Tolerability of zotepine in Indian patients: Preliminary experience.

Zotepine is an antipsychotic used in Japan and Europe for years and recently being introduced in Indian markets. It is claimed to be particularly effective for negative symptoms, and somnolence and weight gain are the most common side effects. Our aim is to share our clinical experience of use of zotepine with respect to its tolerability. We reviewed the first 10 patients who were prescribed zotepine at our center.

Zotepine has been in use in Japan since 1982, in Germany since 1990[1] and in the UK since 1998, but has not yet been approved by Food and Drug Administration (FDA) for use in the USA. It is a dopamine antagonist that has a high affinity for D1- and D2-like receptors and for several serotonin receptors. Its ability to inhibit the reuptake of noradrenaline, together with its serotonergic activity (5-HT6, 5-HT7), may explain its efficacy against negative symptoms.[1]

Zotepine has been compared with three atypical second-generation antipsychotic medications,[1-3] in three short-term trials (n=289). Two studies compared zotepine with clozapine,[34] but there is insufficient evidence to draw firm conclusions as to whether zotepine is as effective as or less effective than clozapine. One study compared zotepine with risperidone, clozapine and remoxipride,[2] and concluded that zotepine is as effective as risperidone and remoxipride. The movement disorders and the cognitive changes appear to be similar to the other three atypical clozapine, risperidone and remoxipride. The use of antiparkinson medication is comparable to risperidone and remoxipride, but may be associated with increased need than necessary with clozapine. Zotepine may be associated with higher prolactin levels than clozapine.[4]

Fenton and colleagues (2003) reviewed randomized trials to determine the effects of zotepine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia, but they did not find clear differences between zotepine and other atypical drugs. The most common adverse effects of zotepine are somnolence, constipation, dry mouth, insomnia, dizziness, asthenia and weight gain.[5]

The review of English medical databases for safety profile of zotepine, incorporating data on placebo-controlled studies as well as studies with comparator compounds, suggested that zotepine induces less extrapyramidal side effects; however, in terms of comparing zotepine's safety with other atypical antipsychotics, more studies are needed to draw final conclusions.[6] In a double-blind study comparing safety and efficacy of zotepine with haloperidol in Taiwanese patients, Zotepine treatment produced fewer extrapyramidal symptoms but had a greater frequency of sedative effects compared to haloperidol.[7] There are no sufficient data of zotepine tolerability from controlled studies.

CASE REPORT

Zotepine is being marketed in India since September 2010 for the treatment of Schizophrenia. By presenting this report, our aim is to share our clinical experience regarding the tolerability and the side effects of zotepine treatment in schizophrenia patients. To our knowledge, there has been no study conducted to assess the safety or efficacy of zotepine in India, so far. Our clinical experience with the first 10 patients who were prescribed zotepine suggested that it causes considerable intolerable side effects. On reviewing their case report forms and prescriptions, it was found that four of them had to discontinue because of side effects and another two needed concomitant medications for the management of the side effects. All the patients were started with low dose (75 mg/day in three divided doses) and escalated to 150 mg/day (in three equally divided doses) on 4th or 5th day depending on tolerability. None of them were given anticholinergic medication from the beginning. Below is the description of patients who needed discontinuation.

A 25-year-old female with 3-year history of schizophrenia presented with predominantly negative symptoms and was prescribed zotepine (gradual escalation to 150 mg/day). She reported severe oculogyric crisis on 10th day of treatment. With intramuscular injection of promethazine, the patient was symptom free for only 3 hours and needed discontinuation of zotepine.

A 38-year-old male previously treated with typical antipsychotics was given zotepine (75 mg/day) as monotherapy for the present episode, which caused somnolence severe enough to impair all his activities including feeding and self-care.

A 34-year-old female was switched to zotepine from risperidone because of insufficient efficacy for her symptoms of schizophrenia. She tolerated zotepine 75 mg/day, but with 150 mg/day dose, she had significant postural giddiness and one fall causing minor injuries. The patient could tolerate risperidone but not zotepine. On physical examination, significant orthostatic hypotension was observed.

A 52-year-old male, with diagnosis of schizophrenia and no medical co-morbidity, developed pedal edema and discoloration of overlying skin which caused subjective distress to discontinue zotepine. Lorazepam was used as concomitant medication for insomnia, but was only need based.

Other two patients who developed side effects with 150 mg/day zotepine use were managed with concomitant medications. One patient reported hand tremors, and the other one reported excessive salivation. Both of them were given trihexyphenidyl and got rid of the side effects. Remaining four patients tolerated zotepine with no or minimal side effects at the end of 2 weeks.

DISCUSSION

Our experience does not conclude the efficacy of zotepine, but it is clearly evident that zotepine is not easily tolerated by our patients. We observed adverse effects with zotepine use similar to typical and few atypical antipsychotic medications. It gives no added benefit in terms of tolerability from the existing antipsychotics. Gradual escalation and proper selection of patients might reduce the incidence of adverse effects with its use. For the selection of suitable patients, who could be prescribed zotepine, more data are required from our population. A comprehensive overview of tolerability requires a review of all the available data, including randomized controlled trials (RCTs), observational studies and post-marketing surveillance studies.