Percepções de familiares sobre uma rede de cuidados de saúde mental infantojuvenil / Family perceptions about a children's mental health network / Percepciones familiares sobre una red de atención de salud mental infantojuvenil

Este artigo pretende conhecer como a rede de cuidados em saúde tem se operacionalizado a partir da percepção de familiares de crianças com demanda de cuidado em saúde mental (SM). Foram realizados dois grupos focais, um com familiares da Atenção Básica (AB) e outro com familiares do Centro de Atenção Psicossocial Infantojuvenil (CAPSij), totalizando 15 participantes. Seguiu-se com a análise lexical do tipo classificação hierárquica descendente, com o auxílio do software R Interface, a fim de análises multidimensionais de textos e questionários (IRaMuTeQ), resultando em cinco classes: A Pílula Mágica; Forças e Fraquezas dos serviços; Procurando por ajuda; Aceitando o diagnóstico da criança e Onde procurei ajuda. Os resultados apontam para dificuldades presentes na AB em identificar e manejar situações de Saúde Mental Infantojuvenil (SMIJ), por meio de uma lógica ainda medicalizante. Ressalta-se que a escola é apresentada como lugar de destaque na produção da demanda por cuidado e a família ainda é pouco convocada à construção das ações. Conclui-se, então, que avanços ainda são necessários para operacionalização de um cuidado pautado nas diretrizes da política de SMIJ.(AU)

This article aims to know how the healthcare network has been operationalized from the perception of family members of children with demand for mental health care (MH). Two focus groups were held, one with family members from Primary Care (PC) and the other with family members from the Child Psychosocial Care Center (CAPSij), totaling 15 participants. A lexical analysis of the descending hierarchical classification type was performed with the help of the software R Interface for multidimensional analyzes of texts and questionnaires (IRAMUTEQ), resulting in five classes: The Magic Pill; Strengths and Weaknesses of services; Looking for help; Accepting the child's diagnosis; and Where did I look for help. The results point to difficulties present in PC in identifying and managing situations of mental health in children and adolescents (MHCA), with a medicalization logic. Note that the school is presented as a prominent place in producing the demand for care, and the family is still not very much involved in the actions. It is, thus, concluded that advances are still needed for operationalization of care guided by MHCA policy guidelines.(AU)

Este artículo tuvo por objetivo conocer cómo opera una red asistencial a partir de la percepción de familiares de niños con demanda de atención en salud mental (SM). Se realizaron dos grupos focales, uno con familiares de Atención Primaria (AP) y otro con familiares del Centro de Atención Psicosocial Infantojuvenil (CAPSij), totalizando 15 participantes. Se realizó análisis léxico del tipo clasificación jerárquica descendente con la ayuda del software Interface de R pour les Analyses Multidimensionnelles de Textes et de Questionnaires (IRAMUTEQ), lo que resultó en cinco clases: "La píldora mágica"; "Fortalezas y debilidades de los servicios"; "En busca de ayuda"; "Aceptar el diagnóstico del niño" y "¿Dónde busqué ayuda?". Los resultados apuntan las dificultades presentes en AP para identificar y manejar situaciones de salud mental infantojuvenil (SMIJ) mediante una lógica aún medicalizante. La escuela tiene un lugar destacado en la producción de la demanda de cuidados y la familia aún no está muy involucrada en la construcción de acciones. Se concluye que se necesitan avances para ofertar una atención guiada por lineamientos de la política del SMIJ.(AU)

Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets.

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia.

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.

Vitamin D and Hyperkinetic Movement Disorders: A Systematic Review.

Background: The importance of vitamin D deficiency in Parkinson's disease, its negative influence on bone health, and even disease pathogenesis has been studied intensively. However, despite its possible severe impact on health and quality of life, there is not a sufficient understanding of its role in other movement disorders. This systematic review aims at providing an overview of the prevalence of vitamin D deficiency, bone metabolism alterations, and fractures in each of the most common hyperkinetic movement disorders (HKMDs). Methods: The study search was conducted through PubMed with keywords or Medical Related Subjects (MeSH) of common HKMDs linked with the terms of vitamin D, osteoporosis, injuries, and fractures. Results: Out of 1585 studies screened 40 were included in our review. They show that there is evidence that several HKMDs, including Huntington disease, Restless Legs Syndrome, and tremor, are associated with low vitamin D serum levels in up to 83% and 89% of patients. Reduced bone mineral density associated with vitamin D insufficiency was described in Huntington disease. Discussion: Our survey suggests that vitamin D deficiency, bone structure changes, and fractures are important but yet under-investigated issues in HKMDs. HKMDs-patients, particularly with a history of previous falls, should have their vitamin D-levels tested and supplemented where appropriate. Highlights: Contrary to Parkinson's disease, vitamin D deficiency, and bone abnormalities are under-investigated in hyperkinetic movement disorders (HKMDs). Several HKMDs, including essential tremor, RLS, and Huntington disease, are associated with vitamin D deficiency in up to 89%, the latter also with reduced bone mineral density. Testing and where appropriate supplementation is recommended.

