Focus on Ziprasidone

Dr Ben Green, MRCPsych, Consultant Psychiatrist and Honorary Senior Lecturer, University of Liverpool, UK

 

Keywords

Schizophrenia - ziprasidone - antipsychotic - neuroleptic - atypical - pharmacology

 

Summary

Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. The initial evidence suggests an effective dosage range of 80-160 mg/day. Clinical trials suggest that the drug is an effective antipsychotic in schizophrenia and schizoaffective disorder with a beneficial effect on negative symptoms and symptoms of depression. The main adverse effects appear to be somnolence (14%) and nausea (10%). Ziprasidone has relatively fewer side effects and yet has at least equivalent efficacy for florid 'positive' symptoms compared to conventional antipsychotics. The additional serotonergic actions deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional antipsychotics make ziprasidone more attractive still. Barring any unforeseen complications appears to a most valuable addition to the antipsychotic agents.

Introduction

Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity, developed by Pfizer ¹. Indeed its most potent action is action at the 5-HT2A site. Ziprasidone has an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than most clinically available antipsychotic agents. Ziprasidone appears to have antipsychotic activity with a low liability for extrapyramidal side effects ². Oral and intramuscular forms are available.

Dosage Regime

Published trials have looked at the short-term efficacy of dosage regimes using 40, 80, 120, and 160 mg/day for schizophrenia and schizoaffective disorder^3,4. Keck et al's trial looked at 139 patient randomised to receive ziprasidone 40 mg/day, 120 mg/day or placebo over 28 days³. It was the 120 mg/day dosage which proved significantly more effective against placebo. Daniel et al's study of over 200 patients demonstrated that both 80mg/day and 160 mg/day were significantly better than placebo at reducing symptoms of schizophrenia with some antidepressant qualities as measured by the Montgomery Asberg Depression Rating Scale (MADRS) at 160 mg/day⁴.

The initial evidence for an effective dosage range would appear to suggest prescriptions of 80-160 mg/day.

Oral and intramuscular forms of the drug exist. Rapid acting intramuscular fixed doses of ziprasidone at 5, 10 and 20 mg have been well-tolerated ⁵. These appear not be associated with extrapyramidal effects, dystonia or excessive sedation, but do control agitation ⁶.

Structure

Ziprasidone, 5-(2-(4-(1,2-Benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indole-2-one, is a benzothiazolylpiperazine with the chemical formula C₂₁H₂₁CN₄OH . HCl)₂H₂O. It is structurally dissimilar to its contemporary antipsychotics.

 

 

Binding Profile

Ziprasidone has pharmacologically important activity at serotonergic, dopaminergic and adrenergic receptors. This pharmacological activity led to early speculation that the agent might have antidepressant or anxiolytic qualities as well as antipsychotic potential, ². Ziprasidone is a potent 5-HT_2A antagonist with an affinity for 5-HT₂ receptors an order of magnitude greater than that observed for D₂ receptors. The emphatic antagonism of 5-HT_2A receptors in the brain may limit the EPS associated with dopamine receptor blockade and also improve efficacy against the negative symptoms of schizophrenia ¹. Ziprasidone also has high affinity for the 5-HT_1A (Ki = 3.4 nM), 5-HT_1D and 5-HT_2C receptor subtypes. Sprouse et al (1999) point out that ziprasidone's high affinity for 5-HT_1A is actually in terms of an agonist relationship, which differs from both clozapine and olanzapine and may produce clinical differences such as better anxiolysis or antidepressant action⁷.

Ziprasidone is a less potent alpha-one antagonist than clozapine, risperidone, olanzapine and quetiapine It has less affinity for the H₁ and M₁ receptors than clozapine, olanzapine and quetiapine ⁸.It may therefore have less potential for sedative side effects than clozapine and olanzapine.

Initial researchers found that prolactin levels did not rise during initial treatment with ziprasidone for a month ⁹. Later researchers have found transient rises though ¹⁰.

