Curcumin as a therapeutic agent in dementia: a mini systematic review of human studies.

Dementia is a leading health problem worldwide, with Alzheimer's disease (AD) representing up to 60% of all dementia cases. A growing interest has recently risen on the potential use of natural molecules in this condition. Curcumin is a polyphenolic compound traditionally used in Indian medicine. Several in vitro and in vivo studies have found a protective effect of curcumin in AD. In the present systematic review we aimed to evaluate the state-of-the-art of clinical trials of curcumin in AD. We retrieved three published studies, while there are several ongoing clinical trials. To date there is insufficient evidence to suggest the use of curcumin in dementia patients. Of note, short-term use of curcumin appears to be safe. Several reasons could be responsible for the discrepancy between in vitro and in vivo findings and human trials, such as low bioavailability and poor study design.

Association between low-activity allele of cathecolamine-O-methyl-transferase (COMT) and Borderline Personality Disorder in an Italian population.

The objective of the present study was to test the association between Borderline Personality Disorder (BPD) and the cathecolamine-O-methyl-transferase (COMT) low-activity (Met158) single nucleotide polymorphism (SNP). In this case-control study, DNA was obtained from venous blood of 19 BPD patients and 36 healthy subjects. COMT-Val158Met single-nucleotide polymorphism was genotyped by predesigned SNP assay. The COMT Met158 allele was over-represented in patients with BPD in comparison to normal subjects (68.4% vs 44.4%, respectively; Fisher exact test, p = .02). In terms of genotype, the Met158Met subjects were more frequent in patients versus controls (47.4% vs 22.2%, respectively), whereas the high-activity genotype Val158Val was under-represented (10.5% vs 33.3%, respectively). The allele encoding for the COMT with low enzymatic efficiency was found to be over-represented in BPD, possibly resulting in excessive synaptic dopaminergic activity and ultimately affecting externalizing behaviours, such as impulsivity and aggressiveness.

Magnetic resonance spectroscopy in the evaluation of treatment efficacy in unipolar major depressive disorder: a review of the literature.

More and more neuroimaging studies are using in vivo proton magnetic resonance spectroscopy (1H-MRS) to explore correlates of response to therapy in major depressive disorder (MDD). Their aim is to further understanding of the effects of neurotransmitter changes in areas involved in MDD and the mechanisms underlying a good treatment response. We set out to summarise the literature from the past fifteen years on biochemical correlates of treatment response in MDD patients, reflected in pre- and post-therapy changes in 1H-MRS measurements. Our literature search identified fifteen articles reporting 1H-MRS studies in MDD treatment; no study used 1P-MRS. Despite the wide diversity of 1H-MRS methods applied, brain regions studied, and metabolite changes found, there emerged strong evidence of a correlation between changes in neurometabolite concentrations, in particular glutamate, N-acetylaspartate and choline, and a good treatment response to pharmacotherapy or antidepressant stimulation techniques.

Aggression in psychiatry wards: a systematic review.

Although fairly frequent in psychiatric in-patient, episodes of aggression/violence are mainly limited to verbal aggression, but the level of general health is significantly lower in nurses who report 'frequent' exposure to violent incidents, and there is disagreement between patients and staff concerning predictors of these episodes. We searched the Pubmed, Embase and PsychInfo databases for English, Italian, French or German language papers published between 1 January 1990 and 31 March 2010 using the key words "aggress*" (aggression or aggressive) "violen*" (violence or violent) and "in-patient" or "psychiatric wards", and the inclusion criterion of an adult population (excluding all studies of selected samples such as a specific psychiatric diagnosis other than psychosis, adolescents or the elderly, men/women only, personality disorders and mental retardation). The variables that were most frequently associated with aggression or violence in the 66 identified studies of unselected psychiatric populations were the existence of previous episodes, the presence of impulsiveness/hostility, a longer period of hospitalisation, non-voluntary admission, and aggressor and victim of the same gender; weaker evidence indicated alcohol/drug misuse, a diagnosis of psychosis, a younger age and the risk of suicide. Alcohol/drug misuse, hostility, paranoid thoughts and acute psychosis were the factors most frequently involved in 12 studies of psychotic patients. Harmony among staff (a good working climate) seems to be more useful in preventing aggression than some of the other strategies used in psychiatric wards, such as the presence of male nurses.

