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Inicio Spanish Journal of Psychiatry and Mental Health Looking to the future after reintroduction of clozapine
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Vol. 16. Núm. 4.
Páginas 266-267 (octubre - diciembre 2023)
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Vol. 16. Núm. 4.
Páginas 266-267 (octubre - diciembre 2023)
Letter to the Editor
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Looking to the future after reintroduction of clozapine
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Leticia I. Muñoz-Manchadoa,b,
Autor para correspondencia
, Jose María Villagrán-Morenoa,b,c, Roberto Palacios-Garrána,b, Jose Ildefonso Pérez-Revueltaa,b,c
a UGC North of Cadiz, Mental Health Inpatient Unit, General Hospital, Jerez de la Frontera, Spain
b Serious Mental Disorder Research Group, Cadiz Biomedical Research and Innovation Institute, Spain
c Department of Psychiatry, University of Cádiz, Cádiz, Spain
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Tablas (1)
Table 1. Summary of the three clinical cases.
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Dear Editor,

Clozapine has superior characteristics among other antipsychotics.1 Evidence and experience support clozapine as the best treatment in terms of efficacy, effectiveness and well-being, the gold standard for treatment resistant schizophrenia (TRS).2–4 It has also shown efficacy in differential psychopathological dimensions: negative, cognitive or affective symptoms.5 It has been demonstrated its results in terms of overall mortality and suicide.6 Despite its superiority, its use has been limited by the possibility of presenting lethal adverse effects.7 The risk of associated neutropenia (number of leukocytes less than 3.0×103/μL or absolute neutrophil count less than 1.5×103/μL) described reaches between 3.8% and 1% depending on studies.9

Rechallenging clozapine after neutropenia is a tough decision and each case should be analyzed individually.11 We present three clinical cases in which, after presenting neutropenia, clozapine was reintroduced, as well as the evolution of years later, in the first and the second ten and in the third four (Table 1).

Table 1.

Summary of the three clinical cases.

  Clinical case 1  Clinical case 2  Clinical case 3 
Genre  Male  Male  Female 
Age  54 years  20 years  37 years 
Diagnosis  Paranoid schizophrenia (F20.0)  Autism spectrum disorder (F84.0)  Paranoid schizophrenia (F20.0) 
Disease evolution time  31 years  18 years  10 years 
Maximum clozapine dose  300mg/day  450mg/day  150mg/day 
Time on clozapine before withdrawal  14 years  1 month  3 years 
Blood counts prior to suppression  Leukocytes: 3.73×103/μLNeutrophils: 0.86×103/μLplatelets: 53×103/μL  1.5×103/μL neutrophils  Neutrophils of 1.46×103/μL 
Secondary effect  Neutropenia  Neutropenia  Neutropenia 
Response strategy  Reintroduction with lithium carbonate  Reintroduction  Reintroduction 
Final resolution  Clozapine maintenance after 10 years of reintroduction  Clozapine maintenance after 10 years of reintroduction  Clozapine maintenance after 4 years of reintroduction 
Clinical case 1

A 55-year-old patient was diagnosed with paranoid schizophrenia since 1990. He started clozapine in 1998, maintaining psychopathological stability with a sustained dose of 300mg/24h. Active consumption of 30 cigarettes per day. In August 2012, neutropenia was detected with numbers of neutrophils: 0.86×103/μL, leukocytes: 3.73×103/μL, and platelets: 53×103/μL. After reducing clozapine and starting aripiprazole (15mg/d), the neutrophil counts normalized in December. The patient presented signs of psychopathological decompensation. Subsequently, intestinal injury in response to imposing auditory hallucinations was described. This caused the need for urgent surgery in January 2013 with a diagnosis of acute abdomen. Different antipsychotic drugs were tested at appropriate doses and in combination, quetiapine, aripiprazole, olanzapine, haloperidol, risperidone; with little response. It was decided restarting treatment with clozapine at a dose of 50mg/day associated with lithium carbonate (600mg). The patient presented progressive psychopathological improvement with no repercussions on haematological figures: plasma lithium levels: 0.54mEq/l; clozapine plasma levels: 191ng/mL; neutrophils: 3.77×10[3]/μL, Leukocytes: 5.98×10[3]/μL; Platelets: 149×10[3]/μL. Subsequently, they normalized, remaining in this way during the ten years of follow-up, also presenting psychopathological stability.

