Risks of combination neuroleptic treatment

P. Inasu

Maister Lodge, Middlesex Road, Hull HU8 0RB, UK

EDITED BY KHALIDA ISMAIL

I agree with Williams et al (2002) 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 (Shiloh 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. Tyson 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 (Bazire & Benefield, 2001) warns about increased risk of agranulocytosis when other antipsychotics are combined with clozapine. There have been case reports (e.g. Godleski & Sernyak, 1996) suggesting such risk. Friedman et al (1997) reported ‘worrisome ECG changes’ when pimozide was combined with clozapine. Waddington et al (1998) 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.

REFERENCES

Bazire, S. & Benefield, W. H. (2001) Psychotropic Drug Directory 2001/2. Dinton: Quay Books.

Friedman, J., Ault, K. & Powchik, P. (1997) Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biological Psychiatry, 42, 522-523.[CrossRef][Medline]

Godleski, L. S. & Sernyak, M. J. (1996) Agranulocytosis after addition of risperidone to clozapine treatment (letter). American Journal of Psychiatry, 153, 735-736.

Shiloh, R., Zemishlany, Z., Aizenberg, D., et al (1997) Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. British Journal of Psychiatry, 171, 569-573.[Abstract]

Tyson, S. C., Devane, C. L. & Risch, S. C. (1995) Pharmacokinetic interaction between risperidone and clozapine. American Journal of Psychiatry, 152, 1401-1402.

Waddington, J. L., Youssef, H. A. & Kinsella, A. (1998) Mortality in schizophrenia. Antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. British Journal of Psychiatry, 173, 325-329.[Abstract]

Williams, L., Newton, G., Roberts, K., et al (2002) Clozapine-resistant schizophrenia: a positive approach. British Journal of Psychiatry, 181, 184-187.[Free Full Text]





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