Seasonal fluctuations in problem behaviors among young adults with autism and intellectual disability.

BACKGROUND: Acute behavioral alterations have been frequently reported in patients with autism. However, the question as to whether behavioral problems undergo seasonal variations in autism remains to be addressed. MATERIAL/METHODS: In a prospective observational study over 29 months, problem behaviors amongst 23 young adults with autism and intellectual disability living in a farm community center were assessed. Behavioral problems were recorded daily using the Rossago Behavioral Checklist. Data were collected on clinical characteristics, drug usage, changes in staff composition, daily schedule, rehabilitative activities, and food administration. RESULTS: Problem behaviors showed significant seasonal fluctuations. The frequency of problem behaviors showed a maximum in mid-April and a minimum in mid-October (mean difference: 1.24 behaviors). CONCLUSIONS: Taken together, these data suggest the occurrence of significant seasonal fluctuations in problem behaviors amongst young adults with autism and intellectual disability. Further studies are needed to shed more light on the mechanisms underlying these fluctuations.

Elevated urine levels of bufotenine in patients with autistic spectrum disorders and schizophrenia.

OBJECTIVE: Previous studies have suggested that the endogeneous psychotomimetic molecule bufotenine (N-N-dimethyl-5-idroxytryptamine) may play a role in the pathogenesis of severe mental disorders. The potential association of bufotenine with the clinical features of autism and schizophrenia is not entirely understood. In this study, we measured urinary levels of bufotenine in subjects with autistic spectrum disorder (ASD), schizophrenia and healthy comparison subjects free of psychiatric symptoms. We also sought to assess whether urine concentrations of this molecule may be associated with the clinical characteristics of psychiatric patients. DESIGN: Urine bufotenine levels were measured using a high-performance liquid chromatography-mass spectrometry (HPLC-MS) assay in young adults with severe ASD (n=15), patients with schizophrenia (n=15), and healthy control subjects (n=18). The Vineland Adaptive Behavior Scale was used to measure adaptive behaviors in ASD individuals. The Brief Psychiatric Rating Scale (BPRS) was used for patients with schizophrenia. RESULTS: Urine bufotenine levels were significantly higher in ASD subjects (3.30 +/- 0.49 microg/L, p<0.05) and patients with schizophrenia (4.39 +/- 0.43 microg/L, p<0.001) compared with controls (1.53 +/- 0.30 microg/L). Among patients with ASD, there was a significant positive correlation between urine bufotenine and hyperactivity scores on the Vineland Adaptive Behavior Scale (r=0.479, p<0.05). No other associations were detected. CONCLUSIONS: Our results indicate that elevated urine levels of the endogeneous psychotomimetic molecule bufotenine may play a role in ASD and schizophrenia, and can be correlated with hyperactivity scores in autism.

Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies.

