The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Early adverse stress and depression severity: A pilot exploration of mediating psychological mechanisms.

OBJECTIVE: To explore the associations between early adverse stress, attachment insecurity in adulthood (anxious and avoidant), pathological personality styles (self-criticism and dependency), difficulties in emotion regulation, and depression severity. METHODS: Cross-sectional study of 178 outpatients diagnosed with major depression in Santiago, Chile. Participants filled the Childhood Trauma Questionnaire Short Form, the Experience in Close Relationships Scale, the Depressive Experience Questionnaire, the Difficulties in Emotion Regulation Scale, and the Patient Health Questionnaire-9 item. Full-information maximum likelihood path analyses with bias-corrected bootstrapped confidence intervals were conducted. RESULTS: Anxious attachment in adulthood and self-criticism mediated the association between early adverse stress and depression severity through their effects on difficulties in emotion regulation. Early adverse stress was not associated with avoidant attachment in adulthood and dependency; these variables were indirectly associated with depression severity. Difficulties in emotion regulation were exclusively directly related to depression severity, mediating the effects of the preceding variables. CONCLUSIONS: Our findings propose an integrative model for psychological mechanisms mediating between early adverse stress and depression. Difficulties in emotion regulation should be considered when treating adults with depression exposed to early adverse stress. The contribution of specific types of early adverse stressors and difficulties in emotion regulation should be further explored.

The contribution of early adverse stress to complex and severe depression in depressed outpatients.

BACKGROUND: To assess whether linear effects or threshold effects best describe the association between early adverse stress (EAS) and complex and severe depression (i.e., depression with treatment resistance, psychotic symptoms, and/or suicidal ideation), and to examine the attributable risk of complex and severe depression associated with EAS. METHODS: A cross-sectional study was conducted using deidentified clinical data (on demographics, presence of complex and severe depression, and exposure to seven types of EAS) from 1,013 adults who were seen in an outpatient mental health clinic in Santiago, Chile, for a major depressive episode. Multivariate logistic regressions were fitted to estimate odds ratios (ORs), using a bootstrap approach to compute 95% bias-corrected confidence intervals (95% BC CIs). A detailed examination of the cumulative risk score and calculations of the attributable risk was conducted. RESULTS: Exposure to at least five EASs was reported by 3.6% of the sample. In the multivariate logistic regression models, there was a marked increase in the odds of having complex and severe depression associated with exposure to at least five EASs (OR = 4.24; 95% BC CI: 1.25 to 9.09), according to a threshold effect. The attributable risk of complex and severe depression associated with exposure to at least one EAS was 36.8% (95% BC CI: 17.7 to 55.9). CONCLUSIONS: High levels of EAS distinctively contribute to complex clinical presentations of depression in adulthood. Patients with complex clinical presentations of depression and history of EAS should need a differentiated treatment approach, particularly those having high levels of EAS.

[Systematic review of treatment alternatives for depressed adults with early adverse stress]. / Tratamiento de la depresión en adultos con estrés adverso temprano: revisión sistemática de su efecto en síntomas relacionados a trauma, ansiedad, desajuste social y calidad de vida.

BACKGROUND: Early adverse stress is a risk factor for the appearance of mental health ailments during adulthood. AIM: To systematically review treatment outcomes on mental health symptoms and functional domains, and of interventions aimed at treating adults with depressive disorders and early adverse stress (EAS). MATERIAL AND METHODS: Systematic review and meta-analysis including experimental and quasi-experimental published studies indexed in the CINAHL, EMBASE, PubMed, and Web of Science databases, which explored the effectiveness of treatment interventions for depressive disorders in adults exposed to EAS. Data on outcomes was extracted from the included studies. A narrative, qualitative approach or a quality-effects model for meta-analysis were used for synthesizing these data. RESULTS: Thirteen studies were included. Psychological or combined treatment interventions for depression in adults exposed to EAS may be effective in reducing trauma-related symptoms and social dysfunction in the short-and mid-term, with small effect size and without substantive heterogeneity. The assessment of anxiety symptoms and health-related quality of life yielded mixed results. CONCLUSIONS: Despite the ubiquity of EAS and its adverse and long-lasting consequences for well-being and health, treatment alternatives are scant. This review suggests that there are treatment interventions for depression in adults exposed to EAS that may achieve integral mental health benefits, alleviating its impact on various symptoms and functional domains, when EAS is explicitly considered in the treatment intervention.

