Treatment of the Neuroleptic-Nonresponsive Schizophrenic Patient

Abstract

The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.

Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment

“…43 However, most recent research reports on the prevalence and incidence of treatment refractory schizophrenia have used relatively stringent research criteria. 40 These figures may be considered as underestimates, in that many of the patients who would be judged clinically as showing an incomplete and unsatisfactory response to antipsychotics will not have been included.…”

The Role of Serotonin in Antipsychotic Drug Action

“…In contrast to the possibly unique effectiveness of clozapine in diminishing positive symptoms in treatment resistant schizophrenic patients, the atypical antipsychotic drugs (with the possible exception of quetiapine) and some 5-HT 2a or 5-HT 2a/2c antagonists, appear to be more effective in decreasing negative symptoms than haloperidol, (Kane et al 1988;Meltzer 1992Meltzer , 1997Moller et al 1995;Tollefson and Sanger 1996). Sertindole, risperidone, ziprasidone, M100907, and ritanserin have all been found effective in treating negative symptoms (Arvanitis and Miller 1997;Arato et al submitted).…”

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Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact thatRecent interest in the role of serotonin (5-HT) in the mechanism of action of antipsychotic drugs is in large part the result of the discovery of the efficacy of clozapine in treating the delusions, hallucinations, and disorganization of schizophrenic patients who failed to respond to classical neuroleptic drugs (Kane et al 1988;Meltzer 1992). It has also been demonstrated that clozapine can improve the negative symptoms of schizophrenia, i.e., affective flattening, anergia, anhedonia, and avolition .

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The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

“…49 With advances in treatment, the prognosis of an individual with a first episode of schizophrenia is less bleak than was once thought, with approximately 20-25% of patients having no further episodes. [50][51][52] However, within the first year, recurrence is observed in up to 25% of patients, 53 rising to almost 50% within 2 years. 50,54,55 Within 12 months it has also been found that 14% of patients are treatment resistant, 56 and over 2 years' duration 20-45% are only partially responsive to antipsychotic medication, 57,58 with 5-10% of patients deriving no benefit at all.…”