In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine

Luykx, Jurjen J.; Stam, Noraly; Tanskanen, Antti; Tiihonen, Jari; Taipale, Heidi

doi:10.1192/bjp.2019.267

Cited by 42 publications

(48 citation statements)

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“…Quetiapine could be frequently initiated due to the favorable side‐effect profile, compared with other antipsychotics 37 . The findings are also in line with a recent Finnish registry study showing that restarting clozapine and switching to oral olanzapine is associated with a lower risk of psychiatric ward re‐admission, treatment failure, and mortality, compared with switching to other antipsychotics 23 …”

Section: Discussionsupporting

confidence: 76%

“…37 The findings are also in line with a recent Finnish registry study showing that restarting clozapine and switching to oral olanzapine is associated with a lower risk of psychiatric ward re-admission, treatment failure, and mortality, compared with switching to other antipsychotics. 23 We found that polypharmacy without clozapine was associated with similar persistence relative to monotherapy in patients discontinuing clozapine. Polypharmacy may reduce symptoms more effectively than monotherapy due to better receptor occupancy, but this could also lead to more or relatively severe side effects, resulting in no difference in persistence.…”

Section: Discussionmentioning

confidence: 66%

“…Due to the lack of studies on these strategies, current guidelines do not provide a clear answer as to which of those treatment options is preferred in patients who discontinue their treatment with clozapine 12,13 . However, a recent Finnish registry study showed that re‐initiation of clozapine and switching to oral olanzapine was associated with a lower risk of psychiatric rehospitalization, treatment failure, and mortality compared with switching to other antipsychotics in patients discontinuing clozapine 23 . Because those results are based on a single cohort in one country using those outcome measures, we reasoned it is worthwhile to evaluate if these antipsychotics are also preferred when looking at other outcome measures and in other countries, such as persistence of use in The Netherlands.…”

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confidence: 99%

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Persistence of Antipsychotic Use After Clozapine Discontinuation: A Real‐World Study Across Antipsychotics

Stam

Taipale

Tanskanen

et al. 2020

Clinical Translational Sci

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Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for ≥ 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P < 0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

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Persistence of Antipsychotic Use After Clozapine Discontinuation: A Real‐World Study Across Antipsychotics

Stam

Taipale

Tanskanen

et al. 2020

Clinical Translational Sci

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“…83,84 It is recognized that the best treatment for psychosis after clozapine has been discontinued is a repeated trial of clozapine. 85 Given the risks associated with treatment failure in our patient group, we took an active approach to supporting neutrophil counts, often using G-CSF.…”

Section: Discussionmentioning

confidence: 99%

“… 83 , 84 It is recognized that the best treatment for psychosis after clozapine has been discontinued is a repeated trial of clozapine. 85 …”

Section: Discussionmentioning

confidence: 99%

Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital

Silva

Higgins

Hammer

et al. 2021

Therapeutic Advances in Psychopharmacology

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Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia; however, its use is prohibited following neutropenias. We review neutrophil biology as applied to clozapine and describe the strategies to initiate clozapine following neutropenia used in a case series of 14 consecutive patients rechallenged in a United Kingdom (UK) high-secure psychiatric hospital. We examine outcomes including the use of seclusion and transfer. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using this routinely collected clinical data, we describe the patient characteristics, causes of neutropenia, the strategies used for rechallenging with clozapine and clinical outcomes. Results: Previous neutropenias were the result of benign ethnic neutropenia, clozapine, other medications and autoimmune-related. Our risk mitigation strategies included: granulocyte-colony stimulating factor (G-CSF), lithium and watch-and-wait. There were no serious adverse events; at follow up half of the patient’s had improved sufficiently to transfer them to conditions of lesser security. There were dramatic reductions in the use of seclusion. Conclusion: Even in this extreme group, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients. This requires careful planning based on an understanding of neutrophil biology and the aetiology of the specific episode of neutropenia.

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Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia

Luykx,

Correll,

Manu

et al. 2024

JAMA Psychiatry

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ImportanceAntipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia.ObjectiveTo estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia.Design, Setting, and ParticipantsThis cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023.ExposuresUse of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (&lt;0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to &lt;1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high.Main Outcomes and MeasuresThe primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference.ResultsThe study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P &lt; .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P &lt; .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P &lt; .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk.Conclusions and RelevanceResults of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

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In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine

Cited by 42 publications

References 27 publications

Persistence of Antipsychotic Use After Clozapine Discontinuation: A Real‐World Study Across Antipsychotics

Persistence of Antipsychotic Use After Clozapine Discontinuation: A Real‐World Study Across Antipsychotics

Clozapine re-challenge and initiation following neutropenia: a review and case series of 14 patients in a high-secure forensic hospital

Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia

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