BACKGROUND: Most of our social interactions involve perception of emotional information from the faces of other people. Furthermore, such emotional processes are thought to be aberrant in a range of clinical disorders, including psychosis and depression. However, the exact neurofunctional maps underlying emotional facial processing are not well defined. METHODS: Two independent researchers conducted separate comprehensive PubMed (1990 to May 2008) searches to find all functional magnetic resonance imaging (fMRI) studies using a variant of the emotional faces paradigm in healthy participants. The search terms were: "fMRI AND happy faces," "fMRI AND sad faces," "fMRI AND fearful faces," "fMRI AND angry faces," "fMRI AND disgusted faces" and "fMRI AND neutral faces." We extracted spatial coordinates and inserted them in an electronic database. We performed activation likelihood estimation analysis for voxel-based meta-analyses. RESULTS: Of the originally identified studies, 105 met our inclusion criteria. The overall database consisted of 1785 brain coordinates that yielded an overall sample of 1600 healthy participants. Quantitative voxel-based meta-analysis of brain activation provided neurofunctional maps for 1) main effect of human faces; 2) main effect of emotional valence; and 3) modulatory effect of age, sex, explicit versus implicit processing and magnetic field strength. Processing of emotional faces was associated with increased activation in a number of visual, limbic, temporoparietal and prefrontal areas; the putamen; and the cerebellum. Happy, fearful and sad faces specifically activated the amygdala, whereas angry or disgusted faces had no effect on this brain region. Furthermore, amygdala sensitivity was greater for fearful than for happy or sad faces. Insular activation was selectively reported during processing of disgusted and angry faces. However, insular sensitivity was greater for disgusted than for angry faces. Conversely, neural response in the visual cortex and cerebellum was observable across all emotional conditions. LIMITATIONS: Although the activation likelihood estimation approach is currently one of the most powerful and reliable meta-analytical methods in neuroimaging research, it is insensitive to effect sizes. CONCLUSION: Our study has detailed neurofunctional maps to use as normative references in future fMRI studies of emotional facial processing in psychiatric populations. We found selective differences between neural networks underlying the basic emotions in limbic and insular brain regions.

Decreased NT-3 plasma levels and platelet serotonin content in patients with hypochondriasis.

OBJECTIVE: Neurotrophins (NT) are a family of closely related proteins, including brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). NTs are deemed to regulate several aspects of neuronal survival, development, and function. Although NTs have been associated to a variety of mental disorders, the potential role of NT alterations in hypochondriasis (HC) has never been investigated. METHODS: In the present study, plasma concentrations of NTs were evaluated in 23 adult patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for HC and 22 healthy controls. Platelet serotonin (5-HT) content was chosen as a measure of serotonergic function. Hypochondriacal symptoms were assessed using the Whiteley Index of Hypochondriasis (WIH). RESULTS: Plasma NT-3 level (P=.004) and platelet 5-HT (P=.008) were significantly lower in patients with HC compared with controls. Correlation analyses showed that the WIH score was significantly and inversely associated with both NT-3 values (r=-.60, P=.002) and platelet serotonin content (r=-.53, P=.009). We used a multivariate regression model to determine independent predictors of the WIH score. After allowance for potential confounders, plasma NT-3 levels remained the unique independent predictor of the WIH (beta=.003, t=-3.5, P=.003). CONCLUSIONS: Decreased NT-3 concentration, alongside with serotonin dysfunction, may represent a biological correlate of HC.

Complications in major depressive disorder therapy: a review of magnetic resonance spectroscopy studies.

Advanced magnetic resonance imaging techniques, such as proton magnetic resonance spectroscopy (H-MRS), have helped to further understanding of the pathophysiology of major depressive disorder (MDD) and to shed light on mechanisms underlying the therapeutic response. Potential complications of MDD therapy constitute an important area of research. Interruption of the absorption of serotonin reuptake inhibitors (SSRIs) is associated with discontinuation syndrome, while electroconvulsive therapy (ECT) can lead to transient and persistent anterograde amnesia. This paper reviews studies, since 1994, that have used H-MRS to evaluate adverse effects and complications of MDD treatment, either with ECT or SSRIs. Three articles have been published on adverse effects and complications of MDD treatment and H-MRS. Two focused on the ECT-induced memory deterioration and showed no sign of hippocampal atrophy in MDD patients with a residual memory deterioration after ECT, but a significant mean increase of the signal from Cho-containing compounds bilaterally, possibly due to an alteration of membrane turnover in the hippocampal region. The third paper showed that placebo-day Cho/Cr metabolite ratios were decreased in subjects with discontinuation syndrome, a finding that possibly reflects the dynamics of rostral anterior cingulate function. In spite of the limits deriving from the small number of papers published, our review demonstrated that H-MRS could be a useful instrument not only in evaluating therapy efficacy, but also for offering new insights into mechanisms underlying MDD treatments.

Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis.

