I agree with Williams et al (Reference Williams, Newton and Roberts2002) regarding the term ‘neuroleptic-resistant schizophrenia’ and the spirit of a ‘positive approach’ in managing it. The need for a biopsychosocial approach is also undisputed. However, the article appears to overemphasise the efficacy of psychotropic combinations and does not mention the associated risks. There is no advice to end the series of treatment trials at any point.

As the article points out, there is only one published randomised control trial (Reference Shiloh, Zemishlany and AizenbergShiloh et al, 1997) studying the efficacy of combining two neuroleptics. It is surprising that the authors did not measure the clozapine levels. There are other publications (e.g. Reference Tyson, Devane and RischTyson et al, 1995) reporting a marked rise in clozapine level when another anti-psychotic was added. The apparent benefit of combining sulpiride with clozapine may have been purely due to an increased serum level of clozapine. In other words, if adequate serum levels were achieved prior to the study, the combination may have produced no additional benefit at all. Other claims of efficacy of combinations based on clinical experience in only one or a few patients form a meagre evidence base.

There are clear risks associated with these combinations. The Psychotropic Drug Directory (Reference Bazire and BenefieldBazire & Benefield, 2001) warns about increased risk of agranulocytosis when other antipsychotics are combined with clozapine. There have been case reports (e.g. Reference Godleski and SernyakGodleski & Sernyak, 1996) suggesting such risk. Friedman et al (Reference Friedman, Ault and Powchik1997) reported ‘worrisome ECG changes’ when pimozide was combined with clozapine. Waddington et al (Reference Waddington, Youssef and Kinsella1998) reported that polypharmacy of antipsychotics was one of the predictors of reduced survival among people with schizophrenia.

As in the case of prescribing doses above British National Formulary recommended limits, there should be clear guidelines regarding the combination of two antipsychotics. This should include detailed discussion with the patient/carers regarding the indications and limitations of such treatment, physical investigations such as electrocardiography and a time-limited plan to review and to return to monotherapy if the combination is not producing any additional benefit.

Neuroleptics may not be able to provide complete remission of schizophrenia in every individual sufferer. Beyond a point the risks may outweigh the benefits, especially when used in combinations and in high doses. Accepting this is not therapeutic nihilism but realism.