An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder.

Discontinuation effects following cessation of 12 and 24 wk of pregabalin treatment for generalized anxiety disorder (GAD) were evaluated in a placebo- and lorazepam-controlled, randomized, double-blind, multicentre trial conducted in 16 countries. The study design consisted of two 12-wk treatment periods (periods 1 and 2), each followed by a 1-wk taper and two post-discontinuation assessments, one immediately following the taper and one 1-wk post-taper. Patients were assigned to receive an initially flexible dose of pregabalin 450-600 mg/d, pregabalin 150-300 mg/d, or lorazepam 3-4 mg/d for 6 wk; responders continued fixed-dose therapy for 6 additional weeks. Patients entering period 2 continued on the same fixed dose or switched to placebo. Discontinuation effects were evaluated with the Physician Withdrawal Checklist (PWC) and reported discontinuation-emergent signs and symptoms. Rebound anxiety was measured with the Hamilton Anxiety Rating Scale. GAD symptoms improved with all treatments and improvements were maintained over 12 and 24 wk. Low levels of discontinuation symptoms were evident in all treatment groups. For patients who received active treatment during both periods, mean (95% confidence interval) increases on the PWC from last visit on active treatment to the second post-discontinuation assessment were: pregabalin 450-600 mg/d: 2.8 (1.6-3.9), pregabalin 150-300 mg/d: 1.7 (0.7-2.8), lorazepam 3-4 mg/d: 2.2 (1.0-3.5). Rates of rebound anxiety were also low at both 12 and 24 wk (0-6%). This suggests that risk of discontinuation symptoms and rebound anxiety are low for pregabalin after 12 and 24 wk of treatment.

Effects of the economic crisis on demand due to mental disorders in Asturias: data from the Asturias Cumulative Psychiatric Case Register (2000-2010).

INTRODUCTION: The economic crisis has negative effects on the population's physical and mental health. Our objective has been to study the association between socioeconomic status and number of people demanding mental health services. METHODS: We performed a correlation analysis of administrative morbidity data (incidence and prevalence) of mental illness (obtained from the Asturias Cumulative Psychiatric Case Register) and three economic indicators (unemployment, consumer price index and gross domestic product). RESULTS: The increase in the unemployment rate is associated with a clear decrease in both new and prevalent mental health demand. CPI has a minor weak positive correlation with the administrative incidence of some mental disorders (Neurotic disorders, Schizophrenia and addictions). GDP does not show a significant correlation with the administrative incidence and it is strongly associated with an increased administrative prevalence that is more intense in the case of alcoholism, neurotic disorders, mental retardation and Z codes (ICD-10). CONCLUSION: The variation of the socioeconomic indicated observed in the economic crisis period in Asturias was not associated with increased care demand for any mental disorders. There is a negative correlation of unemployment rate with care demand.

Systematic depression screening in high-risk patients attending primary care: a pragmatic cluster-randomized trial.

BACKGROUND: Systematic screening for depression in high-risk patients is recommended but remains controversial. The aim of this study was to assess the effectiveness of such screening in everyday clinical practice on depression recognition. METHODS: A pragmatic, cluster randomized, controlled study that randomized primary care physicians (PCPs) in Spain either to an intervention or control group. The intervention group (35-PCPs) received training in depression screening and used depression screening routinely for at least 6 months. The control group (34-PCPs) managed depression in their usual manner. Adherence to (1-6; never-very frequently), feasibility (1-4; unfeasible-very feasible), and acceptance (1-5; very poor-very good) of the screening were evaluated. Underrecognition (primary outcome) and undertreatment rates of major depressive disorder (MDD) in the two groups were compared 6 months after randomization in a random sample of 3737 patients assigned to these PCPs using logistic regression adjusting for the clustering effect. RESULTS: No significant differences were found for recognition rates (58.0% vs. 48.1% intervention vs. control; OR [95%CI] 1.40 [0.73-2.68], p = 0.309). The undertreatment rate did not differ significantly either (p = 0.390). The mean adherence to depression screening was 4.4 ± 1.0 ('occasionally'), the mean feasibility was 3.1 ± 0.5 ('moderately feasible'), and the mean acceptance was 4.2 ± 0.6 ('good'). CONCLUSIONS: This research was not able to show effectiveness of the systematic screening for MDD in high-risk patients on depression recognition in primary care. The poor adherence to screening implementation could partially explain the results. These reflect the difficulties of putting into practice the clinical guidelines usually based on interventional research. TRIAL REGISTRATION: Clinicaltrials.gov NCT01662817.

Quality of life in depressed women over 40 years old.

