4)

C is for CBC (complete blood count) and differential. At baseline and every week for 6 months and then every 2 weeks with clozapine and yearly with other atypicals to rule out possible undiagnosed infections, especially pulmonary and urinary tract infections (1-4,10)

C is for CVAE (cardiovascular adverse events). Especially in older patients with dementia and CVAEs such as stroke, transient ischemic attacks were reported in patients with prior risks of CV diseases and in older patients with dementia-related psychosis. (5,7,8) New focal neurologic signs and symptoms should be evaluated at each visit.

O is for obesity. Measure body mass index at baseline and every 3 months). (1,2,4,9,10) (To calculate, take the patient's weight in pounds and multiply by 705. Divide that number by the patient's height in inches. Divide again by the height in inches. The result is the patient's BMI.)

N is for noncompliance. Monitor regularly, especially when new medications may prolong the action or alter levels of antipsychotic medications. Ask about side effects. Check prolactin levels with risperidone. (3,4)

N is for NMS (neuroleptic malignant syndrome). Older adults may be more vulnerable to develop this adverse effect; (1,10,11) if signs and symptoms appear, discontinue use of antipsychotic immediately. (11) (See article on page 35.)

S is for seizures. Solicit history of seizures, monitor every 3 months for any pre-ictal, ictal or post-ictal phenomenon. (12)


E-FALCONS can aid in reaching the best possible benefit with the least deleterious side effects. Regular monitoring for various metabolic abnormalities and side effects associated with use of antipsychotic medications allows clinicians to alter doses to limit these side effects. (1,3,8)

In some cases, cholesterol-lowering treatment may help to decrease hyperlipidemia. (4,13)

Controlling weight gain is significant because it appears that weight gain raises the risk for other metabolic disorders, including insulin resistance and emergence of type 2 diabetes, and hyperlipidemia. (1,2,4,8,13) Close monitoring for patients with weight gain of 7% or more and switching to another atypical agent may be a viable strategy to avoid potential complications. (4,10)

Various strategies may be employed for weight-related issues, such as lowering the dose, initiating dietary therapy, increasing physical activity, or adjusting adjunctive medications. (1,4,7-11) These, however, can be difficult interventions and a switch to another atypical may be suitable. (9-11) Atypicals least associated with weight gain appear to be seroquel, ziprasidone, quetiapine, and risperdal. (8,10)

Seizure risk appears real in patients at higher doses of clozapine; monitor frequently. (12) In addition, the dose may need to be kept to the lowest possible range, and possibly augmented with typical or other atypical antipsychotics.

Hyperprolactinemia has myriad adverse consequences and should be monitored especially in patients taking risperidone. (3,7)

Older patients with psychosis may have preexisting increased rates of morbidity and mortality due to CV diseases compared with younger adults. (4,5,7) Case reports and series, randomized clinical trials, and observational analytic epidemiological studies have raised concerns that atypical antipsychotic medications may add to the already increased risks of CV diseases, likely due to the development of the adverse effects of weight gain and associated metabolic abnormalities, (2,4,8,9) including hyperglycemia, type 2 diabetes, and hyperlipidemia. (4,9,10,13) This constellation of risk factors, referred to as metabolic syndrome, leads to more complications than those associated with obesity alone. (4,10)

When treatment is initiated with atypical antipsychotics in the geriatric population, clinicians should be keenly aware of preexisting metabolic and CV risk factors, and subsequent treatment-induced risk factors.

In conjuction with general recommendations of identifying high-risk patients and promoting a healthy lifestyle without maladaptive behavioral patterns, clinicians need to exercise prudence in selecting antipsychotic medications with comparable efficacy but fewer adverse effects.

It is our hope that the E-FALCONS acronym will assist clinicians in monitoring possible adverse effects in older patients who are sustaining improved functioning due to the beneficial effects of atypical antipsychotic medications.


The authors thank Dr. Doug Sears for his assistance in summarizing the article, Drs. Robert Hierholzer and Matthew Battista for their mentoring input, Dr. Avak Howsepian for his insightful comments, and Emma E. A. Nichols, administrative support clerk, for technical assistance.


(1.) Meltzer HY, Fatami SH. Treatment of schizophrenia, In: Schatzberg AF, Nemeroff CB, eds. Essentials of Clinical Psychopharmacology. Washington, DC: American Psychiatric Pub; 2001:399-429.

(2.) Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother 2003; 37(12):1849-57.

(3.) Maguire GA. Prolactin elevation with antipsychotic medications: Mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63 (Suppl 4):56-62.

(4.) American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27(2):596-601.

(5.) Berkowitz A. Ziprasidone for dementia in elderly patients: Case review. J Psych Prac 2003; 9:469-73.

(6.) Lemmens P, Brecher M, Van Baelen B. A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: Factors associated with extrapyramidal symptoms. Acta Psychiatr Scand 1999; 99(3):160-70.

(7.) Martin H, Slyk MP, Deymann S, Cornacchione MJ. Safety profile assessment of risperidone and olanzapine in long-term care patients with dementia. J Am Med Dir Assoc 2003; 4(4):183-8.

(8.) Druss BG, Bradford WD, Rosenheck RA, et al. Quality of medical care and excess mortality in older patients with mental disorders. Arch Gen Psychiatry 2001; 58(6):565-72.

(9.) Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 1999; 60(11):767-70.

(10.) Basson B, Kinon B, Taylor C, Szymanski K, Gilmore J, Tollefson G. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 2001; 62(4):231-8.

(11.) Ananth J, Parameswaran BS, Gunatilake S, Burgoyne K, Sidhom T. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry, 2004; 65(4):464-70.

(12.) Amann BL, Pogarell O, Mergl R, et al. EEG abnormalities associated with antipsychotics: A comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol 2003; 18(8):641-6.

(13.) Meyer JM. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry 2001; 62 (Suppl 27):27-34; discussion 40-41.

Dr. Gill is staff psychiatrist and chief, Inpatient Psychiatry Unit, Veterans Affairs Central California Health Care System, Fresno. He is assistant clinical professor of psychiatry, University of California, San Francisco, Fresno Medical Education Program.

Dr. Khouzam is staff psychiatrist and medical director, Chemical Dependence Treatment Program, VACCHS, Fresno. He is associate clinical professor of psychiatry, UCSF FMEP, Fresno. He is also clinical instructor in medicine, Harvard Medical School, Boston, and visiting lecturer, Department of Psychiatry and Behavioral Sciences, University of Oklahoma, College of Medicine, Oklahoma City.

Dr. Tan is staff psychiatrist, VACCHS, Fresno.

Disclosures: The authors have no real or apparent conflicts of interest related to the subject under discussion.

COPYRIGHT 2004 Advanstar Communications, Inc.
COPYRIGHT 2004 Gale Group

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