Showing papers in "Progress in Neuro-psychopharmacology & Biological Psychiatry in 2016"

The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression.

Abstract: Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation, which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus-pituitary-adrenal (HPA) axis have close interactions with pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.

Animal models of major depression and their clinical implications.

Abstract: Major depressive disorder is a common, complex, and potentially life-threatening mental disorder that imposes a severe social and economic burden worldwide. Over the years, numerous animal models have been established to elucidate pathophysiology that underlies depression and to test novel antidepressant treatment strategies. Despite these substantial efforts, the animal models available currently are of limited utility for these purposes, probably because none of the models mimics this complex disorder fully. It is presumable that psychiatric illnesses, such as affective disorders, are related to the complexity of the human brain. Here, we summarize the animal models that are used most commonly for depression, and discuss their advantages and limitations. We discuss genetic models, including the recently developed optogenetic tools and the stress models, such as the social stress, chronic mild stress, learned helplessness, and early-life stress paradigms. Moreover, we summarize briefly the olfactory bulbectomy model, as well as models that are based on pharmacological manipulations and disruption of the circadian rhythm. Finally, we highlight common misinterpretations and often-neglected important issues in this field.

Multivariate classification of autism spectrum disorder using frequency-specific resting-state functional connectivity--A multi-center study.

Abstract: Background Resting-state functional magnetic resonance imaging studies examining low frequency fluctuations (0.01–0.08 Hz) have revealed atypical whole brain functional connectivity patterns in adolescents with autism spectrum disorder (ASD), and these atypical patterns can be used to discriminate individuals with ASD from controls. However, at present it is unknown whether functional connectivity at specific frequency bands can be used to discriminate individuals with ASD from controls, and whether relationships with symptom severity are stronger in specific frequency bands. Methods We selected 240 adolescent subjects (12–18 years old, 112 with autism spectrum disorder (101/11, males/females) and 128 healthy controls (104/24, males/females)) from 6 separate international sites in the Autism Brain Imaging Data Exchange database. Whole brain functional connectivity networks were constructed in the Slow-5 (0.01–0.027 Hz) and Slow-4 (0.027–0.073 Hz) frequency bands, which were then used as classification features. Results An accuracy of 79.17% (p Conclusions Our findings provide preliminary evidence for frequency-specific whole brain functional connectivity indices that may eventually be used to aid detection of ASD.

Classic hallucinogens in the treatment of addictions.

Abstract: Addictive disorders are very common and have devastating individual and social consequences. Currently available treatment is moderately effective at best. After many years of neglect, there is renewed interest in potential clinical uses for classic hallucinogens in the treatment of addictions and other behavioral health conditions. In this paper we provide a comprehensive review of both historical and recent clinical research on the use of classic hallucinogens in the treatment of addiction, selectively review other relevant research concerning hallucinogens, and suggest directions for future research. Clinical trial data are very limited except for the use of LSD in the treatment of alcoholism, where a meta-analysis of controlled trials has demonstrated a consistent and clinically significant beneficial effect of high-dose LSD. Recent pilot studies of psilocybin-assisted treatment of nicotine and alcohol dependence had strikingly positive outcomes, but controlled trials will be necessary to evaluate the efficacy of these treatments. Although plausible biological mechanisms have been proposed, currently the strongest evidence is for the role of mystical or other meaningful experiences as mediators of therapeutic effects. Classic hallucinogens have an excellent record of safety in the context of clinical research. Given our limited understanding of the clinically relevant effects of classic hallucinogens, there is a wealth of opportunities for research that could contribute important new knowledge and potentially lead to valuable new treatments for addiction.

Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson's disease.

