Exploring clozapine use in severe psychiatric symptoms associated with autism spectrum disorder: A scoping review.

BACKGROUND: Patients with autism spectrum disorder (ASD) may experience severe psychiatric symptoms, often unresponsive to conventional pharmacological therapies, highlighting the need for more effective alternatives. AIMS: This study aims to map and synthesize evidence on the use of clozapine as a therapeutic option for managing severe psychiatric symptomatology co-occurring with ASD. METHODS: We conducted a scoping review on multiple sources following the JBI guidelines. The search strategy was inclusive, targeting both peer-reviewed publications and gray literature presenting empirical data on the use of clozapine therapy for patients with ASD accompanied by comorbid psychiatric symptoms. Two independent evaluators performed the selection of studies, data extraction, and critical appraisal. RESULTS: The review included 46 studies, encompassing 122 ASD individuals who received clozapine therapy. The sources of evidence comprise 31 case reports, 8 case series, 6 retrospective observational studies, and 1 quasi-experimental prospective study. The tables present the findings along with a narrative summary. Clozapine treatment demonstrated benefits in four groups of severe and treatment-resistant psychiatric symptoms in ASD patients: disruptive behaviors, psychotic symptoms, catatonia, and mood symptoms. Although side effects were common, tolerability was generally satisfactory. However, severe adverse events, such as seizures, moderate neutropenia, and myocarditis, underscore the need for intensive clinical monitoring. CONCLUSIONS: While clozapine shows promise as a pharmacological intervention for severe psychopathologies in ASD, more rigorous clinical studies are required to elucidate its efficacy and safety in this population. The limited robustness of the evidence calls for caution, signaling an early research stage into this topic.

Successful Clozapine Rechallenge After Clozapine-Induced Severe Anemia: A Case Report.

INTRODUCTION: Clozapine, a second-generation antipsychotic (SGA), is considered the gold standard medication to treat patients with treatment-resistant schizophrenia (TRS). Despite its efficacy, clozapine is associated with adverse effects, notably neutropenia and agranulocytosis. Other hematological adverse effects are less common. Severe anemia is a rare adverse effect seldom reported in the literature and is typically associated with pure red cell aplasia (PRCA). Nevertheless, the benefits of clozapine in managing TRS make rechallenge a reasonable option. CASE REPORT: We present the case of a 35-year-old man with TRS, resistant to previous antipsychotics, who experienced severe anemia during clozapine treatment. An investigation for clozapine-induced anemia revealed PRCA on myelogram. After discontinuing clozapine, the patient's hemoglobin levels recovered. Subsequent treatments with olanzapine, zuclopenthixol, and aripiprazole proved ineffective, leading us to consider a clozapine rechallenge. The rechallenge, monitored for 58 days, resulted in improved psychiatric symptoms and stable hemoglobin levels. The patient remained stable during 6 months of follow-up, with no hematological changes. DISCUSSION: PRCA is a very rare adverse effect of clozapine. The cause of drug-induced PRCA is still unknown; for clozapine, there are no studies. Rechallenge after a severe and rare adverse effect is a complex decision. This case is the first to report a successful clozapine rechallenge following severe anemia without other blood dyscrasias, emphasizing the imperative need for close monitoring during the rechallenge process. Further study is warranted to understand the predictive factors for a successful outcome in clozapine rechallenges.

Randomized, double-blind, sham-controlled trial to evaluate the efficacy and tolerability of electroconvulsive therapy in patients with clozapine-resistant schizophrenia.

There is no established treatment for patients with clozapine-resistant schizophrenia (CRS). Clozapine augmentation strategies with antipsychotics or others substances are effective in comparison with placebo while and Electroconvulsive therapy (ECT) showed to be effective in comparison with treatment as usual (TAU) but not with placebo (sham-ECT). In the present double- blind randomized controlled trial, we compared 40 outpatients who received 20 sessions of ECT (n = 21) or sham-ECT (n = 19) (age = 37.40 ± 9.62, males = 77.5 %, illness duration = 14.95 ± 8.32 years, mean total Positive and Negative Syndrome Scale (PANSS) = 101.10 ± 24.91) who fulfilled well-defined CRS criteria including baseline clozapine plasma levels ≥350 ng/mL. The primary outcome was the ≥50 % PANSS Total Score reduction; secondary outcomes were the scores of the PANSS subscales, PANSS five-factor dimensions, PANSS-6 and the Calgary Depression Rating Scale (CDRS). Treatment response was analyzed by percentage reduction, Linear Mixed Models and effect sizes. At baseline both groups showed no differences except for years of school education (included as a covariate). At endpoint, only 1/19 of the completers (5.26 %) in the ECT group and 0/17 in the sham-ECT group showed a ≥50 % total PANSS score reduction. Both groups showed no significant differences of the total PANSS score (F = 0.12; p = 0.73), Positive (F = 0.27, p = 0.61), Negative (F = 0.25, p = 0.62), and General Psychopathology scores (F = 0.01, p = 0.94) as well for all PANSS five factors, the PANSS-6 and CDRS. Thus, the present study found no evidence that ECT is better than Sham-ECT in patients with CRS. Future sham-ECT controlled studies with larger sample sizes are warranted to test the efficacy of ECT for patients with CRS.

