Treatment-Resistant Schizophrenia - The Role of Clozapine

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SummaryTreatment-resistant schizophrenia is the object of intense interest because of recent developments in its treatment and aetiology. The actual definition of treatment-resistant schizophrenia is, however, still controversial. It should reflect the legitimate and varied needs and perspectives of people with schizophrenia, their family members, mental health care givers, mental health administrators, public health officials, and those who fund the direct and indirect costs of treating schizophrenia.The most common definition of treatment-resistant schizophrenia denotes patients with schizophrenia who, despite at least two adequate trials of classical neuroleptic drugs, have persistent moderate to severe positive, or disorganisation, or negative symptoms together with poor social and work function over a prolonged period of time. This definition reflects the viewpoint of people with this illness, their family members, and mental health care givers. Approximately 30% (range 10–45%) of schizophrenic patients meet these criteria. while this definition is adequate for many purposes, it should be realised that the remaining 70% of schizophrenic patients, whose positive symptoms respond adequately to neuroleptic treatment, may also have clinically significant negative symptoms, poor social and work function, clinically significant cognitive dysfunction, poor quality of life relative to the normal population, and constitute a significant burden to family and society. The lifetime suicide rate in both treatment-resistant and responsive schizophrenic patients is 9–13%, indicating that conventional definitions of neuroleptic response do not convey lower risk of suicide.However, before defining a patient as treatment resistant, it is important to consider whether the patient has received an inadequate duration of treatment, and/or too low, or possibly too high, doses of neuroleptic drugs. Using these stringent criteria, treatment resistance may be present at the time of initial diagnosis and treatment, but if not present initially, it will usually develop subsequently - sometimes not until after multiple acute exacerbations over a period of years.During the first months and years after the diagnosis of schizophrenia has been made, clinicians should be especially alert in identifying a patient as treatment resistant in order to diminish the severe social disability and suicidality which may ensue if it is not recognised and correctly treated. Once present, treatment resistance is usually permanent. However, some treatment-resistant patients may again become responsive to treatment or undergo spontaneous remission of positive symptoms in later life.The treatment of patients with schizophrenia who are treatment resistant is generally much more expensive that that of neuroleptic-responsive patients because their symptomatology and disturbed behaviour leads to more frequent and longer duration hospitalisations.Patients with treatment-resistant schizophrenia may manifest one or more of the classical subtypes of schizophrenia which may differ biologically in terms of neurochemisty and structural brain abnormalities, e.g. ventricular enlargement. They usually have poorer premorbid function, an earlier age at onset of positive symptoms, are more likely to be male than female, and may have various quantitative types of cortical or ventricular abnormalities evident with computer tomography or magnetic resonance imaging scans. There are no established qualitative differences in cognitive dysfunction between the two groups of patients with schizophrenia, but cognitive impairment is more severe in treatment-resistant patients.Treatment-resistant schizophrenia does not usually respond to increased dosages of neuroleptic drugs, switching to other types of neuroleptics, or adding adjunctive agents such as benzodiazepines, anti depressants, anticonvulsants or lithium carbonate. Clozapine has been shown to be more effective than classical neuroleptic drugs in decreasing psychopathology, improving some aspects of cognition, improving quality of life, decreasing hospitalisation, and decreasing suicide attempts and completions. About 20% of the responders to clozapine have a nearly complete remission of positive symptoms and about 40% are able to work or complete school. However, many of the patients who respond better to clozapine than to classical neuroleptic drugs still have residual psychopathology. Further study is needed on whether it is possible to augment the response to clozapine with auxiliary treatments such as classical neuroleptics, antidepressants and anticonvulsants.