Clozapine Rechallenge Research Articles

Psychiatrists' views on clozapine prescribing in Ireland.

Despite proven effectiveness in refractory schizophrenia, clozapine remains underutilised, and it is important to understand potential reasons for this. This study's aim was to examine in a National sample of Consultant Psychiatrists their knowledge of, attitudes and perceived barriers to clozapine use. A novel questionnaire was designed and distributed by email to 275 Consultant Psychiatrists in Republic of Ireland. Twenty-eight percent (n = 77) completed the survey, with 55% of respondents practicing for 15 or more years. Clinicians expressed confidence in managing clozapine treatment and side effects and were well aware of clozapine's clinical effectiveness and guideline-based use. A majority indicated insufficient experience managing rechallenge and half expressed insufficient experience managing adverse events. Perceived patient factors were highlighted as barriers with 69% of respondents reporting patients' concern about effectiveness and 50% regarding tolerability. Sixty-four percent (n = 40) indicated that a specialised/tertiary clozapine service would facilitate initiation, with 57% (n = 36) reporting less frequent blood monitoring would aid clozapine prescribing. A majority identified that access to dedicated staff (81%, n = 51) and dedicated day hospital services (84%, n = 53) would facilitate community initiation. Consultants are familiar with clozapine use and related guidelines. Dedicated staff and facilities for clozapine use is one identified structural change to enhance clozapine prescribing in Ireland. Tertiary service or clinical advice service would assist in clozapine rechallenge cases or in managing significant adverse events. More structured patient education regarding clozapine effectiveness and professional development programmes focused on managing side effects and rechallenge may promote clozapine use.

When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study

Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 109/L to less than 1·0 × 109/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK. This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration. Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2-4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473). Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health. None.

Successful clozapine rechallenge after neutropenia using lithium carbonate : a case report

IntroductionClozapine is widely known as the drug of choice in treating refractory schizophrenia. However, clozapine prescription requires close clinical and biological monitoring to prevent harmful side effects like agranulocytosis, neutropenia and myocarditis.ObjectivesTo show the benefits of lithium carbonate in the clozapine rechallenge of a patient with neutropenia under clozapine.MethodsWe present the clinical case of a patient who developed neutropenia under clozapine, we rechallenged with clozapine after lithium treatment to stimulate hematopoietic functions.ResultsA 42-year-old man diagnosed with refractory schizophrenia, under clozapine for 11 years with a good clinical response at a dosage of 500mg per day (clozapine serum level 328ng/ml), developed a neutropenia (BCC at 840/mm3) within an interval of 2 months. Clozapine treatment was suspended and the patient presented a severe psychotic relapse requiring hospitalization. During hospitalization the patient remained symptomatic under haloperidol 15mg daily. At week 3 of clozapine cessation, neutrophil count reached 1510/mm3. After week 4 we introduced lithium carbonate and while reaching 500mg per day we observed an increase in the neutrophil count to 4850/mm3. We rechallenged with clozapine at week 12 after a poor clinical response, with incremental dosage to 150mg per day in 17 weeks. The blood cell count did not show any abnormalities and the patient had a good clinical response up to 11 months after the clozapine rechallenge.ConclusionsDespite the lack of guidelines assessing clozapine rechallenge after neutropenia, the use of lithium carbonate may be considered to stimulate hematopoietic functions.DisclosureNo significant relationships.

Screening the European pharmacovigilance database for reports of clozapine-related DRESS syndrome: 47 novel cases

Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare adverse reaction. We aimed to screen a large pharmacovigilance database to identify clozapine-related DRESS cases, even if otherwise reported and provide a clinical overview. We screened spontaneous reports of clozapine-related DRESS syndrome in EudraVigilance database applying the European Registry on Severe Cutaneous Adverse Drug Reactions (RegiSCAR) criteria and scores to identify probable/definite DRESS syndrome cases. Clinical and demographic characteristics of included cases were provided and associations between RegiSCAR scores, and time to develop/recover DRESS were assessed. In a total of 262,146 adverse drug reactions reports for 75,190 clozapine-treated patients, 596 cases fulfilled RegiSCAR criteria; ultimately, 51 cases were rated as probable/definite DRESS according to RegiSCAR scores, of which 4 were previously published as case reports. The mean age of patients was 41.06 years (43.1% females), with 13 patients (25.5%) receiving reported co-medication with other DRESS culprit drugs. Median time between clozapine initiation and DRESS symptoms was 25 days. Clozapine dose was associated with days to develop symptoms (Spearman's ρ 0.40, p = 0.03). Organ involvement was reported in all cases followed by fever (n = 49; 96.1%) and eosinophilia (n = 47; 92.2%). Treatment involved clozapine discontinuation for 37 patients (72.5%), while 3.9% (n = 2) of cases ended fatally. Clozapine rechallenge was undertaken in 25 patients (49.0%). The screening of the EudraVigilance database revealed 47 novel clozapine-related DRESS cases, and only one was originally reported as DRESS. Clozapine-related DRESS may occur with clozapine monotherapy not only during dose titration, but also during maintenance treatment.

Clozapine Rechallenge or Continuation Despite Neutropenia, an Extended Follow-up of a Consecutive Quebec Case Series.

Clozapine is the most efficacious antipsychotic for treatment-resistant schizophrenia. However, clozapine-induced neutropenia may warrant treatment discontinuation, hindering recovery. Several case reports describe clozapine rechallenge or continuation despite neutropenia, although many are subject to selective reporting, with incomplete information and short follow-up periods. Thus, consecutive case series, devoid of such bias, with long-term comprehensive follow-up are needed to better assess this practice. This study aimed to describe consecutively the evolution of every patient in the Québec City catchment area for whom clozapine was either reintroduced after neutropenia during a previous clozapine trial or was maintained despite a first neutropenia. Patients were identified through clozapine's national hematological monitoring database and their medical records between January 1, 2000, and October 22, 2017. Twenty-three patients were identified, 8 continued clozapine despite neutropenia, while 15 discontinued clozapine and attempted rechallenge; among the latter, 4 patients were successfully rechallenged after agranulocytosis without the use of granulocyte colony-stimulating factors, which is the largest published consecutively. A total of 6 patients experienced further neutropenia episodes. Every patient who had a neutropenia recurrence also had a possible explanation for neutropenia other than exposure to clozapine. After a median follow-up of 4.8 years, 16 patients were still on clozapine and 3 cases discontinued because of a hematological event. This study adds further data on the subject of clozapine rechallenge or continuation despite neutropenia. Clozapine rechallenge after agranulocytosis may be less perilous than first thought, but a systematic review on this specific subject is needed.

Clinical Outcomes after Clozapine Discontinuation in Patients with Schizophrenia: A Systematic Review.

Clozapine is the gold standard of treatment for patients with treatment-resistant schizophrenia. However, approximately 60% of those patients do not respond to clozapine; moreover, clinical outcomes after clozapine discontinuation are unclear so far. Therefore, we conducted a systematic review to clarify the outcomes after clozapine discontinuation. A systematic literature search was conducted, using MEDLINE and Embase with the following keywords: (clozapine AND (cessation* OR cease* OR withdraw* OR discontinu* OR halt* OR stop* OR switch*) AND (schizophreni* OR schizoaffective)). A total of 28 clinical studies from 27 articles were identified and included in this systematic review. Three randomized controlled trials reported worsening of psychiatric symptoms. In 10 single-arm studies, the results of worsening and improving psychiatric symptoms were inconsistent. In one large retrospective cohort study, clozapine rechallenge, olanzapine, and antipsychotic polypharmacy had lower rehospitalization rates compared to no medication after clozapine discontinuation. In the other 14 retrospective studies, the vast majority showed worsening of clinical status after clozapine discontinuation. Among five studies on clinical outcomes after clozapine rechallenge, four reported improvements in clinical status in more than half of patients who rechallenged clozapine. The remaining study reported that the clozapine discontinuation-rechallenge group had a worse remission assessment score than the clozapine discontinuation-no rechallenge group. Clinical outcomes generally worsen after clozapine discontinuation. Clozapine rechallenge and olanzapine may be considered following clozapine discontinuation. The outcomes after clozapine discontinuation in clozapine non-responders remain inconclusive; therefore, well-designed studies are warranted.