Diffuse Large B-Cell Lymphoma with Cutaneous Manifestations in a Young Patient Using Clozapine for Schizophrenia: A Case Report.

BACKGROUND Non-Hodgkin lymphoma is the most common hematological malignancy in the world. Diffuse large B-cell lymphoma the most common type and the cutaneous involvement due to this neoplasm is rare. Some risk factors, such as exposure to pesticides, alcohol consumption, and tobacco use, are well established. Over the past 10 years, the association between clozapine, which is the criterion standard treatment for refractory schizophrenia, and hematological malignancies has been described. CASE REPORT We report a case of a 44-year-old woman diagnosed with schizophrenia 31 years previously, who had been taking clozapine since 2009, presenting with diffuse cutaneous nodules and subcutaneous masses accompanied by asthenia, dry cough, and a weight loss of 12 kg. Computed tomography revealed multiple enlarged lymph nodes on both sides of the diaphragm, in addition to multiple large subcutaneous masses located on the right flank and on the right upper lateral chest wall (infra-axillary), homogeneous splenomegaly, and heterogeneous nodular areas of hypoenhancement, poorly delimited, in both kidneys. Diffuse large B-cell lymphoma in an advanced stage (IVBX) was diagnosed by skin biopsy, with extranodal involvement. Chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days) was performed and the decision to maintain clozapine was made. At 1.5 years after the initial diagnosis the patient presented with relapse of the disease and is in follow-up. CONCLUSIONS This case report suggests the potential association between clozapine and an increased risk of lymphoma, with a few case reports in the literature reinforcing this association. Additional studies are required to either confirm or dismiss this association, and new guidelines are needed to define the safety and monitoring of the long-term usage of clozapine.

Atypical antipsychotics olanzapine and clozapine increase bone loss in female rats with experimental periodontitis.

BACKGROUND AND OBJECTIVES: Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases. METHODS: In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made. RESULTS: Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis. CONCLUSION: The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations.

Molecular dynamics and free energy calculations of clozapine bound to D2 and H1 receptors reveal a cardiometabolic mitigated derivative.

Most atypical antipsychotics derive from a high dropout of drug treatments due to adverse cardiometabolic side effects. These side effects are caused, in part, by the H1 receptor blockade. The current work sought a clozapine derivative with a reduced affinity for the H1 receptor while maintaining its therapeutic effect linked to D2 receptor binding. Explicit molecular dynamics simulations and end-point free energy calculations of clozapine in complex with the D2 and H1 receptors embedded in cholesterol-rich lipid bilayers were performed to analyze the intermolecular interactions and address the relevance of clozapine-functional groups. Based on that, free energy perturbation calculations were performed to measure the change in free energy of clozapine structural modifications. Our results indicate the best clozapine derivative is the iodine atom substitution for chlorine. The latter is mainly due to electrostatic interaction loss for the H1 receptor, while the halogen orientation out of the D2 active site reduces the impact on the affinity.Communicated by Ramaswamy H. Sarma.

The role of alcohol intake in the pharmacogenetics of treatment with clozapine.

Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1C and other alleles not yet discovered could support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients.

OBJECTIVE: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. METHODS: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. RESULTS: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). CONCLUSIONS: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI95  = 1.041-12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI95  = 1.473-42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Clozapine-associated neutropenia in Latin America: incidence report of 5380 Chilean users.