Abstract: Inflammation is an important pathogenic factor in Parkinson's disease (PD), so that it can contribute to kill dopaminergic neurons of the substantia nigra and to enhance the dopaminergic denervation of the striatum. The cannabinoid type-2 (CB2) receptor has been investigated as a potential anti-inflammatory and neuroprotective target in different neurodegenerative disorders, but still limited evidence has been collected in PD. Here, we show for the first time that CB2 receptors are elevated in microglial cells recruited and activated at lesioned sites in the substantia nigra of PD patients compared to control subjects. Parkinsonian inflammation can be reproduced experimentally in rodents by intrastriatal injections of lipopolysaccharide (LPS) which, through an intense activation of glial elements and peripheral infiltration, provokes a rapid deterioration of the striatum that may extend to the substantia nigra too. Using this experimental model, we recently described a much more intense deterioration of tyrosine hydroxylase (TH)-containing nigral neurons in CB2 receptor-deficient mice compared to wild-type animals, supporting a potential neuroprotective role for this receptor. In the present study, we further explored this issue. First, we found elevated levels of the CB2 receptor measured by qRT-PCR in the striatum and substantia nigra of LPS-lesioned mice, as well as an increase in the immunostaining for this receptor in the LPS-lesioned striatum. Second, we found a significant increase in CD68 immunostaining, which serve to identify activated microglia and also infiltrated peripheral macrophages, in these brain structures in response to LPS insult, which was much more intense in CB2 receptor-deficient mice in the case of the substantia nigra. Next, we observed that the activation of CB2 receptors with a selective agonist (HU-308) reversed LPS-induced elevation of CD68 immunostaining in the striatum and the parallel reduction in TH immunostaining. Lastly, we found that LPS elevated the gene expression of different pro-inflammatory mediators in both the striatum and the substantia nigra, whereas the selective activation of CB2 receptors reduced a part of these mediators, e.g. inducible nitric oxide synthase, although exclusively in the striatum. In conclusion, we have provided the first evidence on the up-regulation of CB2 receptors in glial elements in postmortem tissues of PD patients, which has been confirmed in an inflammatory model of this disease. In addition, we have provided evidence on the benefits derived from their activation in relation with the activation of microglial cells, the infiltration of macrophages and also certain capability of these cells to generate proinflammatory factors.

The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder.

Abstract: Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising.

The use of cannabinoids as anticancer agents

Abstract: It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.

Opposing effects of alcohol on the immune system.

Abstract: Several studies have described a dose-dependent effect of alcohol on human health with light to moderate drinkers having a lower risk of all-cause mortality than abstainers, while heavy drinkers are at the highest risk. In the case of the immune system, moderate alcohol consumption is associated with reduced inflammation and improved responses to vaccination, while chronic heavy drinking is associated with a decreased frequency of lymphocytes and increased risk of both bacterial and viral infections. However, the mechanisms by which alcohol exerts a dose-dependent effect on the immune system remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. This review will summarize our current understanding of the impact of moderate versus excessive alcohol consumption on the innate and adaptive branches of the immune system derived from both in vitro as well as in vivo studies carried out in humans and animal model studies.

A meta-analysis of chemokines in major depression

Abstract: Chemokines are increasingly recognised as playing a role in depression. Here we meta-analyse the data on concentrations of all chemokines in patients diagnosed with a major depression versus healthy controls. We included studies which utilised Diagnostic and Statistical Manual (DSM)-IV diagnostic criteria for major depression, participants free from major medical conditions, studies with healthy controls, and unstimulated measurements of chemokines. We only included chemokines which had ≥ 3 studies performed. Two chemokines and 15 studies in total met criteria for this meta-analysis; 8 for Monocyte Chemotactic Protein (MCP)-1/CCL2 (n = 747), and 7 for Interleukin (IL)-8/CXCL8 (n = 560). There were significantly higher concentrations of CCL2/MCP-1 in depressed subjects compared with control subjects – overall mean difference of 36.43 pg/mL (95% CI: 2.43 to 70.42). There was significant heterogeneity across these studies (I2 = 98.5%). The estimates of mean difference between the control and depression groups did not remain significant when the trim-and-fill procedure was used to correct for publication bias. There was no significant difference in concentrations of IL-8/CXCL8 in depressed subjects compared with control subjects. Significant heterogeneity was found across these studies (I2 = 96.7%). The estimates of mean difference between the control and depression groups remained non-significant when the trim-and-fill procedure was used to correct for publication bias. This meta-analysis reports significantly heterogeneity in this field among studies. There are higher concentrations of the chemokine MCP-1/CCL2 in depressed subjects compared with control subjects, and no differences for IL-8/CXCL8. More high quality research and consistent methodologies are needed in this important area of enquiry.

Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones.

