Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Changes in hypothalamic mu-opioid receptor expression following acute olanzapine treatment in female rats: Implications for feeding behavior.

Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.

Mechanisms underpinning Carpolobia lutea G. Don ethanol extract's neurorestorative and antipsychotic-like activities in an NMDA receptor antagonist model of schizophrenia.

ETHNOPHARMACOLOGICAL RELEVANCE: Persistent ketamine insults to the central nervous system block NMDA receptors and disrupt putative neurotransmission, oxido-nitrosative, and inflammatory pathways, resulting in schizophrenia-like symptoms in animals. Previously, the ethnomedicinal benefits of Carpolobia lutea against insomnia, migraine headache, and insanity has been documented, but the mechanisms of action remain incomplete. AIM OF THE STUDY: Presently, we explored the neuro-therapeutic role of Carpolobia lutea ethanol extract (C. lutea) in ketamine-induced schizophrenia-like symptoms in mice. MATERIALS AND METHODS: Sixty-four male Swiss (22 ± 2 g) mice were randomly assigned into eight groups (n = 8/group) and exposed to a reversal ketamine model of schizophrenia. For 14 days, either distilled water (10 mL/kg; p.o.) or ketamine (20 mg/kg; i.p.) was administered, following possible reversal treatments with C. lutea (100, 200, 400, and 800 mg/kg; p.o.), haloperidol (1 mg/kg, p.o.), or clozapine (5 mg/kg; p.o.) beginning on days 8-14. During the experiment, a battery of behavioral characterizations defining schizophrenia-like symptoms were obtained using ANY-maze software, followed by neurochemical, oxido-inflammatory and histological assessments in the mice brains. RESULTS: A 7-day reversal treatment with C. lutea reversed predictors of positive, negative and cognitive symptoms of schizophrenia. C. lutea also mitigated ketamine-induced neurochemical derangements as evidenced by modulations of dopamine, glutamate, norepinephrine and serotonin neurotransmission. Also, the increased acetylcholinesterase activity, malondialdehyde nitrite, interleukin-6 and tumor necrosis-factor-α concentrations were reversed by C. lutea accompanied with elevated levels of catalase, superoxide dismutase and reduced glutathione. Furthermore, C. lutea reversed ketamine-induced neuronal alterations in the prefrontal cortex, hippocampus and cerebellum sections of the brain. CONCLUSION: These findings suggest that C. lutea reverses the cardinal symptoms of ketamine-induced schizophrenia in a dose-dependent fashion by modulating the oxido-inflammatory and neurotransmitter-related mechanisms.

Long-term effects of adolescent exposure to olanzapine in C57BL/6 J mice and the impact of dietary fish oil supplementation.

RATIONALE: Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure. OBJECTIVES: The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine. METHODS: Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37. RESULTS: In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice. CONCLUSIONS: The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.

Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistance.

Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].

Pretreatment with Carpolobia lutea ethanol extract prevents schizophrenia-like behavior in mice models of psychosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Carpolobia lutea decoction is widely used as a phytotherapeutic against central nervous system-related disorders including insomnia, migraine headache, and mental illness in West and Central Tropical Africa. AIM: This study was designed to investigate the antipsychotic activity of Carpolobia lutea (EECL) in mice models of psychosis. METHODS: Male Swiss mice (n = 5/group) were given EECL (100, 200, 400, and 800 mg/kg), haloperidol (1 mg/kg), clozapine (5 mg/kg) and vehicle (10 mL/kg) orally before amphetamine (5 mg/kg)-induced hyperlocomotion and stereotypy, apomorphine (2 mg/kg)-induced stereotypy, or ketamine (10, 30, and 100 mg/kg)-induced hyperlocomotion, enhancement of immobility and cognitive impairment. RESULTS: EECL (200, 400, and 800 mg/kg) prevented amphetamine- and apomorphine-induced stereotypies, as well as reduced hyperlocomotion induced by amphetamine and ketamine, all of which are predictors of positive symptoms. Regardless of the dose administered, EECL prevented the index of negative symptoms induced by ketamine. Furthermore, higher doses of EECL (400 and 800 mg/kg) also prevented ketamine-induced cognitive impairment, a behavioral phenotype of cognitive symptoms. CONCLUSION: Pretreatment with EECL demonstrated antipsychotic activity in mice, preventing amphetamine-, apomorphine-, and ketamine-induced schizophrenia-like symptoms, with 800 mg/kg being the most effective dose.

