Clozapine Treatment for Aggressive Behaviors in Youths with Neurodevelopmental Disorders.

Objectives: The aim of this study was to assess effectiveness and tolerability of Clozapine in the treatment of aggression in youth with Neurodevelopmental Disorders. Methods: Patients were consecutively admitted at our third-level university hospital with nationwide catchment from June 2018 to October 2022, and followed up to July 2023. Eligibility criteria were as follows: (1) Autism Spectrum Disorder (ASD) and/or Intellectual Disability/Borderline Cognitive Functioning, (2) behavioral dyscontrol with physical aggression; (3) age range between 8 and 18 years; (4) clinical indication for Clozapine treatment after at least two failed trials with other Second-Generation Antipsychotics (SGAs); (5) availability of an at least 6-month-long follow-up. To evaluate the response to Clozapine, we used the Clinical Global Impressions (CGI) rating scales (Clinical Global Impressions-Severity [CGI-S] and Clinical Global Impressions-Improvement [CGI-I]), the Children's Global Assessment Scale (CGAS), and the Aberrant Behavior Checklist (ABC). Results: Twenty-six children and adolescents (21 boys, age 13.47 ± 2.05 years, follow-up duration 9.77 ± 3.50 months) were included in the analysis. Clinical severity (CGI-S) and functional impairment (Clinical Global Assessment Scale) significantly improved, as well as the ABC Total Score and the scores in several subscales. Sixteen patients (61.54%) were responders (CGI-I ≤2), and 13 (50.00%) displayed remission of aberrant behaviors (ΔABC-Total >35), while response/remission condition was not affected by add-on medications and psychotherapy. Most frequent side effects were increased appetite (50.00%), sialorrhea (38.46%), and increased repetitive behaviors (26.92%). Two patients presented epileptic seizures, while no patients presented leucopoenia. Conclusions: Our results suggest that Clozapine may be helpful in ameliorating treatment-resistant aggression in youth with neurodevelopmental conditions. Possible pharmacological strategies for the management of most frequent side effects are also suggested.

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment-resistant schizophrenia.

BACKGROUND: Glutamatergic function abnormalities have been implicated in the etiology of treatment-resistant schizophrenia (TRS), and the efficacy of clozapine may be attributed to its impact on the glutamate system. Recently, evidence has emerged suggesting the involvement of immune processes and increased prevalence of antineuronal antibodies in TRS. This current study aimed to investigate the levels of multiple anti-glutamate receptor antibodies in TRS and explore the effects of clozapine on these antibody levels. METHODS: Enzyme linked immunosorbent assay (ELISA) was used to measure and compare the levels of anti-glutamate receptor antibodies (NMDAR, AMPAR, mGlur3, mGluR5) in clozapine-treated TRS patients (TRS-C, n = 37), clozapine-naïve TRS patients (TRS-NC, n = 39), and non-TRS patients (nTRS, n = 35). Clinical symptom severity was assessed using the Positive and Negative Symptom Scale (PANSS), while cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). RESULT: The levels of all four glutamate receptor antibodies in TRS-NC were significantly higher than those in nTRS (p < 0.001) and in TRS-C (p < 0.001), and the antibody levels in TRS-C were comparable to those in nTRS. However, no significant associations were observed between antibody levels and symptom severity or cognitive function across all three groups after FDR correction. CONCLUSION: Our findings suggest that TRS may related to increased anti-glutamate receptor antibody levels and provide further evidence that glutamatergic dysfunction and immune processes may contribute to the pathogenesis of TRS. The impact of clozapine on anti-glutamate receptor antibody levels may be a pharmacological mechanism underlying its therapeutic effects.

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.

Clozapine Prescripers-Dogmatic or Pragmatic?

Clozapine, amongst antipsychotics, has a unique composite mode of action that might translate into an expanded therapeutic potential on clinical grounds. Sorely, clozapine remains underutilized.

