Early Use of Clozapine for Poorly Responding First-Episode Psychosis

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Journal of Clinical Psychopharmacology (Impact Factor: 3.24). 09/2007; 27(4):369-73. DOI: 10.1097/jcp.0b013e3180d0a6d4
Source: PubMed


Although most patients treated for first-episode schizophrenia will experience considerable improvement with initial antipsychotic therapy, a subgroup experiences significant ongoing positive symptoms. Clozapine has unique efficacy in improving treatment-resistant patients with chronic schizophrenia, but its role in the treatment of first-episode patients remains unclear. A standardized treatment algorithm was implemented in our First Episode Psychosis Program, with patients receiving 2 trials with 2 second-generation antipsychotics (olanzapine, quetiapine, or risperidone at low, medium, and high doses), followed by a trial of clozapine as early as 25 weeks into the start of their treatment. Patients progress along the algorithm according to their response as defined by clinical rating scales. To date, 123 patients with first-episode schizophrenia have been treated according to the algorithm. Of these, 93 (76%) responded to the first trial of an antipsychotic. Only 7 (23%) of the remaining 30 patients responded to a second antipsychotic trial; 13 of the remaining 23 individuals agreed to a trial of clozapine. We compared the clozapine-treated group with a group of 9 patients who refused clozapine and chose to continue the same antipsychotic treatment as before. Subjects who received clozapine experienced a mean Brief Psychiatric Rating Scale change of 19 points (from 53.5 to 34.5) and a change in the Clinical Global Inventory severity rating from 5.4 to 3.5 (from severely ill to mildly ill); those who refused clozapine had a 2-point increase in mean Brief Psychiatric Rating Scale (from 53 to 55) and a 0.6-point increase in the mean Clinical Global Inventory severity rating from 5.4 to 6 (remaining markedly to severely ill). In clinical practice, there is a hesitancy to switch individuals to clozapine given its side effect profile and position as treatment of "last resort." The present findings suggest that clozapine may have an important role in the early treatment of first-episode patients whose psychosis does not remit with other second-generation antipsychotics during the first months of treatment.

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    • "Clozapine is unique in its relatively low affinity for D2 receptors, making it the least risky of the SGAs in terms of extrapyramidal symptoms. Review of this medication heralds it as being the only antipsychotic with superior efficacy in comparison to both haloperidol and olanzapine in adolescents, especially in regard to early onset schizophrenic disorders and treatment-refractory psychosis.20,44 It is approved in Europe for use in youth with treatment-refractory schizophrenia. "
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    ABSTRACT: Objective To review the metabolic consequences of second-generation antipsychotics in youth and current monitoring and intervention guidelines for optimal treatment. Background Second-generation antipsychotics have largely replaced the use of first-generation antipsychotics in treating psychotic disorders in youth. In addition, there has been a dramatic increase in using these medications to treat a variety of nonpsychotic disorders. These medications have significant metabolic side effects, including weight gain. This raises concern, given the problem of pediatric obesity. Materials and methods A review of current literature looking at prescribing practices and possible reasons for the increased use of second-generation antipsychotics in children and adolescents was conducted. Review of the mechanisms for why youth may be particularly vulnerable to the metabolic consequences (particularly weight gain) was similarly completed. In addition, data supporting the efficacy, rationale, and unique side-effect profile of each individual second-generation drug were evaluated to help inform providers on when and what to prescribe, along with current monitoring practices. The current evidence base for possible interventions regarding the management of antipsychotic-induced weight gain was also evaluated. Results and conclusion On the basis of the literature review, there are several speculated reasons for the increase in prescriptions of second-generation antipsychotics. The choice of antipsychotic for youth should be based upon the disorder being treated along with the unique side-effect profile for the most commonly used second-generation antipsychotics. Monitoring strategies are also individualized to each antipsychotic. The current interventions recommended for antipsychotic-induced weight gain include lifestyle management, switching medication to a drug with a lower propensity for weight gain, and pharmacologic (particularly metformin) treatment.
    Adolescent Health, Medicine and Therapeutics 09/2014; 5:171-82. DOI:10.2147/AHMT.S49807
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    • "The response rate climbed up to above 70% again in those patients with non-response that agreed to clozapine.73) Based on their results it is concluded that individuals should be treated with clozapine in a timely and systematic fashion in case of non-response, possibly useful already as a second-line treatment.74) "
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    ABSTRACT: First episode schizophrenia (FES) patients tend to be more responsive to treatment. An adequate response has been associated with a favourable long-term course in FES patients. Yet, despite the generally very favourable response profile around one quarter of the patients shows persisting symptoms of psychosis. To improve the outcome and course of psychosis great effort has emerged in identifying biological and clinical variables associated with non-response in order to identify non-responders as early as possible and adopt specific treatment strategies improving illness outcome. Different antipsychotic treatment regimens have been evaluated in terms of their efficacy in reducing symptoms of FES with psychological interventions gaining increasing importance in the treatment concept of patients suffering from their first illness episode. Therefore, aim of this review is to summarize current evidence on the response patterns, the most important predictors of response/non-response as well as on effective treatment interventions in FES patients.
    Clinical Psychopharmacology and Neuroscience 08/2012; 10(2):78-87. DOI:10.9758/cpn.2012.10.2.78
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    • "This investigation is among the few studies to use clozapine [24–26] within the six months of initial diagnosis in individuals with FEP (predominantly schizophrenia), whose positive symptoms remain prominent following initial treatment, and to offer a comparison and integration of psychological and pharmacological interventions in the early phase of illness. Due to the limitations associated with single-site recruitment and the highly restrictive nature of this patient group, only a small sample was able to be recruited. "
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    ABSTRACT: Here we report the results of a pilot study investigating the relative and combined effects of a 12 week course of clozapine and CBT in first-episode psychosis patients with prominent ongoing positive symptoms following their initial treatment. Patients from our early psychosis service who met the inclusion criteria (n = 48) were randomized to one of four treatment groups: clozapine, clozapine plus CBT, thioridazine, or thioridazine plus CBT. The degree of psychopathology and functionality of all participants was measured at baseline then again at 6, 12 and 24 weeks, and the treatment outcomes for each group determined by statistical analysis. A substantial proportion (52%) of those treated with clozapine achieved symptomatic remission, as compared to 35% of those who were treated with thioridazine. Overall, those who received clozapine responded more rapidly to treatment than those receiving the alternative treatments. Interestingly, during the early treatment phase CBT appeared to reduce the intensity of both positive and negative symptoms and thus the time taken to respond to treatment, as well having as a stabilizing effect over time.
    03/2011; 2011(2090-2085):394896. DOI:10.1155/2011/394896
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