A Case of Neuromuscular Electrical Stimulation for Childhood Stroke Hyperkinesis: A Brief Report.

AIM: Some conditions within specific populations are so rare rigorous evidence is unavailable. Childhood hyperkinesis is one example, yet presents an opportunity to examine sensation's contribution to motor function. METHODS: The patient experienced functional difficulty from hyperkinesis as a result of childhood stroke. Home-based passive neuromuscular electrical stimulation (NMES) was implemented an hour/day, six days/week, over 6 weeks (36 hours). Clinical and robotic measures (Assisting Hand Assessment, Box and Block Test, Jebsen Taylor Test of Hand Function, Kinarm) were administered before and after the intervention and at 9 months. RESULTS: NMES was feasible and well tolerated. Clinically important gains of arm function were maintained at 9 months. Robotic measures showed improved hyperkinesis, namely reduced movement segmentation and improved target approximation, in addition to improved proprioceptive function after NMES. CONCLUSION: This case study illustrates the use of NMES within a previously unexplored population and highlights the potential importance of sensory systems to motor gains.

In vivo evaluation of effects of histamine H3 receptor antagonists on methamphetamine-induced hyperlocomotion in mice.

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H3 receptors, which then bind to the post-synaptic histamine receptor H1 (but not H2 or H4). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.

Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease.

Oscillations are a naturally occurring phenomenon in highly interconnected dynamical systems. However, it is thought that excessive synchronized oscillations in brain circuits can be detrimental for many brain functions by disrupting neuronal information processing. Because synchronized basal ganglia oscillations are a hallmark of Parkinson's disease (PD), it has been suggested that aberrant rhythmic activity associated with symptoms of the disease could be used as a physiological biomarker to guide pharmacological and electrical neuromodulatory interventions. We here briefly review the various manifestations of basal ganglia oscillations observed in human subjects and in animal models of PD. In this context, we also review the evidence supporting a pathophysiological role of different oscillations for the suppression of voluntary movements as well as for the induction of excessive motor activity. In light of these findings, it is discussed how oscillations could be used to guide a more precise targeting of dysfunctional circuits to obtain improved symptomatic treatment of PD.

Pharmacodynamics and metabonomics study of Tianma Gouteng Decoction for treatment of spontaneously hypertensive rats with liver-yang hyperactivity syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Essential hypertension is a prevalence chronic cardiovascular disease, which is treated by traditional Chinese medicine (TCM) in China. Metabolomics approach has achieved more attention in pharmacology studies of natural products. Tianma Gouteng Decoction (TGD) is effective for the therapeutic of hypertension in China. We aimed to investigate antihypertension effect of TGD on spontaneous hypertension rat (SHR) with live-Yang hyperactivity hypertension (Gan Yang Shang Kang, GYSK) and explore the mechanism by metabolomics method. MATERIALS AND METHODS: After establishing the GYSK-SHR model by giving aconite decoction, rats were randomly divided into four groups including model group, TGD qd group (66.88 mg/kg, once a day), TGD bid group (33.44 mg/kg, twice a day), TGD tid group (22.29 mg/kg, three times a day). Blood pressure (BP) and indexes of renin-angiotensin-aldosterone system (RAAS system) were measured. Metabolic profiling of rat plasma samples was performed by UPLC-Q-TOF/MS, which was analyzed with principal component analysis (PCA) and partial least-squares-discriminate analysis (PLS-DA) to explore the relationship between metabolic pathways and hypertension. RESULTS: To better explain the role of TGD on hypertension, we detected three different frequencies of TGD treatment with equal dosage. TGD reduced the BP in GYSH-SHR model and regulated the serum levels of NE, Ang II, ET, 5-HT, CRP, RENIN and ALD especially at TGD bid group. By UPLC-Q-TOF/MS analysis, we found 47 potential biomarkers in GYSK-SHR rats from the plasma metabolites, among which 15 biomarkers were regulated by TGD. Consisted with the antihypertension activity, TGD bid group showed the significantly moderating effect on the regulating biomarkers. CONCLUSIONS: TGD exhibited the antihypertensive activity at the frequency of administration twice a day, which had the association with RAAS system and mediated 15 biomarkers by regulating metabolisms of glycerol phospholipid, sphingomyelin, energy and amino acid.

Maternal B vitamin intake during pregnancy and childhood behavioral problems in Japan: The Kyushu Okinawa Maternal and Child Health Study.

Objectives: The current prebirth cohort study investigated the relationship between maternal B vitamin intake during pregnancy and behavioral problems in Japanese children aged 5 years. Methods: Subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were examined using the Japanese parent-report version of the Strengths and Difficulties Questionnaire. Adjustment was made for maternal age, gestation at baseline, region of residence, number of children, maternal and paternal education, household income, maternal depressive symptoms, alcohol intake, vitamin B complex supplement use, smoking during pregnancy, child's birth weight, child's sex, breastfeeding duration, and smoking in the household during the first year of life. Results: Maternal folate intake during pregnancy was independently inversely associated with childhood low prosocial behavior: the adjusted odds ratio (OR) (95% confidence interval [CI], P for trend) between extreme quartiles was 0.55 (0.37-0.80, 0.0002). Maternal vitamin B6 intake during pregnancy was independently inversely related to childhood hyperactivity problems and low prosocial behavior: the adjusted ORs (95% CIs, P for trend) between extreme quartiles were 0.57 (0.34-0.94, 0.01) and 0.58 (0.40-0.85, 0.0009), respectively. Maternal vitamin B2 intake during pregnancy was independently inversely associated with childhood emotional problems: the adjusted OR (95% CI, P for trend) between extreme quartiles was 0.58 (0.33-0.99, 0.11). Conclusions: Maternal intake of folate, vitamin B6, and vitamin B2 during pregnancy may be protective against childhood low prosocial behavior, hyperactivity problems and low prosocial behavior, and emotional problems, respectively.

