No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
L-Theanine in Schizophrenia and Related Disorders J Clin Psychiatry e1 L-Theanine Relieves Positive, Activation, and Anxiety Symptoms in Patients With Schizophrenia and Schizoaffective Disorder: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, 2-Center Study
Abstract
Objective: L-Theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation properties. This is a first study de-signed to evaluate the efficacy and tolerability of L-theanine augmentation of antipsychotic treatment of patients with chronic schizophrenia and schizo-affective disorder. Method: 60 patients with DSM-IV schizo-phrenia or schizoaffective disorder participated in an 8-week, double-blind, randomized, placebo-controlled study. 400 mg/d of L-theanine was added to ongoing antipsychotic treatment from February 2006 until October 2008. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), the Hamilton Anxiety Rating Scale (HARS), the Cambridge Neuropsychological Test Automated Battery (CANTAB) for neurocognitive functioning, and additional measures of general functioning, side effects, and quality of life. Results: 40 patients completed the study protocol. Compared with placebo, L-theanine aug-mentation was associated with reduction of anxiety (P = .015; measured by the HARS scale) and positive (P = .009) and general psychopathology (P < .001) scores (measured by the PANSS 3-dimensional model). According to the 5-dimension model of psychopathology, L-theanine produced significant reductions on PANSS positive (P = .004) and activa-tion factor (P = .006) scores compared to placebo. The effect sizes (Cohen d) for these differences ranged from modest to moderate (0.09–0.39). PANSS negative and CANTAB task scores, general functioning, side effect, and quality of life measures were not affected by L-theanine augmentation. L-Theanine was found to be a safe and well-tolerated medication. Conclusions: L-Theanine augmentation of antipsychotic therapy can ameliorate positive, acti-vation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. Further long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation.
l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea. Growing evidence has suggested the possible effects of l-theanine on cognition. Previously, we found that l-theanine attenuates MK-801-induced deficit in prepulse inhibition (PPI) in mice. In this study, we examined the effect of l-theanine in increasing the PPI in healthy humans.
The subjects were 14 healthy adults who underwent PPI testing as a measure of sensorimotor gating 90 min after an oral intake of l-theanine (0, 200, 400, or 600 mg). PPI tests were done by examiners who were blind to the dose.
The administration of 200 mg of l-theanine and that of 400 mg, but not 600 mg, significantly increased the % PPI compared to the baseline (0 mg). There was no significant relation between the dose of l-theanine and the startle magnitude or the habituation of startle response. The plasma concentrations of l-theanine correlated with the dose of l-theanine.
The observed effect with 200-400 mg of l-theanine on PPI suggested that l-theanine at a particular dose range increases sensorimotor gating in humans.
Historically, the medicinal use of green tea dates back to China 4700 years ago and drinking tea continues to be regarded traditionally in Asia as a general healthful practice. Numerous scientific publications now attest to the health benefits of both black and green teas, including clinical and epidemiological studies. Although all tea contains beneficial antioxidants, high-quality green and white teas have them in greater concentrations than black tea. Today, scientists believe that the main active ingredients of green tea include the polyphenols, in particular the catechins and the amino acid, theanine. Studies on the health benefits of drinking tea, particularly green tea, are finding exciting results, particularly in cancer research. Modern studies in both Asia and the West have provided encouraging results indicating that drinking green tea contributes to fighting many different kinds of cancers including stomach, oesophageal, ovarian and colon. Recent studies describing the health benefits of these compounds will be reviewed.
L-Theanine (γ-glutamylethylamide) augmentation to antipsychotic therapy ameliorates positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. This study examines the association between circulating levels of neurochemical indicators and the beneficial clinical effects of L-theanine augmentation.
Serum levels of neurochemical indicators such as brain-derived neurotrophic factor (BDNF), dehydroepiandrosterone (DHEA), its sulfate (DHEAS), cortisol, cholesterol, and insulin were monitored in 40 schizophrenia and schizoaffective disorder patients during an 8-week, double-blind, randomized, placebo-controlled trial with L-theanine (400 mg/d). Multiple regression analysis was applied for searching association between improvement in symptom scores and changes in circulating levels of neurochemical indicators for an 8-week trial.
Regression models among L-theanine-treated patients indicate that circulating levels of BDNF and cortisol-to-DHEAS*100 molar ratio were significantly associated with the beneficial clinical effects of L-theanine augmentation. Variability of serum BDNF levels accounted for 26.2% of the total variance in reduction of dysphoric mood and 38.2% in anxiety scores. In addition, the changes in cortisol-to-DHEAS*100 molar ratio accounted for 30% to 34% of the variance in activation factor and dysphoric mood scores and for 15.9% in anxiety scores. Regression models among placebo-treated patients did not reach significant level.
These preliminary results indicate that circulating BDNF and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients.
Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.