A Slow, Cautious, and Successful Clozapine Rechallenge After Myocarditis

A Slow, Cautious, and Successful Clozapine Rechallenge After Myocarditis

Clozapine-induced myocarditis and patient outcomes after drug rechallenge following myocarditis: A systematic case review

Clozapine is underutilized due, in part, to concerns about rare but severe adverse drug reactions, including cardiac inflammation and injury (myocarditis). Risk factors for clozapine-induced myocarditis are limited and predictors for the successful rechallenge of clozapine after an episode of myocarditis are even more poorly understood. We conducted a systematic review, in accordance with the PRISMA recommendation, of published case reports to describe demographic and clinical characteristics of patients with clozapine-induced myocarditis and identify potential markers of clozapine rechallenge success. A total of 180 cases from 88 articles were evaluated. Male cases of clozapine-associated myocarditis were more frequently reported than female cases by a ratio of 6:1. Less than half of patients reported the presence of chest pain (35%) or flu-like symptoms (43%) but increases in troponin or C-reactive protein were present in 87% of cases. Clozapine rechallenge was carried out in 34 (2 female) cases, with successful reintroduction in 22 (2 female) cases (64.7%) and one fatality (2.9%). No demographic or clinical markers were significantly associated with rechallenge success after correction for multiple testing. Standardized reporting of clozapine-induced myocarditis cases is needed to facilitate the identification of factors associated with successful rechallenge.

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals

BackgroundBenign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment.MethodsThis was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again.ResultsThe study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation.ConclusionsCurrent evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

Unravelling cases of clozapine-related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in patients reported otherwise: A systematic review.

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction. Aim was to review reports of clozapine-related reactions fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria for DRESS syndrome reported as such or otherwise, to provide a descriptive overview of demographic patterns, clinical manifestations, and DRESS course and investigate associations between demographic, DRESS parameters, and clinical outcomes. This review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines and registered with PROSPERO (registration number CRD42020156385). We searched PubMed/Embase/PsychInfo/Cochrane for reports of clozapine-related reactions meeting RegiSCAR criteria. Associations between RegiSCAR scores and time-to-recovery with demographic/clinical variables were assessed. Demographic/clinical characteristics of patients with versus without reported DRESS were compared using non-parametrical tests. We identified 26 reports of 27 patients meeting RegiSCAR criteria. Males (n = 19, 70.4%) and patients with schizophrenia (n = 18, 66.7%) were mainly affected. Twelve patients (44.4%) received clozapine-monotherapy. DRESS symptoms manifested within a month after clozapine initiation (n = 24, 88.9%). Lungs and liver were the most common organs involved (n = 12, 44.4%; n = 11, 40.7%), with a mean time to recovery of 33.75 days. Clozapine rechallenge led to DRESS recurrence in four patients. Death rate was 7.4%. No associations were detected between RegiSCAR criteria or days to recovery with any demographic/clinical variables. No differences between patients with versus without reported DRESS were detected. Clozapine-related DRESS may be rare, but also underreported. Clinicians need to be aware of it even in patients under clozapine-monotherapy or without skin rash.

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

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.

Never Say Never: Successful Clozapine Rechallenge After Multiple Episodes of Neutropenia.

Clozapine is a second-generation antipsychotic with a superior efficacy for the management of treatment-resistant schizophrenia but underutilized because of potential side effects. A 59-year-old Caucasian male veteran was transferred from the long-term care unit to the acute psychiatry unit because of suicidality. He was noted as having a long-standing history of psychosis with significant referential and paranoid delusions. He had experienced two previous trials of clozapine; although he had significant response in the past, both trials ended in neutropenia and an absolute neutrophil count <500 cells per microliter, despite the second trial also including supplemental "as-needed" doses of pegfilgrastim to manage decline in neutrophil counts. This particular strategy of filgrastim use was determined to be a weakness of the second trial. A PubMed search identified recent literature that discussed preemptive dosing of filgrastim to prevent neutropenia. Thus, a protocol was established to administer 300 μg filgrastim subcutaneously, three times weekly, concurrently with clozapine initiation. This plan was discussed on local and national levels to achieve consensus before its initiation. Using a revised, patient-specific protocol led to successful initiation of clozapine and the ability to maintain the regimen for over 24 months without interruption or any further suicidal ideation.