Clozapine-induced pneumonitis mimicking an atypical pneumonia.

Clozapine is an antipsychotic used for treatment-resistant schizophrenia with a significant side effect profile, including agranulocytosis, myocarditis and fever. Clozapine-induced fever often occurs in the first 2 weeks of treatment and settle after a few days. We report a case of a woman in her mid-30s who developed fever and infective symptoms suggestive of an atypical pneumonia while on clozapine titration. She was on clozapine for 16 days before developing high-grade fever, dry cough, diarrhoea, headache and photophobia with a very high CRP. We performed an extensive infection workup that returned negative results except for bilateral upper lobe ground glass changes of the lungs on CT. Despite antibiotic therapy, which would cover an atypical pneumonia, her CRP remained elevated and her fever persisted. Focus was directed to clozapine-induced pneumonitis as the cause for her symptoms. Her antibiotics were ceased, and clozapine was downtitrated. With the adjustment of her clozapine dose, her fevers and associated symptoms resolved, and CRP downtrended. Her fevers did not return when clozapine was uptitrated in the community subsequently. Clozapine-induced fever or other immune-allergic reactions should be systematically considered when patients develop fever during the initiation phase of clozapine therapy. Ruling out infective causes is desirable prior to attributing fevers to clozapine especially when they are accompanied by infective symptoms and high inflammatory markers. Careful downtitration of clozapine should be considered rather than abrupt cessation in managing clozapine-induced fevers and subsequent slow uptitration could be considered.

A quality improvement program for managing clozapine-induced constipation in a long-term structured residential setting for persons with serious mental illness.

OBJECTIVES: The goal of this quality improvement project (QIP) was to increase awareness of the serious medical consequences of clozapine-associated constipation to front line nursing staff and patients with schizophrenia. METHODS: The QIP was developed iteratively by psychiatric nurses, psychiatrists and pharmacists with input from patients. The processes involved a literature review, development of educational materials for staff and patients, and the creation of a daily bowel movements log (BML). Implementation involved review of the BML at treatment team meetings, and deployment of pharmacological and non-pharmacological interventions to resolve constipation and increase awareness and knowledge of this clinical concern. OUTCOMES: The initial pilot screened for symptoms of constipation in patients receiving clozapine and non-clozapine antipsychotic agents and intervening as necessary during multidisciplinary team meetings. Patients benefited from relief of constipation and improved bowel habits. Staff benefited from improved knowledge and making requisite changes in workflow and practice. Feedback allowed refinements to be made to the educational materials for patients and staff. Since full implementation, bowel habits are routinely monitored, and interventions are reviewed for effectiveness. Staff satisfaction with this QIP is reflected in answers to a structured questionnaire and in patient reports (n = 50). CONCLUSIONS: Clozapine, the only approved and efficacious medication for treatment-resistant schizophrenia is significantly underutilized. Medically consequential constipation can be a serious barrier to retention of patients benefiting from clozapine. Increased awareness and use of educational materials for patients and staff, routine monitoring of bowel habits combined with pharmacological and non-pharmacological interventions can successfully address this clinical problem.

CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Effect of concomitant use of valproic acid during clozapine initiation on clozapine-induced inflammation among Japanese patients with schizophrenia.

During clozapine initiation, titration speed and concomitant valproate administration have been reported as risk factors for clozapine-induced fever and myocarditis. We tested the risk of concomitant valproate administration by stratifying patients according to titration rate. Concomitant valproate use was only associated with increased inflammatory adverse events in the slower titration group. The frequency of inflammatory adverse events was approximately 30 % during faster titration, regardless of concomitant valproate administration. However, the faster titration group with valproate had a higher frequency of severe adverse effects such as myocarditis. Clinicians should avoid concomitant valproate administration during clozapine initiation, regardless of titration rate.

High rates of myocarditis with clozapine in the Hunter region of Australia.

