Clozapine and agranulocytosis in Spain: Do we have a safer population? A 5-year haematologic follow-up | Revista de Psiquiatría y Salud Mental (English Edition)

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Seguimiento hematológico a 5 años de una cohorte de pacientes tratados con clozapina" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1378 "Ancho" => 2087 "Tamanyo" => 129764 ] ] "descripcion" => array:1 [ "en" => "White blood cell count during first 18 weeks (n=231)." ] ] ] "textoCompleto" => "IntroductionClozapine, a second generation antipsychotic, is the treatment of choice for patients with refractory schizophrenia, as it has proved to be more effective than other existing antipsychotics, both typical and atypical.<a class="elsevierStyleCrossRefs" href="#bib0005">1–7</a> Discovered in 1958, it was the first atypical antipsychotic, effective in the treatment of positive and negative schizophrenic symptoms,<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> which in addition to its favourable profile regarding extrapyramidal adverse effects, generated grand expectations in the scientific and clinical world at that time. However, its development and commercialisation were interrupted in 1975, due to information concerning patients who developed agranulocytosis in Finland while being treated with clozapine.<a class="elsevierStyleCrossRefs" href="#bib0040">8,10,11</a>In later years, studies involving blood monitoring were carried out that showed clinically favourable results.<a class="elsevierStyleCrossRefs" href="#bib0035">7,12</a> The use of clozapine was approved by the Food and Drug Administration (FDA) in 1990 as an exclusive treatment for patients with resistant schizophrenia, who would also be subject to strict blood monitoring. Since then, clozapine was progressively reintroduced in 1993 under strict conditions put forth by the Ministry of Health, who insured its controlled use by limiting its applications and enforcing a strict check of differential white blood cell counts before starting treatment, on a weekly basis for the first 18 weeks and on a monthly basis after that (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>The incidence of agranulocytosis and neutropenia show marked variations, depending on the sample size and the location in which the study was completed.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> In the follow-up cohorts with a larger sample size, an incidence of approximately 1% and 3% was observed for agranulocytosis and neutropenia respectively.<a class="elsevierStyleCrossRefs" href="#bib0070">14–16</a> Of the agranulocytosis cases, 95% appeared within the first 6 months of treatment, with the risk being even greater in the first 3 months.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> The exact mechanism by which clozapine induces agranulocytosis is not completely clear. There is evidence that it involves an immune-mediated reaction<a class="elsevierStyleCrossRef" href="#bib0085">17</a> and that certain factors like ethnicity and age of the populations studied could intervene.<a class="elsevierStyleCrossRefs" href="#bib0070">14–16,18–21</a> We realised how important this drug is for treating resistant patients and how little data regarding the risk of agranulocytosis there is in our population. Consequently, in an effort to evaluate the risk of developing blood dyscrasias, we prepared this prospective 5-year follow-up of a cohort of patients undergoing treatment in the Clozapine Clinic (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Methods and materialsThe study involves a cohort of patients treated in the Clozapine Clinic of Outpatient Care at the Neuroscience Institute in the Hospital Clínico in Barcelona. Patients fulfilled the criteria defined by the ICD-10 for diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder with psychotic symptoms. They began treatment with clozapine due to their resistance to previous antipsychotic treatment. This resistance is defined by the persistence of psychotic symptoms despite consecutive treatment with therapeutic dosages of 2 antipsychotics, administered within 6 months of each other; or also by intolerance to treatment with other antipsychotics due to serious adverse or untreatable neurological reactions (extrapyramidal symptoms or tardive dyskinesia).For these patients, a white blood cell count and absolute neutrophil count were performed, according to current regulations, weekly during the first 18 weeks of treatment and monthly subsequently.The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography in a subgroup of 112 patients. We included all of the patients who joined the study after the technique was available in our laboratory in this subgroup.With reference to the blood evaluations, we considered as criteria for inclusion that the cases had had at least 4 months of follow-up in our centre, and no less than 24 months follow-up for those cases from another centre. The patients who began clozapine treatment before the regulations that dictate follow-up procedure went into effect were also included.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>For the purpose of this study, the definitions used for leucopenia, neutropenia and agranulocytosis are the internationally accepted ones. Leucopenia was defined by a white blood cell count of less than 3×109/L and neutropenia was a neutrophil count between 0.5×109/L and 1.5×109/L. Agranulocytosis was defined as a granulocyte count of less than 0.5×109/L. Likewise, the definitions of neutrophilia and leucocytosis were a neutrophil count of less than 7.5×109/L and a white blood cell count less than 11.5×109/L respectively. In this study, the time criterion was defined as 3 consecutive abnormal counts during the weekly follow-up and 2 during the monthly follow-up.For the analysis of the differences in neutrophil and white blood cell values in the determinations performed, from the initial measure to the following measures, variance analysis was used for repeated measures. To determine the points where significant differences occurred, contrasts that were a priori within subjects were calculated, comparing each determination with the initial one.ResultsThe sample consisted of 271 patients, 63.5% of whom were male. The mean age was 32.3 years (standard deviation [SD] 10.5), with an interval that went from 18.2 to 78.7 years. The dosages administered of clozapine during the follow-up were between 25 and 600mg/day. The mean dose administered was 227.6mg/day (SD 118.7), and the median was 200mg/day.The plasma concentrations of clozapine and norclozapine were monitored in a subgroup of 112 patients from the cohort, composed of 38 females with a mean dose of 207.6mg/day and 74 males with a mean dose of 256mg/day. The plasma