Successful clozapine re-challenge in a case of Atypical Neuroleptic Malignant Syndrome with markedly elevated Creatinine Phosphokinase and no muscle rigidity

Successful clozapine re-challenge in a case of Atypical Neuroleptic Malignant Syndrome with markedly elevated Creatinine Phosphokinase and no muscle rigidity

Successful clozapine rechallenge following recurrent clozapine-associated pancreatitis: a case report

BackgroundAcute pancreatitis is a rare but recognised complication of clozapine leading to termination of treatment.Case presentationWe present the case of a 39-year-old man with treatment-resistant schizoaffective disorder and a history of recurrent acute pancreatitis attributed to clozapine. After 15 years of unremitting symptoms with disruptive and aggressive behaviour, he was admitted for a clozapine rechallenge. Despite experiencing two further episodes of acute pancreatitis during clozapine treatment that led to its temporary withdrawal, clozapine was successfully re-established under gastroenterology consultation with close monitoring which resulted in progressively marked improvement of his mental state.ConclusionsThis case demonstrates that patients who develop pancreatitis during clozapine treatment may be cautiously rechallenged with specialist gastroenterology support.

S1. CLOZAPINE RECHALLENGE FOLLOWING NEUTROPENIA USING GRANULOCYTE COLONY-STIMULATING FACTOR: A QUEBEC CASE SERIES

BackgroundClozapine possesses unique efficacy profile in treatment-resistant schizophrenia but is associated with neutropenia and agranulocytosis, in respectively, 3% and 0.7% of exposed patients. Granulocyte colony-stimulating factor (G-CSF) has been used to allow clozapine continuation or rechallenge in such situation (1,2).MethodsWe aim to describe the use of G-CSF to maintain clozapine despite neutropenia or agranulocytosis in treatment resistant schizophrenia patients in Quebec province, Canada. A national clozapine hematological monitoring database was consulted to identify all patients who have had red event (neutrophil count < 1,5 threshold) since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who have received at least one dose of G-CSF while been exposed to clozapine All patients with an active cancer diagnosis while taking clozapine and G-CSF were excluded. A group of pharmacists specialized in psychiatry in Quebec was also contacted to ensure selecting all cases in the province. In additional to demographic data and clozapine and G-CSF details, Clinical Global Impression severity scale (CGI-S) was used to evaluate psychopathology severity during four critical turning points: before and after clozapine introduction, after agranulocytosis episode and after clozapine rechallenge. All data were collected retrospectively, using patient’s medical files, from January to July 2019.ResultsEight (8) patients (5 males, 3 females), Caucasian, mean age 48 years old, with clozapine median exposition of 4.8 years, were identified. In 7/8 of those, G-CSF was used according to an “as required strategy”, i.e., whenever the patient’s neutrophil count dropped below a pre-determined threshold, varying according to patient between 0,8 à 1,5. In the other patient, a 3-weekly doses were preventively administered. Despite this, a mean number of 4 red events (ranging from 1 to 10 events) were subsequently observed in those patients, leading to clozapine cessation in 4/8 patients. One other patient responded to G-CSF but the clinical team felt uncomfortable to maintain clozapine in such circumstances. No complication (infection for instance) due to low neutrophil counts was observed nor any significant side effect related to G-CSF. However, in all these cases, while clozapine treatment was associated with clinically significant improvement of psychopathology (mean CGI-S decreased from 5.5 to 3.4), clozapine cessation led to an important psychotic deterioration (mean CGI-S of 6.2) at follow up. Fortunately, in patients successfully rechallenged (3/8), a strong clinical improvement was observed, with return to previous response level observed.DiscussionTo our knowledge, this is the largest case series of clozapine rechallenge using G-CSF and adds to the 39 already described cases in which G-CSF was concomitantly used with clozapine (1,2). While an “as required” strategy was mainly used here, a different prophylactic G-CSF use may have led to higher rates of clozapine maintenance, despite red codes, which provides the impetus for further studies.ReferenceMyles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations. Australian and New Zealand Journal of Psychiatry. 2017;51(10):980–9.Lally J, Malik S, Krivoy A, Whiskey E, Taylor DM, Gaughran FP, et al. The use of granulocyte colony-stimulating factor in clozapine rechallenge: A systematic review. Journal of Clinical Psychopharmacology. 2017;37(5):600–4.