An understanding of the neurobiological correlates of vulnerability to psychosis is fundamental to research on schizophrenia. We systematically reviewed data from studies published from 1992 to 2006 on the neurocognitive correlates (as measured by fMRI) of increased vulnerability to psychosis. We also conducted a meta-analysis of abnormalities of activation in the prefrontal cortex (PFC) in high-risk and first episode subjects, and reviewed neuroimaging studies of high-risk subjects that used PET, SPECT and MRS. Twenty-four original fMRI papers were identified, most of which involved tasks that engaged the PFC. In fMRI studies, vulnerability to psychosis was associated with medium to large effect sizes when prefrontal activation was contrasted with that in controls. Relatives of patients affected with psychosis, the co-twins of patients and subjects with an At Risk Mental State (ARMS) appear to share similar neurocognitive abnormalities. Furthermore, these are qualitatively similar but less severe than those observed in the first episode of illness. These abnormalities have mainly been described in the prefrontal and anterior cingulated cortex, the basal ganglia, hippocampus and cerebellum.

Reduced plasma apelin levels in patients with autistic spectrum disorder.

BACKGROUND: Dysregulation of the vasopressin (AVP) system has been implicated in the pathogenesis of autistic spectrum disorder (ASD). Apelin is a recently discovered neuropeptide that could counteract AVP actions and whose receptors are colocalized with vasopressin in hypothalamic magnocellular neurons. Aims of the present study were to investigate circulating levels of apelin in patients with ASD and to assess their correlation with plasma AVP concentrations. METHODS: Plasma levels of apelin and AVP were measured in a total of 18 patients with ASD and 21 age- and gender-matched healthy comparison subjects. The Childhood Autism Rating Scale (CARS) was used to assess the severity of autistic symptoms. RESULTS: Significantly reduced levels of apelin (p < 0.001) and elevated concentrations of AVP (p = 0.02) were found in ASD patients as compared to controls. Additionally, a significant inverse correlation between apelin and AVP levels was found within the ASD group (r = -0.61; p = 0.007), but not in healthy participants (r = -0.26; p = 0.25). Multivariate linear regression analysis showed that only AVP concentrations independently predicted apelin values in ASD individuals (beta = -0.42, t = 2.63, p = 0.014). No correlation was seen between apelin levels and CARS scores (r = -0.10; p = 0.68). CONCLUSIONS: Our findings of a significantly reduced peripheral level of apelin coupled with elevated AVP point to a subtle but definite vasopressinergic dysfunction in autism that could play a role in the etiopathophysiology of this disorder in humans.

Long-term outcome of a cohort of adults with autism and intellectual disability: A pilot prospective study.

BACKGROUND: Autism spectrum disorders (ASD) are a long-life condition frequently associated with intellectual disability. To date, long-term outcome has been investigated mostly in ASD people with average or above-average intelligence and there is a paucity of data about autistic adults with comorbid intellectual disability. AIMS: The aim of the present study is to assess long-term variations of adaptive abilities in a sample of autistic adults with intellectual disability and severe language impairment. METHODS AND PROCEDURES: 22 adults (17 males and 5 females) affected by autism and intellectual disability were recruited and evaluated after their admission in an Italian farm-community. Vineland Adaptive Behavior Scales (VABS) were used as outcome measure for adaptive abilities. After ten years the measurement was repeated in order to study the evolution of patients' skills along time. Additionally, sociodemographic variables, changes in medication and comorbidities were recorded. OUTCOMES AND RESULTS: No statistically significant improvement neither deterioration was found according to VABS raw scores in the entire sample. On the contrary, a significant improvement was evident in standard scores for the Adaptive Behavior Composite Scale and for each domain. CONCLUSIONS AND IMPLICATIONS: In general, our patients remained stable in adaptive abilities. However, our results are not generalisable to the entire autistic population, but only to inpatients with autism and comorbid intellectual disability. New measures should be developed in order to better assess changes in this particular population.

Antidepressants: their effects on cardiac channels, QT prolongation and Torsade de Pointes.

