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Although commonly used in clinical practice, scientific literature about clozapine prescription patterns in Colombia is scarce. A cross-sectional observational study was conducted in an outpatient clinic in Bogotá, Colombia. Between 2016 and 2018, clozapine was prescribed to 2603 patients, mainly for Schizophrenia Spectrum Disorders and Bipolar and Depressive Disorders, at a median dose of 100mg/day. After controlling for other variables, older age was the only variable that explained the use of doses lower than 100mg/day. Clozapine was not only used for Treatment-Resistant Schizophrenia, and further studies are needed to explain these differences., (CC BY NC ND)

Approximately 30% of people with schizophrenia fail to respond to first-line antipsychotic treatment which impacts the burden of the disease. Treatment-resistant schizophrenia (TRS) denotes patients with failure to respond to at least two adequate trials of different antipsychotics. Clozapine is a unique drug approved for treating treatment-resistant schizophrenia, however 1/3 of patients fail to respond to clozapine. Even though different strategies have been proposed for treating clozapine-resistant schizophrenia, the evidence is very limited, unclear, and of poor quality. A formal literature search was conducted and then, panel members were asked to complete 35 questions addressing different aspects of TRS. A modified Delphi method was used to unify expert opinion and achieve consensus. The expert consensus in diagnostic and treatment of TRS is the result of experts from the main national scientific societies under the organization of the Argentine Association of Biological Psychiatric (AAPB). The consensus statement aims to guide on diagnosis and treatment., Competing Interests: The authors have no conflicts of interest to declare.

Background: Clozapine (CZP) is an antipsychotic used in resistant psychosis, but has adverse metabolic effects and is associated with new onset or worsening of epileptic seizures (ES). There is not enough information available regarding its effect on metabolic variables and on ES in patients with epilepsy., Objective: To describe the effect of CZP on the metabolic and hematologic profiles, and on ES in patients with epilepsy and with psychosis and/or aggressive behavior., Methods: A case series of patients with epilepsy and psychosis and/or aggressive behavior that received CZP with an 18-week follow-up. Clinical records were assessed from 2008-2018. 30 patients with epilepsy that received CZP were included. A paired analysis (Student’s t-test or Wilcoxon signed rank test) was performed with metabolic variables (glucose, cholesterol, and triglycerides), hematologic variables, weight, body mass index (BMI), and monthly ES before and after CZP administration., Results: The median age to CZP initiation was 31.9 ± 16.07 years. Median CZP dosage was 193 mg/day. There were changes on BMI (p = 0.001; 3.2 kg/m2 increase, median = 3.08), triglycerides (p = 0.002) and glucose (p = 0.030). Weight increase was 7 kg (p = 0.292; median = 4 kg). Monthly ES mean was decreased from 4.9 (median = 2) to 2.04 (median = 1; p = 0.001)., Conclusions: This study provide information regarding the security profile of CZP in patients with epilepsy with psychosis and/or aggressive behavior. A decrease on monthly ES was observed, as well as moderate increases in triglycerides, glucose and BMI, which coincide with that described by other authors.