[Validation of the Childhood Trauma Questionnaire-Short Form in Chile]. / Validación de la versión en español del Childhood Trauma Questionnaire-Short Form en Chile, en una muestra de pacientes con depresión clínica.

BACKGROUND: Childhood Trauma Questionnaire-Short Form (CTQ-SF) is an instrument to assess child abuse and neglect Aim: to adapt and confirm the psychometric properties of the Spanish version of the CTQ-SF in Chile. MATERIAL AND METHODS: The CTQ-SF was applied to 89 clinically depressed subjects (77.5% women) who consulted at an outpatient mental health clinic. Confirmatory factor analysis (CFA), reliability (Cronbach's α) tests, and convergent validity analyses with clinical markers of complex depression were carried out. RESULTS: The Chilean version of the CTQ-SF demonstrated an acceptable fit to a five-factor model, with adequate psychometric properties. The CFA revealed that a better fit to a five-factor model would be achieved after elimination of two items from the physical neglect scale, the less reliable scale of the questionnaire. The physical abuse scale discriminated between patients with a complex depression versus non-complex depression, and all the CTQ-SF's scales discriminated between patients with high suicide risk and/or history of psychiatric admissions versus those patients without this background. CONCLUSIONS: the Chilean version of the CTQ-SF shows evidence of structural and discriminant validity, and reliability, in a clinical sample. Better alternatives to specifically assess the physical neglect construct should be developed.

Acceptability Study of "Ascenso": An Online Program for Monitoring and Supporting Patients with Depression in Chile.

BACKGROUND: Major depression is a highly prevalent and severe mental disease. Despite the effective treatment options available, the risk of relapse is high. Interventions based on information and communication technologies generate innovative opportunities to provide support to patients after they completed treatment for depression. MATERIALS AND METHODS: This acceptability study evaluated the Internet-based program Apoyo, Seguimiento y Cuidado de Enfermedades a partir de Sistemas Operativos (ASCENSO) in terms of its feasibility and acceptability in a sample of 35 patients in Chile. RESULTS: The study reveals high rates of acceptance and satisfaction among patients who actively used the program. As obstacles, patients mentioned technical problems, a lack of contact with other participants, and an insufficient connection between the program and the health service professionals. CONCLUSIONS: ASCENSO appears to be a promising complement to regular care for depression. Following improvements of the program based on participants' feedback, future research should evaluate its efficacy and cost-effectiveness.

Population-attributable risk of adverse childhood experiences for high suicide risk, psychiatric admissions, and recurrent depression, in depressed outpatients.

Background: Population-attributable risk (PAR) may help estimate the potential contribution of adverse childhood experiences (ACEs) to serious clinical presentations of depression, characterized by suicidality, previous psychiatric admissions, and episode recurrence. Objective: To determine the PAR of ACEs for serious clinical presentations of depression (high suicide risk, previous psychiatric admissions, and recurrent depression) in outpatients with ICD-10 clinical depression. Method: Systematic chart review of 1,013 adults who were assessed and/or treated in a mental health clinic in Santiago, Chile for a major depressive episode. Data were collected on demographics and clinical characteristics of depression. Exposure to ACEs was determined with the Brief Physical and Sexual Abuse Questionnaire, assessing seven types of ACEs. Multivariable logistic regression analysis was used to assess the association between exposure to ACEs and suicidality, previous psychiatric admissions, and recurrence. Predicted probabilities were used for calculations of PAR. Results: Of the 1,001 study participants with complete data, 53.3% had recurrent depression, 13.5% had high suicide risk, and 5.0% had previous psychiatric admissions. Exposure to at least one ACE was recorded for 69.0% of the sample. Exposure to at least one ACE and specific types of ACEs (i.e. childhood sexual abuse and traumatic separation from caregiver) were associated with serious clinical presentations of depression. A dose-response relationship was observed between cumulative exposure to ACEs and the most serious clinical presentations of depression. ACEs were attributed to a significant proportion of disease: 61.6% of previous psychiatric admissions, 45.0% of high suicide risk, and 14.5% of recurrent depression. Conclusions: A substantial proportion of serious clinical presentations of depression among outpatients are associated with ACEs. Early detection of depressive episodes associated with ACEs, and tailored treatment for these patients, may potentially reduce the incidence of serious complications in this population.