concentrations of clozapine and norclozapine were 239.1ng/ml and 138.2ng/ml respectively for women, and 274.7ng/ml and 166.3ng/ml respectively for men.Of the total 231 cases that completed the first 18 weeks of follow-up, 3 cases of leucopenia (1.3%), 7 cases of neutropenia (3.0%) and no cases of agranulocytosis were observed.The sharp increase in the neutrophil and white blood cell numbers during the first few weeks attracted attention. This increase reached its maximum point between the second and third week, with there being a significant difference between these counts and the base count. After this point, the count began to decrease progressively until the difference became significant during the last 4 weeks for the neutrophils and during the last 10 weeks for the white blood cells.During the next 2 years of follow-up, this difference maintained significance (P<0.005 according to Pillai's Trace), although the counts tended to stabilise. One new case of leucopenia and neutropenia was observed of the total sample (n=120).We had a complete monthly follow-up of haematological counts during 5 years for 69 patients. During these years, no new cases of leucopenia or neutropenia were observed and the curve of the count tended to level out towards the limits.Of the 2 cases mentioned, we decided to suspend treatment in 1 of them in an effort to keep neutrophil numbers low and, in the other, due to the emergence of simple epileptic seizures.DiscussionIn the cohort of patients treated with clozapine, a neutropenia prevalence of 3% was observed, concentrated in the first few months of follow-up, which agrees with data published by other authors.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> No patient presented agranulocytosis.The majority of patients in the sample had a diagnosis of resistant psychosis or had presented significant adverse effects associated with the use of other antipsychotic treatments.Estimations on resistant schizophrenia prevalence vary depending on its definition, but it is estimated that between one-fifth and one-third of patients with schizophrenia have a sub-optimal response to antipsychotic treatment. This warrants attention in that, despite current scientific evidence for the benefits of clozapine over other antipsychotics in schizophrenia treatment, this drug continues to be underused.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> In the United States, the percentage of clozapine prescriptions compared to other antipsychotics did not reach 3.5% during the 2008–2009 period.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> In an Italian sample, the percentage observed was 1.5%.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>The prescription of clozapine seems to be limited by its adverse effects like drooling, dizziness, constipation and other symptoms that could potentially increase the morbidity and mortality rate among patients, such as metabolic syndrome, agranulocytosis, myocarditis, cardiomyopathy and a decrease in the seizure threshold. Furthermore, in a recently published study by Tiihonen et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> (in which a 10-year follow-up was carried out for a Finnish cohort of 66,881 patients with a schizophrenia diagnosis), the authors concluded that the patients treated by clozapine had the lowest risk of premature death, compared with the patients who took other antipsychotics and the patients who took no antipsychotics regularly. This protective effect could be partially mediated by the reduction in suicide risk.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The authors suggested that the restrictions on the use of clozapine “may have caused thousands of premature deaths.”The fact that the majority of patients under clozapine treatment are resistant or have previously had significant adverse effects to other antipsychotics makes the decision to suspend clozapine treatment difficult. Many physicians consider reinitiating clozapine in patients with a history of neutropenia despite the risk that it might involve.<a class="elsevierStyleCrossRefs" href="#bib0145">29,30</a>Clozapine can be related to neutropenia both directly (as we previously examined) and indirectly. Examples of the latter include benign ethnic neutropenia, side effects of other drugs administered concomitantly or through interaction with clozapine and medical comorbidity.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Methods described for the management of neutropenia in these patients include co-administering lithium, administering granulopoiesis stimulating factors and managing concomitant drugs rationally. While these treatments do provide a safety margin, they have been used in only a limited number of cases and the level of evidence is still weak.<a class="elsevierStyleCrossRefs" href="#bib0145">29,31,32</a>The protocols associated with clozapine use are extremely costly for the patient and for healthcare services. Current evidence available on the effectiveness and safety of this drug and the results of this study make it appropriate to start reviewing and discussing the protocols for clozapine usage and follow-up. Taking into consideration the greater risk concentrated in the first 6 months of treatment, and the risk of agranulocytosis after the first year–which is equal to that of other drugs not specifying monitoring–we would be in favour of maintaining a weekly follow-up in the first 18 weeks, a monthly follow-up throughout the rest of the first year and a bi-monthly follow-up after that. This change could involve a lower cost for the patient and for healthcare services and could also improve adherence to follow-ups and treatment.Ethical responsibilitiesProtection of human and animal subjectsThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Confidentiality of dataThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.Right to privacy and informed consentThe authors must have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence must be in possession of this document.Conflict of interestDr. Bernardo has received funds for research and/or has acted as a consultant and/or speaker in activities organised by the following companies: Adamet, Almirall, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Mylan, Pfizer, Rocher and Rovi.Dr. Pons has acted as a consultant and/or speaker for the following companies: Janssen-Cilag and Johnson & Johnson." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres115248" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Materials and method" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec102545" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres115249" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusión" ] ] 3 => array:2 [ "identificador" => "xpalclavsec102546" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods and materials" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Ethical responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack37114" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-08-22" "fechaAceptado" => "2011-11-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec102545" "palabras" => array:3 [ 0 => "Agranulocytosis" 1 => "Neutropenia" 2 => "Clozapine" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec102546" "palabras" => array:3 [ 0 => "Agranulocitosis" 1 => "Neutropenia" 2 => "Clozapina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionClozapine is an effective antipsychotic. However, its use has been associated with agranulocytosis. For this reason, it has been restricted for the treatment of resistant schizophrenia under a strict haematologic control. The objective of this work was to assess the risk of haematologic dyscrasias in a sample of clozapine-treated patients in a 5-year period. Materials and methodThis is a follow-up study in a cohort of clozapine-treated patients in which the risk of haematological dyscrasias was assessed. Complete blood cell count was made for each patient in a weekly basis for the first 18 weeks and thereafter monthly. Results271 patients in treatment with clozapine were followed up. The mean age was 32.3 years, with 36.5% women. The mean dose was 2276mg, ranging from 25 to 600mg/day. During the first 18 weeks of follow-up, we observed a 3% incidence of neutropenia and 1.3% of leucopenia. During the next 2 years, only 1 new case of neutropenia and leucopenia was observed (n=120). No new cases were observed during the rest of follow up (n=69). No cases of agranulocytosis were observed. ConclusionsA 3% incidence of neutropenia concentrated in the first months of follow up and no cases of agranulocytosis were observed in our sample. Actual evidence on clozapine effectiveness and safety and the results of this study suggests that a critical revision of follow-up protocols is suitable." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa clozapina es un fármaco de probada efectividad, sin embargo, su uso se asoció a la aparición de agranulocitosis y así, fue restringido para esquizofrenia resistente y con un estricto control hematológico. El objetivo de nuestro trabajo es evaluar el riesgo de discrasias sanguíneas en una población de pacientes en tratamiento con clozapina seguidos durante 5 años. Material y métodosSe trata de una cohorte de pacientes en tratamiento con clozapina en los que se evaluó el riesgo de aparición de alteraciones en la serie blanca, a través de analíticas semanales durante las primeras 18 semanas y mensuales a partir de entonces. ResultadosSe trata de una muestra de 271 pacientes, con un media de edad de 32, 3 años y un 63,5% de hombres. La dosis media administrada fue de 227,6mg/día (25 a 600mg). Durante las primeras 18 semanas de seguimiento, se observó una incidencia de neutropenia de 3,0% y de leucopenia de 1,3%. Durante los dos años siguientes, se encontró un nuevo caso de leucopenia y uno de neutropenia (n=120). No se observaron nuevos casos en los pacientes que completaron 5 años de seguimiento (n=69). A lo largo de todo el seguimiento, no hubo ningún caso de agranulocitosis. ConclusiónSe observó una incidencia de neutropenia del 3%, concentrado en los primeros meses de seguimiento. Ningún paciente presentó agranulocitosis. La evidencia actual disponible sobre efectividad y seguridad de la clozapina y los resultados del presente estudio, hacen adecuado plantearse revisar los protocolos de seguimiento y utilización de este fármaco." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Pons A, et al. Clozapina y agranulocitosis en España: ¿tenemos una población más segura? Seguimiento hematológico a 5 años de una cohorte de pacientes tratados con clozapina. Rev Psiquiatr Salud Ment (Barc.). 2012;5(1):37–42." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1378 "Ancho" => 2087 "Tamanyo" => 129764 ] ] "descripcion" => array:1 [ "en" => "White blood cell count during first 18 weeks (n=231)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2938 "Ancho" => 2523 "Tamanyo" => 289060 ] ] "descripcion" => array:1 [ "en" => "18-week count (n=231)." ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Initial cohort (n=271) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age: mean \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32.3 (18.2–78.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Men \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">172 (63.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 (36.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean clozapine dosage (SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">227.6 (118.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diagnosis</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Schizophrenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">229 (84.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Affective psychosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (15.5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab203030.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Socio-demographic information and mean clozapine dosage." ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Week \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">White blood cells</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neutrophils</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">F value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sig. (P<0.05) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">F value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sig. (P<0.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.00001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n 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title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n 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\t\t\t\t">19.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.00002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.008 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab203029.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Repeated measures analysis of variance. Within-subject contrasts were also performed a priori comparing each measure with the initial one. F and P values (in bold, P<0.05), according to Pillai's Trace, for the white blood cell and neutrophil count during the first 18 weeks of follow-up." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Schizophrenia Consensus Group of British Association for Psychopharmacology" "etal" => false "autores" => array:1 [ 0 => "T.R. 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Original article