Introduction: Clozapine plasma levels are useful to monitor drug compliance, and also to assess and to prevent some side effects. Recently, routine monitoring to all clozapine-treated patients has been proposed to prevent relapses. However, high intra-individual variability in plasma levels has been reported too, although these studies have some limitations., Methods: We analysed differences between 2clozapine plasma levels separated by at least one year in a subgroup of 28 outpatients (82% male, mean age 47.9 years-old) with diagnosis of non-affective psychosis in clinical remission whose clozapine doses and smoking habits remained unchanged., Results: We found a non-significant increase in clozapine plasma levels [.30mg/L (SD=.14) vs. .32 (SD=.17); t=-.858, p=.40] and a significant decrease in norclozapine plasma levels [.27 (SD=.11) vs. .22 (SD=.10); t=3.27; p=.003]. Absolute coefficient of variation (CV) between first and second assessment were calculated. Forty-six and fifty-seven percent of cases had CV 20% in clozapine and norclozapine, respectively. CV of 50% was seen in 20.7% and 13.8% of clozapine and norclozapine test respectively. We discussed potential causes of such high CV., Conclusions: Our study suggest high intra-individual variation even in a subgroup of very stable patients, which suggest that routine monitoring of these levels may be indicated in order to detect significant plasma variations. We think that clinicians should act with caution in case of a sudden decrease in plasma level. In the absence of obvious symptom severity variation, sources of intra-individual fluctuations might be considered first, before assuming poor compliance., (Copyright © 2019 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: International studies on clozapine use usually show lower than expected prescription proportions, under-dosing and delayed initiation of treatment, which has led to a number of initiatives aimed at improving its use and reducing the striking variability observed among practitioners. There are no similar studies on the Spanish population. Therefore we planned initial data collection from 4 territorial samples. We hypothesized that clozapine prescription would also be low and variable in our country. If this hypothesis were confirmed, a reflection on possible strategies would be necessary., Material and Methods: We accessed data on clozapine prescription in Catalonia, Castile and Leon, the Basque Country and the Clinical Management Area of the Hospital 12 de Octubre (Madrid)., Results: Patients diagnosed with schizophrenia under treatment in these territories comprise around .3% of their total population; treatment with clozapine ranges between 33.0 and 57.0 per 10000 inhabitants; patients diagnosed with schizophrenia on current treatment with clozapine range between 13.7% and 18.6% of the total number of patients with this diagnosis. The coefficient of variation between centres and prescribers is often higher than 50%., Conclusions: Although below the figures suggested as desirable in the literature, global prescribing data for clozapine in the areas we studied are not as low as the data collected in other international studies, and are in the range of countries in our environment. However, the variability in prescription is large and apparently not justified; this heterogeneity increases as we focus on smaller areas, and there is great heterogeneity at the level of individual prescription., (Copyright © 2018 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

30% of people with schizophrenia do not respond to antipsychotics. In these cases, treatment with clozapine is indicated, but only 40% of this subpopulation responds to treatment, thus forming a subgroup of resistant patients who do not respond to clozapine and are therefore referred to as ultra-resistant. Between 12 and 20% of people with schizophrenia are ultra-resistant. The objective of this work is to review the possible treatment for ultra-resistance and its scientific evidence. From the review carried out, it is clear that: 1) The addition of a second antipsychotic to clozapine has a partial response, and there is no antipsychotic that shows significant difference compared to others. 2) Of the antiepileptics, the one that generates a slight clinical improvement is sodium valproate, but even so, a complete response is not achieved. Lamotrigine, in turn, generates a therapeutic response in studies with mild to moderately symptomatic patients. 3) The use of inhibitors of d-amino oxidase, such as sodium benzoate, only achieved a slight clinical improvement without achieving a comprehensive therapeutic response. 4) The addition of memantine was not effective. 5) The addition of electroconvulsive therapy generates significant therapeutic response in severely symptomatic patients for both the positive and negative symptomatic dimensions. Electroconvulsive therapy does not generate cognitive alterations, produces improvement in immediate and long-term verbal memory and in executive functions. Currently more robust evidence concerning therapeutic approaches to ultrarresistant schizophrenia are lacking. In particular, randomized and controlled studies with significant number of patients will be valuable of help to make decisions in this subpopulation with an important impairment in their functionality and quality of life.