Introducción: El riesgo atribuible poblacional (RAP) puede ayudar a estimar la potencial contribución de las experiencias adversas infantiles (EAIs) a las presentaciones clínicas serias de la depresión, caracterizadas por riesgo suicida, hospitalizaciones psiquiátricas previas y recurrencia de episodios.Objetivo: Determinar el RAP de las EAIs para las presentaciones clínicas serias de la depresión (alto riesgo suicida, hospitalizaciones psiquiátricas previas y depresión recurrente) en pacientes deprimidos ambulatorios.Método: Revisión sistemática de fichas clínicas de 1.013 adultos que fueron evaluados y/o tratados en una clínica de salud mental en Santiago, Chile por un episodio depresivo mayor. Se recolectaron datos demográficos y sobre características clínicas de la depresión. La exposición a EAIs se determinó con el Brief Physical and Sexual Abuse Questionnaire, evaluándose siete tipos de EAIs. Se usó análisis de regresión logística multivariada para evaluar la asociación entre exposición a EAIs y riesgo suicida, hospitalizaciones psiquiátricas previas y recurrencia. Las probabilidades predichas fueron utilizadas para los cálculos de los RAP.Resultados: De 1.001 participantes del estudio con datos completos, 53,3% tuvieron una depresión recurrente, 13,5% tuvieron alto riesgo suicida, y 5,0% tuvieron hospitalizaciones psiquiátricas previas. La exposición a al menos un EAI se registró en 69,0% de la muestra. La exposición a al menos un EAI y tipos específicos de EAIs (i.e. abuso sexual infantil y la separación traumática del cuidador), se asociaron con presentaciones clínicas serias de la depresión. Se observó una relación dosis-respuesta entre la exposición cumulativa a EAIs y las presentaciones clínicas más serias de la depresión. Las EAIs se atribuyeron una proporción significativa de la enfermedad: 61,6% de las hospitalizaciones psiquiátricas previas, 45,0% del alto riesgo suicida, y 14,5% de depresión recurrente.Conclusiones: Una proporción sustancial de presentaciones clínicas serias de la depresión en pacientes deprimidos ambulatorios se asocian con EAIs. La detección temprana de los episodios depresivos asociados con EAIs y el tratamiento a la medida para estos pacientes podrían potencialmente reducir la incidencia de complicaciones serias en esta población.

Early Adverse Stress and Depressive and Bipolar Disorders: A Systematic Review and Meta-Analysis of Treatment Interventions.

Introduction: A significant proportion of adults with depressive or bipolar disorders exposed to early adverse stressors do not adequately respond to standard treatments. This review aimed at synthesizing the evidence on the effectiveness of treatment interventions for depressive or bipolar disorders in adult individuals (aged 18 years or more) exposed to adverse stress early in life. Methods: Systematic review and meta-analysis including experimental and quasi-experimental published studies indexed in CINAHL, EMBASE, PubMed, and Web of Science databases and/or in reference lists. Data management and critical appraisal (with the Study Quality Assessment Tools) was conducted independently by multiple researchers. A quality-effects model for meta-analysis was used for data synthesis and publication bias was assessed using the Doi plot and LFK index. The main outcome was short-term reductions in depressive symptoms. Results: Eight randomized controlled trials, three controlled before-and-after (pre-post) studies, and three uncontrolled before-and-after studies were included. Studies lacked bipolar disorder patients. Unclear randomization procedures and reporting of blinded outcome assessor, and limited use of intention-to-treat analysis, were relevant potential sources of bias. Meta-analyses indicated that psychological, pharmacological, and combined interventions were effective in reducing depressive symptoms in the short- (Cohen's d = -0.55, 95% CI -0.75 to -0.36, I 2 = 0%) and mid-term (Cohen's d = -0.66, 95% CI -1.07 to -0.25, I 2 = 65.0%). However, a high risk of publication bias was detected for these outcomes. A small number of studies, with mixed results, reported interventions with long-term improvements in depressive symptomatology, and short- and mid-term response to treatment and remission. Conclusion: Despite the well-documented long-lasting, negative, and costly impact of early adverse stressors on adult psychopathology, evidence on treatment alternatives remains scant. Trauma-focused treatment interventions-whether psychological interventions alone or in combination with pharmacotherapy-may have the potential to reduce the severity of depressive symptom in adults who were exposed to early adverse stress. Findings must be interpreted with considerable caution, as important study and outcome-level limitations were observed and gray literature was not considered in this systematic review and meta-analysis.

