Various historical aspects of resistant schizophrenia are described: limitations of treatment efficacy, attempts at proposing therapeutic strategies in non-responding patients, first attempts to define resistance in schizophrenia, and first attempts to distinguish resistance factors. Interest in treatment-refractory schizophrenia was stimulated by several studies in the period 1985–1990, including a pivotal study of clozapine. The need to include biological and psychosocial factors when defining resistance was emphasised by a group who defined a systematic approach to treatment resistance in schizophrenia, including degrees of resistance. The concept of a continuum from full remission to complete refractoriness was proposed by an international study group in 1990. Difficulties in identifying patients with refractory schizophrenia include: variability of schizophrenia diagnostic criteria, lack of consensus concerning good treatment practice with neuroleptic agents, and confusion between resistance, chronicity and severity. A better definition of refractoriness is needed, not only for pharmacological studies but also for a more precise characterisation of a possible subgroup of schizophrenia termed ‘Kraepelinian’.

Treatment-resistant schizophrenia does not exist as a discrete entity, so separating patients who will fail to respond to traditional antipsychotics from those who will respond is impossible with 100% accuracy. However, several predictors of poor clinical outcome have emerged from recent research and knowledge of the processes that lead to poor outcome has become increasingly important with the advent of atypical antipsychotics that may be used in patients with treatment-resistant illness. Much of the variation in outcome can be understood in terms of differences in sample selection, outcome definition and stringency of the diagnostic criteria used. Failure to appreciate these mechanisms may lead to over- or underestimation of the proportion of patients with poor treatment response in clinical and research settings. The importance of factors that predict poor outcome should be judged in terms of their effect size and the degree to which alternative explanations for the association with outcome have been excluded. Although much current research is being focused on specific biological predictors, baseline demographic and illness-related factors, such as ethnic group, sex, social class, type of onset, age of onset and concurrent misuse of alcohol or drugs, have large effects on outcome. Although duration of untreated psychosis before first contact with services may independently predict poor outcome, confounding by variables that are associated with both pathways to care and clinical outcome has not been excluded.

A prospective study in treatment-resistant schizophrenic patients was performed over 10 years to evaluate the therapeutic response to clozapine and the variables related to this treatment. Eighty schizophrenic and schizoaffective patients (according to Diagnostic and Statistical Manual [DSM]-IIIR criteria), considered as refractory (previously resistant to at least two different typical neuroleptics), were studied. The average dose of clozapine was 267 mg/d. The clinical variables considered were: Brief Psychiatric Rating Scale (BPRS), number of admissions before and after clozapine treatment and the Strauss-Carpenter scale as measures of efficacy; Premorbid Adjustment Scale (PAS), to assess personal and social adjustment before illness; Karolinska Personality Scale (KPS) to assess stable traits of personality; and the Simpson-Angus scale as a measure of extrapyramidal symptoms. Sixty percent of patients showed a significant improvement after clozapine treatment. Side-effects were mild and well tolerated, with no cases of haematological disturbance and only five withdrawals because of adverse events. The severity of the episode, according to BPRS score and anxiety as a personal trait, are related to good prognosis. Other relationships between improvement and clinical and demographic variables are discussed.

Evidence indicates that clozapine is effective in the management of treatment-resistant schizophrenia and in affective psychoses. To examine whether affective components within the boundaries of the schizophrenia spectrum imply specific psychopathological characteristics of response to treatment, 60 patients with a treatment-resistant schizophrenia spectrum disorder who were treated with clozapine (75–600 mg/d) were evaluated in a naturalistic, open, follow-up study. The group comprised 41 patients with and 19 without bipolar features (43 men and 17 women, mean age 34.3 years). Patients were evaluated with the Brief Psychiatric Rating Scale (BPRS) during the first year of treatment. The results show a significant improvement in scores in both groups (P < 0.001) compared with the baseline evaluation. A higher percentage of responders was seen in the ‘affective’ group. No typical psychopathological characteristic or symptom cluster predicting the response to treatment was identified. During the study, 15 patients discontinued treatment: six for lack of efficacy, five for non-compliance and four for adverse events. The study confirms the efficacy of clozapine in the treatment of schizophrenia spectrum disorders, particularly in patients with bipolar features.

Controlled clinical trials have shown that the atypical neuroleptic clozapine is highly effective in schizophrenic patients who are unresponsive to conventional neuroleptic agents. The long-term outcome of clozapine treatment was studied in 122 patients who were treated between 1974 and 1991. The mean duration of treatment was 5.2 years. At follow-up, 74 patients (61%) were still receiving clozapine. Only 11 patients discontinued treatment because of adverse events and eight because of poor compliance. Clinical improvement was seen in 87% of patients; 40% had resumed employment after 2 years' treatment. About one-third of patients who received clozapine for 5–10 years continued to improve during this time; this was probably because of a continuing process of socialisation. Thus, clozapine offers important advantages in schizophrenic patients resistant to conventional neuroleptics in terms of long-term efficacy and lack of extrapyramidal side-effects.