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 disorder3,4. 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-HT2A antagonist with an affinity for 5-HT2 receptors an order of magnitude greater than that observed for D2 receptors. The emphatic antagonism of 5-HT2A 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-HT1A (Ki = 3.4 nM), 5-HT1D and 5-HT2C receptor subtypes. Sprouse et al (1999) point out that ziprasidone's high affinity for 5-HT1A 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 studies12a. 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 vomiting12b.

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 doses14a.

 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 gain9a.

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 insignificant15a.

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

Seeger TF; Seymour PA; Schmidt AW; Zorn SH; Schulz DW; Lebel LA; McLean S; Guanowsky V; Howard HR; Lowe JA 3rd; et al. Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. J Pharmacol Exp Ther, 1995 Oct, 275:1, 101-13.

Tandon, R;Harrigan E;Zorn A H. (1997) Ziprasidone; a novel antipsychotic with unique pharmacology and therapeutic potential. Journal of Serotonin Research, 4, 159-177.

Keck, P;,Buffenstein, A;, Ferguson, J;. Feighner J;, Jaffe W;, Harrigan E P;,Morrissey, M R. (1998) Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology, 140, 173-184.

Daniel DG; Zimbroff DL; Potkin SG; Reeves KR; Harrigan EP; Lakshminarayanan M (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. Neuropsychopharmacology, 20:5, 491-505.

Swift R H; Harrigan E P;van Kammen DP (1998) A comparison of fixed-dose, intramuscular (IM) ziprasidone with flexible dose, IM haloperidol, European Psychiatry, 13(4), S304.

Reeves K R. Swift R H; Harrigan EP; Lesem M. (1998) Rapid acting, intramuscular ziprasidone 10 mg and 20 mg in patients with psychosis and acute agitation: results of two double-blind, randomized, fixed-does studies. Poster presentation.

Sprouse JS; Reynolds LS; Braselton JP; Rollema H; Zorn SH Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. Neuropsychopharmacology, 1999 Nov, 21:5, 622-31.

Pickar D (1995) Prospects for pharmacotherapy of schizophrenia The Lancet 345, 557-562.

O'Connor R;Harrigan E P; Heym j et al (1996) The efficacy and safety profile of a new antipsychotic, ziprasidone. Presented at the Xth World Congress of Psychiatry, 23-28 May, Madrid, Spain.

9a. Taylor DM. McAskill R. (2000) Atypical antipsychotics and weight gain--a systematic review. Acta Psychiatrica Scandinavica. 101(6):416-32.

Miceli JJ; Wilner KD; Hansen RA; Johnson AC; Apseloff G; Gerber N. Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteers. Br J Clin Pharmacol, 2000, 49 Suppl 1:, 5S-13S.

Meltzer H, Arato M, O Connor (2000) Path analysis of the ZEUS study provides evidence of a direct effect of ziprasidone on primary negative symptoms in chronic, stable schizophrenia. Schizophr Res 41 (1 Spec Iss): B91.

Sallee FR; Kurlan R; Goetz CG; Singer H; Scahill L; Law G; Dittman VM; Chappell PB Ziprasidone treatment of children and adolescents with Tourette's syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry, 2000 Mar, 39:3, 292-9.

12a Tuunainen A. Wahlbeck K. Gilbody SM. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database of Systematic Reviews [computer file]. (2):CD000966, 2000.

12b. Bagnall A. Lewis RA. Leitner ML. Kleijnen J.Ziprasidone for schizophrenia and severe mental illness. Cochrane Database of Systematic Reviews [computer file]. (2):CD001945, 2000.

Aweeka F; Jayesekara D; Horton M; Swan S; Lambrecht L; Wilner KD; Sherwood J; Anziano RJ; Smolarek TA; Turncliff RZ. The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function. Br J Clin Pharmacol, 2000, 49 Suppl 1:, 27S-33S.

Everson G; Lasseter KC; Anderson KE; Bauer LA; Carithens RL Jr; Wilner KD; Johnson A; Anziano RJ; Smolarek TA; Turncliff RZ. The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function. Br J Clin Pharmacol, 2000, 49 Suppl 1:, 21S-26S.

14a.Prakash C. Kamel A. Cui D. Whalen RD. Miceli JJ. Tweedie D. Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions. British Journal of Clinical Pharmacology. 49 Suppl 1:35S-42S, 2000.

Apseloff G; Mullet D; Wilner KD; Anziano RJ; Tensfeldt TG; Pelletier SM; Gerber N. The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium. Br J Clin Pharmacol, 2000, 49 Suppl 1: 61S-64S.

15a.Miceli JJ Anziano RJ Robarge L Hansen RA Laurent A. The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers. British Journal of Clinical Pharmacology. 49 Suppl 1:65S-70S, 2000.

Muirhead GJ; Harness J; Holt PR; Oliver S; Anziano RJ. Ziprasidone and the pharmacokinetics of a combined oral contraceptive. Br J Clin Pharmacol, 2000, 49 Suppl 1:, 49S-56S.

Wilner KD; Demattos SB; Anziano RJ; Apseloff G; Gerber N Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers. Br J Clin Pharmacol, 2000, 49 Suppl 1:, 43S-47S.

Allison DB; Mentore JL; Heo M; Chandler LP; Cappelleri JC; Infante MC; Weiden PJ (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry, 156:11, 1686-96.

Brook S; Krams M, Gunn KP and the Zirprasidone IM Study Group. (1998) The efficacy and tolerability of intramuscular (IM) ziprasidone versus IM haloperidol in patients with acute, non-organic psychosis. European Psychiatry, 13(4), S303.

Hagger C, Mitchell D, Wise AL, Schulz SC. (1997) Effects on oral ziprasidone and risperidone on cognitive functioning in pataients with schizophrenia or schizoaffective disorder: preliminary data. Eur Neuropsychopharamacolgy 7 Isupl 2):219.

Daniel D, Stern R, Kramer T and the Switch Study Group. Switching from olanzapine to ziprasidone: an interim analysis of a 6-week study. Presented at the 152nd APA. Washington, DC, 15-20 May 1999.

Weiden P, Simpson, G, Kramer T, Harvey P and the Switch Study Group (1999) Switching from conventional antipsychotics to ziprasidone: an interim analysis of a 6-week study. Presented at the 152nd APA. Washington, DC, 15-20 May 1999.


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