Interventional Study to Evaluate the Clinical Effects and Safety of the Nutraceutical Compound BrainUp-10® in a Cohort of Patients with Alzheimer's Disease: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Trial.

BACKGROUND: Clinically-evaluated nutraceuticals are candidates for Alzheimer's disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. OBJECTIVE: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. METHODS: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. RESULTS: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (p = 0.0557), and the alimentary response (p = 0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with p = 0.0321 at week 4 and p = 0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (p = 0.0222). CONCLUSION: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems.

An Adjunctive Internet-Based Intervention to Enhance Treatment for Depression in Adults: Randomized Controlled Trial.

BACKGROUND: Internet-based interventions promise to enhance the accessibility of mental health care for a greater number of people and in more remote places. Their effectiveness has been shown for the prevention and treatment of various mental disorders. However, their potential when delivered as add-on to conventional treatment (ie, blended care) is less clear. OBJECTIVE: The aim of this study is to study the effectiveness of an internet intervention (ASCENSO) implemented in addition to face-to-face treatment as usual (TAU) for depression. METHODS: A 2-arm, parallel-group, randomized controlled trial was conducted in an outpatient private mental health care center in Chile. In all, 167 adults, diagnosed with major depressive disorder, without severe comorbidities, and with internet access, were included. Eighty-four participants were assigned to the intervention group and received medical and psychological TAU from the mental health center plus access to the ASCENSO online platform. The control group (n=83) received only TAU. The ASCENSO platform includes psycho-educational information, depressive symptom monitoring and feedback, and managing emergencies based on the principles of cognitive behavioral therapy. Emergency management was mental health provider-assisted. TAU includes access to primary care physicians and psychiatrists, to a brief individual psychotherapy, and to medication when needed. The baseline questionnaires were administered in person, and 6- and 9-months assessments were conducted online. Depression symptoms and quality of life were measured by self-administered questionnaires, and treatment adherence was determined via the Mental Health Center's internal records. The usage of ASCENSO was assessed by server logs. Reduction on depressive symptomatology was considered as the primary outcome of the intervention and quality of life as a secondary outcome. RESULTS: Of the 84 participants in the intervention group, 5 participants (6%) never accessed the online platform. Of the remaining 79 participants who accessed ASCENSO, 1 (1%, 1/79) did not answer any of the symptom questionnaire, and most participants (72/79, 91%) answered the monitoring questionnaires irregularly. The ASCENSO intervention implemented in addition to face-to-face care did not improve the outcome of the usual care delivered at the mental health center, either in terms of reduction of depressive symptoms (F2,6087= 0.48; P=.62) or in the improvement of quality of life (EQ-5D-3L: F2,7678=0.24; P=.79 and EQ-VAS: F2,6670= 0.13; P=.88). In contrast, for the primary (F2,850=78.25; P<.001) and secondary outcomes (EQ-5D-3L: F2,1067=37.87; EQ-VAS: F2,4390= 51.69; P<.001) in both groups, there was an improvement from baseline to 6 months (P<.001), but there was no change at 9 months. In addition, no effects on adherence to or use of TAU were found. Finally, the dropout rate for the face-to-face treatment component was 54% (45/84) for the intervention group versus 39% (32/83) for the control group (P=.07). CONCLUSIONS: The fact that the adjunctive access to ASCENSO did not improve outcome could be due to both the rather high effectiveness of TAU and to patients' limited use of the online platform. TRIAL REGISTRATION: ClinicalTrials.gov NCT03093467; https://clinicaltrials.gov/ct2/show/NCT03093467.

