CNS Drugs

, Volume 9, Issue 2, pp 153–175


A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Schizophrenia
Adis Drug Evaluation

DOI: 10.2165/00023210-199809020-00006

Cite this article as:
Prakash, A. & Lamb, H.M. Mol Diag Ther (1998) 9: 153. doi:10.2165/00023210-199809020-00006



Zotepine is an atypical antipsychotic with high affinity for serotonin 5- HT2A and 5- HT2C and dopamine D2, D3, D1 and D4.2 receptors and is a potent inhibitor of reuptake of nor adrenaline (norepinephrine). The major metabolite of zotepine, norzotepine is pharmacologically active and possesses affinity for dopaminergic receptors similar to the parent compound. Pharmacodynamic data suggest that at low doses the drug increases dopaminergic neurotransmission, while at higher doses it acts as a dopaminergic receptor antagonist.

In double- blind trials zotepine 150 to 300 mg/day was as effective as typical antipsychotics such as haloperidol, chlorpromazine, perazine and thiothixene in controlling symptoms of schizophrenia. Although improvement occurred with both zotepine and haloperidol in patients with predominantly negative schizophrenic symptoms, only zotepine achieved significant reductions in most individual negative symptom scores versus baseline. Results from 1 study suggest that maintenance therapy with zotepine for up to 1 year was effective in preventing relapse in schizophrenic patients. In 2 trials in patients with treatment- resistant schizophrenia, some improvement occurred in most patients after the initiation of zotepine either in place of previous drugs or as add- on therapy.

Zotepine is generally well tolerated; constipation, dry mouth, insomnia, sleepiness, asthenia and bodyweight gain are the commonly encountered adverse effects. The incidence of extrapyramidal symptoms with zotepine is low (8 to 29%) and significantly less than that seen with haloperidol and chlorpromazine; however, there were no differences between zotepine and some other typical antipsychotics in this respect. Dosages ≥ 300 mg/day are associated with an increased risk of generalised convulsions.

Thus, zotepine is as effective as typical antipsychotic agents in the management of acute exacerbations of schizophrenia and may be useful for the prevention of relapse. Initial trials have found the drug to be effective in the management of patients with negative schizophrenic symptoms and those with treatment- resistant schizophrenia.

Pharmacodynamic Properties

Zotepine is a dibenzothiepine tricyclic antipsychotic agent which has high affinity for serotonin 5-HT2A and 5-HT2C receptors and dopamine D2, D3, D1 and D4.2 receptors. Norzotepine, the major metabolite of zotepine in humans and animals, is pharmacologically active and shows affinity for dopaminergic receptors which is similar to that of zotepine. In rats and mice, zotepine potently inhibited noradrenaline (norepinephrine) reuptake. In addition to showing central antidopaminergic and antiserotonergic activities in animal models, zotepine was as effective as haloperidol and more effective than clozapine in inhibiting N-methyl D-aspartate glutamate receptor antagonist—induced animal behaviours.

Administration of zotepine in animals revealed a dichotomic effect on dopaminergic receptors; at low doses zotepine increases dopaminergic activity, while at higher doses it has an inhibitory effect on dopaminergic neurotransmission. There was improvement in cognitive dysfunction in 13 patients treated with zotepine (150 to 450 mg/day) over 6 weeks. Administration of zotepine 150 to 250 mg/day for 4 weeks did not significantly affect thyroid function tests, although blood thyroxine levels tended to decrease from pretreatment values.

Pharmacokinetic Properties

Data on the pharmacokinetics of zotepine in humans are limited consequently animal data have been included where necessary for completeness. There is almost complete absorption of zotepine after oral administration in animals. Plasma concentrations of zotepine peaked at approximately 13 to 31 μg/L about 3 hours after a single oral dose of zotepine 50mg in healthy volunteers. Most of the drug is metabolised by the liver and only 0.03 to 0.07% of the drug is excreted unchanged in urine. There appears to be some degree of enterohepatic circulation. The elimination half-life of zotepine ranges from about 15 to 24 hours. Zotepine plasma concentrations are elevated in the elderly and in patients receiving concomitant benzodiazepines but not anticholinergic drugs.

Therapeutic Efficacy

In double-blind comparative trials, zotepine was as effective as typical antipsychotic agents in the management of patients with positive and negative schizophrenic symptoms. There are no trials comparing the efficacy and tolerability of zotepine with those of other atypical antipsychotics such as risperidone, quetiapine or amisulpiride in patients with schizophrenia.

Administered in a double-blind fashion, zotepine (150 to 300 mg/day) was as effective as haloperidol (6 to 20 mg/day) in improving schizophrenic symptoms. In other double-blind trials the efficacy of zotepine was similar to that of chlorpromazine, perazine and thiothixene.

Zotepine was also effective in treating patients with predominantly negative schizophrenic symptoms in noncomparative and comparative studies. One 7-week, double-blind, randomised trial reported significant improvements over baseline in 4 of 5 negative schizophrenic symptoms with zotepine (50 to 150 mg/day) but not with haloperidol (2 to 6 mg/day). Zotepine (106 to 396 mg/day) was as effective as perazine (214 to 575 mg/day) in treating patients with negative schizophrenic symptoms.

In a multicentre trial, administration of zotepine (up to ≈300 mg/day), alone or in combination with other drugs, was associated with significant improvement in 29 of 35 patients with treatment-resistant schizophrenia. The administration of zotepine 50 to 500 mg/day for 1 to 36 months (mean 12 months) lead to a moderate to marked improvement in the overall severity of disease in 17 of 22 patients with treatment resistant schizophrenia.

A placebo-controlled, double-blind study in 121 patients with schizophrenia with a recent history of relapse found zotepine (150 to 300 mg/day) to be significantly better than placebo in preventing relapse over 26 weeks.


Randomised, double-blind comparative studies have reported a significantly lower incidence of extrapyramidal symptoms (EPS) with zotepine (8 to 29%) than with haloperidol and chlorpromazine. However, the incidence of EPS with zotepine was similar to that seen with perazine and thiothixene.

At the dosage used to manage schizophrenic patients zotepine was generally well tolerated. Adverse events seen in zotepine recipients include insomnia, reduced salivation, sleepiness, constipation, asthenia and bodyweight gain (individual incidence 10 to 39%). Aretrospective review of 110 schizophrenic patients found significantly greater bodyweight gain in patients treated with zotepine than in those treated with typical antipsychotics for ≥2 weeks (3.6 vs 1.3kg). An increase in the risk of generalised convulsions has been observed with zotepine at dosages >300 mg/day (above the maximum recommended dosage for nonsevere disease), especially if being administered in combination with other antipsychotic agents. Monitoring of tolerability of zotepine is recommended in the elderly. No clinically relevant haematological abnormalities have been reported to date.

Dosage and Administration

Zotepine should be initiated at total daily doses of 75 to 150mg in 3 divided doses. Based on the clinical response the daily dose may be gradually increased up to 300mg. In severely ill, hospitalised patients 450 mg/day may be used. Monitoring of EEG is recommended in patients receiving zotepine >300 mg/day concurrently with other antipsychotic agents.

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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