Ziprasidone's weak anticholinergic activity suggests a low potential for impairing cognitive abilities, which may indicate an advantage in the elderly who are prone to anticholinergic cognitive effects.

Clinical Indications

In a double-blind study of some two hundred or so patients on ziprasidone against 100 patients on placebo Daniel et al (1999) found that doses of 80 or 160 mg/day were statistically significantly more effective than placebo in improving the positive and negative syndrome scale (PANSS) total, Brief Psychiatric Rating Scale (BPRS) total, BPRS core items, Clinical Global Impression of Severity (CGI-S), and PANSS negative subscale scores (p < .05) ⁴. Ziprasidone 160 mg/day was useful too for depressive symptoms and the authors inferred that ziprasidone was useful for acute exacerbations of schizophrenia or schizoaffective disorder.

The efficacy of ziprasidone against negative symptoms is further evidenced by a study by Meltzer et al ¹¹.This randomised, double blind, parallel group study of nearly 300 individuals was conducted at 26 centres. Measurements were made using the PANSS, Simpson-Angus and Barnes Akathisia scales, the Clinical Global Impression of Improvement (CGI-I) and the Abnormal Involuntary Movements Scale (AIMS). There was a significant ongoing clinical improvement in negative symptoms over one year, observable by 6 months of treatment.

Haloperidol has been the traditional treatment of choice for Tourette's syndrome, but this is an antipsychotic with a high potential for generating extrapyramidal side effects (EPSEs). The early onset of Tourette's syndrome means that younger patients are therefore often exposed to antipsychotics such as haloperidol. An interesting pilot study by Sallee et al (2000) using ziprasidone for Tourette's against a placebo found that ziprasidone was well tolerated and effective. It would be more interesting still to see a study that compared ziprasidone to haloperidol for this disorder ¹².

Efficacy

Tuunainen et al’s Cochrane review of the new antispychotics (2000) erred very much on the side of caution and called for trials of sufficient power, with longer duration, measuring clinically important outcomes, to assess the true comparative clinical effectiveness, tolerability and cost effectiveness of newer drugs in relation to clozapine. Tuunainen et al looked at 22 papers derived from eight studies^12a. The specific Cochrane review for ziprasidone by Bagnall et al (2000) cautiously concluded that ziprasidone may be an effective antipsychotic with less extrapyramidal effects than haloperidol, but it also may cause more nausea and vomiting^12b.

Pharmacokinetics

Ziprasidone tends to show predictable linear pharmacokinetics. The mean Cmax and AUC (0,12 h) increase with increasing dose, with apparent dose-proportionality between 20 and 60 mg dose levels ¹⁰. Steady state was achieved after one day. Trough-to-peak ratios at steady state ranged from 2 to 5.  The dose of the drug does not need to be altered in mild -to-moderate renal impairment ¹³ or mild to moderate hepatic impairment ¹⁴.

Ziprasidone is highly protein-bound (>99%) and thoroughly metabolised with less than 1% being excreted unmodified in faeces or urine. There are no active metabolites.

There is little effect on cytochrome P-450 (CYP) isoforms. Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with simultaneously administered CYP substrates, at clinically effective doses^14a.

 Adverse effects

Ziprasidone is generally well-tolerated ¹⁰.The most frequent side-effects are mild or moderate headache. A minority of patients suffer first-dose postural hypotension because of alpha blockade. Ziprasidone is associated with a mild histaminergic sedative effect that becomes less pronounced as treatment continues. There are no drug-related changes in electrocardiogram or clinical laboratory variables reported. In Daniel's 1999 study the percentage of patients experiencing adverse events was similar for 80 mg/day and 120 mg/day treatment groups, and resultant discontinuation was rare ⁴. The most frequent adverse events associated with ziprasidone in Daniel's study were generally mild dyspepsia, nausea, dizziness, and transient somnolence. Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain. According to Allison et al's meta-analysis study weight gain attributable to ziprasidone therapy is only 0.44 kg on average. Taylor and McAskill’s systematic review of eighty papers and reports concluded that ziprasidone did not appear to be linked to weight gain^9a.