M200. CLOZAPINE-INDUCED HEPATOTOXICITY: TWO CASE REPORTS

BackgroundLiver function tests (LFT) abnormalities secondary to antipsychotics (AP) are common, early, and often mild and transient. Up to 60% of patients on clozapine experience an increase in LFT, at medium-range doses (200–400mg), and usually dose-dependent, with spontaneous resolution in half the cases, no dose reduction needed. Fatal outcomes are extremally rare, with an incidence around 0.001%. The hepatotoxic effects of clozapine have received considerable less attention than its cardiometabolic and hematologic counterparts. Consequently, there are few independents guidelines on how to handle such cases. Our objective is to report 2 cases of mild clozapine-induced liver injury and discuss possible protocols of early detection and management.MethodsWe described 2 cases of clozapine induced hepatitotoxicity in patients with schizophrenia.ResultsCASE 1: 33 y/o, male, caucasian, 5y of illness. Had previously used risperidone and paliperidone, and was currently taking olanzapine, without good response. Clozapine 25mg/d was introduced – in addition to olanzapine 15mg/d – with a 25mg increase every 2d. On D12 of clozapine (150mg/day), he reported nausea, diarrhea and dizziness, worsening the next few days, with confusion and choluria. Blood tests detected increases of ALT (242U/L), serum bilirubin (total 1.59mg/dL; direct 1.29g/dL; indirect 0.3mg/dL) and ESR (60mm/1sth). He was admitted and AP were interrupted. After 48h, presented full clinical recovery. Leukocyte blood count and ESR were still high in the first week, but LFT and bilirubins progressively decreased. All exams normalized in 1m. After 2w, olanzapine was reintroduced, with no LFT changes.CASE 248 y/o, female, caucasian, 15y of illness. Partial response to risperidone and olanzapine. 20d after clozapine was introduced (75mg/d), she reported nausea, vomiting, choluria, abdominal pain and headache. Presented elevated AST (88U/L), ALT (77U/L), CK (732U/L), GGT (141U/L) and ALP (161U/L), decreased Hb (9.6g/dL), mild leukocytosis (10,800/mm3), mild leukocyturia and hematuria, though bilirubin and platelet levels were normal. Clozapine was immediately suspended and olanzapine 10mg/d reintroduced progressively, maintaining partial remission of positive symptoms. Blood counts and LFT were normalized within 1m and no hospitalization was required.DiscussionBoth cases illustrate different presentations of hepatotoxicity by clozapine. Case 1 had no LFT dosage before the introduction and no indicative hepatic risk. With a regular dose evaluation, developed a severe hepatic injury. Case 2 had a history of side effects to previous antipsychotics. She started with normal LFT levels and evolved with mild hepatic injury due to the slow dose increase.In both cases LFT weren’t requested periodically until clinical symptoms emerged. At this point, it was fundamental to instruct the patient to report any warning clinical signs.A serialized LFT protocol wouldn’t show benefits to prevent hepatotoxicity in the outcome of our cases. However, some authors recommend monitoring them 4–6m after starting AP, specially the first 4–5w, since it could predict a bad outcome of severe hepatitis. Previous studies point ALT>3ULN or ALP>2ULN or any rise of transaminases with CK or bilirrubin altered as sensitive markers for liver damage. In such cases, the AP should be suspended.There is no consistent data regarding the indication of clozapine rechallenge after hepatotoxicity. Yet, the early onset of drug injury (1–6w) and the rapid rise in ALT on rechallenge may be a contraindication of a new try or continuous use of the drug.Considering guidelines on clozapine induced hepatotoxicity are not clear, we suggest the topic to be revisited and better established.