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress-Induced Damage in Patients with Bipolar Disorder.

Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive-behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.

From GWAS to drug screening: repurposing antipsychotics for glioblastoma.

BACKGROUND: Glioblastoma is currently an incurable cancer. Genome-wide association studies have demonstrated that 41 genetic variants are associated with glioblastoma and may provide an option for drug development. METHODS: We investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a 'pathway/gene-set analysis' approach. RESULTS: The in-silico screening led to the discovery of 12 candidate drugs. DepMap portal revealed that 42 glioma cell lines show higher sensitivities to 12 candidate drugs than to Temozolomide, the current standard treatment for glioblastoma. CONCLUSION: In particular, cell lines showed significantly higher sensitivities to Norcyclobenzaprine and Protriptyline which were predicted to bind targets to disrupt a certain molecular function such as DNA repair, response to hormones, or DNA-templated transcription, and may lead to an effect on survival-related pathways including cell cycle arrest, response to ER stress, glucose transport, and regulation of autophagy. However, it is recommended that their mechanism of action and efficacy are further determined.

Berberine, a Herbal Metabolite in the Metabolic Syndrome: The Risk Factors, Course, and Consequences of the Disease.

In recent years, the health of patients exposed to the consequences of the metabolic syndrome still requires the search for new solutions, and plant nutraceuticals are currently being intensively investigated. Berberine is a plant alkaloid possessing scientifically determined mechanisms of the prevention of the development of atherosclerosis, type 2 diabetes, and obesity, as well as cardiovascular complications and cancer. It positively contributes to elevated levels of fasting, postprandial blood glucose, and glycosylated hemoglobin, while decreasing insulin resistance. It stimulates glycolysis, improving insulin secretion, and inhibits gluconeogenesis and adipogenesis in the liver; by reducing insulin resistance, berberine also improves ovulation. The anti-obesity action of berberine has been also well-documented. Berberine acts as an anti-sclerotic, lowering the LDL and testosterone levels. The alkaloid exhibits an anti-inflammatory property by stalling the expression of cyclooxygenase 2 (COX-2) and prostaglandin E2. Berberine is neuroprotective and acts as an antidepressive. However, the outcomes in psychiatric patients are nonspecific, as it has been shown that berberine improves metabolic parameters in schizophrenic patients, acting as an adjuvant during antipsychotic treatment. Berberine acts as an anticancer option by inducing apoptosis, the cell cycle arrest, influencing MAPK (mitogen-activated protein kinase), and influencing transcription regulation. The inhibition of carcinogenesis is also combined with lipid metabolism.

New bone-generative effect of Salvia officinalis L. in the expanded midpalatal suture : An in vivo and in vitro study.

PURPOSE: The aims of this study were to evaluate the effects of systemic administration of Salvia officinalis Linnaeus (L.) leaf extract on new bone formation in the expanded premaxillary suture in rats in vivo and to examine the antioxidant effects and phenolic profile of Salvia officinalis (SO) leaf and root extracts in vitro. METHODS: Fourteen male Sprague Dawley rats were allocated to two groups: SO group (n = 7) and control group (n = 7). An open-loop spring was attached to the upper incisors of each rat to expand the premaxillae. A 5-day expansion period followed by a 12-day retention period was observed. The rats in the SO group received systemic administration of 20 mg SO/kg/day via the orogastric route for 17 days. Histomorphometric examinations were carried out to examine the amount of new bone formation, number of capillaries, and intensity of inflammatory cell response. Immunohistochemical analysis was conducted to examine the number of osteoblasts and osteoclasts. Leaf and root extracts of SO were also analyzed for antioxidant activity and phenolic compounds in vitro. RESULTS: Statistical analysis showed that the following were higher in the SO group than in the control group: new bone formation, number of osteoblasts and osteoclasts, intensity of inflammatory cell response (neutrophils, lymphocytes, and macrophages), and number of capillaries. The major compound identified in SO leaf extract was rosmarinic acid, while luteolin derivatives, salvianolic acid F, and medioresinol were also present. CONCLUSIONS: Salvia officinalis L. from leaf extract provided antioxidant effects and stimulated enhanced new bone formation in the expanded midpalatal suture after maxillary expansion in rats.