Clozapine and agranulocytosis in Spain: Do we have a safer population? A 5-year haematologic follow-up

Clozapina y agranulocitosis en España: ¿tenemos una población más segura? Seguimiento hematológico a 5 años de una cohorte de pacientes tratados con clozapina

Alexander Ponsa, Juan Undurragab,

Corresponding author

jundurra@clinic.ub.es
juanundu@gmail.com

Corresponding author.

, Albert Batallac, Miquel Bernardod

a Programa Esquizofrènia Clínic, Hospital Clínic de Barcelona, Departamento de Psiquiatría y Psicobiología Clínica, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

b Programa de Trastorno Bipolar, Hospital Clínic de Barcelona, Departamento de Psiquiatría y Psicobiología Clínica, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain

c Programa Esquizofrènia Clínic, Hospital Clínic de Barcelona, Departamento de Psiquiatría y Psicobiología Clínica, Universitat de Barcelona, Barcelona, Spain

d Programa Esquizofrènia Clínic, Hospital Clínic de Barcelona, Departamento de Psiquiatría y Psicobiología Clínica, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain

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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">White blood cell count during first 18 weeks &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>231&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Clozapine&#44; a second generation antipsychotic&#44; is the treatment of choice for patients with refractory schizophrenia&#44; as it has proved to be more effective than other existing antipsychotics&#44; both typical and atypical&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;7</span></a> Discovered in 1958&#44; it was the first atypical antipsychotic&#44; effective in the treatment of positive and negative schizophrenic symptoms&#44;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> which in addition to its favourable profile regarding extrapyramidal adverse effects&#44; generated grand expectations in the scientific and clinical world at that time&#46; However&#44; its development and commercialisation were interrupted in 1975&#44; due to information concerning patients who developed agranulocytosis in Finland while being treated with clozapine&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10&#44;11</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In later years&#44; studies involving blood monitoring were carried out that showed clinically favourable results&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;12</span></a> The use of clozapine was approved by the Food and Drug Administration &#40;FDA&#41; in 1990 as an exclusive treatment for patients with resistant schizophrenia&#44; who would also be subject to strict blood monitoring&#46; Since then&#44; clozapine was progressively reintroduced in 1993 under strict conditions put forth by the Ministry of Health&#44; who insured its controlled use by limiting its applications and enforcing a strict check of differential white blood cell counts before starting treatment&#44; on a weekly basis for the first 18 weeks and on a monthly basis after that &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The incidence of agranulocytosis and neutropenia show marked variations&#44; depending on the sample size and the location in which the study was completed&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In the follow-up cohorts with a larger sample size&#44; an incidence of approximately 1&#37; and 3&#37; was observed for agranulocytosis and neutropenia respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> Of the agranulocytosis cases&#44; 95&#37; appeared within the first 6 months of treatment&#44; with the risk being even greater in the first 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The exact mechanism by which clozapine induces agranulocytosis is not completely clear&#46; There is evidence that it involves an immune-mediated reaction<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and that certain factors like ethnicity and age of the populations studied could intervene&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16&#44;18&#8211;21</span></a> We realised how important this drug is for treating resistant patients and how little data regarding the risk of agranulocytosis there is in our population&#46; Consequently&#44; in an effort to evaluate the risk of developing blood dyscrasias&#44; we prepared this prospective 5-year follow-up of a cohort of patients undergoing treatment in the Clozapine Clinic &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods and materials</span><p id="par0020" class="elsevierStylePara elsevierViewall">The study involves a cohort of patients treated in the Clozapine Clinic of Outpatient Care at the Neuroscience Institute in the Hospital Cl&#237;nico in Barcelona&#46; Patients fulfilled the criteria defined by the ICD-10 for diagnosis of schizophrenia&#44; schizoaffective disorder or bipolar disorder with psychotic symptoms&#46; They began treatment with clozapine due to their resistance to previous antipsychotic treatment&#46; This resistance is defined by the persistence of psychotic symptoms despite consecutive treatment with therapeutic dosages of 2 antipsychotics&#44; administered within 6 months of each other&#59; or also by intolerance to treatment with other antipsychotics due to serious adverse or untreatable neurological reactions &#40;extrapyramidal symptoms or tardive dyskinesia&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">For these patients&#44; a white blood cell count and absolute neutrophil count were performed&#44; according to current regulations&#44; weekly during the first 18 weeks of treatment and monthly subsequently&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography in a subgroup of 112 patients&#46; We included all of the patients who joined the study after the technique was available in our laboratory in this subgroup&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">With reference to the blood evaluations&#44; we considered as criteria for inclusion that the cases had had at least 4 months of follow-up in our centre&#44; and no less than 24 months follow-up for those cases from another centre&#46; The patients who began clozapine treatment before the regulations that dictate follow-up procedure went into effect were also included&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">For the purpose of this study&#44; the definitions used for leucopenia&#44; neutropenia and agranulocytosis are the internationally accepted ones&#46; Leucopenia was defined by a white blood cell count of less than 3<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L and neutropenia was a neutrophil count between 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L and 1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; Agranulocytosis was defined as a granulocyte count of less than 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; Likewise&#44; the definitions of neutrophilia and leucocytosis were a neutrophil count of less than 7&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L and a white blood cell count less than 11&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L respectively&#46; In this study&#44; the time criterion was defined as 3 consecutive abnormal counts during the weekly follow-up and 2 during the monthly follow-up&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">For the analysis of the differences in neutrophil and white blood cell values in the determinations performed&#44; from the initial measure to the following measures&#44; variance analysis was used for repeated measures&#46; To determine the points where significant differences occurred&#44; contrasts that were <span class="elsevierStyleItalic">a priori</span> within subjects were calculated&#44; comparing each determination with the initial one&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The sample consisted of 271 patients&#44; 63&#46;5&#37; of whom were male&#46; The mean age was 32&#46;3 years &#40;standard deviation &#91;SD&#93; 10&#46;5&#41;&#44; with an interval that went from 18&#46;2 to 78&#46;7 years&#46; The dosages administered of clozapine during the follow-up were between 25 and 600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; The mean dose administered was 227&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;SD 118&#46;7&#41;&#44; and the median was 200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The plasma concentrations of clozapine and norclozapine were monitored in a subgroup of 112 patients from the cohort&#44; composed of 38 females with a mean dose of 207&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;day and 74 males with a mean dose of 256<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; The plasma concentrations of clozapine and norclozapine were 239&#46;1<span class="elsevierStyleHsp" style=""></span>ng&#47;ml and 138&#46;2<span class="elsevierStyleHsp" style=""></span>ng&#47;ml respectively for women&#44; and 274&#46;7<span class="elsevierStyleHsp" style=""></span>ng&#47;ml and 166&#46;3<span class="elsevierStyleHsp" style=""></span>ng&#47;ml respectively for men&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Of the total 231 cases that completed the first 18 weeks of follow-up&#44; 3 cases of leucopenia &#40;1&#46;3&#37;&#41;&#44; 7 cases of neutropenia &#40;3&#46;0&#37;&#41; and no cases of agranulocytosis were observed&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The sharp increase in the neutrophil and white blood cell numbers during the first few weeks attracted attention&#46; This increase reached its maximum point between the second and third week&#44; with there being a significant difference between these counts and the base count&#46; After this point&#44; the count began to decrease progressively until the difference became significant during the last 4 weeks for the neutrophils and during the last 10 weeks for the white blood cells&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">During the next 2 years of follow-up&#44; this difference maintained significance &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005 according to Pillai&#39;s Trace&#41;&#44; although the counts tended to stabilise&#46; One new case of leucopenia and neutropenia was observed of the total sample &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>120&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">We had a complete monthly follow-up of haematological counts during 5 years for 69 patients&#46; During these years&#44; no new cases of leucopenia or neutropenia were observed and the curve of the count tended to level out towards the limits&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Of the 2 cases mentioned&#44; we decided to suspend treatment in 1 of them in an effort to keep neutrophil numbers low and&#44; in the other&#44; due to the emergence of simple epileptic seizures&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">In the cohort of patients treated with clozapine&#44; a neutropenia prevalence of 3&#37; was observed&#44; concentrated in the first few months of follow-up&#44; which agrees with data published by other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> No patient presented agranulocytosis&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The majority of patients in the sample had a diagnosis of resistant psychosis or had presented significant adverse effects associated with the use of other antipsychotic