Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport.

In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b+/- mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b+/- neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.

Real-world effectiveness of antipsychotic monotherapy and polytherapy in 1543 patients with acute-phase schizophrenia.

PURPOSE: The effectiveness of antipsychotic treatments in the acute phase of schizophrenia in actual clinical practice remains somewhat unclear. Therefore, the purpose of the present naturalistic, multi-center study conducted from 1 year starting in September 2017 was to examine the response rate to an initial or second antipsychotic in newly admitted patients with acute-phase schizophrenia, as well as the response rate and quality of augmentation with two antipsychotics in patients who failed to respond to both the initial and second antipsychotics. RESULTS: In total, there were 660 (42.8%) and 243 (15.7%) responders to an initial and a second antipsychotic, respectively; thus, 58.5% of all patients were responders to an initial or second antipsychotic. Among 581 nonresponders (37.7%), the initial antipsychotic or a third antipsychotic was added to the second antipsychotic. Among these patients, 89.8% showed a Clinical Global Impression-Improvement score ≤3 (from 'minimally improved' to 'very much improved'). The rates of adverse events such as hyperglycemia, hyper-low-density lipoprotein cholesterolemia, hypertriglyceridemia, hyperprolactinemia, QTc prolongation, and extrapyramidal symptoms were not high in patients receiving augmentation with two antipsychotics compared with all patients, and no serious adverse events were reported. CONCLUSION: Antipsychotic augmentation may be an option in acute-phase treatment for patients who do not respond to either an initial or a second antipsychotic.

Cysteine-rich whey protein isolate (Immunocal®) ameliorates deficits in the GFAP.HMOX1 mouse model of schizophrenia.

Schizophrenia is a neuropsychiatric disorder that features neural oxidative stress and glutathione (GSH) deficits. Oxidative stress is augmented in brain tissue of GFAP.HMOX1 transgenic mice which exhibit schizophrenia-relevant characteristics. The whey protein isolate, Immunocal® serves as a GSH precursor upon oral administration. In this study, we treated GFAP.HMOX1 transgenic mice daily with either Immunocal (33mg/ml drinking water) or equivalent concentrations of casein (control) between the ages of 5 and 6.5 months. Immunocal attenuated many of the behavioral, neurochemical and redox abnormalities observed in GFAP.HMOX1 mice. In addition to restoring GSH homeostasis in the CNS of the transgenic mice, the whey protein isolate augmented GSH reserves in the brains of wild-type animals. These results demonstrate that consumption of whey protein isolate augments GSH stores and antioxidant defenses in the healthy and diseased mammalian brain. Whey protein isolate supplementation (Immunocal) may constitute a safe and effective modality for the management of schizophrenia, an unmet clinical imperative.

Antioxidant and anti-inflammatory nutrient status, supplementation, and mechanisms in patients with schizophrenia.

Over 50 million people around the world suffer from schizophrenia, a severe mental illness characterized by misinterpretation of reality. Although the exact causes of schizophrenia are still unknown, studies have indicated that inflammation and oxidative stress may play an important role in the etiology of the disease. Pro-inflammatory cytokines are crucial for normal central nervous development and proper functioning of neural networks and neurotransmitters. Patients with schizophrenia tend to have abnormal immune activation resulting in elevated pro-inflammatory cytokine levels, ultimately leading to functional brain impairments. Patients with schizophrenia have also been found to suffer from oxidative stress, a result of an imbalance between the production of free radicals and the ability to detoxify their harmful effects. Furthermore, inflammation and oxidative stress are implicated to be related to the severity of psychotic symptoms. Several nutrients are known to have anti-inflammatory and antioxidant functions through various mechanisms in our body. The present review evaluates studies and literature that address the status and supplementation of omega-3 polyunsaturated fatty acids, vitamin D, B vitamins (B6, folate, B12), vitamin E, and carotenoids in different stages of schizophrenia. The possible anti-inflammatory and antioxidant mechanisms of action of each nutrient are discussed.

A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia.