Biomedical Implications of Plant-based Principles as Antidepressants: Prospects for Novel Drug Development.

BACKGROUND: Depression is the most common mental disorder. The symptoms of depression include loss of energy, changes in appetite, more or less sleep, anxiety, low concentration, uncertainty, restlessness, feelings of worthlessness, guilt, or despair, and thoughts of self-harm or suicide. In order to provide safe, efficient, and cost-effective medication, the plant-based principles in isolation or combination with traditional antidepressants are gaining increasing attention for depression therapy. METHODS: This study includes the information regarding the present review and its contents collected from published literature materials in different international journals. We have used different search engines such as PubMed, Medline, ResearchGate, Google Semantic Scholar, and Science Direct. For this purpose, the data obtained were properly organized and analyzed to include in this article. RESULTS: Most of the phytomolecules isolated from the medicinal plants display antidepressant effects through the synaptic regulation of levels of neurotransmitters such as dopamine, serotonin, and noradrenaline in different parts of the brain. The mechanism of action of phytomolecules also involves negative regulation of the activities of monoamine oxidase (MAO) and acetylcholinesterase (AChE) and prevention of hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, the strong antioxidative and anti-inflammatory potential of these phytochemicals offer synergy to their antidepressant as well as antipsychosomatic functions. CONCLUSION: The application of phytochemicals has proved it to be a safe, cost-effective, and efficient therapeutic agent to treat patients suffering from mild to severe states of depression and other psychiatric disorders. The potential phytochemicals may be further optimized using in silico tools to develop better antidepressants and antipsychotic agents in the future.

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.

Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.

Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.

Cardiac voltage-gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC-related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life-threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart-related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well-studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson's disease models.

Current treatments for Parkinson's disease (PD) provide only symptomatic relief, with no disease-modifying therapies identified to date. Repurposing FDA-approved drugs to treat PD could significantly shorten the time needed for and reduce the costs of drug development compared with conventional approaches. We developed an efficient strategy to screen for modulators of ß-glucocerebrosidase (GCase), a lysosomal enzyme that exhibits decreased activity in patients with PD, leading to accumulation of the substrate glucosylceramide and oxidized dopamine and α-synuclein, which contribute to PD pathogenesis. Using a GCase fluorescent probe and affinity-based fluorescence polarization assay, we screened 1280 structurally diverse, bioactive, and cell-permeable FDA-approved drugs and found that the antipsychotic quetiapine bound GCase with high affinity. Moreover, quetiapine treatment of induced pluripotent stem cell-derived (iPSC-derived) dopaminergic neurons from patients carrying mutations in GBA1 or LRRK2 led to increased wild-type GCase protein levels and activity and partially lowered accumulation of oxidized dopamine, glucosylceramide, and α-synuclein. Similarly, quetiapine led to activation of wild-type GCase and reduction of α-synuclein in a GBA mutant mouse model (Gba1D409V/+ mice). Together, these results suggest that repurposing quetiapine as a modulator of GCase may be beneficial for patients with PD exhibiting decreased GCase activity.

Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections.

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

Prevention and reversal of ketamine-induced experimental psychosis in mice by the neuroactive flavonoid, hesperidin: The role of oxidative and cholinergic mechanisms.

