Drug strategies and treatment-resistant schizophrenia

Objectives: The aims of the paper are to review the notion of treatment resistance in schizophrenia and consider the factors important in determining non-responsiveness to standard neuroleptic treatment, and to review the strategies currently available in the treatment of such patients, including an evaluation of recently-introduced, novel drug treatments. Method: A selective review of the literature relating to treatment resistance was undertaken using medline searches, followed by cross-checking for further articles identified in these references. Results: The various treatment approaches available are considered, including adjunctive treatment with lithium or carbamazepine. The risks and benefits of high dose antipsychotic treatment are discussed. The possible benefits and side-effects of new treatments, particularly the atypical neuroleptics, are also reviewed. Conclusions: The reasons why a proportion of patients with schizophrenia fail to respond to standard neuroleptic treatment are ill-understood. Nevertheless, initial assessment should include identification of any factors that may be related to a patient's poor response, such as poor compliance, substance use or epilepsy. This may help to determine an appropriate treatment strategy. There is a need to be systematic and to ensure that patients be given an adequate trial of each treatment tested in terms of duration and dosage. The available evidence does not support the use of high doses of neuroleptics for the majority of patients. Adjunctive treatments, such as lithium, carbamazepine or benzodiazepines may be beneficial in non-responsive patients, particularly if certain target symptoms are present. Atypical neuroleptics, particularly clozapine, have proved particularly effective in non-responsive patients as well as those sensitive to the motor side-effects of standard drugs. However, the high risk of agranulocytosis with clozapine is a problem; also, the drug and the necessary haematological monitoring are expensive. There are hints that some of the other, new, atypical neuroleptics have some benefit in non-responsive patients, but controlled studies are required.