The cardiovascular side effects of older antidepressants, such as tricyclic antidepressants, are well established and are known to be linked to their capacity to inhibit cardiac and vascular ion channels. Newer compounds, such as selective serotonin reuptake inhibitors, mirtazapine and venlafaxine, have been reported to have a more benign cardiovascular profile, although they also share antagonistic properties with regard to voltage-dependent ion channels in different tissues. The electrophysiological effects that antidepressants exert on ion channels may affect the cardiac action potential (AP), lengthening both depolarization and repolarization phases, widening the QRS complex, prolonging the QT interval or causing Brugada-like electrocardiogram patterns. Lengthening of the depolarization phase can slow conduction through the His-Purkinje system and myocardium, while slowing repolarization can lead to early after depolarizations and Torsade de Pointes (TdP). In this review, we discuss data from experimental animal models regarding the effects of antidepressants on the cardiac AP, as well as antidepressant-induced QT prolongation in humans and sudden death in patients treated with antidepressants. It appears that although various experimental studies may lead to an understanding of the mechanisms involved in the modulation of cardiac electrical activity, there are significant discrepancies between in vitro data describing the action of antidepressants on the AP, data from clinical trials on QT prolongation by antidepressants and risk of TdP. The role of genetic polymorphisms of potassium-channel-encoding genes in determining the individual risk of cardiac arrhythmias and the limits of QT use as a marker of risk are discussed. Extensive pharmacokinetic and pharmacodynamic studies are required to determine the doses and plasma ranges of each drug that are associated with the greatest risk of arrhythmic complications.

Alterations of circulating endogenous secretory RAGE and S100A9 levels indicating dysfunction of the AGE-RAGE axis in autism.

An excess accumulation of advanced glycation end products (AGEs) has been reported in autism brains. Through their interaction with their putative receptor RAGE, AGEs can promote neuroinflammation, oxidative stress and neuronal degeneration. To shed more light on the possible alterations of the AGEs-RAGE axis in autism, hereto we measured plasma levels of endogenous secretory RAGE (esRAGE) and its proinflammatory ligand S100A9 in 18 young adults with autistic spectrum disorder (ASD) and 18 age- and gender-matched healthy comparison subjects. The Childhood Autism Rating Scale (CARS) was used to assess the severity of autistic symptoms. Significantly reduced levels of esRAGE (P = 0.0023) and elevated concentrations of S100A9 (P = 0.0012) were found in ASD patients as compared to controls. In autistic patients, there was a statistically significant positive correlation between CARS scores and S100A9 levels (r = 0.49, P = 0.035), but no significant correlation was seen between esRAGE and S100A9 values (r = -0.23, P = 0.34). Our results of a significantly reduced peripheral level of esRAGE coupled with elevated S100A9 point to a subtle but definite dysfunction of the AGEs/RAGE axis in autism that could play a role in the pathophysiology of this disorder.

Elevated plasma levels of lipoprotein(a) in psychiatric patients: a possible contribution to increased vascular risk.

An increased incidence of adverse cardiovascular events has been reported in psychiatric patients, but the exact mechanisms underlying this association are still uncertain. Elevated plasma level of lipoprotein(a) [Lp(a)] is an independent risk factor for atherothrombotic disease in the general population. To study the implications of Lp(a) in psychiatric patients, we measured the plasma levels of Lp(a) in 74 patients with psychiatric disorders (39 schizophrenia, 10 major depression, 13 bipolar disorder and 12 personality disorder) and 74 healthy controls. The Lp(a) levels of the patient groups with schizophrenia, major depression and bipolar disorder were significantly higher than that of the control group. The median Lp(a) value of these diagnostic groups was comparable with those reported in patients with prior atherothrombotic events. On the other hand, no differences were found among personality disorder and controls. Our findings suggest that the elevation of plasma Lp(a) may contribute to increased cardiovascular risk in several patients with psychiatric disorders.

Neurophysiology and neurobiology of the musical experience.