Abstract: The aim of this work was to compare achievements in milestones of community functioning in highly disabling psychiatric conditions, including treatment resistant schizophrenia (TRS), schizophrenia (responsive to antipsychotics), bipolar disorder, and anxiety/depressive diseases. Also, we investigated the predictors of community functioning outcomes across several domains. Among consecutive patients screened, 188 met inclusion criteria and 118 ultimately entered the study. Diagnosis of TRS was made by stringent criteria, including historic and perspective evaluations and excluding potential confounding factors. Achievements in functional milestones of everyday living were recorded. Performances in discrete cognitive tasks were assessed. The Positive and Negative Syndrome Scale, the Personal and Social Performance Scale, the Drug Attitude Inventory-10, and the Quality of Life Enjoyment and Satisfaction Questionnaire were administered. TRS patients showed the highest impairment in community functioning among diagnostic groups. TRS was found to have more severe psychopathology, more impaired cognitive functioning, and poorer psychosocial adjustment compared to all the other groups. In the whole sample, the main predictors of community functioning were the diagnostic group (with TRS diagnosis associated with worst functioning) and achievements in the other functional milestones. In psychotic patients, however, the main predictors of community functioning were clinical and psychopathological variables. These results may support the hypothesis that TRS represents a separate schizophrenia subtype, with its own neurobiology, psychopathology and clinical course. Our results identify a group of modifiable predictors to be addressed to prevent community disability.

Role of calcium, glutamate and NMDA in major depression and therapeutic application

Abstract: Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

Stress is a principal factor that promotes tobacco use in females.

Abstract: Tobacco use is a major economic and health problem. It is particularly concerning that women consume more tobacco products, have a more difficult time quitting smoking, and are less likely to benefit from smoking cessation therapy than men. As a result, women are at higher risk of developing tobacco-related diseases. Clinical evidence suggests that women are more susceptible to anxiety disorders, and are more likely to smoke in order to cope with stress than men. During smoking abstinence, women experience more intense anxiety than men and report that the anxiety-reducing effects of smoking are the main reason for their continued tobacco use and relapse. Consistent with this, pre-clinical studies using rodent models suggest that females display more intense stress during nicotine withdrawal than males. This review posits that in women, stress is a principal factor that promotes the initiation of tobacco use and relapse behavior during abstinence. Studies are reviewed at both the clinical and pre-clinical levels to provide support for our hypothesis that stress plays a central role in promoting tobacco use vulnerability in females. The clinical implications of this work are also considered with regard to treatment approaches and the need for more research to help reduce health disparities produced by tobacco use in women.

Resting state vagal tone in borderline personality disorder: A meta-analysis.

Abstract: Borderline personality disorder (BPD) is the most common personality disorder in clinical settings. It is characterized by negative affectivity, emotional liability, anxiety, depression, as well as disinhibition (i.e., impulsivity and risk taking), all of which have been linked to lower resting state vagal tone, which may be indexed by vagally-mediated heart rate variability (vmHRV). Here, we aimed to quantify the current evidence on alterations in resting state vmHRV in individuals with BPD, relative to healthy controls. A rigorous search of the literature, according to the “ Preferred Reporting Items for Systematic Reviews and Meta-Analyses ”, revealed 5 studies suitable for meta-analysis, reporting vmHRV in individuals with BPD (n = 95), relative to healthy controls (n = 105). Short-term measures of resting state vmHRV were extracted and subjected to meta-analysis using both random- and fixed effect models in RevMan . BPD displayed lower resting state vmHRV relative to healthy controls in random- (Hedges' g = − 0.59, 95% CI [− 1.11; − 0.06], k = 5) and fixed-effect meta-analysis (Hedges' g = − 0.56, 95% CI [− 0.86; − 0.27], k = 5). Control for potential publication bias did not change observed findings. Lowered resting state vagal tone may be an important trait characteristic underlying BPD. As prior studies have observed lowered vmHRV in a variety of psychiatric disorders, we propose that lowered vmHRV may reflect a common psychophysiological mechanism underlying difficulties in emotion regulation and impulsivity, in particular.

Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances.

Abstract: The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.

Maternal separation induces neuroinflammation and long-lasting emotional alterations in mice.

