clozapine and Infections

Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms.. Individuals with schizophrenia are at two to five times more likely to develop pneumonia than the general population, in particular, when receiving clozapine. Delayed-onset distinguishes clozapine-associated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper-B cell interactions may inform future clinical studies.. The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. On the basis of available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as other potentially autoantibody-mediated diseases.

Topics: Antibodies; Antipsychotic Agents; B-Lymphocytes; Clozapine; Humans; Immunomodulation; Infections; Risk

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.

Topics: Antipsychotic Agents; Clozapine; Humans; Infections; Schizophrenia

To examine the risk of infection in patients prescribed clozapine compared with patients prescribed paliperidone palmitate long-acting injection (PPLAI).. A retrospective, 1-year, cohort study conducted on events occurring in eligible patients beginning treatment for the first time with clozapine or PPLAI between June 2017 and June 2019 in a UK mental health trust providing in-patient and out-patient services.. The study included 64 patients starting clozapine and 120 patients starting PPLAI. Incidence of infection was greater in clozapine starters than in PPLAI starters (28% vs 6%;. Patients starting clozapine showed a substantially increased likelihood of infection compared with patients starting PPLAI.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Delayed-Action Preparations; Female; Humans; Incidence; Infections; Male; Middle Aged; Paliperidone Palmitate; Retrospective Studies; Schizophrenia; United Kingdom

Topics: Clozapine; Humans; Infections; Inflammation; Male

A 23-year old male with a history of schizophrenia treated with clozapine 900 mg/d was admitted to the hospital for a gastrointestinal infection. The trough serum concentration of clozapine at admission was 9074 nmole/L, that is, almost 4-fold the upper limit of the reference range. The patients did not report any adverse effects of clozapine. The clozapine concentration 1 month earlier had been 1919 nmole/L, which is well within the reference range. There seems to be 2 different mechanisms explaining the increase in clozapine levels in this patient. First, a downregulation of CYP enzyme activities, which primarily seems to be mediated by interleukin-6, takes place during infection and inflammation. Second, the concentration of the acute phase protein α1-acid glycoprotein (AGP; orosomucoid) increases during infection and inflammation. As approximately 95% of clozapine is bound to AGP, the concentration of clozapine will increase in parallel with the increase in AGP. A therapeutic drug monitoring analysis measures the total drug concentration (ie, the concentration of unbound plus plasma protein bound drug), whereas the concentration of free drug exerts its pharmacological effects. Thus, this second mechanism will, in contrast to the first mechanism, not affect the clinical effect of clozapine. Although the patient was also treated with ciprofloxacin, which has been reported to inhibit the metabolism of clozapine, the clozapine levels did not further increase. This case illustrates the complex interrelationship between serum levels of clozapine and an intercurrent infection treated with potentially interacting antibiotics.

Topics: Adult; Anti-Bacterial Agents; Antipsychotic Agents; Ciprofloxacin; Clozapine; Drug Interactions; Drug Monitoring; Humans; Infections; Inflammation; Male; Schizophrenia; Young Adult

Between January 1999 and May 2000, the Netherlands Pharmacovigilance Foundation LAREB received five reports of patients with clozapine intoxication attributed to inflammation. The reports all concerned men with schizophrenia, aged 63, 54, 41, 45 en 42 years. The occurrence of increased clozapine levels during inflammation, and normalisation after recovery, strongly suggest a causal relationship. No other possible explanations were found. A three to five-fold increase occurred in most instances, but one patient experienced a ten-fold increase compared with the basal levels of clozapine. Three of the patients developed a delirium as an intoxication symptom, probably due to anticholinergic effects on the central nervous system. In case of an inflammatory reaction in patients on clozapine treatment, the physician should be aware of the possibility of clozapine intoxication and delirium. Measuring clozapine levels during infection and dosing based on these levels can minimise the adverse effects of clozapine intoxication.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Clozapine; Delirium; Humans; Infections; Male; Middle Aged; Netherlands; Schizophrenia