The CANTAB battery was administered to a large group (n = 787) of elderly volunteers in the age range from 55 to 80 years. This battery, which is based on tests used to identify the neural substrates of learning and memory in non-human primates, has now been extensively used in the assessment of various forms of dementia and also validated on patients with neurosurgical lesions of the frontal and temporal lobes. The tests employed were pattern and spatial recognition, simultaneous and delayed matching to sample, learning of visuospatial paired associates, a matching to sample, reaction time task and a test of spatial working memory. The sample was banded into different IQ bands based on performance on 5 standard tests of intelligence. The MMSE was also administered to exclude cases of possible dementia (n = 16) in the normal sample. In general, performance declined with age and IQ, but these factors did not interact. A factor analysis (with varimax rotation) identified 4 factors with eigenvalues greater than 1, which accounted for over 60% of the variance. Factor 1 was equated with general learning and memory ability and loaded significantly with the Intelligence scores; factor 2 was related to speed of responding and loaded most heavily with Age. Comparisons were also made of performance on CANTAB of those subjects with dementing scores on the MMSE and the lowest 5th percentile of the population sample. The results are discussed in terms of the utility of the CANTAB battery for the assessment of dementia and of the implications for theories of changes in cognitive function during normal aging.
The Positive and Negative Syndrome Scale (PANSS) is widely used as a method for the assessment of symptoms of schizophrenia but the most complete model of how symptoms are structured has not been determined. Using the methods of confirmatory factor analysis with a large sample of 1,233 of schizophrenic subjects this study examined the goodness of fit of 20 previously proposed models. None of these proposed models met criteria for adequate fit to the empirical data. The sample was then stratified and half of the data was used to calibrate a new model. The model was validated in the second half of the data. The new pentagonal model uses 25 of the 30 items of the PANSS in 5 factors: positive, negative, dysphoric mood, activation, and and autistic preoccupation. Patients who varied widely in age, severity, and chronicity of illness did not differ in their overall symptom structure. The results of this study also implicated some problems in the validity of the PANSS as currently configured when used to assess symptoms of schizophrenia.
L-Theanine (delta-glutamylethylamide) is one of the predominant amino acids ordinarily found in green tea, and historically has been used as a relaxing agent. The current study examined the acute effects of L-theanine in comparison with a standard benzodiazepine anxiolytic, alprazolam and placebo on behavioural measures of anxiety in healthy human subjects using the model of anticipatory anxiety (AA). Sixteen healthy volunteers received alprazolam (1 mg), L-theanine (200 mg) or placebo in a double-blind placebo-controlled repeated measures design. The acute effects of alprazolam and L-theanine were assessed under a relaxed and experimentally induced anxiety condition. Subjective self-reports of anxiety including BAI, VAMS, STAI state anxiety, were obtained during both task conditions at pre- and post-drug administrations. The results showed some evidence for relaxing effects of L-theanine during the baseline condition on the tranquil-troubled subscale of the VAMS. Alprazolam did not exert any anxiolytic effects in comparison with the placebo on any of the measures during the relaxed state. Neither L-theanine nor alprazalam had any significant anxiolytic effects during the experimentally induced anxiety state. The findings suggest that while L-theanine may have some relaxing effects under resting conditions, neither L-theanine not alprazolam demonstrate any acute anxiolytic effects under conditions of increased anxiety in the AA model.
The Extrapyramidal Symptom Rating Scale (ESRS) was developed to assess four types of drug-induced movement disorders (DIMD): Parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). Comprehensive ESRS definitions and basic instructions are given. Factor analysis provided six ESRS factors: 1) hypokinetic Parkinsonism; 2) orofacial dyskinesia; 3) trunk/limb dyskinesia; 4) akathisia; 5) tremor; and 6) tardive dystonia. Two pivotal studies found high inter-rater reliability correlations in both antipsychotic-induced movement disorders and idiopathic Parkinson disease. For inter-rater reliability and certification of raters, >or=80% of item ratings of the complete scale should be +/-1 point of expert ratings and >or=70% of ratings on individual items of each ESRS subscale should be +/-1 point of expert ratings. During a cross-scale comparison, AIMS and ESRS were found to have a 96% (359/374) agreement between TD-defined cases by DSM-IV TD criteria. Two recent international studies using the ESRS included over 3000 patients worldwide and showed an incidence of TD ranging from 10.2% (2000) to 12% (1998). ESRS specificity was investigated through two different approaches, path analyses and ANCOVA PANSS factors changes, which found that ESRS measurement of drug-induced EPS is valid and discriminative from psychiatric symptoms.
