Juliana Castro

Beneficial effects of vitamin C and vitamin E on reserpine-induced oral dyskinesia in rats: critical role of striatal catalase activity.

Oral dyskinesias are implicated in a series of neuropathologies and have been associated to an increase in oxidative stress. Several antioxidants, including vitamin E, decrease reserpine-induced oral dyskinesia (OD) in rodents and we have described a protective role of striatal catalase against the development of OD. The aim of this study was to verify the effects of vitamin C alone or in combination with vitamin E on reserpine-induced OD as well as to determine a possible role of catalase in the antidyskinetic property of these vitamins. Different doses of vitamin C attenuated reserpine-induced increase in OD. A similar treatment with an effective dose of vitamin C concomitant to an effective dose of vitamin E potentiated the antidyskinetic effect of both vitamins when administered alone. The administration of these vitamins alone produced an increase in striatal catalase activity that likewise was potentiated by their combined administration. In addition, the antidyskinetic property of vitamin E and vitamin C was abolished by a concomitant treatment with the catalase inhibitor aminotriazole. These results indicate a beneficial effect of these vitamins and reinforce the critical role of striatal catalase against the development of oral dyskinesias.

Effects of long-term continuous exposure to light on memory and anxiety in mice

The studies on the relationship between the light/dark cycle and memory function mostly used protocols of acute disruption of the circadian rhythm. The aim of the present study is to verify the effects of long-term continuous exposure to light on memory, anxiety and motor parameters of mice tested in the plus-maze discriminative avoidance task. Mice were conditioned to choose between the two enclosed arms (one aversive and one non-aversive) while avoiding the open arms of a modified elevated plus-maze apparatus. Memory was evaluated by the time spent in the aversive enclosed arm, anxiety was evaluated by the time spent in the open arms and locomotor behavior was evaluated by number of entries in the arms of the maze. The results showed that long-term (35-42 days) continuous light exposure did not modify memory or anxiety parameters but increased locomotor activity. While the increase in locomotor behavior is in line with previous studies, the unexpected absence of alterations in memory and anxiety (reported to be influenced by the circadian rhythm) is discussed.

Do sleep abnormalities and misaligned sleep/circadian rhythm patterns represent early clinical characteristics for developing psychosis in high risk populations?

Sleep architecture changes, such as slow-wave sleep (SWS) percentage variations and reductions in latency and density of rapid eye movement (REM), are found in most patients with schizophrenia and are considered to be an important part of the pathophysiology of the disorder. In addition to these sleep parameters changes, disruptions in sleep homeostasis and the sleep/circadian rhythm also occur in these patients. Sleep/circadian rhythm abnormalities negatively affect neocortical plasticity and cognition and often precede the diagnosis of the illness. Thus, it has been suggested that the sleep/circadian rhythm might be involved in the pathophysiology of psychosis. Recent advances in the identification of individuals at a high risk for developing schizophrenia allow us to investigate several neurobiological processes involved in the development of psychosis. In this article, we review the current evidence of the effects of sleep parameter abnormalities, disruptions in sleep homeostasis and misalignments of sleep circadian rhythm on the early stages of schizophrenia. In addition, we discuss the preliminary evidence of sleep and circadian rhythm abnormalities during the prodromal stages of psychosis and propose that these abnormalities can be explored as potential predictors, as an adjunct to clinical diagnosis, of developing a psychotic disorder in at risk populations.

Effects of baclofen on reserpine-induced vacuous chewing movements in mice.

We have described that GABA mimetic drugs present the ability to inhibit the expression of reserpine-induced oral movements. In this respect, oral movements is associated with important neuropathologies. This study investigates the effects of an acute or a repeated treatment of different doses of the GABA(B) agonist baclofen, as well as withdrawal from these treatments, on the development and/or expression of reserpine-induced vacuous chewing movements (VCM). Male mice received two injections of vehicle or of 1mg/kg reserpine separated by 48 h. In the first experiment, 24h later, animals were acutely treated with vehicle or baclofen (1, 2 or 4 mg/kg). In the second experiment, animals were treated with vehicle or baclofen (1 or 4 mg/kg) for four consecutive days receiving a concomitant injection of 1mg/kg reserpine (or vehicle) on Days 2 and 4. Twenty-four hours later, animals received vehicle or baclofen. Thirty minutes after the last injection, they were observed for quantification of VCM and open-field general activity. The acute administration of all the doses of baclofen abolished the manifestation of reserpine-induced VCM. Repeated treatment with 1mg/kg baclofen induced tolerance to the ability of an acute injection of this dose to reduce VCM. Treatment with baclofen (4 mg/kg) did not modify spontaneous VCM. Acute administration of the highest dose induced a decrease in general motor activity and a potentiation of the reserpine-induced decrease in general activity. These results reinforce the involvement of GABAergic hypofunction in the expression of oral movements and suggest that a repeated treatment with baclofen induces compensatory changes in GABAergic transmission that can attenuate its acute property to decrease VCM.

