Body mass index, waist circumference, insulin, and leptin plasma levels differentiate between clozapine-responsive and clozapine-resistant schizophrenia.

BACKGROUND: Between 25% and 50% of patients suffering from treatment-resistant schizophrenia fail to achieve a clinical response with clozapine. The rapid identification and treatment of this subgroup of patients represents a challenge for healthcare practice. AIMS: To evaluate the relationship between metabolic alterations and the clinical response to clozapine. METHODS: A multicenter, observational, case-control study was performed. Patients diagnosed with schizophrenia treated with clozapine were eligible (minimum dose 400 mg/d for at least 8 weeks and/or clozapine plasma levels ⩾ 350 µg/mL). According to the Positive and Negative Syndrome Scale (PANSS) total score, patients were classified as clozapine-responsive (CR) (<80 points) or clozapine non-responsive (CNR) (⩾80 points). Groups were compared based on demographic and treatment-related characteristics, together with body mass index (BMI), waist circumference, insulin, leptin, and C-reactive protein plasma levels. Plasma levels of clozapine and its main metabolite, nor-clozapine, were measured in all the participants. In addition, the potential relationship between PANSS scores and leptin or insulin plasma levels was assessed. RESULTS: A total of 46 patients were included: 25 CR and 21 CNR. BMI and waist circumference, fasting insulin and leptin plasma levels were lower in the CNR group, while C-reactive protein was not different. Moreover, significant negative correlations were observed between PANSS positive and general psychopathology subscores, on one hand, and insulin and leptin plasma levels, on the other hand, as well as between PANSS negative subscores and leptin plasma levels. CONCLUSIONS: Our results suggest that the lack of metabolic effect induced by clozapine is associated with the lack of clinical response.

Multidimensional evaluation of a 12-month intensive outpatient program for the treatment of substance use disorder. Experience in Argentina / Evaluación multidimensional de un programa de tratamiento ambulatorio intensivo de 12 meses para el trastorno por uso de sustancias. Experiencia en Argentina.

OBJECTIVE: The purpose of this study was to asess the efficacy of an intensive outpatient treatment (IOT) for substance use disorder (SUD) using a multidimensional approach. METHODS: All the patients consecutively admitted to a private institution between May 2019 and May 2020 were invited to participate in the study. The program consisted in a 12-month set of psychosocial, medical and recreative interventions requiring an attendance of at least 9 hours per week. Efficacy was evaluated at admission and every three months by the Addiction Severity Index (ASI). Quality of life was evaluated at admission and at the end of the treatment by the WHOQOL-Bref questionnaire. A comparison of parameters obtained at admission between the group that completed and the one that abandonned the treatment was also performed to detect potential predictors of early dropout. Six months after the end of the treatment, the participants were contacted in order to repeat an evaluation through the ASI and the WHOQOL-Bref scales. RESULTS: 41 participants (73% male, age 42.8 ± 16 years) were included. 14 participants dropped out at a median time of 88 days. Among those who completed the treatment improvements were observed in different clinical dimensions: in alcohol and drug consumption (3 months), in medical problems (6 months), in family/social relationships (9 months), in psychological scores (12 months) and in the four dimensions of WHOQOL-Bref. No changes were observed in legal problems and in the employment status. Only legal problems and family/social relationships at admission were significantly different among patients who completed versus those who dropped-out. Six months after discharge, no differences in WHOQOL-Bref scores were observed in the 15 participants who could be located and accepted the assessment. A little but statistically significant worsening was observed in the psychological problems dimension of the ASI in post-discharge follow-up. The rest of the ASI dimensions remained unchanged 6 months after concluding the treatment. CONCLUSION: This is one of the few studies performed in a latinamerican setting assessing the efficacy of a long-term IOT for SUD. It confirms previous works from developed countries, showing the potential benefits of IOTs implementation in our region.

