Relapse contribute to treatment resistance?Antipsychotic response in first- vs. second-episode schizophrenia

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Abstract

Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.

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Most cited references 25

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Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

Oliver Howes, Rob McCutcheon, Ofer Agid … (2017)

Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.

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What does the PANSS mean?

Stefan Leucht, John M Kane, Werner Kissling … (2005)

Despite the frequent use of the Positive and Negative Syndrome Scale (PANSS) for rating the symptoms of schizophrenia, the clinical meaning of its total score and of the cut-offs that are used to define treatment response (e.g. at least 20% or 50% reduction of the baseline score) are as yet unclear. We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions (CGI). PANSS and CGI ratings at baseline (n = 4091), and after one, two, four and six weeks of treatment taken from a pooled database of seven pivotal, multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking. Being considered "mildly ill" according to the CGI approximately corresponded to a PANSS total score of 58, "moderately ill" to a PANSS of 75, "markedly ill" to a PANSS of 95 and severely ill to a PANSS of 116. To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%. The results provide a better framework for understanding the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations. Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds. In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.

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Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis.

Stefan Leucht, Magdolna Tardy, Katja Komossa … (2012)

Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues. We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses. We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27%vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33-0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2-3). Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference -0·62, 95% CI -1·15 to -0·09) and fewer aggressive acts (2%vs 12%; RR 0·27, 95% CI 0·15-0·52; NNTB 11, 6-100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10%vs 6%; RR 2·07, 95% CI 2·31-3·25), had movement disorders (16%vs 9%; 1·55, 1·25-1·93), and experienced sedation (13%vs 9%; 1·50, 1·22-1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21-0·41) more than did oral drugs (0·46, 0·37-0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04-0·55) and fluphenazine (0·23, 0·14-0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17-0·39) than in most blinded studies (0·42, 0·35-0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length. Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs. German Ministry of Education and Research. Copyright © 2012 Elsevier Ltd. All rights reserved.