OBJECTIVE: To study the causes of clozapine treatment discontinuation and measure clozapine-induced myocarditis (CIM) rates in an Australian region, to compare the observed rates of CMI with reports from Australia and the world, and discuss factors related to CIM incidence rates in the region. METHODS: The study is a retrospective clinical audit of 327 patients prescribed clozapine. All patients were monitored by the mandatory CIM monitoring protocol for the first six weeks of treatment. The validity of a diagnosis of CIM was assessed using six criteria. Socio-demographic and clinical factors and clozapine prescription practices were analysed for their association with CIM. The study could not examine co-existing medical illness, co-prescribed psychotropic medication, genetics, and environmental factors. RESULTS: CIM occurred in 9.8 % of the cohort after a mean treatment duration of 19.5 days. The diagnosis of CIM was considered valid in all cases. Gender, age at the start of treatment, ethnicity, cumulative clozapine dose, dose titration, and clozapine/norclozapine ratio were unrelated to CIM. CONCLUSION: The CIM rate in the Hunter region was higher than in the rest of Australia and the world and increased after adopting the monitoring protocol. Over-diagnosis, patient's age and gender, ethnicity, cumulative clozapine dose, dosing titration, and clozapine metabolism rate were unrelated to the high occurrence rates. The possible role of comorbid illnesses, co-prescribed psychiatric medications, genetic, and environmental factors in the etiology of CIM requires further study. The reasons underlying the high rates of CIM in the Hunter region need further exploration.

Potential impact on mental health in patients with treatment-resistant schizophrenia - clozapine augmentation with long-acting parenteral antipsychotics: a case series.

INTRODUCTION: The rate of pharmacoresistance among in patients diagnosed with schizophrenia is around 30%. Clozapineis the drug of choice for these patients; however, an adequate response to treatment doesn't always occur. One of the possible augmentation approaches, specifically for non-adherent patients, is the administration of long-acting parenteral antipsychotics. Our goal was to evaluate previous experiences of administering a combination of the atypical antipsychotic clozapine and long-acting injectable antipsychotics to pharmacoresistant patients at the Department of Psychiatry the Czech Republic and to assess the safety and effectiveness of such administration. METHODS: A retrospective evaluation of patient case studies was conducted for those who were hospitalized in the Ward for the therapy of Psychotic disorders between 2016 and 2020 and had a medication history of combining clozapine and depot antipsychotics. RESULTS: Over half of the patients had no illness relapses during the observed period. The clinical manifestation of adverse effects from combination therapy appears low in our patient sample, primarily involving mild and pharmacologically manageable side effects (tachycardia). Only one of the cases recorded neutropenia, which led to discontinuation of clozapine; the patient was maintained on long-acting injectable antipsychotics medication. CONCLUSION: From our findings, it can be inferred that augmenting clozapine with depot antipsychotics is a potential therapeutic intervention that pharmacoresistant patients could benefit from. However, it is essential to emphasize that this therapeutic approach should only be administered after carefully considering the patient's existing treatment. It should be strictly individualized based on the treating physician's or clinical pharmacist's sufficient professional experience.

Rare variants in pharmacogenes influence clozapine metabolism in individuals with schizophrenia.

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (ß = -0.054, SE = 0.019, P-value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (ß = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles.

Clozapine Use in 22q11.2 Deletion Syndrome: A Systematic Review of the Literature.