OBJECTIVES: This study aims to determine quality of life and satisfaction in depressed Spanish women over 40 years old in the outpatient psychiatry setting. Secondarily, the association between several characteristics of depressed patients and quality of life was assessed. MATERIAL AND METHODS: Cross-sectional, descriptive study, carried out in the Spanish psychiatry setting in 2008. A total of 365 Spanish psychiatrists participated. 1069 patients older than 18 years old signed the informed consent. Depressive symptoms were assessed using the 17 Item Hamilton for Depression Rating Scale (HAM-D17). The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scale assessed the patient's satisfaction and life enjoyment. RESULTS: Were included a total of 942 patients with the following characteristics: mean age of 52.46 years, medical comorbidity in 62.9%, and a history of psychiatric disorders in 79.6%. HAM-D17 mean score of 21.39. According to the Q-LES-Q questionnaire, Global satisfaction mean score was of 35.2%, the highest mean scores were achieved in the treatment satisfaction and the lowest mean scores in free time activities. The quality of life was influenced by the intensity of depressive symptoms and physical comorbidity. CONCLUSION: The study results show an impairment of quality of life in depressed women attending outpatient psychiatric centers. This decrease in the quality of life is associated with depressive symptoms and medical comorbidity.

Screening for anxiety and depression in Primary Care: Utility of 2 brief scales adapted to the ICD-11-PC.

INTRODUCTION: The World Health Organization has developed a new classification of mental disorders in Primary Health Care (PHC), the ICD-11-PHC, in which there are changes in the diagnostic criteria of anxiety and depression disorder. In addition, 2 screening instruments have been developed for the detection of anxious and depressive symptoms according to the criteria of the new classification. OBJECTIVES: To evaluate the capacity of the Spanish version of the 2 brief scales Dep5 and Anx5 to identify cases of depression and anxiety in PHC in Spain. METHOD: A cross-sectional study conducted by 37 PHC physicians who selected 284 patients with suspected emotional distress. This sample was administered the screening scales (Anx5 and Dep5) and a diagnostic instrument (Clinical Interview Schedule-Revised) contemplating the new ICD-11 criteria as used as gold standard. RESULTS: The Anx5, using a cut-off point of 3, showed a sensitivity of 0.75 and specificity of 0.53. Using a cut-off point of 4, the Dep5 showed a sensitivity of 0.48 and a specificity of 0.8. The 2 scales together, with a cut-off point of 3 for each, classified correctly 73,57% as cases or non-cases. The diagnosis most frequently observed was anxious depression. CONCLUSIONS: The screening scales for anxious and depressive symptoms (Anx5 and Dep5) are simple and easy-to-use instruments for assessing anxious and depressive symptoms in PHC. The reliability and validity data of each of the scales separately are limited but the figures improve when they are used together.

Screening for anxiety and depression in Primary Care: Utility of 2 brief scales adapted to the ICD-11-PC. / Detección de ansiedad y depresión en Atención Primaria: utilidad de 2 escalas breves adaptadas a los nuevos criterios CIE-11-AP.

INTRODUCTION: The World Health Organization has developed a new classification of mental disorders in Primary Health Care (PHC), the ICD-11-PHC, in which there are changes in the diagnostic criteria of anxiety and depression disorder. In addition, 2 screening instruments have been developed for the detection of anxious and depressive symptoms according to the criteria of the new classification. OBJECTIVES: To evaluate the capacity of the Spanish version of the 2 brief scales Dep5 and Anx5 to identify cases of depression and anxiety in PHC in Spain. METHOD: A cross-sectional study conducted by 37 PHC physicians who selected 284 patients with suspected emotional distress. This sample was administered the screening scales (Anx5 and Dep5) and a diagnostic instrument (Clinical Interview Schedule-Revised) contemplating the new ICD-11 criteria as used as gold standard. RESULTS: The Anx5, using a cut-off point of 3, showed a sensitivity of 0.75 and specificity of 0.53. Using a cut-off point of 4, the Dep5 showed a sensitivity of 0.48 and a specificity of 0.8. The 2 scales together, with a cut-off point of 3 for each, classified correctly 73,57% as cases or non-cases. The diagnosis most frequently observed was anxious depression. CONCLUSIONS: The screening scales for anxious and depressive symptoms (Anx5 and Dep5) are simple and easy-to-use instruments for assessing anxious and depressive symptoms in PHC. The reliability and validity data of each of the scales separately are limited but the figures improve when they are used together.

Can interleukin-2 and interleukin-1ß be specific biomarkers of negative symptoms in schizophrenia? / ¿Pueden ser la interleucina-2 y la interleucina-1ß biomarcadores específicos de la sintomatología negativa en la esquizofrenia?

