Benefit-risk evaluation of olanzapine, risperidone and sertindole in the treatment of schizophrenia

Schizophrenia is a severe, incapacitating and often chronic psychiatric disorder that accounts for 20 % of all chronic medical disability. It affects 1 % of the population worldwide, and occurs with equal frequency in men and women. The disease usually develops in early adulthood, and lasts for at least several decades in 75 % of patients, at huge economic cost to society. In the UK, the total direct healthcare costs attributable to schizophrenia in 1994 were pound 397 million, 1.6 % of the total healthcare budget (Davies and Drummond 1994), whilst total costs are around pound 2.6 billion (Knapp 1997). Compared with other functional psychoses, schizophrenia still has the poorest outcome and is often used as a proxy for other severe and enduring psychotic illnesses. Schizophrenia manifests itself as a diverse range of severe psychosocial symptoms; these can be divided into positive symptoms, which include hallucinations, delusions and thought disorder, and negative symptoms, which include blunted emotions, social withdrawal and a reduction in spontaneous behaviour. Together these symptoms often result in serious suicidal tendencies. Indeed, 10-15 % of patients with schizophrenia die by suicide (Kaplan et al. 1994). Conventional antipsychotics, such as haloperidol, art: generally effective in controlling the positive symptoms of schizophrenia, but have minimal efficacy against the negative symptoms. Conventional antipsychotics have the added disadvantage of causing a range of severe side effects, most notably extrapyramidal symptoms (EPS), which makes many patients unwilling to take these compounds for any length of time. Since the introduction of clozapine, a range of atypical antipsychotics, including olanzapine, risperidone and sertindole, has been developed. These drugs provide improved efficacy against both the positive and negative symptoms of schizophrenia and carry a much lower risk of causing the severe and unpleasant side effects associated with conventional antipsychotic agents. The superior efficacy and safety profiles of the atypical antipsychotic drugs compared with conventional agents stem from differences in their receptor binding affinities (Meltzer et al. 1989; Nyberg et al. 1995;Amt and Skarsfeldt 1998; Kasper et al. 1998a). As a new class of antipsychotics, the atypical agents are frequently grouped together, with efficacy and safety being reported for the group as a whole. It can certainly be said that the atypical antipsychotics as a class of drugs improve the quality of Life of patients with schizophrenia, and offer substantial advantages over conventional treatments. However, each atypical compound has its own specific efficacy and tolerability profiles, and it is the specific risk factors, such as the tendency to cause weight gain, sedation, anticholinergic effects, or cognitive dysfunction, that must be assessed in order to determine the overall value of a particular drug. So far, no such comparisons have been made for the atypical antipsychotics olanzapine, risperidone, and sertindole. This paper presents a comprehensive evaluation of the relative benefit-risk profiles of olanzapine, risperidone, and sertindole, based on data available from public regulatory documents and published clinical trial results for these drugs.