Multi-Parametric Quantitative MRI for Measuring Myelin Loss in Hyperglycemia-Induced Hemichorea

Hyperglycemia-induced hemichorea (HGHC) is a rare but characteristic hyperkinetic movement disorder involving limbs on one side of the body. In a 75-year-old woman with a left-sided HGHC, conventional brain MR imaging showed very subtle T1-hyperintensity and unique gadolinium enhancement in the basal ganglia contralateral to movements. Multi-parametric MRI was acquired using pulse sequence with quantification of relaxation times and proton density by multi-echo acquisition. Myelin map was reconstructed based on new tissue classification modeling. In this case report of multi-parametric MRI, quantitative measurement of myelin change related to HGHC in brain structures and its possible explanations are presented. This is the first study to demonstrate myelin loss related to hyperglycemic insult in multi-parametric quantitative MR imaging.

Effect of Supplementation With Omega-3 Fatty Acids, Magnesium, and Zinc on Canine Behavioral Disorders: Results of a Pilot Study.

Recent discoveries have shown that the chances of a dog developing a behavioral disorder may depend upon a number of factors including nutrition. The current pilot study was designed to provide an assessment of the efficacy of a dietary supplement containing omega-3 fatty acids, magnesium, and zinc on some common behavioral disorders in a population of Iranian domestic dogs. In total, 48 dogs including 6 dogs without any behavior disorder (control group) and 42 dogs with at least 1 common behavioral disorder, namely excessive activity, inappropriate elimination, fearfulness, destructiveness, and aggression toward unfamiliar people and dogs (test group), were given daily oral dose of gelatin capsules of fish oil supplements containing 330 mg eicosapentaenoic acid and 480 mg docosahexaenoic acid. Moreover, all dogs received 12-15 mg/kg of magnesium citrate and 5 mg/kg of zinc sulfate. Data were obtained using a questionnaire that dog owners were invited to fill out 2 times before (Days 0 and 42) and 2 times after the supplement treatment period (Days 84 and 126). The questionnaire asked owners whether their dog had exhibited any of the 6 common behavioral disorders on a 5-point Likert-like scale ranging from 0 (never or very rarely) to 4 (very often). The results showed no significant changes for any of the evaluated behavior disorders scale in the control group. In dogs with behavior disorders, results showed a significant reduction in the median score for the severity of fearfulness (P = .0083), destructiveness (P = .002), and inappropriate elimination (P < .001). In addition, there were no significant differences in the median score for the severity of excessive activity (P = .162), aggression toward dogs (P = .281), and aggression toward unfamiliar people (P = .09) during the course of the study. Results of the study reported here support the hypothesis that a combination of omega-3 fatty acids, magnesium, and zinc may improve some of the behavioral disorders.

Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice.

RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome.

BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.

Permeation of Polymethoxyflavones into the Mouse Brain and Their Effect on MK-801-Induced Locomotive Hyperactivity.

Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3',4'-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus.

Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice.

Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression.

The "induced hyperactivity" test for the de-risking of potential off-target activity of antihypertensive drugs.

INTRODUCTION: Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the "induced hyperactivity" test for CNS de-risking of Compound X. METHODS: Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). RESULTS: Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. CONCLUSION: The relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.

Magnetic resonance imaging findings of bilateral thalamic involvement in severe paroxysmal sympathetic hyperactivity: a pediatric case series.

PURPOSE: Paroxysmal sympathetic hyperactivity is a complication of brain injury that has mainly been described in the adult brain injury literature. METHODS: We present a case series of three pediatric patients that developed paroxysmal sympathetic hyperactivity of varying severity following hypoxic brain injury. RESULTS: Comparison of brain magnetic resonance imaging revealed bilateral and symmetric global ischemic changes in all three cases. However, the thalamus was not affected in the patient with the mild case of paroxysmal sympathetic hyperactivity. In contrast, bilateral and symmetric damage to the thalamus was observed in the two severe cases. CONCLUSIONS: Our case series suggests that in hypoxic brain injury, evidence of bilateral ischemic injury to the thalamus on magnetic resonance imaging may be an important early predictor of severity and length of paroxysmal sympathetic hyperactivity. While this is an interesting observation, definite proof of our hypothesis requires further research including analysis of larger numbers of patients and comparison of MRI findings in children with hypoxic brain injury that do not develop paroxysmal sympathetic hyperactivity.