Introduction: Clozapine is an antipsychotic drug that has shown to be more effective than other antipsychotics in the treatment of schizophrenia, but its use is limited due to its side effects, particularly by the risk of causing agranulocytosis. A study was made on the variations in white cell and neutrophil counts in patients treated with clozapine in a Long-term Psychiatric Unit., Methods: A retrospective observational study was conducted with a sample of women of our long-term psychiatric care unit who had been treated with clozapine. A study was made on the variations in white cell and neutrophil counts during the first 18 weeks of treatment, as well as the onset of leukopenia, neutropenia, agranulocytosis, and the influence of concomitant drugs., Results and Conclusions: The study included 55 patients on treatment with clozapine. The incidence rate of neutropenia was 1.82% (95% CI; 0.05-10.13). The incidence rate of leukopenia and agranulocytosis was 0%. An increase in white cell and neutrophil counts from baseline to week 3-4 was observed. Only small variations were observed after this time, but the counts remained higher than the initial values. These changes were statistically significant in the white cell count: One-way repeated ANOVA with Greenhouse-Geisser correction F (11.47, 37) = 2.114 (P= .011); and in neutrophils: One-way repeated ANOVA with Greenhouse-Geisser correction F (10.3, 37)=3.312 (P=.0002), and MANOVA F (18, 37)=2.693 (P=.005), ŋ 2 P =0.567. The influence of concomitant drugs (lithium, valproic and biperiden) was not significant on the overall increase found in white cells or neutrophils (MANOVA)., (Copyright © 2016 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels., Material and Methods: Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels., Results: We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed., Conclusion: Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability., (Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

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.

Clozapine constitutes the treatment of choice in patients with schizophrenia with persisting symptoms despite antipsychotics at adequate dose and treatment duration. However, an important proportion does not respond to optimal doses of clozapine, so the addition of a second antipsychotic might increase clinical response. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 17 systematic reviews comprising 62 studies addressing the question of this article, including 26 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding a second antipsychotic to clozapine in patients with refractory schizophrenia probably leads to little or no difference in clinical response, and increases adverse effects.

Clozapine is considered to be the most effective antipsychotic drug for patients with treatment resistant schizophrenia, but up to a third of the patients do not respond to this treatment. Various strategies have been tried to augment the effect of clozapine in non-responders, one of these strategies being electroconvulsive therapy. However, its efficacy and safety are not yet clear. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 55 studies, among them six randomized controlled trials addressing clozapine-resistant schizophrenia. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded electroconvulsive therapy probably augments response to clozapine in patients with treatment resistant schizophrenia, but it is not possible to determine if it leads to cognitive adverse effects because the certainty of the evidence is very low.

Objective: Assess the cost-effectiveness of the antipsychotics for treatment of schizophrenia., Methods: A five-year Markov model was built form patients with schizophrenia on the stage of maintenance. Costs were taken from the perspective of the Colombian health care system (Sistema General de Seguridad Social en Salud). The effectiveness was measured in years of life under the same maintenance plan., Results: The Markov model indicated clozapine as the as the most cost-effective alternative between the first line antipsychotics and haloperidol is it when comparing other antipsychotics., Conclusion: Clozapine it's the cost-effectiveness strategy among the first line of antipsychotics and haloperidol is it among the other antipsychotics. Strategies prioritizing the use of cost-effective antipsychotics could improve the resources allocation in the Colombian health care system., (Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Objectives: To guide the clinician in taking decisions on the best strategies for assessing and monitoring the risk of blood disorders in adults diagnosed with schizophrenia in pharmacological treatment., Method: A clinical practice guideline was developed following the guidelines of the Methodological Guide of the Ministry of Social Protection to collect evidence and grade recommendations. De novoliterature researchwas performed., Results: With the use of antipsychotics there isriskofreducción in the leukocyte count and the risk of agranulocytosis,the later associated with the use of clozapine, although it is a rare event(0.8%) can be fatal; this effect occurs most frequently in the first twelve weeks of treatment and the risk is maintained aroundthe first year of it., Conclusion: The recommendations were considered strongin all hematologic related monitoring.A blood count should be taken at the start of pharmacological treatment. If the patient is started on clozapine one shouldbe taken weekly during the first three months, monthly until completing one year and every six months thereafter. If there is a decrease in white blood cell count the patient should be monitored regularly, stopping if is a less than 3,500 cells/mm(3) and consider referral if is less than 2,000 cells/mm(3)., (Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Approximately 12,000 individuals are treated with clozapine per year in Argentina. The use of this antipsychotic is associated with the occurrence of various side effects; the most serious of these is agranulocytosis, which can be fatal but reversible if detected early. For this reason, clozapine is under a pharmacovigilance intensive program centered by the National Administration of Drugs, Foods and Medical Devices. The present paper reviewed the current legislation for the use of clozapine in Argentina and compared the data obtained from the pharmacovigilance system with those reported in other countries. Further, difficulties that may arise during the reexposure of patients to clozapine are discussed.