treatments&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Estimations on resistant schizophrenia prevalence vary depending on its definition&#44; but it is estimated that between one-fifth and one-third of patients with schizophrenia have a sub-optimal response to antipsychotic treatment&#46; This warrants attention in that&#44; despite current scientific evidence for the benefits of clozapine over other antipsychotics in schizophrenia treatment&#44; this drug continues to be underused&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In the United States&#44; the percentage of clozapine prescriptions compared to other antipsychotics did not reach 3&#46;5&#37; during the 2008&#8211;2009 period&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In an Italian sample&#44; the percentage observed was 1&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The prescription of clozapine seems to be limited by its adverse effects like drooling&#44; dizziness&#44; constipation and other symptoms that could potentially increase the morbidity and mortality rate among patients&#44; such as metabolic syndrome&#44; agranulocytosis&#44; myocarditis&#44; cardiomyopathy and a decrease in the seizure threshold&#46; Furthermore&#44; in a recently published study by Tiihonen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> &#40;in which a 10-year follow-up was carried out for a Finnish cohort of 66&#44;881 patients with a schizophrenia diagnosis&#41;&#44; the authors concluded that the patients treated by clozapine had the lowest risk of premature death&#44; compared with the patients who took other antipsychotics and the patients who took no antipsychotics regularly&#46; This protective effect could be partially mediated by the reduction in suicide risk&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The authors suggested that the restrictions on the use of clozapine &#8220;may have caused thousands of premature deaths&#46;&#8221;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The fact that the majority of patients under clozapine treatment are resistant or have previously had significant adverse effects to other antipsychotics makes the decision to suspend clozapine treatment difficult&#46; Many physicians consider reinitiating clozapine in patients with a history of neutropenia despite the risk that it might involve&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Clozapine can be related to neutropenia both directly &#40;as we previously examined&#41; and indirectly&#46; Examples of the latter include benign ethnic neutropenia&#44; side effects of other drugs administered concomitantly or through interaction with clozapine and medical comorbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Methods described for the management of neutropenia in these patients include co-administering lithium&#44; administering granulopoiesis stimulating factors and managing concomitant drugs rationally&#46; While these treatments do provide a safety margin&#44; they have been used in only a limited number of cases and the level of evidence is still weak&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;31&#44;32</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The protocols associated with clozapine use are extremely costly for the patient and for healthcare services&#46; Current evidence available on the effectiveness and safety of this drug and the results of this study make it appropriate to start reviewing and discussing the protocols for clozapine usage and follow-up&#46; Taking into consideration the greater risk concentrated in the first 6 months of treatment&#44; and the risk of agranulocytosis after the first year&#8211;which is equal to that of other drugs not specifying monitoring&#8211;we would be in favour of maintaining a weekly follow-up in the first 18 weeks&#44; a monthly follow-up throughout the rest of the first year and a bi-monthly follow-up after that&#46; This change could involve a lower cost for the patient and for healthcare services and could also improve adherence to follow-ups and treatment&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethical responsibilities</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors must have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; The author for correspondence must be in possession of this document&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">Dr&#46; Bernardo has received funds for research and&#47;or has acted as a consultant and&#47;or speaker in activities organised by the following companies&#58; Adamet&#44; Almirall&#44; Bristol-Myers Squibb&#44; Eli Lilly&#44; Janssen-Cilag&#44; Mylan&#44; Pfizer&#44; Rocher and Rovi&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Dr&#46; Pons has acted as a consultant and&#47;or speaker for the following companies&#58; Janssen-Cilag and Johnson &#38; Johnson&#46;</p></span></span>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clozapine is an effective antipsychotic&#46; However&#44; its use has been associated with agranulocytosis&#46; For this reason&#44; it has been restricted for the treatment of resistant schizophrenia under a strict haematologic control&#46; The objective of this work was to assess the risk of haematologic dyscrasias in a sample of clozapine-treated patients in a 5-year period&#46;</p> <span class="elsevierStyleSectionTitle">Materials and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This is a follow-up study in a cohort of clozapine-treated patients in which the risk of haematological dyscrasias was assessed&#46; Complete blood cell count was made for each patient in a weekly basis for the first 18 weeks and thereafter monthly&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">271 patients in treatment with clozapine