Systematic information about Latino clozapine users is still scarce. Our aim was to evaluate the risk of clozapine-associated neutropenia in a Chilean cohort using the last Food and Drug Administration's recommendations for clozapine monitoring. Findings should improve clinical practice and promote changes in clozapine guidelines in Latin America. We conducted a retrospective observational study of 5380 Chilean clozapine users that started clozapine treatment between 2003 and 2015. The absolute risk of severe neutropenia was 0.61% (33/5380) with an incidence of 0.086 cases per 100 person-years of follow-up. 87.9% of cases with severe neutropenia appeared during first 18 weeks. Cases of mild neutropenia were 3.9% of total sample and occurred almost constantly without a specific risk time. 77.5% of cases of moderate or severe neutropenia didn't present an event of mild neutropenia before. 22.8% of clozapine users (1227/5380) discontinued treatment for any cause and 4.2% (225/5380) due to neutropenia in any severity level. Clozapine-associated neutropenia risk in Latino users is similar than in the rest of the world. The evidence of a very low risk for severe neutropenia and the behaviour of mild neutropenia cases confirm the feasibility of changes in Latin American clozapine guidelines using current Food and Drug Administration's recommendations as a model.

Olfactory deficit as a result of clozapine withdrawal syndrome in an animal model of schizophrenia: preliminary results.

Clozapine is an antipsychotic that produces serious withdrawal effects in schizophrenic patients. Olfactory deficits are well known as part of negative symptoms, but it is not known whether antipsychotic use and/or withdrawal are implicated. Then, we tested clozapine withdrawal in association with two widely used schizophrenia models: Neonatal immune challenge by Polycitidilic-polyinosinic acid (polyI:C) and ketamine. PolyI:C (or saline) was injected subcutaneously in neonatal period, dose of 5 mg/kg from 2 to 6 Post Natal Days, and ketamine or saline at the dose 25mg/kg intraperitoneally (i.p.), daily for 7 days from 53 to 60 post natal day. Clozapine 10mg/kg (or saline) was administered i.p. from 46 to 60 post natal day. Olfactory discrimination test (sensorial and cognitive deficit) was performed at 61 post natal day, 24h after the last injections. The association of PolyI:C, ketamine and clozapine disrupted Olfactory Discrimination, equating time in familiar and non-familiar compartments. PolyI:C plus ketamine increased crossings between compartments. It was produced, for the first time, an olfactory deficit induced by clozapine withdrawal in Wistar rats subjected to schizophrenia animal models.

Early treatment resistance in a Latin-American cohort of patients with schizophrenia.

BACKGROUND: Failure to respond to antipsychotic medication in schizophrenia is a common clinical scenario with significant morbidity. Recent studies have highlighted that many patients present treatment-resistance from disease onset. We here present an analysis of clozapine prescription patterns, used as a real-world proxy marker for treatment-resistance, in a cohort of 1195 patients with schizophrenia from a Latin-American cohort, to explore the timing of emergence of treatment resistance and possible subgroup differences. METHODS: Survival analysis from national databases of clozapine monitoring system, national disease notification registers, and discharges from an early intervention ward. RESULTS: Echoing previous studies, we found that around 1 in 5 patients diagnosed with schizophrenia were eventually prescribed clozapine, with an over-representation of males and those with a younger onset of psychosis. The annual probability of being prescribed clozapine was highest within the first year (probability of 0.11, 95% confidence interval of 0.093-0.13), compared to 0.018 (0.012-0.024) between years 1 and 5, and 0.006 (0-0.019) after 5years. Age at psychosis onset, gender, dose of clozapine used, and compliance with hematological monitoring at 12months, was not related to the onset of treatment resistance. A similar pattern was observed in a subgroup of 230 patients discharged from an early intervention ward with a diagnosis of non-affective first episode of psychosis. CONCLUSIONS: Our results highlight that treatment resistance is frequently present from the onset of psychosis. Future studies will shed light on the possible different clinical and neurobiological characteristics of this subtype of psychosis.

Correlación de las concentraciones plasmáticas de clozapina con el síndrome metabólico / Correlation of plasma concentrations of clozapine with the metabolic syndrome

La clozapina ha demostrado ser el antipsicóticomás efectivo para la esquizofrenia resistente, perotambién está vinculada con un mayor riesgo de producir alteraciones metabólicas en los pacientes. Se realizó un estudio prospectivo de pacientes de la Policlínica del Hospital Vilardebó donde se correlacionaron las siguientes variables: dosis diaria de clozapina, concentración plasmática de clozapina y su principal metabolito norclozapinaa predosis, cociente metabólico clozapina/norclozapina, sexo, edad, estatus fumador, duración del tratamiento con clozapina, marca comercialde clozapina utilizada, comedicación con ácido valproico, comedicación con antipsicóticos,comedicación con litio y consumo de café enrelación con el síndrome metabólico (definido porla Asociación Latinoamericana de Diabetes). Laúnica covariable significativa como dependiente del síndrome metabólico fue la concentración plasmática en valle de clozapina. El modelo que se encontró para dicha explicación es el siguiente: P(SM)=Exp(-1.69+0.00358*CZP)/((1+Exp(-1.69+0.00358*CZP)). A mayores concentraciones de clozapina el riesgo de síndrome metabólico aumenta. Esto puede tener implicancias en la clínica, ya que a pacientes con altas concentraciones de clozapina se deberían buscar estrategias para disminuir el impacto metabólico que pueda existir

