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Renato de Filippis,1 Raffaele Gaetano,1 Georgios Schoretsanitis,2 Giuseppe Verde,1 Cesare Anthony Oliveti,3 John M Kane,2,4,5 Cristina Segura-Garcia,6 Pasquale De Fazio1 1Psychiatry Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; 2The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY, USA; 3Correnti - Centri Assistenziali Mons. Oliveti, Crotone, Italy; 4Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, NY, USA; 5Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA; 6Psychiatry Unit, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, ItalyCorrespondence: Pasquale De FazioPsychiatry Unit, Department Health Sciences, University Magna Graecia of Catanzaro, Viale Europa 88100, Catanzaro, ItalyTel/Fax +39 0961 712393Email defazio@unicz.itBackground: Clozapine is well known for its efficacy and clinical superiority compared to other antipsychotics in treatment-resistant schizophrenia (TRS). However, it is frequently underutilized worldwide because of its acute adverse events, as well as for its long-term cardiometabolic and hematological consequences.Objective: The aim of the study was to evaluate 5-year safety in chronic TRS inpatients with continuous clozapine use.Methods: Patients with TRS and clozapine treatment were evaluated for 5 years. All participants were assessed using the Brief Psychiatric Rating Scale (BPRS), Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C), Social Performance Scale (PSP) and Short Portable Mental Status Questionnaire (SPMSQ). Clinical, cardiometabolic and hematological data were collected periodically. General linear models (GLM) repeated measures controlling for CLZ dose were utilized to determine differences in variables across the time.Results: Overall, 189 inpatients were screened for study participation. The final sample included twenty-one TRS patients (16 males, 76%) with an average age of 57.6 years, all with 5-year continuous use of clozapine (mean dose 266 mg/day). There was not a significant effect of time on BPRS (p=0.774), PSP (p=0.855) and SPMSQ (p=0.066); differences remained not significant after controlling for CLZ dose (p=0.585, p=0.467 and p=0.105, respectively). No changes were found in blood and clinical parameters except for red blood cell count, which decreased over time (p=0.024; η2= 0.952). Patients reported a significant BMI decrease (− 8.98 kg, p=0.008) between baseline and 5 years last observation.Conclusion: The findings show how the application of a structured dietary, clinical and therapeutic monitoring program in psychiatric care facilities could allow the safe and effective long-term cardiometabolic and hematological management of clozapine. The unique role that clozapine plays in the current treatment of patients with TRS requires greater clinical awareness. Although its acute and chronic side effects are notorious, its safety management is feasible and broadens its potential practical application.Keywords: clozapine, psychiatric care facilities, safety, schizophrenia, tolerability, treatment-resistant schizophrenia

Clozapine (CLZ) is the drug of choice for the treatment of resistant schizophrenia; however, its suitable use is limited by the complex adverse effects' profile. The best-described adverse effects in the literature are represented by agranulocytosis, myocarditis, sedation, weight gain, hypotension, and drooling; nevertheless, there are other known adverse effects that psychiatrists should readily recognize and manage. This review covers the "rare" and "very rare" known adverse effects of CLZ, which have been accurately described in literature. An extensive search on the basis of predefined criteria was made using CLZ and its combination with adverse effects as keywords in electronic databases. Data show the association between the use of CLZ and uncommon adverse effects, including ischemic colitis, paralytic ileus, hematemesis, gastroesophageal reflux disease, priapism, urinary incontinence, pityriasis rosea, intertriginous erythema, pulmonary thromboembolism, pseudo-pheochromocytoma, periorbital edema, and parotitis, which are influenced by other variables including age, early diagnosis, and previous/current pharmacological therapies. Some of these adverse effects, although unpredictable, are often manageable if promptly recognized and treated. Others are serious and potentially life-threatening. However, an adequate knowledge of the drug, clinical vigilance, and rapid intervention can drastically reduce the morbidity and mortality related to CLZ treatment.