Short-term clinical trials of omega-3 polyunsaturated fatty acids (n-3 PUFA) as add-on therapy in patients with schizophrenia revealed mixed results. The majority of these studies used an 8- to 12-week intervention based on ethyl-eicosapentaenoic acid. A randomized placebo-controlled trial was designed to compare the efficacy of 26-week intervention, composed of either 2.2 g/day of n-3 PUFA, or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. Seventy-one patients (aged 16-35) were enrolled in the study and randomly assigned to the study arms. The primary outcome measure of the clinical evaluation was schizophrenia symptom severity change measured by the Positive and Negative Syndrome Scale (PANSS). Mixed models repeated measures analysis revealed significant differences between the study arms regarding total PANSS score change favouring n-3 PUFA (p = 0.016; effect size (ES) = 0.29). A fifty-percent improvement in symptom severity was achieved significantly more frequently in the n-3 PUFA group than in the placebo group (69.4 vs 40.0%; p = 0.017). N-3 PUFA intervention was also associated with an improvement in general psychopathology, measured by means of PANSS (p = 0.009; ES = 0.32), depressive symptoms (p = 0.006; ES = 0.34), the level of functioning (p = 0.01; ES = 0.31) and clinical global impression (p = 0.046; ES = 0.29). The findings suggest that 6-month intervention with n-3 PUFA may be a valuable add-on therapy able to decrease the intensity of symptoms and improve the level of functioning in first-episode schizophrenia patients.

Improvement of Psychotic Symptoms and the Role of Tissue Plasminogen Activator.

Tissue plasminogen activator (tPA) mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms.

Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review.

Schizophrenia is a chronic condition that impacts significantly not only on the individual and family, but the disorder also has wider consequences for society in terms of significant costs to the economy. This highly prevalent condition affects approximately 1% of the worldwide population, yet there are few therapeutic options. The predominant treatment strategy for schizophrenia is anti-psychotic medication (with or without additional talking therapy) even though this approach lacks efficacy in managing the negative symptoms of the condition, is not effective in one-third of the patient group and the side effects of the medication can be severe and debilitating. In recent years, a number of pathophysiological processes have been identified in groups of people with schizophrenia including oxidative stress, one-carbon metabolism and immune-mediated responses. A number of studies have shown that these altered physiological mechanisms can be ameliorated by nutritional interventions in some individuals with schizophrenia. This review briefly describes the aforementioned processes and outlines research that has investigated the utility of nutritional approaches as an adjunct to anti-psychotic medication including antioxidant and vitamin B supplementation, neuroprotective and anti-inflammatory nutrients and exclusion diets. Whilst none of these interventions provides a 'one-size-fits-all' therapeutic solution, we suggest that a personalised approach warrants research attention as there is growing agreement that schizophrenia is a spectrum disorder that develops from the interplay between environmental and genetic factors.

Neonatal MK-801 treatment differentially alters the effect of adolescent or adult MK-801 challenge on locomotion and PPI in male and female rats.

Schizophrenia is a neurodevelopmental disorder and is typically "triggered" by subsequent insults in life. The N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induces locomotor hyperactivity and prepulse inhibition (PPI) deficits, which can mimic the schizophrenia phenotype. In this experiment, we assessed whether neonatal exposure to MK-801 (postnatal days 5-14) could induce sensitization to both hyperactivity and PPI deficit caused by later-life acute MK-801 treatment during adolescence or adulthood. Our results showed that the hyperactivity induced by an acute MK-801 challenge was enhanced in male and female rats after neonatal MK-801 treatment. Notably, in the PPI test, adult female rats neonatally exposed to MK-801 exhibited a significantly greater reduction in PPI in response to acute MK-801 administration, whereas male rats receiving neonatal MK-801 treatment expressed attenuated PPI disruption in adulthood. Our data indicate that a combination of neonatal and later-life NMDA receptor blockades could induce sensitization in the locomotor activity of both sexes in adolescence and adulthood. In addition, a sex difference was observed in the effects of this treatment regime on PPI.

Reduced serum non-enzymatic antioxidant defense and increased lipid peroxidation in schizophrenic patients on a hypocaloric diet.