Many lines of evidence suggest that oxidative stress resulting in reactive oxygen species (ROS) generation and inflammation play a pivotal role in the age-associated cognitive decline and neuronal loss in neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases. One cardinal chemical pathology observed in these disorders is the accumulation of iron at sites where the neurons die. The buildup of an iron gradient in conjunction with ROS (superoxide, hydroxyl radical and nitric oxide) are thought to constitute a major trigger in neuronal toxicity and demise in all these diseases. Thus, promising future treatment of neurodegenerative diseases and aging depends on availability of effective brain permeable, iron-chelatable/radical scavenger neuroprotective drugs that would prevent the progression of neurodegeneration. Tea flavonoids (catechins) have been reported to possess potent iron-chelating, radical-scavenging and anti-inflammatory activities and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. Recent studies have indicated that in addition to the known antioxidant activity of catechins, other mechanisms such as modulation of signal transduction pathways, cell survival/death genes and mitochondrial function, contribute significantly to the induction of cell viability. This review will focus on the multifunctional properties of green tea and its major component (-)-epigallocatechin-3-gallate (EGCG) and their ability to induce neuroprotection and neurorescue in vitro and in vivo. In particular, their transitional metal (iron and copper) chelating property and inhibition of oxidative stress.
Dropout rates in randomized clinical trials of antipsychotic drugs have consistently been reported to be high, and the use of a placebo-controlled design is hypothesized to be one of the reasons for this.
To investigate this hypothesis in a meta-analysis of available data from pertinent clinical trials.
Comprehensive search of PubMed- and MEDLINE-listed journals.
Double-blind randomized controlled clinical trials of the second-generation antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole meeting the following criteria: unselected patient population with a diagnosis of schizophrenia or schizoaffective disorder, change in psychopathologic symptoms as the primary end point, and trial duration of 12 weeks or less.
Sample size, mean age, baseline disease severity, dropout rate, trial design, trial duration, and publication year.
Thirty-one trials meeting the inclusion criteria were found, comprising 10 058 subjects. Weighted mean dropout rates in the active treatment arms were significantly higher in placebo-controlled trials (PCTs) than in active-control trials: 48.1% (PCTs) vs 28.3% (active-control trials) for second-generation antipsychotics (odds ratio, 2.34; 95% confidence interval, 1.58-3.47) and 55.4% (PCTs) vs 37.2% (active-control trials) for classical antipsychotics (odds ratio, 2.10; 95% confidence interval, 1.29-3.40). Within PCTs, attrition rates were significantly higher in the placebo arms than with second-generation antipsychotics (60.2% vs 48.1%; odds ratio, 1.63; 95% confidence interval, 1.37-1.94). Within the subset of trials in which both second-generation and classical antipsychotics were used, dropout rates were significantly higher with classical antipsychotics.
Use of a placebo-controlled design had a major effect on the dropout rates observed. Because high dropout rates affect the generalizability of such studies, it is suggested that, in addition to the PCTs, studies with alternative designs need to be considered when evaluating an antipsychotic's clinical profile.
In an investigation of the mechanisms of the neuroprotective effects of theanine (gamma-glutamylethylamide) in brain ischemia, inhibition by theanine of the binding of [H-3](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), [H-3]kainate, and [H-3](E)-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H-indole-2- carboxylic acid (MDL 105,519) to glutamate receptors was studied in terms of its possible inhibiting effects on the three receptor subtypes (AMPA, kainate, and NMDA glycine), with rat cortical neurons. Theanine bound the three receptors, but its IC50 of theanine was 80- to 30,000-fold less than that of L-glutamic acid.
L-Theanine is an amino acid found in green tea leaf and in its infusion, and is known to control excitement caused by caffeine. It is also known that the oral administration of L-theanine to rats results in a decrease of serotonin and increase of catecholamines in their brain. L-Theanine has been confirmed to be safe in animal experiments.
We found recently that oral intake of L-theanine caused a feeling of relaxation among the human volunteers examined. These observations led us to do experiments on the effects of administration of L-theanine on the brain electric waves. Eight female university students were selected as volunteers. Four of them were ranked to be Grade I (the highest anxiety) and the remaining four, Grade V (the lowest anxiety) in an investigation done by the manifest anxiety scale method. A dose of oral administration of 200mg of L-theanine dissolved in 100ml of water resulted in the generation of a-electric waves in the occipital and parietal regions of the brains of the subjects. The emission intensity of α-brain waves (integrated as a function of investigation times and area) was significantly greater in the group of Grade I than that of Grade V.
These results indicate the possibility for L-theanine to be applied to foods and beverages as a new type of functional food ingredient for its relaxation effect.
Theanine is the main amino acid component in tea. It usually constitutes between 1 and 2% of the dry weight of the tea leaves. It is as prevalent in tea as all other free amino acids combined. Both enantiomers of theanine were found to have a similar sweet taste, with little or no aftertaste. It was found that black and half-green teas (except for Formosa Oolong) contained as much, or more, theanine as green teas. No correlation was found between the absolute concentration of theanine in tea and its enantiomeric composition. An inverse correlation was found between certain grades of tea (e.g., pekoe, Flowery Orange Pekoe, etc.) and the percent of d-theanine present. This could provide the basis for a reproducible, scientific method to grade and/or evaluate teas. Theanine slowly racemizes in aqueous solution. It also undergoes hydrolysis, particularly at basic pH values. By monitoring these processes, information may be gleaned on the production, storage, handling, and shipping of tea and tea products. Keywords: Racemization; beverage; d-amino acid; tea grades; cyclodextrin column; column switching
Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing the concentration of DOX in the tumor through the inhibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppression of the glutamate transporter in tumor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump.