Objective: Clozapine is the first choice in drug-resistant schizophrenia but also causes important weight changes. This might discourage clinicians concerned about the risk of developing health problems. To assess this issue we measured change in body mass index (cBMI) induced by clozapine at 18 and 56 weeks., Methods: Baseline body weight and height were measured and weight weekly thereafter during the first 18 weeks of treatment. After that, measurements were made monthly. Steady clozapine dose, clozapine and norclozapine blood concentrations, concomitant medication, gender and age were recorded., Results: At 18 weeks (n=76) mean cBMI was 1.83 kg/m(2). Baseline BMI was inversely correlated with cBMI. At 56 weeks (n=57) cBMI was 2.67 kg/m(2) and was inversely correlated with basal BMI. Multiple regression analysis replicated the results. When split with BMI categories, obese patients had lesser risk for further weight gain., Conclusions: Obesity should not discourage clinicians from starting clozapine in drug-resistant patients., (Copyright © 2012 SEP y SEPB. Published by Elsevier Espana. All rights reserved.)

Patients with schizophrenia have a shorter life expectancy and their risk of dying from a cardiovascular disease is higher than the general population. Both facts have been attributed to the raised presence of metabolic syndrome. There is a big amount of scientific publications that deals with the relationship between schizophrenia, antipsychotic treatment, and the development of metabolic syndrome. There is also information about recommendations and clinical guides to achieve an adequate prevention, screening, and treatment of the disease. The aim of this review is to update the current information about this issue and to understand related etiologic factors, differences between antipsychotic drugs, and the current recommendations for patient's care., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Objective: Functional status and quality of life outcomes in Latin American outpatients with schizophrenia were compared after 12 months of monotherapy treatment with olanzapine, risperidone or typical antipsychotics., Method: Both outcomes were assessed as part of a prospective, large (N= 7658), international (27 countries), observational study., Results: from the Latin American subpopulation (N= 2671; 11 countries) are presented. Compared to typical antipsychotics, olanzapine and risperidone were associated with significantly (p < 0.05) greater odds of employment and social activity, and significantly greater improvements in quality of life. Olanzapine was also associated with significantly greater odds of living independently, compared to typical antipsychotics., Conclusion: This study indicates that functional status and quality of life outcomes are likely to be more favorable when Latin American outpatients with schizophrenia are treated with olanzapine or risperidone monotherapy, rather than typical antipsychotics.

Aims: The most important and serious neuropsychiatric disorders in Parkinson's disease (PD) are the medication-induced psychoses. They are remarkably frequent and are linked to a dopaminergic over-stimulation caused by the drugs administered over a long period of time. This complication increases the morbidity and mortality rates in PD and in the past it was very difficult to treat. Yet, the atypical antipsychotics have transformed its prognosis., Development: We review the general pharmacology of the atypical antipsychotics, in particular clozapine and olanzapine, which we have wide experience with. We present two series in which these drugs were used with the psychosis in PD. Our studies were performed using a strict prospective methodology, with scales that are valid for psychosis, and the patients' motor signs. Both atypical antipsychotics were seen to improve the positive and negative symptoms of the patients, giving rise to no or scarce improvement of the motor signs of PD. The side effects of the two drugs were not important. Our two series are compared with others from the literature, with similar results as regards the improvements in the psychoses and the absence or only slight deterioration of Parkinson's disease., Conclusions: The psychoses induced by medication in PD are frequent and severe. The appearance of the atypical antipsychotics has come as a true 'revolution' in their treatment, owing to the good results obtained in the treatment of the psychoses and the scant deterioration of the motor signs of PD.