Effects of gabaergic drugs on reserpine-induced oral dyskinesia

Recently we have described the antidyskinetic property of the GABA mimetic drugs valproic acid and topiramate on reserpine-induced oral dyskinesia. In this respect, oral dyskinesia has been associated with important neuropathologies. The present study investigates the effects of different doses of the GABA(A) agonist tetrahydroisoxazolopyridine (THIP), of the GABA(B) agonist baclofen as well as of the GABA(A) modulator diazepam on the manifestation of reserpine-induced orofacial dyskinesia. Male Wistar rats received two injections of vehicle or of 1mg/kg reserpine separated by 48 h. Twenty-four hours later, animals were acutely treated with vehicle or THIP (2, 4 or 8 mg/kg), baclofen (1, 2 or 4 mg/kg) or diazepam (1, 2 or 4 mg/kg) and were observed for quantification of oral dyskinesia and open-field general activity. In order to verify the effects of these drugs per se on spontaneous oral movements, male Wistar rats were acutely treated with vehicle, 8 mg/kg THIP, 4 mg/kg baclofen or 4 mg/kg diazepam and observed for quantification of oral dyskinesia. The two highest doses of THIP or of baclofen abolished the manifestation of reserpine-induced oral dyskinesia while the lowest dose of baclofen attenuated it. Diazepam did not modify reserpine-induced oral dyskinesia at any dose tested. The highest doses of these drugs did not modify spontaneous oral movements. Reserpine-induced decrease in open-field general activity was not modified by any of the doses of THIP and diazepam or by the two lowest doses of baclofen. The highest dose of baclofen potentiated the increase in the duration of immobility induced by reserpine. These results reinforce the involvement of GABAergic hypofunction in the expression of oral dyskinesias, and support the potential therapeutic use of THIP and baclofen in the treatment of oral dyskinesias.

Circadian rest–activity rhythm in individuals at risk for psychosis and bipolar disorder

BACKGROUND At-risk mental states (ARMS) are clinical syndromes that are associated with higher risk, compared with the general population, for developing psychosis and bipolar disorder. Circadian rhythm misalignments have been proposed to be part of this early phase of the clinical course. OBJECTIVE To compare circadian rhythm of activity and rest changes between ARMS individuals and a healthy control group. METHODS Forty volunteers of both genders, aged between 13 and 27years old, participated in this study (n=20 ARMS group, and n=20 healthy controls). The ARMS individuals were classified as ultra-high risk for psychosis according to the CAARMS (Comprehensive Assessment of At-risk Mental State) or at high risk for bipolar disorder according to criteria proposed by Bechdolf and colleagues. Participants used an actigraph for fifteen days, kept a sleep diary, and completed the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, and a Morningness-Eveningness Questionnaire. RESULTS Compared with healthy volunteers, the ARMS group presented worse sleep quality (P=0.010); longer nap durations (P=0.038), shorter wake times (P=0.001), higher total sleep times (P=0.011), and shorter activity duration (P=0.021), sleep rhythms were more fragmented, the circadian rest-activity rhythms were less synchronized with the dark-light cycle and had lower amplitudes of motor activity. CONCLUSION The results suggest alterations in the circadian rest-activity rhythms (and likely in sleep-wake cycle patterns) in ARMS individuals compared with healthy controls. It is possible that circadian rhythms of activity and rest changes are one of the prodromal clinical and behavioral expressions of the brain changes that underlie ARMS individuals.

Abnormalities in sleep patterns in individuals at risk for psychosis and bipolar disorder

AIM To compare patterns of sleep and the presence of sleep disturbances in individuals in at-risk mental states (ARMS) for psychosis and bipolar disorder (BD) with a healthy control (HC) group. METHODS This was a comparative study involving 20 individuals in ARMS for psychosis or BD, according to the Comprehensive Assessment of At-Risk Mental States, and 20 age- and sex-matched healthy controls. Quality of sleep in the previous month was assessed using the Pittsburgh Sleep Quality Index, diurnal somnolence was evaluated using The Epworth Sleepiness Scale, and chronotype was determined using the Questionnaire of Morningness/Eveningness (QME). All of the participants underwent polysomnography (PSG) during the entire night for two consecutive nights. The first night aimed to adapt the subject to the environment, and only the data from the second night were used for the analysis. RESULTS Compared with the HC group, individuals in the ARMS group reported significantly worse sleep quality, as measured by the Pittsburgh Sleep Quality Index. Both groups had scores consistent with daytime sleepiness on the Epworth Sleepiness Scale, and there were no differences with regard to chronotype between the groups, with a predominance of the indifferent type in both groups. In the PSG assessment, we observed increased Sleep Latency (SL) and increased Rapid Eye Movement Sleep Onset Latency (REMOL) in the ARMS group, compared to the HC group. CONCLUSION The results of this study indicated that sleep abnormalities could be found early in the course of mental diseases, even in at-risk stages, and support the further investigation of their predictive value in the transition to psychosis and BD.