Since ancient times, it has been said that drinking green tea brings relaxation. The substance that is responsible for a sense of relaxation, is theanine. Theanine is a unique amino acid found almost solely in tea plants and the main component responsible for the exotic taste of ‘green’ tea. It was found that L-theanine administered intraperitoneally to rats reached the brain within 30 min without any metabolic change. Theanine also acts as a neurotransmitter in the brain and decreased blood pressure significantly in hypertensive rats. In general, animals always generate very weak electric pulses on the surface of the brain, called brain waves. Brain waves are classified into four types, namely α,β,δ and θ-waves, based on mental conditions. Generation of α-waves is considered to be an index of relaxation. In human volunteers, α-waves were generated on the occipital and parietal regions of the brain surface within 40 min after the oral administration of theanine (50–200 mg), signifying relaxation without causing drowsiness. With the successful industrial production of L-theanine, we are now able to supply Suntheanine™ (trade name of L-theanine) which offers a tremendous opportunity for designing foods and medical foods targeting relaxation and the reduction of stress. Taiyo Kagaku Co., Ltd, Japan won the 1998 ‘Food Ingredient Research Award’ for development of Suntheanine™ at Food Ingredients in Europe (Frankfurt). The judges felt it was a particularly well-documented and fascinating piece of research.
Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.
We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.
We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.
Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.
The pre-test-post-test design (PPD) is predominant in trials of psychotherapeutic treatments. Missing data due to withdrawals present an even bigger challenge in assessing treatment effectiveness under the PPD than under designs with more observations since dropout implies an absence of information about response to treatment. When confronted with missing data, often it is reasonable to assume that the mechanism underlying missingness is related to observed but not to unobserved outcomes (missing at random, MAR). Previous simulation and theoretical studies have shown that, under MAR, modern techniques such as maximum-likelihood (ML) based methods and multiple imputation (MI) can be used to produce unbiased estimates of treatment effects. In practice, however, ad hoc methods such as last observation carried forward (LOCF) imputation and complete-case (CC) analysis continue to be used. In order to better understand the behaviour of these methods in the PPD, we compare the performance of traditional approaches (LOCF, CC) and theoretically sound techniques (MI, ML), under various MAR mechanisms. We show that the LOCF method is seriously biased and conclude that its use should be abandoned. Complete-case analysis produces unbiased estimates only when the dropout mechanism does not depend on pre-test values even when dropout is related to fixed covariates including treatment group (covariate-dependent: CD). However, CC analysis is generally biased under MAR. The magnitude of the bias is largest when the correlation of post- and pre-test is relatively low.
The transmethylation hypothesis of schizophrenia was reviewed with considerations that large doses of methionine when combined with a monoamine oxidase inhibitor lead to exacerbation of psychotic symptoms in a significant percentage of chronic schizophrenic patients. It was noted that nicotinic acid in the dosage of 3,000 mg/day can neither prevent nor counteract the psychopathology thus induced.
The Calgary Depression Scale (CDS) is a nine item structured interview scale, in which each item has a four point measure, each point anchored by descriptors. The scale has been specifically developed to assess depression in schizophrenics. This article describes the testing of the reliability and validity of the CDS. The scale is assessed and compared to three established measures, the Hamilton Depression Rating Scale (HDRS) the Beck Depression Inventory (BDI) and a depression measure derived from the Brief Psychiatric Rating Scale (BPRS). Confirmatory factor analysis demonstrated that the CDS is unidimensional, measuring the same construct in both in- and outpatients. The scale has high internal consistency, significant strong correlations with scores on the Hamilton, Beck and BPRS depression measures, and the presence of a major depressive episode. All items of the CDS significantly discriminate between the presence and absence of a major depressive episode. It is concluded that the CDS is a parsimonious reliable scale which is suitable for assessing depression across both the acute and residual stages of schizophrenia.
Chlorpromazine (CPZ) equivalents are often used as a relative measure of the antipsychotic potency of neuroleptics. We review the CPZ equivalents of 33 neuroleptics and illustrate why imprecisions or discrepancies will be difficult to eliminate from these values. We nevertheless underline that CPZ equivalents can be clinically useful, since they facilitate the choice of doses of different neuroleptics that should induce comparable antipsychotic effects.
The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized
measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale
(PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS
was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative
symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring
positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the
four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely
correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually
exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with
antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both
typological and dimensional assessment.