Correlación de las concentraciones plasmáticas de clozapina con el síndrome metabólico / Correlation of plasma concentrations of clozapine with the metabolic syndrome

La clozapina ha demostrado ser el antipsicóticomás efectivo para la esquizofrenia resistente, perotambién está vinculada con un mayor riesgo de producir alteraciones metabólicas en los pacientes. Se realizó un estudio prospectivo de pacientes de la Policlínica del Hospital Vilardebó donde se correlacionaron las siguientes variables: dosis diaria de clozapina, concentración plasmática de clozapina y su principal metabolito norclozapinaa predosis, cociente metabólico clozapina/norclozapina, sexo, edad, estatus fumador, duración del tratamiento con clozapina, marca comercialde clozapina utilizada, comedicación con ácido valproico, comedicación con antipsicóticos, comedicación con litio y consumo de café enrelación con el síndrome metabólico (definido porla Asociación Latinoamericana de Diabetes). Laúnica covariable significativa como dependiente del síndrome metabólico fue la concentración plasmática en valle de clozapina. El modelo que se encontró para dicha explicación es el siguiente: P(SM)=Exp(-1.69+0.00358*CZP)/((1+Exp(-1.69+0.00358*CZP)). A mayores concentraciones de clozapina el riesgo de síndrome metabólico aumenta. Esto puede tener implicancias en la clínica, ya que a pacientes con altas concentraciones de clozapina se deberían buscar estrategias para disminuir el impacto metabólico que pueda existir.

Clozapine has proven to be the most effective antipsychotic for resistant schizophrenia, but it is also linked to an increased risk of producing metabolic alterations in patients. A prospective study of patients from the Vilardebó Hospital Polyclinic where the following variables were correlated: daily dose of clozapine, plasma concentration of clozapine and its main metabolite norclozapinaa predose, metabolic ratio clozapine / norclozapine, sex, age, smoking status, duration of the treatment with clozapine, trademark of clozapine used, comedication with valproic acid, comedication with antipsychotics, comedication with lithium and consumption of coffee related to the metabolic syndrome (defined by the Latin American Diabetes Association). The only significant covariate as dependent on the metabolic syndrome was the plasma concentration in clozapine. The model found for this explanation is as follows: P (SM) = Exp (-1.69 + 0.00358 * CZP) / ((1 + Exp (-1.69 + 0.00358 * CZP)) At higher concentrations of clozapine the risk of Metabolic syndrome increases This may have clinical implications, since patients with high concentrations of clozapine should seek strategies to reduce the metabolic impact that may exist.

[Proposal of informed consent by representation for treatment with clozapine]. / Propuesta de consentimiento informado por representación para el tratamiento con clozapina.

Clozapine-induced agranulocytosis, a potentially serious adverse effect, is a limiting factor for its therapeutic use, leading to the suspension of the drug. Its annual incidence in Argentina is 0.05%. In 2000, under provision number 935, the ANMAT approved the Monitoring Program for Ambulatory and Inpatient Patients Treated with Clozapine. In this provision arises the obligation to sign the informed consent where the patient is informed of the risks and benefts of the treatment. In psychiatric care practice patients may not possess, because of their altered psychic state, the level of competence necessary to sign informed consent for their treatment with clozapine. The objective of the present work is to analyze the doctrine of Informed Consent by Representation for the users of clozapine, as well as to propose a decision algorithm for its application in clinical practice.

[Treatment-resistant schizophrenia: Neutropenia with olanzapine and clozapine, and stabilization with two depot antipsychotics]. / Esquizofrenia resistente: neutropenia con olanzapina y clozapina, y estabilización con dos antipsicóticos de depósito.

This case report describes a case of a woman with treatment-resistant schizophrenia, who experienced neutropenia induced by olanzapine and clozapine, and reached symptomatic stabilization with a combination of two depot antipsychotics. This report presents a brief review about the incidence of haematologic events by antipsychotics and the evidence of antipsychotic combination in the treatment.