Currently, prevailing evidence have identified cholinergic and oxidative pathways as important therapeutic targets for abating ketamine-induced schizophrenia-like behavior. Thus, this study evaluated the ability of hesperidin, a naturally occurring antioxidant and neuroprotective flavonoid, to prevent and reverse ketamine-induced schizophrenia-like behaviors and changes in cholinergic, oxidative and nitrergic status in mice. Forty-eight male Swiss mice were allotted into the preventive and reversal studies with 4 groups (n = 6) each. In the preventive study, groups 1 and 2 received vehicle (10 mL/kg/p.o./day), while groups 3 and 4 had hesperidin (100 mg/kg/p.o./day) for 14 days, but ketamine (20 mg/kg/i.p./day) was concurrently given to groups 2 and 4 from days 8-14. In the reversal study, groups 1 and 3 received vehicle, groups 2 and 4 were pretreated with ketamine for 14 days. Nevertheless, groups 3 and 4 additionally received hesperidin from days 8-14. Thereafter, schizophrenia-like behavior from exploratory activity, open-field (positive symptoms), Y-maze (cognitive symptoms) and social interaction (negative symptoms) tests were evaluated. Brain levels of oxidative/nitrergic (glutathione, superoxide-dismutase, malondialdehyde and nitrite levels) and cholinergic (acetylcholinesterase activity) markers were measured in the prefrontal-cortex, striatum and hippocampus. Hesperidin prevents and reverses ketamine-induced hyperactivities, social withdrawal and cognitive impairment. Also, hesperidin prevented and reversed ketamine-induced decrease in glutathione and superoxide-dismutase levels in the prefrontal-cortical, striatal and hippocampal brain regions in mice. Consequently, hesperidin attenuated ketamine-induced increase in malondialdehyde, nitrite levels and acetylcholinesterase activities in the prefrontal-cortex, striatum and hippocampus, respectively. The study showed that hesperidin prevents and reverses ketamine-induced schizophrenia-like behavior through inhibition of oxidative/nitrergic stress and acetylcholinesterase activity in mice brains. Therefore, these findings suggest that hesperidin dietary supplementation could provide natural nutritional intervention to protect against epigenetic-induced mental ill-health like schizophrenia, and thus serve as an important agent for nutritional psychiatry.

Initial Results of Tests Using GSR Biofeedback as a New Neurorehabilitation Technology Complementing Pharmacological Treatment of Patients with Schizophrenia.

Galvanic skin response (GSR) Biofeedback uses training to reduce tension and anxiety and improve concentration and self-regulation. The study was aimed to evaluate this method as a form of rehabilitation and quantify the outcomes achieved by patients undergoing training using this technique. Six schizophrenic patients were enrolled in the study and underwent training based on the relaxation training module (CENTER), concentration training module (BALANCE), and self-regulation training module (INSECTS). Training sessions were held twice a week for 6 weeks. From the total group of subjects involved in the study, two patients had a statistically significant increase in measured values after the CENTER exercise, indicating that relaxation was achieved. Four patients showed a statistically significant decrease in measured values after the BALANCE exercise, which was reflective of an improvement in concentration. Three patients had a statistically significant decrease in measured values after the INSECTS exercise, which indicated an improvement in self-regulation. GSR Biofeedback may be used to complement the pharmacological treatment of patients diagnosed with schizophrenia.

The endocannabinoid system as a therapeutic target for schizophrenia: Failures and potentials.

Owing to its psychotropic effects, Cannabis has been stigmatized by its recreational use leading to a dramatic decline in the experimentations about its medical use in the twentieth century. The medical properties of the plant - known since ancient times - have received increased attention over recent years; yet, the research on its potential application in the field of psychiatry is still nascent. In this connection, the non-psychotropic cannabidiol (CBD) has emerged as a phytocannabinoid compound with promising antipsychotic effects. In addition, advances in our understanding of the endocannabinoid system, along with accumulating evidence implicating this system in the pathophysiology of schizophrenia, have stimulated research by the pharmaceutical industry to explore whether alteration of this system can be of medical benefit. This review examines the current state of evidence regarding the clinical potential of cannabinoid-based drugs as a treatment for schizophrenia, while discussing various limitations with the therapeutic approaches considered so far. In the second part, the author highlights the most promising strategies, as well as the most interesting directions one could follow, in the emerging field of cannabinoid therapies for schizophrenia.

The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.