Ziprasidone is associated with transient prolactin elevation, which is not dose-related, and which attenuates with chronic administration ¹⁰.

Table One: Main adverse effects with ziprasidone 80-160 mg/day in initial clinical trials ².

Adverse Event	Percentage of patients on ziprasidone (n=702)	Percentage of patients on placebo (n=273)
Somnolence	14%	7%
Nausea	10%	7%
Constipation	9%	8%
Dyspepsia	8%	7%
Akathisia	8%	7%
Dizziness	8%	6%
Diarrhoea	5%	4%

 

Some adverse effects traditionally associated with conventional antipsychotics, such as postural hypotension, were found to be very rare with ziprasidone.

Interactions

There are no significant interactions with lithium although Apseloff et al (2000) did note a mean increase in serum lithium levels of 0.06 mmol/l in healthy subjects taking a moderate dose of lithium and ziprasidone ¹⁵. Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady-state exposure to ziprasidone that is believed to be clinically insignificant^15a.

In terms of oral contraceptives, Muirhead et al, (2000) found that ziprasidone could be administered with ethinyloestradiol and levonorgestrel without loss of contraceptive efficacy or risk of adverse events¹⁶.

There is no interaction with aluminium and magnesium hydroxide antacids or cimetidine ².

In a study on 24 extensive metaboliser subjects Wilner et al (2000) found that Ziprasidone does not to inhibit the clearance of drugs metabolized by the 2D6 isoenzyme of cytochrome P450 (CYP2D6) ¹⁷. Unlike clozapine and olanzapine ziprasidone is not metabolised by CYP1A2 and cigarette smoking ( a CYP1A2 inducer) is unlikely to affect the metabolism of ziprasidone ².

Comparison with other antipsychotics

Performance with regard to weight gain appears satisfactory compared to other antipsychotics. In a meta-analysis Allison et al (1999) found that whereas placebo was associated with a mean weight reduction of 0.74 kg antipsychotics usually led to weight gain¹⁸.Mean weight changes were as follows: thioridazine an increase of 3.19 kg, clozapine, 4.45 kg; olanzapine, 4.15 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Their meta-analysis did not consider quetiapine.

The intramuscular form of ziprasidone is better tolerated in acute psychosis compared to haloperidol, which had a greater potential for acute movement disorders ¹⁹.

Cognitive functioning in small, open label, randomised trial indicated a trend towards better cognitive functioning in schizophrenia with one years' ziprasidone compared to risperidone. However the small nature of the study really means that this is a potential area for more research, rather than an established finding ²⁰.

Studies looking at switching from other antipsychotics have occasionally demonstrated improvements in psychopathology and negative symptoms, such as Daniel et al's study looking at switching from olanzapine to ziprasidone in 58 outpatients over a short period ²¹.They found improvements in attention, vigilance, verbal learning and memory. Switching from conventional maintenance antipsychotics seemed to be associated with improvements in psychopathology, cognitive functioning and EPS (and consequent reduction in the need for anticholinergic medication) after 6 weeks therapy with ziprasidone ²².

Conclusion

Ziprasidone is one of a new generation of antipsychotic drugs with relatively fewer side effects and equal efficacy for florid 'positive' symptoms. The additional serotonergic actions of these new antipsychotics deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional antipsychotics make ziprasidone more attractive still. Barring any unforeseen complications, which become apparent after more widespread prescribing ziprasidone appears to a most valuable addition to the antipsychotic agents. Health economic evaluations have yet to be published.

 

Correspondence: Dr Ben Green, MRCPsych, Senior Lecturer in Psychiatry, University Department of Psychiatry, Royal Liverpool University Hospital, The University of Liverpool, UK.

Email: bengreen@liverpool.ac.uk

References

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