INTRODUCTION: Evidence suggests the existence of cytokine disturbances in patients with schizophrenia but their association with psychopathology is still unclear. The aim of the current study was to determine if pro-inflammatory cytokine levels (tumor necrosis factor-α, interleukin (IL)-6, IL-2, IL-1ß, IL-1RA) are increased in stable outpatients compared with healthy subjects, and to analyze if they could be specific biomarkers of clinical dimensions in schizophrenia. METHODS: We studied 73 stable outpatients with schizophrenia in their first 10 years of illness and 73 age- and sex-matched healthy controls. An accurate assessment of clinical dimensions (positive, negative, depressive, cognitive) was performed in patients. RESULTS: Only IL-6 levels were significantly increased in patients after controlling for body mass index, waist circumference, smoking, and psychopharmacological treatment, compared with healthy subjects. After adjusting for several confounders, multiple linear regression models identified that Positive and Negative Syndrome Scale negative symptoms, general psychopathology, and global severity are predicted by IL-1ß concentrations, while motivation and pleasure domain of Clinical Assessment Interview for Negative Symptoms and Personal and Social Performance global functioning scores are predicted by IL-2 levels. Cognitive performance, positive, and depressive symptom severity did not correlate with any cytokine. CONCLUSIONS: Our findings suggested that IL-6 concentrations are elevated in stable patients with schizophrenia. Whereas IL-2 specifically marks severity of the motivation and pleasure domain of negative symptoms, IL-1ß is not specific to this dimension as it also predicts severity of general and global symptomatology.

Oxidative stress biomarkers and clinical dimensions in first 10 years of schizophrenia. / Biomarcadores de estrés oxidativo y dimensiones clínicas en los 10 primeros años de esquizofrenia.

INTRODUCTION: Several studies have described increased oxidative stress parameters in patients with schizophrenia. The objectives of the current study were to identify potential oxidative stress biomarkers in stable patients during first 10 years of schizophrenia and determine if they are associated with specific clinical dimensions. MATERIAL AND METHODS: Seventy-three clinically stable outpatients with schizophrenia and 73 sex and age-matched healthy controls were recruited. Sociodemographic, clinical and biological data were collected at enrollment. Blood biomarkers included homocysteine, the percentage of hemolysis, lipid peroxidation subproducts, and as an antioxidant biomarker, catalase activity in erythrocytes. RESULTS: Comparative analyses after controlling for smoking and metabolic syndrome evidenced a significant increase in catalase activity in patients. Also, lower lipid peroxidation levels showed an association with negative symptoms. CONCLUSIONS: In conclusion, compensatory antioxidant mechanisms might be increased in stable patients with schizophrenia at early stages. Furthermore, there may be an inverse relationship between oxidative stress and negative dimension.

Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients. / Variaciones en las concentraciones plasmáticas de clozapina en pacientes con esquizofrenia y trastorno esquizoafectivo.

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.

Suicide, unemployment, and economic recession in Spain. / Suicidio, desempleo y recesión económica en España.

INTRODUCTION: The aim of the present work is to determine the association between unemployment and suicide, and to investigate whether this association is affected by changes in the economic cycle or other variables such as age and sex. METHODS: A time-trend analysis was conducted to study changes in the number of suicides between 1999 and 2013 in Spain. Pearson's correlation coefficients and regression models were used to find the association between unemployment and suicide. RESULTS: A significant positive association was found between unemployment and suicide in the pre-crisis period in men. In that period (1999-2007), each 1% annual increase in unemployment was associated with a 6.90% increase in the annual variation of suicide in the total population, and with a 9.04% increase in the annual variation of suicide in working age men. CONCLUSIONS: The correlation between unemployment and suicide is significant in periods of economic stability, but has weakened during the recent financial crisis. Unemployment and suicide have a complex relationship modulated by age, sex and economic cycle.

Changes in administrative prevalence of mental disorders over a 13-year period in Asturias (northern Spain).

INTRODUCTION: The study of administrative prevalence from cumulative psychiatric case registers allows the mental health state of the studied region and the functioning of its Health Services to be estimated. METHODS: Data were extracted from the Asturias Cumulative Psychiatric Case Register (RACPAS) between January 1st 1998 and December 3 th 2010. Characteristics of the population of the catchment area were studied, and their relationship with the administrative prevalence was analyzed. RESULTS: The mean population in the studied period was 1,078,406 inhabitants. The Fritz index and the Youth and replacement indices of the active population decreased throughout the period. There was no significant increase in the prevalence of organic mental disorders, psychosis, mood disorders, and substance use in males, or behavioral disorders associated with somatic factors and physiological dysfunctions in females. There were significant gender differences in the prevalence of all disorders, except for personality disorders and organic mental disorders. Population ageing had a significant influence on the increase in the prevalence of most mental disorders in both males and females. CONCLUSIONS: A slight general increase in the administrative prevalence of mental disorders is observed during the studied period, and it was influenced by population ageing.