Spanish Adaptation and Validation of the Outcome Questionnaire OQ-30.2.

This study assessed the psychometric properties of a Spanish version of the Shortened Outcome Questionnaire (OQ-30.2, Lambert et al., 2004) validated with a sample of 546 patients in an outpatient mental health clinic and 100 non-clinical adults in Chile. Our results show that this measure has similar normative data to the original measure, with a cutoff score for the Chilean population set at 43.36, and the reliable change index at 14. This Spanish OQ-30.2 has good internal consistency (α = 0.90), has concurrent validity with the Depressive, Anxious, and Somatoform disorders measuring scale (Alvarado and Vera, 1991), and is sensitive to change during psychotherapy. Consistent with previous studies, factorial analyses showed that both, the one-factor solution for a general scale and the three-factor solution containing three theoretical scales yielded poor fit estimates. Overall, our results are similar to past research on the OQ-45 and the OQ-30. The short version has adequate psychometric properties, comparable to those of the OQ-45, but provides a gain in application time that could be relevant in the setting of psychotherapy research with large samples, frequent assessments over time, and/or samples that may require more assistance completing items (e.g., low-literacy). We conclude that this measure will be a valuable instrument for research and clinical practice.

Depression and Attachment: How do Personality Styles and Social Support Influence This Relation?

The purpose of this study is to improve the current understanding of the relation between depression and attachment through the evaluation of the role of personality styles (dependent vs self-critical) and social support in this association. These variables were studied in a clinical sample of 70 depressed outpatients (83% women; M=41.47 years, SD=12.91). Depressive symptomatology was assessed through the Beck Depression Inventory, adult attachment through the Experiences in Close Relationships Scale, social support through the Social Support Questionnaire and dependency and self-criticism through the Depressive Experiences Questionnaire. Mediational and moderation regression analyses were performed. Results show that the association between the dimensions of attachment (anxiety and avoidance) and depression was partially mediated by self-criticism. Furthermore, results demonstrate the role of social support as a moderating variable: when the level of satisfaction with social support was low and the anxiety dimension in the attachment scale was high, as avoidance increased, depressive symptoms increased as well. Results are discussed in relation to their importance for understanding the complex interplay of the variables involved in depression.

Tratamiento de la depresión en adultos con estrés adverso temprano: revisión sistemática de su efecto en síntomas relacionados a trauma, ansiedad, desajuste social y calidad de vida / Systematic review of treatment alternatives for depressed adults with early adverse stress

BACKGROUND: Early adverse stress is a risk factor for the appearance of mental health ailments during adulthood. AIM: To systematically review treatment outcomes on mental health symptoms and functional domains, and of interventions aimed at treating adults with depressive disorders and early adverse stress (EAS). MATERIAL AND METHODS: Systematic review and meta-analysis including experimental and quasi-experimental published studies indexed in the CINAHL, EMBASE, PubMed, and Web of Science databases, which explored the effectiveness of treatment interventions for depressive disorders in adults exposed to EAS. Data on outcomes was extracted from the included studies. A narrative, qualitative approach or a quality-effects model for meta-analysis were used for synthesizing these data. RESULTS: Thirteen studies were included. Psychological or combined treatment interventions for depression in adults exposed to EAS may be effective in reducing trauma-related symptoms and social dysfunction in the short-and mid-term, with small effect size and without substantive heterogeneity. The assessment of anxiety symptoms and health-related quality of life yielded mixed results. CONCLUSIONS: Despite the ubiquity of EAS and its adverse and long-lasting consequences for well-being and health, treatment alternatives are scant. This review suggests that there are treatment interventions for depression in adults exposed to EAS that may achieve integral mental health benefits, alleviating its impact on various symptoms and functional domains, when EAS is explicitly considered in the treatment intervention.

