In the Aftermath of Clozapine Discontinuation
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The British Journal of Psychiatry (2020) Page 1 of 8. doi: 10.1192/bjp.2019.267 In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine Jurjen J. Luykx, Noraly Stam, Antti Tanskanen, Jari Tiihonen and Heidi Taipale Background Mortality risk was lowest for reinitiation of clozapine (aHR 0.18; – P Although clozapine is often discontinued, there is a paucity of 95% CI 0.09 0.36; < 0.0001) and oral olanzapine (aHR 0.26; 95% – P guidelines and evidence on treatment options after clozapine CI 0.17 0.40; < 0.0001). discontinuation. Moreover, it is currently unknown whether Conclusions reinstating clozapine in patients formerly using clozapine should be avoided. Clozapine and olanzapine are the most effective and safest treatment options in those discontinuing clozapine for undefined Aims reasons. Clozapine should therefore be reconsidered in patients To compare the real-world effectiveness of antipsychotics after with schizophrenia who previously discontinued this compound. clozapine cessation. Declaration of interest Method J.T., H.T. and A.T. have participated in research projects funded From Finnish registry data (1995–2017), we identified 2250 by grants from Janssen-Cilag and Eli Lilly to their employing patients with schizophrenia who had been using clozapine institution. J.T. reports personal fees from the Finnish Medicines for ≥1 year before treatment cessation. The primary analysis Agency (Fimea), European Medicines Agency, Eli Lilly, Janssen- consisted of adjusted within-individual analyses of psychiatric Cilag, Lundbeck and Otsuka; is a member of advisory board for ward readmission owing to psychosis and treatment failure. Lundbeck and has received grants from the Stanley Foundation Secondary analyses concerned between-individual mortality and Sigrid Jusélius Foundation. The other authors report no differences. conflict of interest. Results Keywords Compared with no use of antipsychotics, risk of psychiatric Schizophrenia; antipsychotics; clozapine; psychiatric ward ward readmission was lowest for reinitiation of clozapine readmission; discontinuation. (adjusted hazard ratio (aHR) 0.49; 95% CI 0.40–0.61; P < 0.0001), oral olanzapine (aHR 0.58; 95% CI 0.48–0.71; P < 0.0001) and Copyright and usage antipsychotic polypharmacy (aHR 0.62; 95% CI 0.53–0.72; © The Authors 2020. This is an Open Access article, distributed P < 0.0001). Risk of treatment failure was lowest for aripiprazole under the terms of the Creative Commons Attribution licence long acting injectable (aHR 0.42; 95% CI 0.27–0.65; P < 0.0001), (http://creativecommons.org/licenses/by/4.0/), which permits reinitiation of clozapine (aHR 0.49; 95% CI 0.43–0.57; P < 0.0001) unrestricted re-use, distribution, and reproduction in any and oral olanzapine (aHR 0.69; 95% CI 0.61–0.77; P < 0.0001). medium, provided the original work is properly cited. Current treatment options after clozapine cessation sufficient numbers of participants are included in subanalyses, Clozapine has proven superior efficacy over other antipsychotics1,2 little benefit is found for pharmacological augmentation and com- and is also the only drug registered for treatment of therapy-resist- bination strategies, with the exception of electroconvulsive 13 ant schizophrenia (TRS) in several countries.2,3 Clozapine is super- therapy being supported in one high-quality study. ior to other antipsychotics in reducing positive symptoms and Furthermore, to our knowledge no randomised trials into treat- psychiatric ward admissions in patients with TRS.4,5 TRS is com- ment options in patients with schizophrenia who are intolerant monly defined as ‘failure to respond to two or more antipsychotics or unresponsive to clozapine have been published. In sum, pos- (one of which should be a second-generation antipsychotic) given sibly because of a lack of power and the current paucity of high- in an adequate dose for at least 6–8weeks’.6,7 Around 30% of quality clinical trials, little is known about the optimal treatment patients with schizophrenia are treatment resistant.8,9 Of those, strategies in those discontinuing clozapine. approximately 60% do not respond to clozapine.10 Moreover, around 20% of those who initiate clozapine discontinue treatment because of limited tolerability.11,12 Real-world studies versus randomised trials For those unresponsive to clozapine, three strategies may be A statistically powerful approach to shed light on the comparative tried: augmentation with non-antipsychotic treatment modalities, effectiveness of treatment options in schizophrenia is a large and combinations of antipsychotics and switching. At present, guide- unselected registry study. Randomised clinical trials (RCTs) often lines do not provide a clear answer as to the preferred of those focus on short-term symptom reduction. Because schizophrenia is options for patients who discontinue their treatment with cloza- a lifelong illness, observational studies could reflect real-world pine.6,8 On a similar note, a recent meta-analysis on clozapine impact better than RCTs by focusing on long-term outcomes, combination and augmentation strategies in patients with TRS such as relapse prevention.14,15 By ‘real world’, we refer to data concluded that most studies supporting such strategies are of drawn from registry and observational studies. Furthermore, low quality.13 Moreover, when only high-quality studies with patients who enrol in RCTs often have better treatment adherence 1 Luykx et al and less severe symptoms than patients in a naturalistic setting, defined daily doses), dispensed drug and drug substance coded hampering generalisability to clinical practice.16 To minimise this with Anatomical Therapeutic Chemical (ATC) codes (http://www. issue of selection bias (i.e. selective inclusion of participants whocc.no/atc/structure_and_principles/). All residents of Finland leading to spurious findings), a potential pitfall in observational have been assigned a unique personal identification number, which studies, within-individual analyses may be applied to national regis- enables linkage between nationwide registers. try data. Exposure periods of each individual may thus be compared Antipsychotic use was identified with ATC code N05A, with the with non-exposure periods of the same individual, a strategy with exception of lithium (which is listed under N05A). Antipsychotics proven benefit to resolve important clinical dilemmas.14,15 were categorised into oral and long-acting injectable antipsychotics (LAIs) according to the drug product information in the Prescription Register data. Drug use periods were constructed Rationale and aims of the current study 24 from dispensings by the PRE2DUP method. The method is Given the lack of guidelines and evidence on treatment options based on modelling of each drug (per drug form) for each person after clozapine discontinuation, we set out to investigate the com- separately, by computing sliding averages of defined daily doses parative effectiveness (i.e. treatment benefit ascertained in a non- according to individual drug use patterns. The PRE2DUP method clinical trial setting) of pharmacological treatment options in takes into account ward admissions (when drugs are provided by patients with schizophrenia who terminate clozapine treatment. the caring unit and not recorded in the registers), stockpiling of We hypothesised that in patients formerly using clozapine, this drugs and changes in doses. compound should be best avoided because of either limited efficacy For the current analyses, we identified all clozapine use periods or lack of tolerability, reasoning that patients who had discontinued that ended with discontinuation of use (n = 7037). To ensure that clozapine would be relatively resistant to its efficacy and/or suscep- patients had been stable on clozapine before discontinuation, we tible to its adverse drug reactions. Moreover, there is also evidence required that clozapine use had been ongoing for at least 1 year of reduced effectiveness of antipsychotics after reintroduction or (n = 3585 use periods). We excluded clozapine use periods that – sustained use, in particular for clozapine.17 19 We realise that dis- were followed by clozapine reinitiation within <1 year. From the continuing clozapine may follow more than one pathway, primarily remaining 2313 use periods, we chose the first use period per lack of efficacy, low tolerability and patients’ decisions. Importantly, person, resulting in the final study population of 2250 clozapine dis- such scenarios reflect clinical practice where patients may stop clo- continuers (Supplementary Fig. 1 available at https://doi.org/10. zapine for unknown reasons or stop attending follow-up consulta- 1192/bjp.2019.267). tions. Moreover, physicians are often unable to retrospectively The main outcome variables in our study used for our primary assess the reason for clozapine discontinuation in a given patient. analyses were psychiatric ward readmission (psychosis determined Given the estimated fairly high likelihood of non-responsiveness to as ICD-10 codes F20–F29 recorded as the main diagnosis of admis- clozapine in patients with TRS (60%),10 we conducted a national sion) and treatment failure, which encompassed (a) any changes in registry study applying within- and between-individual analyses to antipsychotic treatment (switching, addition of another anti- a range of clinically relevant outcomes in patients with schizophrenia psychotic