Clozapine associated cardiotoxicity: Issues, challenges and way forward.

To review the published literature on clozapine associated cardiotoxicity (CACT), summarize diagnostic features, and evaluate monitoring procedures for safe clozapine re-challenge. Clozapine-associated Myocarditis (CAM) - Incidence of early myocarditis (≤2 months) is infrequent but serious. Clinical diagnosis is confounded by variability in presentation and non-specificity of symptoms. Re-challenge considerations include clozapine impact on symptomatic severity and associated disability and risk of suicidality. Re-challenging is recommended only after full clinical resolution of myocarditis and cardiac function impairment, under closely controlled conditions, starting at very low dosage, extremely slow titration and frequent assays of lab and cardio biomarkers. Clozapine associated cardiomyopathy (CAC) -develops later but mortality has been reported at 12.5-24.0%. Re-challenge is generally not recommended due to paucity of outcome data. Monitoring Cardiac Toxicity: Plausible steps include closer clinical monitoring, repeated assays of biomarkers, and echocardiographic studies, and cardiac MRI changes with unremarkable findings of cardiac dysfunction with echocardiography. Subclinical clozapine associated cardiotoxicity is more prevalent than CAM and CAC. Diagnosis is often challenging due to non specific presentation. Active monitoring is recommended. Rechallenging is feasible but should be done under close monitoring conditions. A protocol is proposed based on literature review and clinical experience in order to reduce the risk of CACT. Clozapine-associated myocarditis and cardiomyopathy may have been underreported worldwide. Identification of subclinical cardiotoxic effects can improve outcomes by earlier recognition before clinical manifestations of cardiac impairments. A pragmatic close clinical monitoring protocol including cardiac biomarkers aimed at timely detection of cardiac toxicity, in the initial phase of treatment is proposed.

Rechallenge of clozapine in a patient with a history of clozapine-induced myocarditis

Clozapine is the only antipsychotic with proven efficacy in treatment-resistant schizophrenia, but some life-threatening side effects limit its use. Here we report a patient with clozapine-induced myocarditis and successful rechallenge. The patient still uses clozapine and has not developed myocarditis over 36 months of observation. It may be possible to use clozapine even after myocarditis and thus improve symptoms and functionality of schizophrenia patients.

Clozapine Rechallenge Following Neuroleptic Malignant Syndrome: A Systematic Review.

Neuroleptic malignant syndrome (NMS) has been described with most antipsychotics, most commonly first generation. Clozapine has also been associated with NMS. We conducted a systematic review to identify all studies investigating or describing (a) clozapine rechallenge following suspected NMS associated with clozapine, (b) clozapine use after suspected NMS associated with another antipsychotic, and (c) rechallenge with nonclozapine antipsychotics after suspected clozapine-associated NMS. We identified 51 reports detailing 67 cases. Thirty-eight described clozapine administration after NMS on a nonclozapine antipsychotic; 12 described a clozapine rechallenge after an NMS on clozapine monotherapy; and 17 described the use of nonclozapine antipsychotics after an NMS on clozapine. The outcome of clozapine rechallenge was favorable (no recurrence of NMS) in 92% (n = 11) of cases after an NMS on clozapine and in 79% (n = 30) of those prescribed clozapine following NMS on a nonclozapine antipsychotic. Most (82%; n = 14) cases after NMS on clozapine had no recurrence of NMS on receiving a nonclozapine antipsychotic.No mortality was reported with any of these interventions. Our findings suggest that rechallenge following clozapine NMS is possible, and with careful risk-benefit analysis consideration, a clozapine rechallenge can be made. A publication bias in favor of cases in which rechallenge was successful is probable and is an important limitation.