Music, a universal art form that exists in every culture around the world, is integral to a number of social and courtship activities, and is closely associated with other creative behaviours such as dancing. Recently, neuroimaging studies have allowed researchers to investigate the neural correlates of music processing and perception in the brain. Notably, musical stimuli have been shown to activate specific pathways in several brain areas associated with emotional behaviours, such as the insular and cingulate cortex, hypothalamus, hippocampus, amygdala, and prefrontal cortex. In addition, neurochemical studies have suggested that several biochemical mediators, such as endorphins, endocannabinoids, dopamine and nitric oxide, may play a role in the musical experience. A growing body of evidence also indicates that music therapy could be useful in the clinical management of numerous neurological and psychiatric disorders. Indeed, music therapy could be effective in patients with neurodegenerative disorders, such as Alzheimer's dementia and Parkinson?s disease, as well as in psychiatric illnesses, such as schizophrenia, depression, anxiety and autism spectrum disorders. Unfortunately, there is still a shortage of rigorous scientific data supporting the clinical application of music therapy, and there is thus a need to confirm and expand the preliminary findings regarding the potential and actual effectiveness of music therapy. This need should be addressed through prospective, randomized, controlled, single-blinded investigations of the short- and long-term effects of music therapy in diverse clinical conditions.

Pharmacological Modulation of GABA Function in Autism Spectrum Disorders: A Systematic Review of Human Studies.

Autism spectrum disorders are an emerging health problem worldwide, but little is known about their pathogenesis. It has been hypothesized that autism may result from an imbalance between excitatory glutamatergic and inhibitory GABAergic pathways. Commonly used medications such as valproate, acamprosate, and arbaclofen may act on the GABAergic system and be a potential treatment for people with ASD. The present systematic review aimed at evaluating the state-of-the-art of clinical trials of GABA modulators in autism. To date there is insufficient evidence to suggest the use of these drugs in autistic subjects, even if data are promising. Of note, short-term use of all the reviewed medications appears to be safe. Future well designed trials are needed to elucidate these preliminary findings.

Repetitive TMS on Left Cerebellum Affects Impulsivity in Borderline Personality Disorder: A Pilot Study.

The borderline personality disorder (BPD) is characterized by a severe pattern of instability in emotional regulation, interpersonal relationships, identity and impulse control. These functions are related to the prefrontal cortex (PFC), and since PFC shows a rich anatomical connectivity with the cerebellum, the functionality of the cerebellar-PFC axis may impact on BPD. In this study, we investigated the potential involvement of cerebello-thalamo-cortical connections in impulsive reactions through a pre/post stimulation design. BPD patients (n = 8) and healthy controls (HC; n = 9) performed an Affective Go/No-Go task (AGN) assessing information processing biases for positive and negative stimuli before and after repetitive transcranial magnetic stimulation (rTMS; 1 Hz/10 min, 80% resting motor threshold (RMT) over the left lateral cerebellum. The AGN task consisted of four blocks requiring associative capacities of increasing complexity. BPD patients performed significantly worse than the HC, especially when cognitive demands were high (third and fourth block), but their performance approached that of HC after rTMS (rTMS was almost ineffective in HC). The more evident effect of rTMS in complex associative tasks might have occurred since the cerebellum is deeply involved in integration and coordination of different stimuli. We hypothesize that in BPD patients, cerebello-thalamo-cortical communication is altered, resulting in emotional dysregulation and disturbed impulse control. The rTMS over the left cerebellum might have interfered with existing functional connections exerting a facilitating effect on PFC control.

The role of gender, psycho-social factors and anthropological-cultural dimensions on pain in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Pain is frequent in patients undergoing neurorehabilitation, but there is a number of still unanswered questions on this topic. The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was constituted with the purpose to identify the best practices that can be used in this context. In this article we summarize the existing evidence and recommendations provided by the ICCPN about the role of gender, psycho-social factors and anthropological-cultural dimensions on pain in neurorehabilitation. Sex, gender, psycho-social variables, anthropological and cultural features may influence pain expression, and its pharmacological and non-pharmacological outcome, but the role of these factors has not been consistently explored in neurorehabilitation. There is a number of psychological factors that can be correlated with or represent a predictor for pain, or may influence the treatment and outcome of neurorehabilitation programs. All these factors should be considered when designing these programs, and future studies should incorporate them as potential covariates that may influence outcome.