The effects of i.p. administered theanine (L-N-ethylglutamine), a constituent of Japanese green tea, on the levels of norepinephrine (NE) and serotonin (5-HT) in the brain of rats with or without coadministration of caffeine were investigated, and compared with those of glutamine.Theanine decreased the NE level, whereas no change was observed with glutamine or caffeine.The decrease of NE induced by theanine was reversed by caffeine. In rats pretreated with pargline, a monoamine oxidase inhibitor, theanine significantly increased the NE level compared with the control. However, it did not enhance the NE levels increased by caffeine. Thus, theanine may decrease the NE levels by releasing this neurotransmitter.Theanine did not alter the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in rats pretreated with or without pargyline, indicating that this amide affects neither 5-HT synthesis nor its degradation. Caffeine increased the levels of 5-HT and 5-HIAA in normal rats to similar extents.This effect was depressed by theanine. In rats pretreated with pargyline, the levels of 5-HT and 5-HIAA were not altered by caffeine, and theanine did not modify the outcome. It may be concluded that the action of theanine is related to the possible inhibition of 5-HT release by caffeine. The effect of glutamine on the levels of 5-HT was somewhat different form that of theanine.
Theanine (N-ethylglutamine), a flavourous constituent of tea leaves, was studied in respect of the influence on the central nervous system in mice.Theanine was shown to inhibit the convulsive action of caffeine, but was ineffective against pentetrazole, picrotoxin, strychnine, pipradrol and bemegride as well as L-glutamine. Neither theanine nor L-glutamine effected on the prolongation of the sleeping time after the injection of hexobarbital sodium in mice. Using 14C-labeled theanine, it was found that the intraperitoneally administered theanine was taken up by brain tissue with out undergoing the metabolic changes in a 30minutes. The intracerebral level of γaminobutyric acid was shown to increase significantly at 30minutes following the intraperitoneal administration of theanine in mice.
There is growing interest in deficit symptoms in studies of the course and treatment response of schizophrenia. However, existing clinical assessment instruments focus primarily on productive symptoms. The authors describe the Quality of Life Scale (QLS), a 21-item scale based on a semistructured interview designed to assess deficit symptoms and thereby fill an important gap in the range of instruments now available. Data regarding reliability and training in the use of the QLS are presented. A factor analysis of the items yields results compatible with the conceptual model on which the scale is based. The factor analysis was also performed separately by sex and was fundamentally similar for men and women.
In order to examine the effect of neuroleptic medication on the factor structure of schizophrenic symptomatology, 517 DSM-III-R schizophrenic in-patients enrolled in a multicenter phase II drug study were evaluated on their pre-existing neuroleptic at screening on the Positive and Negative Syndrome Scale (PANSS) and after a one-week drug-free period. Separate principal components analyses of the PANSS were done at each time point. PANSS total and component scores were assessed for differences utilizing paired t-tests. Both factor analyses confirmed the five factor model (negative, positive, cognitive, excitement and depression components) explaining 51.7 and 56.2% of the variances at each time point. After medication wash-out psychopathology significantly worsened as measured by total PANSS score and by each of the components. The overall worsening of component scores appeared global and uniform, as evidenced by the fact that at washout, the proportion of individual component scores to total psychopathology remained constant for most components. The lack of change of most components in proportion to the psychopathology total is evidence for the stability of these individual psychopathological dimensions of patients while on and off neuroleptics. The results further support the validity of the five-factor model of schizophrenic psychopathology as measured by the PANSS.
The abilities of green tea extract and its three major components to inhibit lipid peroxidation in low-density lipoprotein (LDL) catalyzed by copper were tested in vitro using malondialdehyde as a parameter of antioxidant activity. The results demonstrated that green tea extract markedly delays peroxidation with a dose-dependent pattern. Of the three components, polyphenols had the strongest action. Similar action was also shown in the theanine-treated group but was weaker than in the former, whereas caffeine had a very limited effect. Based on these data, it is concluded that green tea extract can effectively inhibit peroxidation and that this activity is due largely to the polyphenols it contains. According to the ultraviolet spectra, copper chelation is suggested to be one of the possible mechanisms of LDL antiperoxidation.
Theanine, r-glutamylethylamide, is one of the major components of amino acids in Japanese green tea. Effect of theanine on brain amino acids and monoamines, and the striatal release of dopamine (DA) was investigated. Determination of amino acids in the brain after the intragastric administration of theanine showed that theanine was incorporated into brain through blood-brain barrier via leucine-preferring transport system. The concentrations of norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5HIAA) in the brain regions were unaffected by the theanine administration except in striatum. Theanine administration caused significant increases in serotonin and/or DA concentrations in the brain, especially in striatum, hypothalamus and hippocampus. Direct administration of theanine into brain striatum by microinjection caused a significant increase of DA release in a dose-dependent manner. Microdialysis of brain with calcium-free Ringer buffer attenuated the theanine-induced DA release. Pretreatment with the Ringer buffer containing an antagonist of non-NMDA (N-methyl-D-aspartate) glutamate receptor, MK-801, for 1 hr did not change the significant increase of DA release induced by theanine. However, in the case of pretreatment with AP-5, (+/-)-2-amino-5-phosphonopentanoic acid; antagonist of NMDA glutamate receptor, the theanine-induced DA release from striatum was significantly inhibited. These results suggest that theanine might affect the metabolism and/or the release of some neurotransmitters in the brain, such as DA.
