Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Zeldox (Pfizer)
20 mg, 40 mg, 60 mg and 80 mg capsules
Approved indication: schizophrenia and bipolar I disorder
Australian Medicines Handbook section 18.2

Ziprasidone is one of several atypical antipsychotic drugs now available in Australia.1,2 It binds to dopamine and serotonin receptors in the brain. At D2, 5HT2A and 5HT1D receptors it acts as an antagonist while at 5HT1A receptors it acts as an agonist. The mechanism of action of ziprasidone in schizophrenia and bipolar disorder is unknown.

The recommended dose range for both indications is 80-160 mg a day. It should be taken twice daily with food as this increases its bioavailability. It is eliminated by metabolism with most of the metabolites being excreted in the faeces. The half-life of 6–10 hours is prolonged if the patient has impaired liver function.

Short-term trials (4–6 weeks) of ziprasidone in a variety of doses for schizophrenia have had conflicting results, but in most the drug has been better than placebo. A longer study (52 weeks) of 294 inpatients with stable symptoms of schizophrenia found that those given ziprasidone had a lower rate of relapse and a longer time to relapse than those given a placebo. Its efficacy is probably similar to that of haloperidol.3

Ziprasidone has also been approved for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Two short-term (3 weeks) double-blind phase III studies (of around 200 patients each) compared ziprasidone (80–160 mg a day) to placebo in a 2:1 ratio. In both trials, ziprasidone improved mania-related symptoms.4,5

A trial of 437 patients compared ziprasidone to haloperidol (a typical antipsychotic) or placebo. Both drugs improved the symptoms of mania in patients compared to placebo, although haloperidol seemed to be more effective. This was reflected in the observation that less haloperidol-treated patients discontinued because of 'lack of efficacy' than ziprasidone-treated patients (8.8% vs 20.2%).

In another bipolar disorder trial, ziprasidone was compared to placebo as an additional treatment in 204 patients taking lithium. There seemed to be no obvious extra benefit of taking ziprasidone as well as lithium in terms of recovery from a manic episode.

The number of dropouts in trials of patients with bipolar disorder was generally high. One of the main reasons for discontinuation was 'lack of efficacy', which accounted for 12.9-20.2% of ziprasidone-treated patients, 8.8% of haloperidol-treated patients, 6.9% of ziprasidone plus lithium-treated patients and 13.6% of patients taking lithium alone. In patients treated with placebo, the dropout rate due to 'lack of efficacy' varied from 28.8% to 36.4%.

In terms of safety, the most common ziprasidone-related adverse events in patients with bipolar disorder included somnolence and movement disorders such as extra pyramidal syndrome. However, extra pyramidal effects were less common in ziprasidone-treated patients compared to haloperidol-treated patients.

Severe drug-related adverse events were observed in the trial of patients taking ziprasidone and lithium. These included seizure, neuroleptic malignant syndrome and a higher rate of extra pyramidal syndrome (22 of 101 patients) compared to patients taking lithium alone (3 of 103 patients).

For schizophrenia, somnolence was reported in 14% of patients. Ziprasidone caused fewer extra pyramidal adverse effects than haloperidol, but more nausea and vomiting.3 In the longer-term trial 7–10% of patients discontinued ziprasidone because of adverse effects. Ziprasidone may cause less weight gain than other atypical antipsychotic drugs.3

Some of the adverse effects of ziprasidone may be explained by its action at receptors. Antagonism of alpha1 adrenergic receptors can produce postural hypotension while antagonism of histamine H1 receptors may contribute to somnolence. As somnolence is a common adverse event, patients should be cautioned about driving and operating machinery while taking this drug.

There has been concern that ziprasidone prolongs the QTc interval on the ECG. This has been observed in patients with schizophrenia and patients with bipolar disorder, although these changes were clinically significant in only a few patients. For this reason, ziprasidone should be avoided in patients with a history of cardiac illness and should not be used with other drugs that increase the QTc interval. Patients may need to have an ECG at baseline and after they have started treatment.

Atypical antipsychotic drugs may have more effect than older drugs on the negative symptoms of schizophrenia, such as apathy. There is little evidence to suggest that ziprasidone is any better than other new drugs for schizophrenia. It appeared to be as effective as risperidone at improving psychotic symptoms in patients with schizophrenia.6 A Cochrane review concluded that 'well planned, conducted and reported long-term randomised trials are needed if ziprasidone is to be accepted into everyday use'.3

Prescribers should be aware that ziprasidone should only be used as a short-term treatment for acute bipolar manic and mixed episodes and not for long-term maintenance. It is intended as a monotherapy and so should not be used in combination with other drugs prescribed for the treatment of bipolar disorder.

References

  1. Keks NA. Are atypical antipsychotics advantageous? – the case for. Aust Prescr 2004;27:146-9.
  2. Carr V. Are atypical antipsychotics advantageous? – the case against. Aust Prescr 2004;27:149-51.
  3. Bagnall A, Kleijnen J, Leitner M, Lewis R. Ziprasidone for schizophrenia and severe mental illness. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001945. DOI: 10.1002/14651858.CD001945.
  4. Keck PE, Versiani M, Potkin S, West SA, Giller E, Ice K, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 2003;160:741-8.
  5. Potkin SG, Keck PE, Segal S, Ice K, English P. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol 2005;25:301-10.
  6. Addington DEN, Pantelis C, Dineen M, Benattia I, Romano SJ. Efficacy and tolerability of ziprasidone versus risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: an 8-week, double-blind, multi center trial. J Clin Psychiatry 2004;65:1624-33.