were followed up&#46; The mean age was 32&#46;3 years&#44; with 36&#46;5&#37; women&#46; The mean dose was 2276<span class="elsevierStyleHsp" style=""></span>mg&#44; ranging from 25 to 600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; During the first 18 weeks of follow-up&#44; we observed a 3&#37; incidence of neutropenia and 1&#46;3&#37; of leucopenia&#46; During the next 2 years&#44; only 1 new case of neutropenia and leucopenia was observed &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>120&#41;&#46; No new cases were observed during the rest of follow up &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#41;&#46; No cases of agranulocytosis were observed&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A 3&#37; incidence of neutropenia concentrated in the first months of follow up and no cases of agranulocytosis were observed in our sample&#46; Actual evidence on clozapine effectiveness and safety and the results of this study suggests that a critical revision of follow-up protocols is suitable&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La clozapina es un f&#225;rmaco de probada efectividad&#44; sin embargo&#44; su uso se asoci&#243; a la aparici&#243;n de agranulocitosis y as&#237;&#44; fue restringido para esquizofrenia resistente y con un estricto control hematol&#243;gico&#46; El objetivo de nuestro trabajo es evaluar el riesgo de discrasias sangu&#237;neas en una poblaci&#243;n de pacientes en tratamiento con clozapina seguidos durante 5 a&#241;os&#46;</p> <span class="elsevierStyleSectionTitle">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se trata de una cohorte de pacientes en tratamiento con clozapina en los que se evalu&#243; el riesgo de aparici&#243;n de alteraciones en la serie blanca&#44; a trav&#233;s de anal&#237;ticas semanales durante las primeras 18 semanas y mensuales a partir de entonces&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se trata de una muestra de 271 pacientes&#44; con un media de edad de 32&#44; 3 a&#241;os y un 63&#44;5&#37; de hombres&#46; La dosis media administrada fue de 227&#44;6<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#237;a &#40;25 a 600<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46; Durante las primeras 18 semanas de seguimiento&#44; se observ&#243; una incidencia de neutropenia de 3&#44;0&#37; y de leucopenia de 1&#44;3&#37;&#46; Durante los dos a&#241;os siguientes&#44; se encontr&#243; un nuevo caso de leucopenia y uno de neutropenia &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>120&#41;&#46; No se observaron nuevos casos en los pacientes que completaron 5 a&#241;os de seguimiento &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#41;&#46; A lo largo de todo el seguimiento&#44; no hubo ning&#250;n caso de agranulocitosis&#46;</p> <span class="elsevierStyleSectionTitle">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se observ&#243; una incidencia de neutropenia del 3&#37;&#44; concentrado en los primeros meses de seguimiento&#46; Ning&#250;n paciente present&#243; agranulocitosis&#46; La evidencia actual disponible sobre efectividad y seguridad de la clozapina y los resultados del presente estudio&#44; hacen adecuado plantearse revisar los protocolos de seguimiento y utilizaci&#243;n de este f&#225;rmaco&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Pons A&#44; et al&#46; Clozapina y agranulocitosis en Espa&#241;a&#58; &#191;tenemos una poblaci&#243;n m&#225;s segura&#63; Seguimiento hematol&#243;gico a 5 a&#241;os de una cohorte de pacientes tratados con clozapina&#46; Rev Psiquiatr Salud Ment &#40;Barc&#46;&#41;&#46; 2012&#59;5&#40;1&#41;&#58;37&#8211;42&#46;</p>"
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    ]
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">White blood cell count during first 18 weeks &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>231&#41;&#46;</p>"
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">172 &#40;63&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Women</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">99 &#40;36&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">229 &#40;84&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Repeated measures analysis of variance&#46; Within-subject contrasts were also performed <span class="elsevierStyleItalic">a priori</span> comparing each measure with the initial one&#46; <span class="elsevierStyleItalic">F</span> and <span class="elsevierStyleItalic">P</span> values &#40;in bold&#44; <span class="elsevierStyleItalic"><span class="elsevierStyleBold">P</span></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">0&#46;05</span>&#41;&#44; according to Pillai&#39;s Trace&#44; for the white blood cell and neutrophil count during the first 18 weeks of follow-up&#46;</p>"
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        "texto" => "<p id="par0150" class="elsevierStylePara elsevierViewall">We gratefully acknowledge the support of the <span class="elsevierStyleGrantSponsor" id="gs0005">Government of Catalu&#241;a&#44; the Commission for Universities and the Development Office of the Department of Innovation&#44; Universities and Enterprise &#40;DIUE&#41;</span><span class="elsevierStyleGrantNumber" refid="gs0005">2009SGR1295</span> and of the <span class="elsevierStyleGrantSponsor">Carlos III Health Institute&#44; Biomedical Research Centre in the Mental Health Network</span> &#40;<span class="elsevierStyleItalic">CIBERSAM</span> in English&#59; for JU&#44; AP&#44; AB and MB&#41; and with the support of the Josep Font Research Grant from the <span class="elsevierStyleGrantSponsor">Clinical Hospital of Barcelona</span> &#40;for JU&#41;&#46;</p>"
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Article information

