Ziprasidone (Zeldox): another atypical antipsychotic listed for acute mania in bipolar disorder

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Approved indications and PBS listings differ between antipsychotics | Evidence of efficacy in acute mania, not for maintenance therapy | Dosing is twice daily with food | Safety issues | References

Ziprasidone (Zeldox) was PBS listed on 1 April 2009 for treating acute mania or mixed episodes in people with bipolar I disorder. The streamlined authority listing allows ziprasidone monotherapy for up to 6 months. Ziprasidone was previously PBS listed for schizophrenia only.

Mood stabilisers (e.g. lithium) remain the mainstay for treatment and maintenance (prophylaxis) of mania in bipolar disorder. Atypical antipsychotics are sometimes recommended, particularly for severe episodes of acute mania, because of their faster onset of effect (1–2 days).1–4

Approved indications and PBS listings differ between antipsychotics

Acute mania: quetiapine (Seroquel) and risperidone (Risperdal) are the other atypical antipsychotics PBS listed for acute mania.5 Of these, only risperidone can currently be prescribed on the PBS as adjunctive therapy (see Table 1).

Mixed episodes: ziprasidone is PBS-listed for use in mixed episodes of bipolar 1 disorder.

Maintenance therapy: olanzapine is currently the only atypical antipsychotic with a PBS listing for maintenance therapy in bipolar disorder.

Table 1.
Indications and PBS listings for atypical antipsychotic drugs in bipolar I disorder



Drug TGA-approved indication(s) PBS listed TGA-approved indication(s) PBS listed

Olanzapine (Zyprexa)

Yes (monotherapy or adjunctive therapy)




Quetiapine (Seroquel)

Yes (monotherapy or adjunctive therapy)

Yes (monotherapy)

Yes (adjunctive therapy only)


Risperidone (Risperdal)


Yes (adjunctive therapy only)



Ziprasidone (Zeldox)

Yes (monotherapy), mixed episodes

Yes (monotherapy)



Evidence of efficacy in acute mania, not for maintenance therapy

The evidence for ziprasidone for reducing symptoms of acute mania comes from 2 short (3 week) blinded randomised controlled trials.6,7 Like many trials in bipolar disorder, generalisability is hampered by small sample size, numerous exclusion criteria (e.g. people with cardiovascular disease) and high dropout rates — in one trial, 50% of all patients did not complete the study.7 The evidence base for 'real life' effectiveness is limited.

Evidence for maintenance therapy or adjunctive use (e.g. with lithium) is lacking, and ziprasidone is not currently TGA approved for either indication.8 One unpublished trial failed to find a benefit when ziprasidone was added to lithium therapy.8

Dosing is twice daily with food

Unlike most other atypical antipsychotics, ziprasidone must be taken twice daily with food. Absorption of ziprasidone may be significantly reduced if taken without food.8 Ensure that people taking ziprasidone are aware of these requirements, especially if switching from another antipsychotic, most of which are dosed once daily without food. Check compliance before increasing dose if symptoms do not improve.

Safety issues

Common adverse effects with ziprasidone include headache, sedation, somnolence, dizziness, extrapyramidal symptoms and nausea.4,8

Safety data on use in mania beyond 3 weeks is limited and can only be extrapolated from longer term studies of ziprasidone in schizophrenia.9,10 More experience is needed to adequately characterise its adverse effect profile relative to other atypical antipsychotics.

Metabolic effects and diabetes

Metabolic effects such as weight gain and lipid changes appear less likely with ziprasidone than with other antipsychotics.4,9 Whether this means that ziprasidone has a lower risk of new-onset diabetes is uncertain. Observational studies have found an increased incidence of new type 2 diabetes with other atypical antipsychotics (olanzapine, quetiapine, risperidone and clozapine) compared with conventional antipsychotics.11–13 While no increased risk with ziprasidone has been observed to date, fewer epidemiological data are available because ziprasidone is a newer drug.11 The exact mechanism by which antipsychotics increase diabetes risk is uncertain and it is not clear if weight gain alone is the causal factor.11

Extrapyramidal symptoms

Extrapyramidal symptoms (EPS) occur with short-term ziprasidone use — 11% of patients with acute mania developed EPS, compared with 2% for placebo in one 3-week trial.6 EPS may be more likely in short-term use for mania than with some other atypical antipsychotics, but better data are needed to be sure.14 In an 18-month schizophrenia trial, there were similar rates of EPS-related discontinuations between atypical antipsychotics (4% with ziprasidone and 2% to 3% with olanzapine, risperidone and quetiapine)* and no difference was found between antipsychotics in EPS symptom ratings.9 All atypical antipsychotics can cause EPS, although to a lesser extent than conventional antipsychotics such as haloperidol.4,15

*Statistical significance was not reported for ziprasidone discontinuations compared with other atypical antipsychotics.

QT prolongation

Before prescribing, consider whether the patient has risk factors for QT prolongation. Ziprasidone prolongs the QTc interval.4,8 The clinical significance of this effect is currently not fully known. While clinical trials have not detected clinically significant QT prolongation8, there have been postmarketing reports of torsades de pointes in patients with multiple risk factors taking ziprasidone.8 Ziprasidone is contraindicated in significant cardiovascular disease, including arrhythmias, and in people with other conditions or taking other drugs that may prolong the QT interval (including some antibiotics, antifungals, antidepressants and anti-arrhythmic agents).8 Ziprasidone may not be appropriate for people at risk of electrolyte imbalances (e.g. hypokalemia, people taking diuretics), which may increase the risk of QT prolongation. For those at risk of electrolyte imbalances, measure potassium and magnesium levels both before starting ziprasidone and during treatment.8

A small but increased risk of sudden cardiac death has been observed for all antipsychotics — consider the individual's cardiovascular risk profile before prescribing an antipsychotic, and an ECG before and shortly after starting antipsychotic treatment.16,17


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