OBJETIVO: Evaluar la eficacia de un tratamiento ambulatorio intensivo (TAI) para el trastorno por uso de sustancias (TUS) utilizando un enfoque multidimensional. Métodos: Se incluyeron todos los pacientes admitidos consecutivamente en una institución privada entre mayo de 2019 y mayo de 2020. El programa duró 12 meses y consistió en un conjunto de intervenciones médicas, psicosociales y recreativas, con una intensidad ≥ 9 horas/semana. La eficacia fue evaluada comparando los puntajes en el Índice de Severidad de Adicción (ASI) a lo largo del programa y en el cuestionario WHOQOL-Bref al inicio y al finalizar. En 15 pacientes se realizó una nueva medición seis meses después de concluido el tratamiento. MÉTODOS: Se incluyeron todos los pacientes admitidos consecutivamente en una institución privada entre mayo de 2019 y mayo de 2020. El programa duró 12 meses y consistió en un conjunto de intervenciones médicas, psicosociales y recreativas, con una intensidad ≥ 9 horas/semana. La eficacia fue evaluada comparando los puntajes en el Índice de Severidad de Adicción (ASI) a lo largo del programa y en el cuestionario WHOQOL-Bref al inicio y al finalizar. En 15 pacientes se realizó una nueva medición seis meses después de concluido el tratamiento. RESULTADOS: Se incluyeron 41 participantes (73% hombres, edad 42,8 ± 16 años). 14 participantes abandonaron (media 88 días). En los participantes que completaron el tratamiento, se observaron mejoras en los índices de alcohol y drogas (a los 3 meses), en problemas médicos (a los 6 meses), en las relaciones sociales y familiares (a los 9 meses) y en problemas psicológicos (a los 12 meses) así como  en las cuatro dimensiones del WHOQOL-Bref. Estas mejoras persistieron en la evaluación 6 meses post-alta cuando sólo un empeoramiento leve en la dimensión de problemas psicológicos del ASI fue objetivado. Conclusión: Este es uno de los pocos estudios realizados en un ámbito latinoamericano que evalúa la eficacia de un TAI para el TUS. Confirma trabajos previos de países desarrollados, mostrando los beneficios potenciales de la implementación de TAIs en nuestra región. CONCLUSIÓN: Este es uno de los pocos estudios realizados en un ámbito latinoamericano que evalúa la eficacia de un TAI para el TUS. Confirma trabajos previos de países desarrollados, mostrando los beneficios potenciales de la implementación de TAIs en nuestra región.

Comparison between HET-CAM protocols and a product use clinical study for eye irritation evaluation of personal care products including cosmetics according to their surfactant composition.

The hen's egg test on chorioallantoic membrane (HET-CAM) is one of the most frequently used alternative tests for prediction of ocular irritation of cosmetic products. There are different HET-CAM protocols widely accepted, but there is no information about which of the protocols better correlates with the results obtained in product use clinical study under the conditions of use. Two Fix Time Methods (FTM) -Lüepke and the ICCVAM guideline - and two Reaction Time Methods (RTM) -ECVAM DBALM Prot. No. 47 and No. 96- were employed to test 18 cosmetic products. Simultaneously, they were evaluated by an ophthalmological clinical test. A unified classification system was used, and products were classified into four irritation levels: non-irritant, weak, moderate and severe irritant. The duration of use (rinse-off or leave-on), and the concentration and type of surfactants were taken into account in the analysis. All the products that were classified as non-irritant by any HET-CAM protocols were also safe in the product use clinical study. The product that was found to be non-safe in the product use clinical evaluation was also unsuitable by most of the HET-CAM protocols. These results were employed to develop an algorithm that allows selecting the appropriate HET-CAM protocol for each type of product to be tested.

[Practical notes on locating and critically reading scientific bibliography to guide clinical decisions, with a focus on quantitative research]. / Apuntes prácticos para localizar y leer críticamente bibliografía científica que oriente decisiones clínicas con foco en la investigación cuantitativa.

In clinical practice it is increasingly imperative to obtain updated information for decision making. For health professionals, it is of great value to collect the experience that other workers in the disciplinary field have synthesized in the form of articles, reviews or different types of reports. Moreover, having tools that allow weighing the internal and external validity of the publications found, provides skills that today are essential for a clinical practice that guarantees patients the best standards of care. These notes are intended to guide readers in obtaining and assessing the information available for reasoned decision making.

[Association between mental illness, obesity and metabolic syndrome. Effect of the treatment with psychotropic drugs]. / Asociación entre enfermedad mental, obesidad y síndrome metabólico. Efecto de los tratamientos psicofarmacológicos.