Validación de la versión en español del Childhood Trauma Questionnaire-Short Form en Chile, en una muestra de pacientes con depresión clínica / Validation of the Childhood Trauma Questionnaire-Short Form in Chile

Background: Childhood Trauma Questionnaire-Short Form (CTQ-SF) is an instrument to assess child abuse and neglect Aim: to adapt and confirm the psychometric properties of the Spanish version of the CTQ-SF in Chile. Material and Methods: The CTQ-SF was applied to 89 clinically depressed subjects (77.5% women) who consulted at an outpatient mental health clinic. Confirmatory factor analysis (CFA), reliability (Cronbach's α) tests, and convergent validity analyses with clinical markers of complex depression were carried out. Results: The Chilean version of the CTQ-SF demonstrated an acceptable fit to a five-factor model, with adequate psychometric properties. The CFA revealed that a better fit to a five-factor model would be achieved after elimination of two items from the physical neglect scale, the less reliable scale of the questionnaire. The physical abuse scale discriminated between patients with a complex depression versus non-complex depression, and all the CTQ-SF's scales discriminated between patients with high suicide risk and/or history of psychiatric admissions versus those patients without this background. Conclusions: the Chilean version of the CTQ-SF shows evidence of structural and discriminant validity, and reliability, in a clinical sample. Better alternatives to specifically assess the physical neglect construct should be developed.

The CUIDEME Study: determinants of burden in chilean primary caregivers of patients with dementia.

BACKGROUND: Caring for a person with dementia is associated with well-documented increases in burden and distress and decreases in mental health and wellbeing. Studies assessing burden in caregivers of patients with dementia and its determinants are scarce in Latin America. OBJECTIVE: The main objective of this study was to assess the extent and the determinants of burden in informal primary caregivers of patients with dementia in Chile. METHODS: A descriptive study was conducted using clinically validated scales to assess dementia characteristics and to measure caregiver variables. Family socio-demographic characteristics and functional status, patient functional dependency and behavioral disturbances, and caregiver psychiatric morbidity were analyzed as independent variables to determine caregiver burden. RESULTS: Two hundred and ninety-two informal caregivers were included. There were more female (80%) than male caregivers, consisting mainly of daughters and spouses of the patients. Severe burden was reported in 63% of the caregivers, and 47% exhibited psychiatric morbidity. Burden was associated with caregiver psychiatric distress, family dysfunction, severity of neuropsychiatric symptoms and functional disability, but neither patient age, gender, nor socioeconomic status impacted burden. CONCLUSION: Our results underscore the importance of assessing the consequences of dementia in both caregivers and patients in order to evaluate the real biopsychosocial impact of dementia, as well as the importance of planning appropriate and effective public health interventions in Latin American countries. In addition, interventions targeting caregiver psychological distress, caregiver familial dysfunction, patient neuropsychiatric disorders, and patient functional disability could potentially diminish caregiver burden.

The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.

INTRODUCTION: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. METHODS: In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. RESULTS: A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). CONCLUSION: Extended-release memantine was efficacious, safe, and well tolerated in this population.

Importancia de los cambios iniciales en la psicoterapia con adolescentes / Relevance of early changes in psychotherapy with adolescents

Esta investigación tiene por objetivo estudiar los Indicadores de Cambio Genéricos (ICG) en psicoterapias con adolescentes, realizadas en contexto natural. Específicamente focaliza en la evolución de los ICG al interior de la etapa inicial de la terapia y su relación con la adherencia al tratamiento. Participaron 19 adolescentes, con diferentes diagnósticos, en modalidad de terapia individual de diferentes orientaciones teóricas. Evaluadores entrenados identificaron los ICG en las tres sesiones iniciales. Los resultados indican que se observa una evolución al interior de la etapa inicial de la terapia, en el sentido de un predominio de los indicadores jerárquicamente más bajos en la primera sesión en relación a la segunda y la tercera. Además los ICG máximos alcanzados en la fase inicial permiten predecir en forma significativa la probabilidad de terminar el proceso terapéutico.