Following the administration of theanine, the brain tryptophan content significantly increased or tended to increase, but the contents of serotonin and 5-hydroxyindole acetic acid (5HIAA) decreased. The use of inhibitors of serotonin metabolism enable us to speculate that theanine reduced serotonin synthesis and also increased serotonin degradation in the brain.
Several decades of research attempting to explain schizophrenia in terms of the dopamine hyperactivity hypothesis have produced disappointing results. A new hypothesis focusing on hypofunction of the NMDA glutamate transmitter system is emerging as a potentially more promising concept. In this article, we present a version of the NMDA receptor hypofunction hypothesis that has evolved from our recent studies pertaining to the neurotoxic and psychotomimetic effects of PCP and related NMDA antagonist drugs. In this article, we examine this hypothesis in terms of its strengths and weaknesses, its therapeutic implications and ways in which it can be further tested.
In this study, the inhibiting action of theanine on the excitation by caffeine at the concentration regularly associated with drinking tea was investigated using electroencephalography (EEG) in rats. First, the stimulatory action by caffeine i.v. administration at a level higher than 5 micromol/kg (0.970 mg/kg) b.w. was shown by means of brain wave analysis, and this level was suggested as the minimum dose of caffeine as a stimulant. Next, the stimulatory effects of caffeine were inhibited by an i.v. administration of theanine at a level higher than 5 micromol/kg (0.781 mg/kg) b.w., and the results suggested that theanine has an antagonistic effect on caffeine's stimulatory action at an almost equivalent molar concentration. On the other hand, the excitatory effects were shown in the rat i.v. administered 1 and 2 micromol/kg (0.174 and 0.348 mg/kg) b.w. of theanine alone. These results suggested two effects of theanine, depending on its concentration.
This paper describes some of the statistical considerations in the intent-to-treat design and analysis of clinical trials. The pivotal property of a clinical trial is the assignment of treatments to patients at random. Randomization alone, however, is not sufficient to provide an unbiased comparison of therapies. An additional requirement is that the set of patients contributing to an analysis provides an unbiased assessment of treatment effects, or that any missing data are ignorable. A sufficient condition to provide an unbiased comparison is to obtain complete data on all randomized subjects. This can be achieved by an intent-to-treat design wherein all patients are followed until death or the end of the trial, or until the outcome event is reached in a time-to-event trial, irrespective of whether the patient is still receiving or complying with the assigned treatment. The properties of this strategy are contrasted with those of an efficacy subset analysis in which patients and observable patient data are excluded from the analysis on the basis of information obtained postrandomization. I describe the potential bias that can be introduced by such postrandomization exclusions and the pursuant effects on type I error probabilities. Especially in a large study, the inflation in type I error probability can be severe, 0.50 or higher, even when the null hypothesis is true. Standard statistical methods for the analysis of censored or incomplete observations all require the assumption of missing at random to some degree, and none of these methods adjust for the potential bias introduced by post hoc subset selection. Nor is such adjustment possible unless one posits a model that relates the missing observations to other observed information for each subject-models that are inherently untestable. Further, the subset selection bias is confounded with the subset-specific treatment effect, and the two components are not identifiable without additional untestable assumptions. Methods for sensitivity analysis to assess the impact of bias in the efficacy subset analysis are described. It is generally believed that the efficacy subset analysis has greater power than the intent-to-treat analysis. However, even when the efficacy subset analysis is assumed to be unbiased, or have a true type I error probability equal to the desired level alpha, situations are described where the intent-to-treat analysis in fact has greater power than the efficacy subset analysis. The intent-to-treat design, wherein all possible patients continue to be followed, is especially powerful when an effective treatment arrests progression of disease during its administration. Thus, a patient benefits long after the patient becomes noncompliant or the treatment is terminated. In such cases, a landmark analysis using the observations from the last patient evaluation is likely to prove more powerful than life-table or longitudinal analyses. Examples are described.
We examined the protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in field CA1 of the gerbil hippocampus. One microliter of theanine from each three concentrations (50, 125 and 500 microM) was administered through the lateral ventricle 30 min before ischemia. Transient forebrain ischemia was induced by bilateral occlusion of the common carotid arteries for 3 min under careful control of brain temperature at approximately 37 degrees C. Seven days after ischemia, the number of intact CA1 neurons in the hippocampus was assessed. Ischemia-induced neuronal death in hippocampal CA1 region was significantly prevented in a dose-dependent manner in the theanine-pretreated groups. These findings indicate that theanine might be useful clinically for preventing ischemic neuronal damage.
