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Ben Green MB, ChB, MRCPsych

Halton Hospital,
Runcorn, Cheshire, UK.


Zotepine is a broad spectrum antipsychotic drug manufactured by Knoll pharmaceuticals and BASF pharma. It has been in use in Germany since 1990 and in Japan since 1982. The most common dose is 150 mg daily. It should be started at doses of 75 to 150 mg in 3 divided doses. It can be gradually increased to 300 mg.

It appears to be active against positive symptoms of schizophrenia (Welch et al, 1998) . In short term trials, compared with placebo. chlorpromazine and haloperidol zotepine has significantly more efficacy in reducing negative symptoms(Welch et al, 1998). Short term cognitive function (as tested by maze tests on computers) improved with zotepine (Meyer-Lindenberg et al, 1997).

It is less likely to produce EPS than haloperidol (Reynolds, Kilpatrick and Bratty, 1998).


Acute and chronic schizophrenia (Palmgren et al, 1998)


Zotepine has a high affinity for D1 and D2-like receptors and for 5HT2a, 5HT2c 5ht6 and 5ht7 receptors. It also inhibits the re-uptake of noradrenaline and this along with its serotonergic activity may account for its efficacy against negative symptoms.

The primary route of metabolism is N-demethylation which forms an active metabolite, norzotepine. Norzotepine also has an affinity for dopaminergic receptors.

Zotepine increases dopaminergic activity at low doses but at higher doses has an inhibitory effect on neurotransmission.

Zotepine has a concentration dependent effect on serum prolactin levels - at high elevels in stimulates prolactin secretion and at low cocentratiions it has an inhibitory effect.

Cytochrome P450 is probably involved in metabolism.


A substituted dibenzothiepine tricyclic agent.


In a multicentre study accumulating experience of over 152.78 patient years, doses of between 75 mg to 450 mg daily reduced BPRS and SANS total scores from baseline to endpoint by 20%. Improvements in EPMS and AIMS were also significant. (Palmgren et al, 1998).

In a 6 month placebo controlled trial amongst 119 patients zotepine (n=63) reduced the number of relapses in chronic schizophrenia and had no more EPS than placebo (Cooper SJ et al, 1998) .

There is some evidence that zotepine is useful in treatment resistant schizophrenia. There was a marked improvement in 10/22 patients with treatment resistant schizophrenia (Harada et al, 1987).

Cautions and contra-indications

High doses can lower the epileptic threshold.

Side Effects

Palmgren et al (1998) recorded weight gain as the most frequent side effect - in 31% patients. This weight gain compares badly with that of typical antipsychotics. Somnolence was the second most frequent side effect affecting about 14% of patients. Constipation, asthenia, dry mouth, akathisia, EPS and lab abnormalities such as increases in AST, ALT, and GGT also occurred in a significant minority. Uric acid levels may decrease.


Co-administration of benzodiazepines results in higher serum concentrations. of zotepine. In vitro data suggests a low potential for interactions with imipramine, prcyclidine, norfluoxetine and ketoconazole.




Focus on Zotepine © Psychiatry On-Line 1998-99
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Version 2.0

Last Amended: 23 March 1999

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