Introduction: We compare the prevalence of obsessive-compulsive symptoms in schizophrenic patients in treatment with clozapine and those who receive classic antipsychotic drugs., Method: Outpatients with schizophrenia treated with clozapine (n = 56) or classic antipsychotic drugs (n = 54) at the Honorio Delgado-Hideyo Noguchi Specialized Institute in Mental Health (Lima-Peru), were evaluated for the presence of obsessive-compulsive symptoms by means of the Obsessive-Compulsive Disorder Module of Structured Clinical Interview for DSM-IV and Yale-Brown Obsessive-Compulsive Symptoms Checklist., Results: 46.4 % of patients treated with clozapine presented obsessive-compulsive symptoms while this occurred in 20.4 % of those with classic antipsychotic drugs (p = 0.005). In addition, 21.4 % of patients with clozapine and 13 % of those treated with classic antipsychotics presented obsessive-compulsive disorder according to DSM-IV criteria (p = 0.31)., Conclusion: In schizophrenic patients, treatment with clozapine is associated with a higher rate of obsessive-compulsive symptoms than treatment with classic antipsychotic drugs.

Background: Schizophrenic patients have a high comorbidity with substance use disorders. However, there are few studies on the efficacy of antipsychotics on psychopathology and on their repercutions on substance abuse., Methods: All studies about pharmacological treatment of schizophrenic patients with substance abuse, included in Medline over the last ten years were analyzed., Results: Of the 17 studies reviewed, most were prospective with small samples (< 30 patients, 5 studies) or case reports (7 studies). Objectives were to assess the efficacy on schizophrenic symptoms and the effect of the treatment on substance use. Atypical antipsychotics were the most studied. These pharmacological agents were effective at reducing symptoms and had few side effects. They also managed lo reduce substance abuse in 66-75% of patients., Conclusions: In spite of underlyng methodological problems of these studies, the findings suggest that atypical antipsychatics could be the treatment of choice in these patients.

The purpose of this work is to review the main investigations on the cognitive and cerebral effects of clozapine treatment in schizophrenic patients. We remark the differential effects in respect to other neuroleptics. Memory is the neuropsychological function more widely investigated. Clozapine produces visual memory impairment, but not the verbal memory deficit observed following the classical neuroleptic treatment. The effect of clozapine in the cortico-subcortical circuitry points to a differential effects on frontal lobe functions. It has been observed positive effects in controlled verbal fluency and also in visuoconstructive functions. However, in these studies retest effects are not controlled. There are several magnetic resonance imaging works that found a decrease of caudate nuclei volume, in contrast to the increase observed after treatment with classical neuroleptics. The differential effects on neuropsychological functions may be caused by the differential action of antipsychotics on the fronto-estriatal structures. In the future research it is necessary to perform studies including together neuropsychological and functional neuroimaging data in order to clarify the mechanisms responsible of positive and negative psychopharmacological effects.

The recent advances in the investigation of schizophrenia were reviewed. Three major fields are considered relevant: 1. Genetic studies with the remarkable finding of the 6pter-p22 chromosome linkage study, which will lead to better understanding about inheritance of disease in the future; 2. The new x-ray techniques, including our own investigations showing smaller brain size in our patients, and 3. The prominent new antipsychotic drugs, as effective as the older drugs but with fewer side effects.

Clozapine is an atypical antipsychotic drug with a very low incidence of extrapyramidal effects, used in the treatment of schizophrenic patients refractory or intolerant to classical neuroleptics. Its use is limited due to the potential risk of producing agranulocytosis in 1 to 2% of patients. Despite the severity of this complication, the Federal Drug Administration allowed its use as long as its prescription is associated to a drug surveillance program that controls regularly the white cell count of patients using the drug. Three hundred three patients (210 male) have been admitted to a clozapine drug surveillance program. Two patients had a transitory leukopenia with less than 2000 leukocytes/ml and less than 1000 neutrophyls/ml, that reverted after discontinuing the drug. One patient, whose case is described, had a severe agranulocytosis with less than 500 neutrophyls/ml that required hospital admission.