INTRODUCTION: Growing evidence suggests that oxidative stress (OS) may be associated with the pathophysiology underlying schizophrenia (SZ). Some studies indicate that nutritional supplements offer protection from OS, but there is no data about the effect of a hypocaloric diet on OS in this population. Therefore, we aimed to study the effect of a hypocaloric dietary intervention on OS in subjects with SZ. METHODS: A cross-sectional study of 96 participants in outpatient treatment for SZ comprised patients separated into two groups: one group of subjects followed a hypocaloric diet (HD) program (n=42), while the other group followed a regular diet (RD) with no nutritional restrictions (n=54). The serum total radical-trapping antioxidant parameter (TRAP), total antioxidant reactivity (TAR) and thiobarbituric acid reactive species (TBARS) levels were assessed. RESULTS: TRAP levels were lower and TBARS levels were higher in the HD group than in the RD group (p=0.022 and p=0.023, respectively). There were no differences in TAR levels between the groups. Additionally, there was a positive correlation between TRAP and TBARS levels after adjusting for BMI and clozapine dose (partial correlation=0.42, p<0.001). There were no correlations among the length of illness or diet and the levels of TRAP, TBARS, and TAR. CONCLUSIONS: Subjects with SZ on a hypocaloric diet displayed different OS parameters than those not following a HD. Serum TRAP levels were lower and TBARS levels were higher among SZ subjects with HD compared to SZ subjects without HD. Lower TRAP levels may reflect decreased oxidative stress, whereas higher TBARS levels most likely reflect a biochemical reaction to the decreased TRAP levels. Additionally, TAR levels were similar between groups, suggesting a similar quality of antioxidant defenses, despite quantitative differences between the two dietary protocols in SZ patients under outpatient care.

Ácidos graxos ômega 3 e tratamento da esquizofrenia: [revisão] / Omega 3 fatty acid and schizophrenia treatment: [review]

CONTEXTO: A esquizofrenia é uma desordem psiquiátrica complexa e debilitante cujo tratamento de base é realizado com medicamentos antipsicóticos. No entanto, evidências sugerem que a suplementação dietética com ácidos graxos ômega 3 (n-3) pode ser benéfica em diversas desordens psiquiátricas. OBJETIVO: Revisar a eficácia do n-3 como coadjuvante no tratamento farmacológico da esquizofrenia. MÉTODOS: Realizou-se uma pesquisa nas bases de dados eletrônicas Medline, Lilacs e SciELO. A estratégia de busca também incluiu a busca em árvore. Todos os estudos randomizados e controlados relevantes foram incluídos nesta revisão, independentemente do ano de publicação. RESULTADOS: Até o momento, foram divulgados seis estudos randomizados, duplo-cegos placebo controlados; cinco deles apresentaram resultados positivos na melhora dos sintomas da esquizofrenia, assinalando, ainda, superioridade do ácido graxo eicosapentaenoico (EPA) em relação ao ácido graxo docosaexaenoico. Em geral, o consumo de 2 g/dia de EPA conjuntamente com a medicação antipsicótica usual parece reduzir a sintomatologia da esquizofrenia, particularmente os sintomas positivos. CONCLUSÃO: A terapia nutricional com EPA mostrou-se útil como coadjuvante no tratamento da esquizofrenia. Por conseguinte, sugere-se que os pacientes esquizofrênicos sejam encorajados a consumir refeições balanceadas e saudáveis ricas em EPA e, caso a quantidade ideal não seja atingida pela dieta, a suplementação pode ser benéfica.

BACKGROUND: Schizophrenia is a complex and debilitating psychiatric disorder, whose primary pharmacological intervention is the use of antipsychotics. There is, however, growing evidence that dietary supplementation with omega 3 fatty acids (n-3) may be beneficial in several psychiatric conditions. OBJECTIVE: To review the efficacy of n-3 as a treatment for schizophrenia. METHODS: Electronic searches of the following databases were performed: Medline, Lilacs e SciELO. The search strategy also included cited reference searching. All relevant randomized controlled trials were included in the review. RESULTS: To date, five out of six randomized, double-blind, and placebo controlled studies obtained improvement in the symptoms of the psychosis. Besides, an advantage in the intake of eicosapentaenoic fatty acid (EPA) in relation to docosahexaenoic fatty acid was designated. Essentially, the intake of 2 g/day of EPA in addition to the standard medication was effective in decreasing the symptoms of schizophrenia. DISCUSSION: The nutritional therapy with EPA revealed to be useful as coadjutant in the treatment of schizophrenia. Therefore, we suggest that the schizophrenic patients should be encouraged to consume balanced and healthy meals rich in EPA and, if the ideal amount is not reached by the diet, the supplementation is likely to be beneficial.

Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia.

1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.

Polyunsaturated fatty acid (fish or evening primrose oil) for schizophrenia.