This research is focused on the study Generic Change Indicators (GCI) in psychotherapies with adolescents conducted in natural settings. Specifically, it is centered on the evolution of GCI during the initial stage of therapy and their relation with treatment adherence. The participants were 19 adolescents with various diagnoses, who were receiving individual therapy with different theoretical approaches. Trained raters identified the CGI in the three initial sessions. The results reveal an evolution during the initial therapy stage, with hierarchically lower indicators dominating the first session and then decreasing in the second and third. In addition, the maximum CGI reached in the initial phase significantly predict the likelihood of completing the therapeutic process.

Refractory depression in a patient with peripheral resistance to thyroid hormone (RTH) and the effect of triiodothyronine treatment.

We here described a 39-year-old woman with a severe chronic mood disorder, refractory to antidepressive therapy who showed a significant improvement after a self-prescription of high doses of liothyronine (T(3)). A modified Refetoff protocol was carried out to study the role of thyroid hormones on her clinical and biochemical responses. Depression severity was assessed by the HAM-D and MADRS Depression Rating Scales. Sequencing of Thyroid Receptors (TR) alpha1 and beta1 genes was done. At the final stage of the study, plasma T3 and free T3 were >800 ng/dl (80-180) and 1409 pg/dl (230-420), respectively. No changes in the cardiovascular parameters, alkaline phosphatase isoenzymes, creatinine kinase, or ferritin were observed. However, an improvement in mood was detected by specific scores (HAM-D 24 to 8; MADRS 40 to 11). No mutations in DNA- and hormone-binding-domains of TRbeta1 and TRalpha1 genes were found in proband, suggesting that the defect could be due to an unknown mutation in either the TR gene or a post receptor abnormality. These results support the existence of a peripheral RTH manifestation as a refractory chronic depression reverted by high doses of T(3). Screening for RTH in refractory chronic depression may provide an alternative treatment for this psychiatric condition.

[High prevalence of thyroid dysfunction among psychiatric inpatients]. / Alta prevalencia de disfunción tiroidea en pacientes psiquiátricos hospitalizados.

BACKGROUND: Thyroid dysfunction is frecuent in psychiatric outpatients and in the general Chilean population but there is no information about the prevalence of thyroid diseases in Chilean psychiatric inpatients. AIM: To retrospectively assess the frequency of thyroidal diseases in psychiatric inpatients. MATERIAL AND METHODS: Clinical charts and thyroid assessment of 241 psychiatric inpatients (147 women, mean age 33+/-16 years) attended in a University Psychiatric Clinic, were reviewed. Psychiatric diagnosis at discharge was made according to DSM IV criteria and endocrine diagnosis was made based on international criteria. RESULTS: Forty nine patients (20.7%) had thyroid abnormalities. Forty four patients had hypothyroidism (18.3%) and five had hyperthyroidism (2.35%). No specific associations were found between gender or psychiatric diagnosis and endocrine abnormalities. CONCLUSIONS: In this sample, the prevalence of thyroid abnormalities was similar to other reports in psychiatric inpatiens and higher than in the general population in Chile.

Neurobehavioral and psychological changes induced by hyperthyroidism: diagnostic and therapeutic implications.

Clinical studies have demonstrated that neuropsychiatric symptoms may be common and often the only symptoms of patients affected by hyperthyroidism. The correct diagnosis of hyperthyroidism is crucial for optimal treatment because the neuropsychiatric symptoms tend to parallel resolution as the biochemical parameters of hyperthyroidism are normalized. For these reasons, a routine evaluation in every patient consulting for emotional pathologies is recommended, independent of other manifestations of thyroid disease. The effect of high levels of thyroid hormones in the CNS has been related to changes in the presence of alpha- and beta-adrenergic postsynaptic receptors, or more recently to changes in the serotonin concentration. However, the available information is incomplete and many questions remain to be answered in order to explain how the thyroid hormone modifies the CNS response. Increased knowledge of the molecular targets (i.e., genes) of thyroid hormones in the brain may help to provide an answer to these questions.