BACKGROUND: 22q11.2 deletion syndrome confers significant risk for the development of schizophrenia. While current recommendations regarding the management of psychotic symptoms in affected individuals are generally in keeping with treatment guidelines for general schizophrenia populations, evidence for the use of clozapine has come from case reports and retrospective observational data. As no reviews on the topic currently exist, a systematic review of clozapine use in 22q11.2 deletion syndrome was completed. METHODS: In November 2023, a literature search was completed using both PubMed and Scopus to identify English-language articles that reported the use of clozapine in humans with 22q11.2 deletion syndrome. RESULTS: Twenty-six articles describing 57 individuals were deemed eligible for inclusion. Most individuals had a diagnosis of treatment-resistant schizophrenia. Where reported, the mean or median dose of clozapine was relatively low, and the majority of individuals exhibited a good response (approximately 65.5% across individual case reports/series). While seizures were unsurprisingly the most commonly reported serious adverse effect, the majority of individuals were able to remain on (or be restarted on) clozapine by having their dose decreased and/or by adding an anticonvulsant (most commonly valproate). CONCLUSIONS: This review reaffirms that individuals with 22q11.2 deletion syndrome may benefit from clozapine therapy even at a low dose, assuming they meet criteria for treatment-resistant schizophrenia and provided no contraindications exist. However, given the increased incidence of seizures in 22q11.2 deletion syndrome, the use of prophylactic anticonvulsant therapy should be considered, and hypoparathyroidism/hypocalcemia screened for and corrected before the initiation of clozapine. It is also recommended that clozapine blood levels be monitored.

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis.

Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that EVs are also a source of DAMPs in the induction of the immune response preceding drug-induced agranulocytosis, the proteome and immunogenicity of clozapine- (agranulocytosis-associated drug) and olanzapine- (non-agranulocytosis-associated drug) exposed EVs were compared in two preclinical models: THP-1 macrophages and Sprague-Dawley rats. Compared with olanzapine, clozapine induced a greater increase in the concentration of EVs enriched from both cell culture media and rat serum. Moreover, treatment of drug-naïve THP-1 cells with clozapine-exposed EVs induced an inflammasome-dependent response, supporting a potential role for EVs in immune activation. Proteomic and bioinformatic analyses demonstrated an increased number of differentially expressed proteins with clozapine that were enriched in pathways related to inflammation, myeloid cell chemotaxis, wounding, transforming growth factor-ß signaling, and negative regulation of stimuli response. These data indicate that, although clozapine and olanzapine exposure both alter the protein cargo of EVs, clozapine-exposed EVs carry mediators that exhibit significantly greater immunogenicity. Ultimately, this supports the working hypothesis that drugs associated with a risk of IDRs induce cell stress, release of proinflammatory mediators, and early immune activation that precedes severe reaction onset. Further studies characterizing EVs may elucidate biomarkers that predict IDR risk during development of drug candidates. SIGNIFICANCE STATEMENT: This work demonstrates that clozapine, an idiosyncratic drug-induced agranulocytosis (IDIAG)-associated drug, but not olanzapine, a safer structural analogue, induces an acute proinflammatory response and increases extracellular vesicle (EV) release in two preclinical models. Moreover, clozapine-exposed EVs are more immunogenic, as measured by their ability to activate inflammasomes, and contain more differentially expressed proteins, highlighting a novel role for EVs during the early immune response to clozapine and enhancing our mechanistic understanding of IDIAG and other idiosyncratic reactions.

Clozapine metabolism and cardiotoxicity: A prospective longitudinal study.

BACKGROUND: Clozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful. METHODS: The Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board. RESULTS: Sixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis. CONCLUSIONS: The assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.

Change in absolute neutrophil count after COVID-19 infection in patients using clozapine versus other antipsychotics.

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P  = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.

Clozapine-related tachycardia: A conundrum to identify and treat.

OBJECTIVE: This study examined the rates and persistence of clozapine-induced tachycardia and heart-rate differences in patients treated with ß-blockers in the largest sample of patients with a psychotic disorder to date. METHOD: An audit of medical files for 101 patients who attended a clozapine community clinic and analysis of monthly measurements of resting heart rates. RESULTS: 51% met the clinical criteria for tachycardia. Heart rates were stable over time. ß-blockers were associated with small but significant reductions in heart rates. CONCLUSION: The cardiovascular risks of clozapine are often overlooked. ß-blockers are useful in lowering heart rates but they may be insufficient to reduce cardiac risk.