Clinical case 2

A 21-year-old patient with coagulation factor V and VII deficiency and follow-up in Neurology for suspected epilepsy. He has been going to mental health since January 2003, with a diagnosis of autism spectrum disorder. In 2009, the start of clozapine was evaluated after different antipsychotics that had been insufficient for the behavioural control of the patient, starting in December. In January 2010, neutrophils of 1.5×103neutrophils/μL appeared. One month after clozapine withdrawal, neutrophil levels returned to normal. At this time, treatment with clozapine was discontinued, starting with quetiapine, risperidone, olanzapine, aripiprazole, psychostimulants and clonazepam, which was insufficient. Finally, in September 2013, clozapine was reintroduced with close analytical monitoring. In the ten years of evolution in which the patient continues with clozapine, no analytical alterations have been observed.

Clinical case 3

A 38-year-old woman began her mental health follow-up in 2011. She attended urgently due to the presence of commentator-type auditory hallucinations and insomnia. No evidence of previous diseases of interest or consumption of substances of abuse. Start of treatment with risperidone; later changes to aripiprazole (30mg/day). In 2014, she was diagnosed with paranoid schizophrenia. A switch was made to olanzapine (20mg/day), later to paliperidone (15mg/day) and ziprasidone (8mg/day). In January 2016, a clozapine regimen was started, presenting an improvement in the patient's positive and negative symptoms with a 150mg/day dose. In 2019, a progressive decrease in neutrophils appeared again with minimum levels of 1.46×103/μL, requiring a reduction in the dose of clozapine until its withdrawal in August 2019. In October, neutrophil levels were 3.02×103/μL, delusional ideation reappearing of reference and control, pseudo-perceptions and negative symptomatology. Clozapine was rechallenge in November 2019. Serial tests have been performed since the reintroduction without a decrease in neutrophil levels.

A review of three clinical cases from our Mental Health management area in which clozapine was reintroduced after discontinuation of treatment due to an episode of neutropenia has been carried out. The importance of these cases lies both in the rechallenge and in the positive evolution that they have had years later. It is recommended to restart clozapine in TRS if it was interrupted due to moderate leukopenia or neutropenia but not with the presence of agranulocytosis.10 According to the bibliography, the tendency to reintroduce should be different depending on the adverse effect presented. The normalization of haematological values and the study of the cause of neutropenia are essential before reintroduction. It is recommended to monitor haematological values every two weeks for at least 3 months after reintroduction.

Further reading
[8]
J.M. Vermeulen, G. van Rooijen, M.P.J. van de Kerkhof, A.L. Sutterland, C.U. Correll, L. de Haan.
Clozapine and long-term mortality risk in patients with schizophrenia: a systematic review and meta-analysis of studies lasting 1.1–12.5 years.
Schizophr Bull, 45 (2019), pp. 315
References
[1]
D. Siskind, L. McCartney, R. Goldschlager, S. Kisely.
Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis.
Br J Psychiatry, 209 (2016), pp. 385-392
[2]
S.W. Lewis, T.R.E. Barnes, L. Davies, R.M. Murray, G. Dunn, K.P. Hayhurst, et al.
Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia.
Schizophr Bull, 32 (2006), pp. 715-723
[3]
J. McEvoy.
Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment.
Am J Psychiatry, 163 (2006), pp. 600
[4]
A. Essali, N. Al-Haj Haasan, C. Li, J. Rathbone.
Clozapine versus typical neuroleptic medication for schizophrenia.
Cochrane Database Syst Rev, 2009 (2009),
[5]
C. Okhuijsen-Pfeifer, E.A.H. Huijsman, A. Hasan, I.E.C. Sommer, S. Leucht, R.S. Kahn, et al.
Clozapine as a first- or second-line treatment in schizophrenia: a systematic review and meta-analysis.
Acta Psychiatr Scand, 138 (2018), pp. 281
[6]
J.J. Luykx, N. Stam, A. Tanskanen, J. Tiihonen, H. Taipale.
In the aftermath of clozapine discontinuation: comparative effectiveness and safety of antipsychotics in patients with schizophrenia who discontinue clozapine.
Br J Psychiatry, 217 (2020), pp. 498-505
[7]
D. De Berardis, G. Rapini, L. Olivieri, D. Di Nicola, C. Tomasetti, A. Valchera, et al.
Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine.
Ther Adv Drug Saf, 9 (2018), pp. 237
[9]
P. Manu, D. Sarpal, O. Muir, J.M. Kane, C.U. Correll.
When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature.
Schizophr Res, 134 (2012), pp. 180-186
[10]
A. Mijovic, J.H. MacCabe.
Clozapine-induced agranulocytosis.
Ann Hematol, 99 (2020), pp. 2477-2482
[11]
T.L. Demler, E. Trigoboff.
Are clozapine blood dyscrasias associated with concomitant medications?.
Innov Clin Neurosci, 8 (2011), pp. 35-41
Copyright © 2023. Sociedad Española de Psiquiatría y Salud Mental (SEPSM)
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