ISSN: 21735050
Original language: English

DOI:10.1016/j.rpsmen.2012.04.007

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Year/Month	Html	Pdf	Total

2024 November	8	0	8
2024 October	26	4	30
2024 September	61	13	74
2024 August	51	13	64
2024 July	48	10	58
2024 June	42	5	47
2024 May	29	14	43
2024 April	37	2	39
2024 March	50	10	60
2024 February	64	6	70
2024 January	47	3	50
2023 December	52	3	55
2023 November	31	5	36
2023 October	53	3	56
2023 September	30	0	30
2023 August	15	2	17
2023 July	22	4	26
2023 June	16	4	20
2023 May	28	1	29
2023 April	21	1	22
2023 March	14	3	17
2023 February	17	2	19
2023 January	21	3	24
2022 December	30	9	39
2022 November	29	9	38
2022 October	21	6	27
2022 September	22	12	34
2022 August	27	9	36
2022 July	24	7	31
2022 June	18	6	24
2022 May	30	19	49
2022 April	35	14	49
2022 March	30	15	45
2022 February	28	9	37
2022 January	46	7	53
2021 December	44	12	56
2021 November	30	11	41
2021 October	28	9	37
2021 September	34	13	47
2021 August	28	18	46
2021 July	57	10	67
2021 June	35	10	45
2021 May	51	14	65
2021 April	93	17	110
2021 March	42	6	48
2021 February	43	4	47
2021 January	56	12	68
2020 December	29	5	34
2020 November	34	10	44
2020 October	28	6	34
2020 September	29	11	40
2020 August	23	2	25
2020 July	44	11	55
2020 June	29	7	36
2020 May	22	5	27
2020 April	24	3	27
2020 March	33	6	39
2020 February	28	5	33
2020 January	33	6	39
2019 December	25	10	35
2019 November	22	3	25
2019 October	32	4	36
2019 September	35	4	39
2019 August	28	3	31
2019 July	28	16	44
2019 June	56	30	86
2019 May	135	67	202
2019 April	54	15	69
2019 March	26	0	26
2019 February	28	10	38
2019 January	25	5	30
2018 December	26	5	31
2018 November	44	3	47
2018 October	34	3	37
2018 September	17	7	24
2018 August	19	2	21
2018 July	21	3	24
2018 June	10	5	15
2018 May	38	5	43
2018 April	53	8	61
2018 March	11	4	15
2018 February	11	2	13
2018 January	11	8	19
2017 December	14	0	14
2017 November	7	2	9
2017 October	17	4	21
2017 September	10	2	12
2017 August	12	4	16
2017 July	17	6	23
2017 June	25	1	26
2017 May	28	1	29
2017 April	26	2	28
2017 March	18	57	75
2017 February	13	1	14
2017 January	15	3	18
2016 December	28	8	36
2016 November	16	4	20
2016 October	28	3	31
2016 September	26	3	29
2016 August	20	6	26
2016 July	25	2	27
2016 June	23	8	31
2016 May	18	6	24
2016 April	24	9	33
2016 March	28	7	35
2016 February	18	10	28
2016 January	23	7	30
2015 December	18	6	24
2015 November	16	3	19
2015 October	25	4	29
2015 September	11	5	16
2015 August	25	7	32
2015 July	20	8	28
2015 June	8	0	8
2015 May	18	3	21
2015 April	21	6	27
2015 March	35	15	50
2015 February	28	7	35
2015 January	31	3	34
2014 December	34	9	43
2014 November	20	2	22
2014 October	30	7	37
2014 September	39	2	41
2014 August	25	1	26
2014 July	20	3	23
2014 June	25	3	28
2014 May	26	4	30
2014 April	6	2	8
2014 March	15	3	18
2014 February	13	1	14
2014 January	12	0	12
2013 December	17	5	22
2013 November	22	10	32
2013 October	38	8	46
2013 September	24	4	28
2013 August	28	8	36
2013 July	17	3	20

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