True intention-to-treat analyses are rare in reports of randomized clinical trials. To highlight the complex issues that arise in conducting and interpreting data from intention-to-treat analyses in studies with substantial levels of protocol violation (e.g. attrition, noncompliance, or withdrawal of participants), data from a clinical trial of treatment for cocaine dependence were analyzed using three strategies to manage missing data: Strategy 1 addressed the effectiveness of treatments based on data collected from participants up to the point of dropout. Strategy 2 addressed the effectiveness of treatments based on data from the full intended duration of the protocol including data collected after participant dropout. The third strategy used a more novel approach, which used an intention-to-treat strategy for the full duration of the trial and the full sample, but also evaluated the effect of treatment retention outcomes by including an independent variable to reflect active treatment retention as a time-varying covariate. Conclusions about the relative efficacy of the study treatments varied to some extent depending on the analytic strategy used. These findings suggest that investigators should make every effort to conduct intent-to-treat analyses, but also to make use of multiple analytic strategies to fully understand the effects of the treatments studied. Moreover, regardless of the strategy used, investigators should clearly describe their handling of data from participants who violate the protocol.
In an investigation of the mechanisms of the neuroprotective effects of theanine (gamma-glutamylethylamide) in brain ischemia, inhibition by theanine of the binding of [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), [3H]kainate, and [3H](E)-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H-indole-2-carboxylic acid (MDL 105,519) to glutamate receptors was studied in terms of its possible inhibiting effects on the three receptor subtypes (AMPA, kainate, and NMDA glycine), with rat cortical neurons. Theanine bound the three receptors, but its IC50 of theanine was 80- to 30,000-fold less than that of L-glutamic acid.
The positive and negative syndrome scale (PANSS) is widely used in psychiatric research. Reflecting this common use, considerable attention has been applied to the psychometric properties of this instrument. However, despite the publication of numerous studies and analyses, it remains uncertain how best data from the PANSS should be analysed to best model the symptoms of schizophrenia. A resolution to these concerns seemed to be offered following the publication in 1997 of a large multisite factor analysis that produced the 'pentagonal model', which has subsequently been included in the 2000 revision of the PANSS user manual. However, to date, an independent confirmatory analysis of this model has not yet been published. The aim of this study was to test this model in a new independent sample with confirmatory factor analysis (CFA). Independent confirmation of the fit of the model is required to ensure that its implementation is informed by confirmation of its psychometric properties. CFA was performed in a sample of 347 subjects with schizophrenia. The analysis found that the model had inadequate goodness of fit. The use of the pentagonal model has similar difficulties as earlier models and more research is required to ascertain the optimal method for measuring symptom dimensions in research and clinical settings.
Several clinical and research applications require an estimation of therapeutic dose equivalence across antipsychotic medications. Since the advent of the newer atypical antipsychotics, new dose equivalent estimations have been needed.
The reported minimum effective dose was identified for each newer atypical antipsychotic medication and for haloperidol across all available fixed-dose placebo-controlled studies. Reported minimum effective dose equivalence ratios to haloperidol were then converted to chlorpromazine equivalents using the "2 mg of haloperidol equals 100 mg of chlorpromazine" convention.
To identify the fixed-dose studies, the following sources were searched until June 2002: MEDLINE, the bibliographies of identified reports, published meta-analyses and reviews, Cochrane reviews, Freedom of Information Act material available from the Food and Drug Administration, and abstracts from several scientific meetings from 1997 to 2002.
Doses equivalent to 100 mg/day of chlorpromazine were 2 mg/day for risperidone, 5 mg/day for olanzapine, 75 mg/day for quetiapine, 60 mg/day for ziprasidone, and 7.5 mg/day for aripiprazole.
These equivalency estimates may be useful for clinical and research purposes. The source of the dose equivalency estimation is evidence-based and consistent across medication.
Fear is an adaptive component of the acute "stress" response to potentially-dangerous (external and internal) stimuli which threaten to perturb homeostasis. However, when disproportional in intensity, chronic and/or irreversible, or not associated with any genuine risk, it may be symptomatic of a debilitating anxious state: for example, social phobia, panic attacks or generalized anxiety disorder. In view of the importance of guaranteeing an appropriate emotional response to aversive events, it is not surprising that a diversity of mechanisms are involved in the induction and inhibition of anxious states. Apart from conventional neurotransmitters, such as monoamines, gamma-amino-butyric acid (GABA) and glutamate, many other modulators have been implicated, including: adenosine, cannabinoids, numerous neuropeptides, hormones, neurotrophins, cytokines and several cellular mediators. Accordingly, though benzodiazepines (which reinforce transmission at GABA(A) receptors), serotonin (5-HT)(1A) receptor agonists and 5-HT reuptake inhibitors are currently the principle drugs employed in the management of anxiety disorders, there is considerable scope for the development of alternative therapies. In addition to cellular, anatomical and neurochemical strategies, behavioral models are indispensable for the characterization of anxious states and their modulation. Amongst diverse paradigms, conflict procedures--in which subjects experience opposing impulses of desire and fear--are of especial conceptual and therapeutic pertinence. For example, in the Vogel Conflict Test (VCT), the ability of drugs to release punishment-suppressed drinking behavior is evaluated. In reviewing the neurobiology of anxious states, the present article focuses in particular upon: the multifarious and complex roles of individual modulators, often as a function of the specific receptor type and neuronal substrate involved in their actions; novel targets for the management of anxiety disorders; the influence of neurotransmitters and other agents upon performance in the VCT; data acquired from complementary pharmacological and genetic strategies and, finally, several open questions likely to orientate future experimental- and clinical-research. In view of the recent proliferation of mechanisms implicated in the pathogenesis, modulation and, potentially, treatment of anxiety disorders, this is an opportune moment to survey their functional and pathophysiological significance, and to assess their influence upon performance in the VCT and other models of potential anxiolytic properties.
