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Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set ( N =514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p =0.02; 100 mg equiv., p <0.001), as well as Clinical Global Impression Severity scores ( p ⩽0.006) and PANSS negative and positive symptom Marder factor scores ( p ⩽0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5–6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.

Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.

Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.

The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.

Objective: The aim of this study was to evaluate the efficacy and safety of two dose ranges of risperidone in adolescents with schizophrenia. Methods: In a 6-week, randomized, double-blind, placebo-controlled study, adolescents aged 13–17 years with acute exacerbation of schizophrenia were randomized to placebo, flexible doses of risperidone 1–3 mg/day, or risperidone 4–6 mg/day. Assessments included the Positive and Negative Syndrome Scale (PANSS), clinical response (≥20% reduction in PANSS total score), adverse event (AE) monitoring, and extrapyramidal symptom (EPS) scale ratings. Results: A total of 160 subjects received placebo (n = 54), risperidone 1–3 mg/day (n = 55), or risperidone 4–6 mg/day (n = 51). Significant improvements occurred in both risperidone groups versus placebo (p < 0.001) in PANSS total change scores (placebo, −8.9 [16.1]; risperidone 1–3 mg, −21.3 [19.6]; risperidone 4–6 mg, −21.2 [18.3]) and clinical response rates (35%, 65%, 72%, respectively). Overall AE rates were more common in risperidone groups (75% and 76%) versus placebo (54%). Risperidone 4–6 mg/day had a higher incidence of extrapyramidal disorder, dizziness, and hypertonia than risperidone 1–3 mg. No prolactin-related AEs occurred. Overall EPS severity was low. Conclusions: Risperidone 1–3 mg/day and 4–6 mg/day were well tolerated and effective in adolescents experiencing acute episodes of schizophrenia. The benefit–risk profile suggests that a dose of 1–3 mg/day might be optimal for this population.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Muchos animales se encuentran entretejidos en las visiones cósmicas de diferentes culturas del mundo. En este contexto varias especies han sido idealizadas como referentes que sintetizan atributos apreciados por el hombre como poder, valor, nobleza, así como fuerzas de la naturaleza o de lo desconocido. Con frecuencia son animales grandes los que han capturado la atención humana desde sus orígenes, como lo refleja el arte parietal antiguo. Probablemente esto obedece a que se les consideró importantes para la vida cotidiana y también a su supuesta influencia en mitos de mundos paralelos. En varias culturas alrededor del mundo se ha asignado a los osos un sitio prominente. Se conocen rituales y cultos relacionados con la presencia del oso en distintos grupos humanos en Asia, en pueblos originarios de Norteamérica y culturas de los Andes. Estas manifestaciones ocurren, por lo general, en sociedades que se encuentran asentadas en territorios dentro las principales áreas de distintas especies de osos. Sin embargo, en partes marginales de territorios ocupados por osos, las referencias culturales a ellos son escasas. Por ejemplo, no se había reportado la representación de estos mamíferos en las culturas que se desarrollaron en Mesoamérica. Trabajos arqueológicos recientes en el sitio de Tancama (Querétaro, México), ocupado por un grupo de afinidad Huasteca cuya mayor actividad se dio en el período clásico (entre 500 y 700 d.C.; fechas de C14), han revelado una escultura de barro asociada con restos de uno de los edificios principales, que representa un oso de cuerpo entero (se determinó como un oso negro, Ursus americanus, dado que es la única especie presente en el área). Además de la escultura, se encontraron vasijas y fragmentos cerámicos, excavados en otros edificios, que muestran rasgos diagnósticos de la cabeza de un oso. El presente estudio analiza este primer y singular hallazgo para Mesoamérica, enfatizando su relevancia para la región. Se analizan las relaciones entre la efigie principal de oso como parte de un edificio y las numerosas vasijas con representaciones ursiformes, para explorar el posible significado cultural local de esta especie animal.

Many economists advocate the use of tradable water rights as the most efficient system for allocating scarce water resources among alternative economic uses. According to this view, a private market in tradable water rights would maximize the economic value of the resource; would help to reduce costly public infrastructure investment and would foster private investment in irrigation. The case of Chile, which in 1981 established a system of tradable water rights, is fairly unique and provides important lessons for other LDC's. The paper reviews the major issue and controversies that have surrounded the practical implementation of this system in Chile. The paper contends that the system in Chile has worked reasonably well although some amendments may be needed. Among other things, a more complete definition of non-consumptive rights is called for and transaction costs arising from incomplete legalization of water titles, lack of infrastructure, and free rider problems need to be reduced. However, all in all, fine tuning of the system, rather than drastic reform, seems the most advisable policy recommendation. In this sense, the conclusions of the paper differ from some policy prescriptions recently proposed by the government. Finally, the paper emphasizes some particular characteristics of the Chilean experience that have contributed to an adequate functioning of the system and that should be taken into account when implementing similar schemes in other countries