Persons with mental disorders present higher morbimortality than that observed in general population. Among the factors contributing with this situation we can mention an increase in the incidence of obesity and metabolic syndrome, with their burden of cardiovascular and cancer risks. This review summarizes the evidence about the comorbid presence of schizophrenia, unipolar depression and bipolar disorder on one side and metabolic syndrome or obesity on the other. We also review the different causes of such comorbidity, in particular the adverse effects of psychotropic drugs, diverse biological factors predisposing to the increase in body weight and the measures that can be taken in order to attenuate or prevent metabolic disease in persons affected by mental illness.

Day hospital treatment for people with severe mental illness according to users' perspectives: what helps and what hinders recovery?

BACKGROUND: Scarce information is available about how users experience treatment at mental health day hospitals, particularly in South America. AIMS: To explore users' perspectives about elements of day hospital treatment that facilitate or hinder the recovery process in a mental health facility in Buenos Aires, Argentina. METHODS: Semi-structured individual interviews (n = 8) and focus groups (n = 4) were carried out with a convenience sample of users of a mental health day hospital program based on a formulation, testing and redevelopment of propositions approach. Results were analyzed through grounded theory techniques. RESULTS: Categories indicating recovery were: starting to do things, being able to see themselves from a new perspective, mood improvement and changes in interpersonal relationships. Aspects facilitating recovery were: activities organized by the facility, the group approach, the care provided by facility workers and the physical environment. Hindering aspects were: heterogeneity of users in terms of age, severity, diagnosis and being underestimated by staff. CONCLUSIONS: Being active again was considered to be the main recovery indicator in this cultural context and participating in activities led by skilled facilitators was the most beneficial factor of the program according to the users.

Pharmacokinetics of a novel spot-on formulation of praziquantel for dogs.

Praziquantel (PZQ) is an anthelmintic drug used both in humans and animals that can be administered through various routes. There are transdermal formulations for cats, but only oral or subcutaneous dosage forms for dogs. Given the fact that the cat's skin and the dog's skin have different characteristics, which in turn affect bioavailability, we developed a PZQ spot-on formulation for dogs. This study was aimed at determining the plasmatic behavior of topically administered PZQ (Labyes®) in adult dogs. Dogs were administered PZQ (14.5mg/kg PZQ, from a solution of 100mg/ml). Blood samples were drawn before treatment onset and at the following time points after PZQ administration: 1, 2, 4, 6, 12, 24 and 48h. PZQ plasma concentration was determined by ultra-high performance liquid chromatography (UPLC) coupled to tandem mass spectrometry (MS/MS). Observed maximum concentration (Cmax), area under the concentration-time curve from the time of drug administration to infinity (AUCinf) and time to maximum concentration (Tmax) were calculated for each animal, and mean±SD for each parameter was obtained. Results were as follows: Cmax=56.0±15ng/ml; AUCinf=910.2±220ng*h/ml, Tmax=5.0±1.1h. This is the first study to provide pharmacokinetic data of a praziquantel spot-on formulation for dogs.

Working memory training triggers delayed chromatin remodeling in the mouse corticostriatothalamic circuit.

Working memory is a cognitive function serving goal-oriented behavior. In the last decade, working memory training has been shown to improve performance and its efficacy for the treatment of several neuropsychiatric disorders has begun to be examined. Neuroimaging studies have contributed to elucidate the brain areas involved but little is known about the underlying cellular events. A growing body of evidence has provided a link between working memory and relatively long-lasting epigenetic changes. However, the effects elicited by working memory training at the epigenetic level remain unknown. In this study we establish an animal model of working memory training and explore the changes in histone H3 acetylation (H3K9,14Ac) and histone H3 dimethylation on lysine 27 (H3K27Me2) triggered by the procedure in the brain regions of the corticostriatothalamic circuit (prelimbic/infralimbic cortex (PrL/IL), dorsomedial striatum (DMSt) and dorsomedial thalamus (DMTh)). Mice trained on a spontaneous alternation task showed improved alternation scores when tested with a retention interval that disrupts the performance of untrained animals. We then determined the involvement of the brain areas of the corticostriatothalamic circuit in working memory training by measuring the marker of neuronal activation c-fos. We observed increased c-fos levels in PrL/IL and DMSt in trained mice 90min after training. These animals also presented lower immunoreactivity for H3K9,14Ac in DMSt 24h but not 90min after the procedure. Increases in H3K27Me2, a repressive chromatin mark, were found in the DMSt and DMTh 24h after the task. Altogether, we present a mouse model to study the cellular underpinnings of working memory training and provide evidence indicating delayed chromatin remodeling towards repression triggered by the procedure.

Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

RATIONALE: Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. OBJECTIVE: Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. METHODS: Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. RESULTS: In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. CONCLUSION: In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.

[Dysthimia or chronic depression: what do we know about its pharmacological treatment?]. / Distimia o depresión crónica: ¿qué sabemos acerca de su tratamiento farmacológico?

The term dysthymia is applied to a clinical picture characterized by depressive feelings of low intensity and chronic evolution. Psychiatric nosology includes it among the mood disorders or among neurosis and personality disorders. This ambiguity has empirical consequences, since bibliography examining the efficacy of the different treatments is relatively scarce, in particular if we consider the incidence of the dysthymic disorder, that rounds 3% of general population. In this work the history of the nosology of dysthimia, the efficacy of pharmacological approaches and a brief mention about the efficacy of adding psychotherapy are summarized. Current literature indicates that antidepressants, independently of the group they form part of, are better than placebo, that maintenance treatment should be recommended and that psychotherapy could bring an additional benefit.

[Physiopathogeny in psychiatry: discovery, construction or discovery plus construction? The "case" of depression]. / Fisiopatogenia En Psiquiatría: ¿descubrimiento, construcción o descubrimiento + construcción? El "caso" de la depresión.

This work summarizes the efforts made in the last twenty years towards the discovery of the physiopathogeny of mental diseases. It takes the "case" of major depression and reviews the different theories proposed to explain its physiopathogeny beginning with the role of excitatory aminoacids, glucocorticoids and trophic neurofactors in the '90s, the neurogenesis at the beginning of '00s and the genetics, the epigenetics and the research on neural networks in the last years. Result of these scientific efforts seem to be a construction which has at the same time the strength of the evidences employed in its building and the weakness that emerges from the reductionism necessary to obtain them.

Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice.

RATIONALE: Repetitive cocaine exposure has been shown to induce GABAergic thalamic alterations. Given the key role of T-type (Ca(V)3) calcium channels in thalamocortical physiology, the direct involvement of these calcium channels in cocaine-mediated effects needs to be further explored. OBJECTIVE: The objective of this study was to investigate the effect of T-type calcium channel blockers on acute and repetitive cocaine administration that mediates thalamocortical alterations in mice using three different T-type blockers: 2-octanol, nickel, and mibefradil. METHODS: During in vitro experiments, whole-cell patch-clamp recordings were conducted in ventrobasal (VB) thalamic neurons from mice treated with acute repetitive cocaine administration (3 x 15 mg/kg, i.p., 1 h apart), under bath application of mibefradil (10 µM), 2-octanol (50 µM), or nickel (200 µM). After systemic administration of T-type calcium channel blockers, we evaluated locomotor activity and also recorded GABAergic neurotransmission onto VB neurons in vitro. RESULTS: Bath-applied mibefradil, 2-octanol, or nickel significantly reduced both GABAergic neurotransmission and T-type currents of VB neurons in cocaine-treated mice. In vivo i.p. pre-administration of either mibefradil (20 mg/kg and 5 mg/kg) or 2-octanol (0.5 mg/kg and 0.07 mg/kg) significantly reduced GABAergic mini frequencies onto VB neurons. Moreover, both mibefradil and 2-octanol were able to decrease cocaine-induced hyperlocomotion. CONCLUSION: The results shown in this study strongly suggest that T-type calcium channels play a key role in cocaine-mediated GABAergic thalamocortical alterations, and further propose T-type channel blockers as potential targets for future pharmacological strategies aimed at treating cocaine's deleterious effects on physiology and behavior.

[How do Argentinean psychiatrists treat bipolar depression?]. / ¿Cómo tratan los psiquiatras argentinos la depresión bipolar?

We show the results of a survey on bipolar depression treatment using a sample of 359 argentine psychiatrists in the context of The National Psychiatry Congress that took place in the City of Buenos Aires, between September 26th and 29th, 2007. The objective was to study the attendant psychiatrists' prescribing habits in the treatment of bipolar depression. The discussion is based on the comparison between the answers and the recommendations taken from the main consensus, guidelines and from articles published by experts. The differences found point to the distance often present between guidelines and expert consensus series (based on patients meeting the strict criteria used in randomized controlled studies) on one hand, and a clinician's everyday real world practice, on the other hand.