Treatment-Resistant Schizophrenia

Clinical analyses show that patients with treatment-resistant schizophrenia are more likely to be male, have earlier onset of illness (younger than 20 years of age), more psychiatric hospitalizations and psychotic episodes, fewer remission periods, a longer duration of untreated psychosis, and a history of substance abuse.¹¹ Because cognitive and negative symptoms do not respond adequately to antipsychotic drugs, the overall response to these agents is heavily weighted to changes in positive symptoms. However, patients with treatment-resistant schizophrenia often have persistent negative symptoms and prominent cognitive impairment. Therefore, IPAP suggests 2 forms of treatment-resistant schizophrenia:

• Kraepelinian schizophrenia with severe, persistent cognitive deterioration

• Deficit schizophrenia with prominent primary negative symptoms

Among neurobiological findings in treatment-resistant schizophrenia, those from brain imaging studies have been the most prominent. These suggest a relationship between ventricular and sulcal enlargements.¹² No particular structural abnormalities of the brain are closely correlated with poor response to antipsychotic drugs.

Pharmacological treatment

The effective management of treatment-resistant schizophrenia has been a longstanding challenge. In 1988, Kane and colleagues⁶ demonstrated that clozapine(Drug information on clozapine) was effective in treatment-resistant schizophrenia. Since then, atypical antipsychotics have virtually replaced typical antipsychotics. Reviews, meta-analyses, and practical long-term trials clearly indicate that clozapine is the most effective drug in treatment-resistant schizophrenia (Table 4).^11,13

Recently, IPAP proposed an algorithm as a practical guideline for treatment-resistant schizophrenia (Figure).

Findings from double-blind, open-label trials and practical studies suggest that clozapine is more efficacious than atypical antipsychotics for treatment-resistant schizophrenia.^6,14 Meta-analyses and comprehensive reviews conclude that clozapine is more effective than typical antipsychotics for the treatment of positive and negative symptoms.^15,16 Although not all studies unequivocally confirm the superior efficacy of clozapine, practical, long-term trials have reported that this agent diminishes psychopathology, improves quality of life, and is associated with lower rates of discontinuation.^17,18

On the basis of meta-analyses, the Cochrane Center (http://www.cochrane.org) has concluded that clozapine is clearly more effective at improving active positive psychotic symptoms than either atypical or typical antipsychotics. It is not clear, however, whether clozapine is more effective in treating negative symptoms and improving long-term outcomes.

A number of double-blind trials have found that atypical antipsychotics are superior to typical antipsychotics, particularly for the treatment of positive symptoms.¹⁹ The studies also indicate that efficacy varies among the atypical antipsychotics.^15,19,20 For example, olanzapine(Drug information on olanzapine) and risperidone(Drug information on risperidone) are superior to other atypical antipsychotics in clinical efficacy against positive symptoms.^15,19, These data suggest that atypical antipsychotics are a heterogeneous group, and their efficacy and adverse effects may vary. Interestingly, a recent meta-analysis reported that only some atypical antipsychotics—such as clozapine, amisulpride(Drug information on amisulpride), olanzapine, and risperidone—were more efficacious than typical antipsychotics.²¹