Mask Off? Lithium Augmentation for Clozapine Rechallenge After Neutropenia or Agranulocytosis

Boazak, Mina; Goldsmith, David R.; Cotes, Robert O.

doi:10.4088/pcc.18l02282

Cited by 21 publications

(20 citation statements)

References 15 publications

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“…26 Whenever clozapine seems the only viable antipsychotic treatment option in patients with schizophrenia, adding lithium may increase neutrophil counts, but recently authors have cautioned against lithium discontinuation in such patients. 27 If clinicians are concerned about past or future serious adverse drug reactions in a specific patient previously on clozapine, several good treatment options other than clozapine remain, based on our data. Oral olanzapine was the second-best-performing antipsychotic in our analyses as this compound was always among the four best-performing drugs in both monotherapy and antipsychotic polypharmacy.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2020

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Background Although clozapine is often discontinued, there is a paucity of guidelines and evidence on treatment options after clozapine discontinuation. Moreover, it is currently unknown whether reinstating clozapine in patients formerly using clozapine should be avoided. Aims To compare the real-world effectiveness of antipsychotics after clozapine cessation. Method From Finnish registry data (1995–2017), we identified 2250 patients with schizophrenia who had been using clozapine for ≥1 year before treatment cessation. The primary analysis consisted of adjusted within-individual analyses of psychiatric ward readmission owing to psychosis and treatment failure. Secondary analyses concerned between-individual mortality differences. Results Compared with no use of antipsychotics, risk of psychiatric ward readmission was lowest for reinitiation of clozapine (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 antipsychotic polypharmacy (aHR 0.62; 95% CI 0.53–0.72; P < 0.0001). Risk of treatment failure was lowest for aripiprazole long acting injectable (aHR 0.42; 95% CI 0.27–0.65; P < 0.0001), reinitiation of clozapine (aHR 0.49; 95% CI 0.43–0.57; P < 0.0001) and oral olanzapine (aHR 0.69; 95% CI 0.61–0.77; P < 0.0001). Mortality risk was lowest for reinitiation of clozapine (aHR 0.18; 95% CI 0.09–0.36; P < 0.0001) and oral olanzapine (aHR 0.26; 95% CI 0.17–0.40; P < 0.0001). Conclusions Clozapine and olanzapine are the most effective and safest treatment options in those discontinuing clozapine for undefined reasons. Clozapine should therefore be reconsidered in patients with schizophrenia who previously discontinued this compound.

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Section: Discussionmentioning

confidence: 92%

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

et al. 2020

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“…Oral lithium has also been used to stimulate leucocyte production, but requires careful monitoring and there are concerns such as possible masking of an impending clozapine-induced agranulocytosis and whether it is safe to discontinue lithium once the WCC has recovered. 50 This is important because lithium will not protect against clozapine-induced agranulocytosis, and hence, it should not be used in rechallenging patients who have suffered a fall in the WCC that necessitated clozapine withdrawal.…”

Section: Adverse Events On Clozapinementioning

confidence: 99%

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

Flanagan

Lally

Gee

et al. 2020

British Medical Bulletin

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Background Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events. Sources of data Published literature. Areas of agreement Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure. Areas of controversy It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate. Growing points There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely. Areas timely for developing research There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage.

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“… 49 It enhances production of endogenous G-CSF, directly stimulating differentiation of stem cells and protecting neutrophils from the toxicity of some drugs. The case reports of lithium to support clozapine rechallenge were reviewed by Manu et al 50 and Boazak et al , 51 showing high rates of success.…”

Section: Idiosyncratic Drug-induced Neutropeniamentioning

confidence: 99%

“…52 , 53 As an adjunct to clozapine rechallenge, the familiarity psychiatrists have with the use of lithium, patient acceptability, low cost and the attitude of downstream services are helpful. 50 , 51 , 54 However, lithium’s effect on neutrophil production, although significant, is markedly less than the alternative of G-CSF and there is an uncertain risk of reversible neurotoxicity. 55 There is a case report of the use of lithium with clozapine resulting in fatal agranulocytosis.…”

Section: Idiosyncratic Drug-induced Neutropeniamentioning

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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Mask Off? Lithium Augmentation for Clozapine Rechallenge After Neutropenia or Agranulocytosis

Cited by 21 publications

References 15 publications

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

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

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

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

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