BACKGROUND: Limited evidence gives support to an hypothesis suggesting that the symptoms of schizophrenia may result from altered neuronal membrane structure and metabolism. The latter are dependent on blood plasma levels of certain essential fatty acids (EFAs) and their metabolites. Several studies have shown those with schizophrenia often have low levels of the particular EFAs necessary for normal nerve cell membrane metabolism. OBJECTIVES: To review the effects of supplementing standard antipsychotic treatment with polyunsaturated fatty acids, whether essential (EFAs) or non-essential, for those with schizophrenia and, in recent updates to also evaluate the effects of EFA's as a sole antipsychotic treatment. To evaluate the relative efficacy of different types of fatty acid supplementation. SEARCH STRATEGY: Relevant randomised trials were identified by searching the following electronic databases: Biological Abstracts (1985-1998), CINAHL (1982-1998), Cochrane Library (Issue 4, 1999), Cochrane Schizophrenia Group's Register (February 2000), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). In addition, reviewers searched references of included and excluded studies and contacted authors to identify further studies. SELECTION CRITERIA: All randomised clinical trials of polyunsaturated fatty acid supplementation to standard treatment or as primary intervention for schizophrenia (however defined) versus standard care. DATA COLLECTION AND ANALYSIS: Reviewers evaluated data independently and analysed on an intention-to-treat basis. They assumed that people who left the study early or were lost to follow-up had no improvement. Where possible and appropriate relative risk (RR) and their 95% confidence intervals (CI) were calculated. The number needed to treat (NNT) was estimated. For continuous data weighted mean differences (WMD) and their 95% confidence intervals were calculated. Data were inspected for heterogeneity and publication biases. MAIN RESULTS: Four relatively small trials (total n=204) showed low levels of loss to follow up and adverse effects for those taking essential fatty acids. Early results from a few trials suggest a positive effect of eicosapentaenoic acid (EPA) over placebo for scale-derived mental state outcomes. The data, however, is limited making these results difficult to analyse and interpret with confidence. A single small study (n=30) investigated the value of using EPA as sole treatment for people hospitalised for relapse. Results suggest that EPA may help one third of people avoid instigation of standard antipsychotic drugs for 12 weeks (RR 0.6, CI 0.4-0.91). There were no clear effects of primrose oil (omega-6) EFA supplementation. REVIEWER'S CONCLUSIONS: All data are preliminary, but results look encouraging for fish oil. EPA does not seem harmful, may be acceptable to people with schizophrenia and have moderately positive effect. A further trial is soon to be reported from the USA and more are underway or planned in the South Africa and Norway. Considering that EPA may be an acceptable intervention, large, long simple studies reporting clincially meaningful data should be anticipated.

Clozapina, uma alternativa no tratamento dos transtornos afetivos bipolares resistentes e esquizoafetivos / Clozapine, on option in the therapy in bipolar refractory affective disorders and schizoaffectives

A clozapina é um psicofármico antigo que ainda hoje tem revolucionado o tratamento dos transtornos peiquiátricos. Essa droga foi desenvolvida na década de 60 e aprovada pelo FDA(Food and Drug Administration) em 1984 para o tratamento da esquizofrenia refratária. Dados recentes demonstram que ela também pode ser útil no controle dos quadros afetivos bipolares resistentes nos subtipos de ciclagem rápida, quadros mistos e nos transtornos esquizoafetivos

The choroid plexus and system disease in mental illness. III. The exogenous peptide hypothesis of mental illness.

Based on the apparent existence of a second (choroid plexial) blood-brain barrier offering a new brain attack mechanism on the periventricular primary personality brain (Rudin, 1980) and which may be breached to produce the schizophreniform psychosis characteristic of systemic lupus erythematosus (Rudin, 1981), we here assess the evidence that viruses and exogenous peptides, including especially the glutens of cereal grains, may be the primary triggers for schizophrenia. Schizophrenia would then be supposed to result as one expression of gene-determined combined transport organ dysfunction with underlying basal laminar immunopathy at the tissue level and possibly a prostaglandin disorder at the chemical and membrane level in turn, finally disrupting neurotransmission in the periventricular limbic system. We conclude that the evidence warrants test of the hypothesis, including a clinical trial under national auspices employing an elemental diet, plasmapheresis, immunosuppression together with an antiviral regimen.