Chronic Hospitalization vs. Poor Symptom Response
Studies of treatment-refractory schizophrenia have long been hampered by a lack of consistency in definition. Commonly, treatment resistance was considered roughly equivalent to chronic or frequent hospitaliza-tion (2). However, current and persistent positive symptoms of psychosis and at least moderate overall severity of illness should be present in order for treatment resistance to be diagnosed (35,36), since chronic hospitalization can occur despite low levels of symptoms (4). Moreover, many patients with presistent psychosis may not meet hospitalization criteria in some communities. It is now generally recognized that chronic hospitalization alone may not accurately in predict the likelihood of response to an antipsychotic trial (37,38).
For various reasons, many people with schizophrenia who have been chronically hospitalized may not be truly refractory to drug treatment. Inadequate psychosocial programming, poor compliance with prescribed drug therapy, or a history of committing violence (38) are all risk factors for chronic hospitalization. Therefore, optimized medication and treatment trials should be employed before a patient's illness is considered nonresponsive. In addition, the effects of drug noncompliance and extrapyramidal side effects (EPS) can both mimic treatment resistance (10,21). A course of at least 1 to 2 years of unambiguous and persistent positive symptoms should be one of the criteria for treatment-refractory schizophrenia.
While most definitions of treatment-refractory schizophrenia have focused on the persistence of positive symptoms of psychosis, there has been a growing awareness of the problems presented by persistent negative symptoms. Moreover, lozapine and other second-generation antipsychotics have all been shown to have superior efficacy in reducing negative-symptom ratings in double-blind clinical trials (6,39-41). There is some controversy as to whether these drugs treat primary negative symptoms or whether their effect is due to secondary benefits (8,42,43). However, categorizing as refractory the illness of patients who have persistent negative symptoms may be clinically useful, because these patients often benefit from a change in their drug therapy to a new antipsychotic.
Violence Associated with Treatment-Refractory Schizophrenia
Violence in schizophrenia has long been considered a problem (44). People with schizophrenic symptoms have a markedly higher rate of perpetrating serious violence toward others (45). Patients with refractory schizophrenia are also more likely to be victims of violence, probably because of their tendency to be chronically hospitalized (46).
There has recently been some therapeutic optimism regarding this problem. Clozapine is more effective than traditional antipsychotic therapy in reducing violent behavior and hostility (47,48). Risperidone treatment has also been seen to decrease hostility (49). This raises the question of whether effectiveness against hostility, rather than being a particular property of clozapine, may be a phenomenon of the reduced EPS liability or other effects shared by the second-generation antipsy-chotics. It has been recognized that treatment with low-potency conventional antipsychotics that have reduced EPS liability is associated with improvement in violent behavior rates compared with haloperidol therapy (44). However, this finding may have been due to the increased sedation seen with these drugs.
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