In the present study, we examined the neuroprotective effect of gamma-glutamylethylamide (theanine) on the ischemic brain damage in a middle cerebral artery occlusion model in mice. Theanine was injected i.p. 3 h after the occlusion or immediately before and 3 h after the occlusion. Theanine (1 mg/kg) significantly decreased the size of the cerebral infarcts 1 day after the occlusion. In contrast, theanine did not affect the cerebral blood flow, brain temperature and physiological variables (pH, pCO(2), pO(2) and hematocrit) in this model. These results suggest that theanine directly provides neuroprotection against focal cerebral ischemia and may be clinically useful for preventing cerebral infarction.
Tea drinking has been suggested to be beneficial in neurodegenerative diseases where depressive mood is a common symptom. Nevertheless, it is not known whether there are any associations between tea drinking and depression in general populations. In this study we investigated these associations in a sample of the Finnish general population (n = 2011) using a postal questionnaire and the Beck Depression Inventory (BDI). Those who reported drinking tea daily were less depressed than the others. They had a lower mean BDI score and also a lower prevalence of depression. None of those whose daily tea intake was five cups or more had depression. Several potential confounding factors were included in the final sex- and age-adjusted multivariate logistic regression model which suggested that those who drink tea daily may have a significantly reduced risk of being depressed (adjusted odds ratio 0.47, 95% confidence interval 0.27-0.83). In conclusion, an inverse relationship between daily tea drinking and the risk of being depressed was found in a relatively large general population sample. Nevertheless, the underlying mechanisms are unresolved and further studies are needed.
We sought to identify a core subset of Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) items that maintains the validity and psychometric properties of the basic version. A parsimonious subset of items from the Q-LES-Q that can accurately predict the basic Q-LES-Q domain mean scores was sought and evaluated in 339 inpatients meeting DSM-IV criteria for schizophrenia, schizoaffective, and mood disorders. Three additional data sets were used for validation. Assessments included Q-LES-Q, Quality of Life Scale, Lancashire Quality of Life Profile, rating scales for psychopathology, medication side effects, and self-reported emotional distress, self-esteem, self-efficacy, and social support. We found that 18-items predicted basic Q-LES-Q domains (physical health, subjective feelings, leisure time activities, social relationships) and general index scores with high accuracy. Q-LES-Q-18 showed high reliability, validity, and stability of test-retest ratings. Thus, Q-LES-Q-18, a brief, self-administered questionnaire may aid in monitoring quality of life outcomes of schizophrenia, schizoaffective, and mood disorder patients.
Except for water, tea is the most widely consumed beverage worldwide, primarily because of its perceived relaxant effects.[1][1]–[3][2] Recently, interest has peaked in one component of green tea, theanine, which was isolated and identified in 1949 by a Japanese scientist.[1][1],[4][3] Its
Green tea has been widely acknowledged in Japan to induce a pleasurable mental feeling. Recent laboratory studies have suggested positive psychological effects as a result of consuming green tea. The present study examined whether green tea consumption in everyday life in Japan is associated with positive mental health.
A cross-sectional study was performed in February-March 2002.
The subjects of the study consisted of a general population of 600 Japanese aged 20-69 years. Responses of 380 subjects, obtained by home-visit interview, were analysed. The questionnaire inquired about consumption of brewed green tea and other beverages, perceived mental health status, lifestyle and others. The 12-item General Health Questionnaire (GHQ 12) was used for the assessment of mental ill-health (GHQ score >or=4).
After adjustments for age, area, perceived mental stress, lifestyle and daily caffeine intake, the consumption of brewed green tea was not statistically associated with any decrease in risk of mental ill-health among either males or females (odds ratio (OR)=0.78, 95% confidence interval (CI)=0.47-1.29 for males; OR=0.77, 95% CI=0.51-1.14 for females). Daily caffeine intake (100 mg) inclusive of green tea, black tea, coffee and other caffeine-containing beverages was associated with a higher risk of mental ill-health among females (OR=1.26, 95% CI=1.01-1.56).
The results provide population-based evidence on the consumption of brewed green tea in everyday life and mental health, together with information on consumption patterns of various beverages and lifestyles.