Effects of topiramate on oral dyskinesia induced by reserpine

Recently, we have described the antidyskinetic property of the GABA mimetic drug valproic acid on reserpine-induced oral dyskinesia, an animal model that has been related to tardive as well as acute dyskinesias, which are associated with important neuropathologies. The present study investigates the effects of different doses of the GABA mimetic anticonvulsant topiramate on the manifestation of reserpine-induced orofacial dyskinesia. Female EPM-M1 mice received two injections of control solution or of 0.5 mg/kg reserpine separated by 48 h. Twenty-four hours after the second reserpine or control solution injection, animals were acutely treated with control solution or topiramate (1, 3, 10 or 30 mg/kg) and were observed for quantification of oral dyskinesia or general activity in an open-field. In order to verify the effects of topiramate per se on oral dyskinesia or general activity, female EPM-M1 mice were acutely treated with control solution or 1, 3, 10 or 30 mg/kg topiramate and observed for quantification of oral dyskinesia and general activity. The highest dose of topiramate completely abolished the manifestation of reserpine-induced oral dyskinesia whereas the doses of 3 and 10 mg/kg significantly attenuated it. None of the doses of the anticonvulsant modified spontaneous locomotion frequency or oral movements, whereas spontaneous rearing frequency was decreased by 3, 10 and 30 mg/kg topiramate. The highest dose of topiramate did not modify general activity in reserpine-treated mice. These results support the potential therapeutic use of topiramate in the treatment of oral dyskinesias.

Depressive symptoms and sleep: a population-based polysomnographic study.

The goals of the present study were to determine the prevalence of depression in the adult population of Sao Paulo, Brazil and to explore the relationship among sociodemographic, physical and psychological factors, sleep-related symptoms and polysomnography parameters. Participants of a cross-sectional study (N = 1101) were administered questionnaires and submitted to polysomnography. A score > 20 in the Beck Depression Inventory was used to describe depression. Results revealed that the prevalence of depression was 10.9%. Estimates were higher in women and were significantly higher among housewives, non-workers and individuals with lower education and income. A combination of sleep-related symptoms and impaired quality of life was 2.5 times more frequent among depressed than non-depressed. Co-morbid insomnia and anxiety were positively associated to depressive symptomatology. There were no alterations in the polysomnography parameters, in either group. The occurrence of sleep apnea with values on the apnea-hypopnea index ≥ 5 was similar and frequent in both groups (around 30%). The findings suggest that depressive symptoms were associated with low education, low income, severe comorbid symptomatology, and impaired quality of life. Considering the high prevalence of sleep apnea, these results point to potential social and financial burdens associated with the depressive symptomatology and various sleep diagnoses.

Circadian rhythm disturbances and conversion to psychosis in ultra high-risk youth

tolerance since the start of treatment. Nefopam was also introduced for the management of hemorrhoid pain as needed, at 20 mg/d (po). After an additional 35 days of treatment with clozapine at 350 mg/d, one night the patient had hematemesis and diffuse abdominal pain. The next morning, she experienced vomiting and complained of epigastric pain. The patient was treated with domperidone (30 mg/d) and metoclopramide (20 mg/d, po, as needed). Clinical examination revealed reflux esophagitis (grade 4) associated with a hiatal hernia (4 cm). A blood test showed plasma clozapine levels of 980 mg/l (laboratory alert level is plasma concentration 4 1,000 mg/L). In this context, pantoprazole was introduced at a dosage of 20 mg/d, whereas domperidone was stopped after 1 week. Clozapine was gradually reduced to 200 mg/d. After 15 days, gastroesophageal symptoms had diminished and clozapine levels had fallen to 633 mg/L (therapeutic reference range = 350-600 mg/L). About 2 months after esophagitis, a gastroscopic control was performed, demonstrating complete esophageal healing. Table 1 synthesizes the clozapine dose changes following intoxication along with the plasma levels of clozapine. Some disorders affecting the gastrointestinal tract, including cases of esophagitis with hiatal hernias, have been reported with the use of clozapine, but very few have been published. These gastrointestinal disturbances appear in connection with hypomotility and changes in digestive secretion induced by clozapine, as a result of its antiserotoninergic and anticholinergic properties. Anticholinergic medications are often implicated in exacerbating gastroesophageal reflux disease by decreasing lower esophageal sphincter pressure and consequently causing or aggravating heartburn, but such conditions were not identified in our patient before the occurrence of esophagitis. In our patient, the combined use of clozapine, tropatepine, and aripiprazole (stopped a week before the adverse effect but with a long half-life) may have enhanced the effects of clozapine by contributing to anticholinergic and antiserotoninergic effects respectively (nefopam was only administered on 2 days: 4 and 24 days before esophagitis). However, the dramatic increase in clozapine blood concentration seems sufficient to account for the adverse effect. To the best of our knowledge, this is the first case of clozapine-induced severe esophagitis correlated to a measured-level of plasma clozapine to be published in the literature.