Abstract: Early life experiences play a key role in brain function and behaviour. Adverse events during childhood are therefore a risk factor for psychiatric disease during adulthood, such as mood disorders. Maternal separation is a validated mouse model for maternal neglect, producing negative early life experiences that result in subsequent emotional alteration. Mood disorders have been found to be associated with neurochemical changes and neurotransmitter deficits such as reduced availability of monoamines in discrete brain areas. Emotional alterations like depression result in reduced serotonin availability and enhanced kynurenine metabolism through the action of indoleamine 2, 3-dioxygenase in response to neuroinflammatory factors. This mechanism involves regulation of the neurotransmitter system by neuroinflammatory agents, linking mood regulation to neuroinmunological reactions. In this context, the aim of this study was to investigate the effects of maternal separation with early weaning on emotional behaviour in mice. We investigated neuroinflammatory responses and the state of the tryptophan-kynurenine metabolic pathway in discrete brain areas following maternal separation. We show that adverse events during early life increase risk of long-lasting emotional alterations during adolescence and adulthood. These emotional alterations are particularly severe in females. Behavioural impairments were associated with microglia activation and disturbed tryptophan-kynurenine metabolism in brain areas related to emotional control. This finding supports the preeminent role of neuroinflammation in emotional disorders.

Therapeutic potential of cannabis-related drugs.

Abstract: In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.

Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.

Abstract: Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice.

Neuropathological relationship between major depression and dementia: A hypothetical model and review.

Abstract: Major depression (MDD) is a chronic psychiatric condition in which patients often show increasing cognitive impairment with recurring episodes. Neurodegeneration may play an important component in the pathogenesis of MDD associated with cognitive complaints. In agreement with this, patients with MDD show decreased brain volumes in areas implicated in emotional regulation and cognition, neuronal and glial cell death as well as activation of various pathways that can contribute to cell death. Therefore, the aim of this review is to provide an integrative overview of potential contributing factors to neurodegeneration in MDD. Studies have reported increased neuronal and glial cell death in the frontal cortex, amygdala, and hippocampus of patients with MDD. This may be due to decreased neurogenesis from lower levels of brain-derived neurotrophic factor (BDNF), excitotoxicity from increased glutamate signaling, and lower levels of gamma-aminobutyric acid (GABA) signaling. In addition, mitochondrial dysfunction and oxidative stress are found in similar brain areas where evidence of excitotoxicity has been reported. Also, levels of antioxidant enzymes were reported to be increased in patients with MDD. Inflammation may also be a contributing factor, as levels of inflammatory cytokines were reported to be increased in the prefrontal cortex of patients with MDD. While preliminary, studies have also reported neuropathological alterations in patients with MDD. Together, these studies suggest that lower BDNF levels, mitochondrial dysfunction, oxidative stress, inflammation and excitotoxicity may be contributing to neuronal and glial cell death in MDD, leading to decreased brain volume and cognitive dysfunction with multiple recurrent episodes. This highlights the need to identify specific pathways involved in neurodegeneration in MDD, which may elucidate targets that can be treated to ameliorate the effects of disease progression in this disorder.

5-HT2C receptors in psychiatric disorders: A review.

Abstract: 5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.

Diminished caudate and superior temporal gyrus responses to effort-based decision making in patients with first-episode major depressive disorder

Abstract: Background: Anhedonia, the loss of interest or pleasure in reward processing, is a hallmark feature of major depressive disorder (MDD), but its underlying neurobiological mechanism is largely unknown. The present study aimed to examine the underlying neural mechanism of reward-related decision-making in patients with MDD.

Maternal gut and fetal brain connection: Increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure.

Abstract: Background A growing body of evidence indicates that gut microbiota characteristics may be closely related to mental dysfunctions. However, no studies have investigated fetal brain development in relation to the maternal gut microbiota, despite the extensive use of antibiotics in obstetric practice. Objective To determine how periconceptional exposure to SuccinylSulfaThiazole (SST), a non-absorbable antibiotic, can affect behavior in rat offspring. This antibiotic drug has previously been shown to substantially perturb the gut microbiota in rats following a 28-day exposure. Methods Female Wistar rats were divided in two groups: control, or exposed during one month before breeding until gestational day 15 to a diet containing 1% SST. We administered behavioral tests to offspring, i.e., open field (post-natal day 20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensory gating) (P45). Results Both male and female offspring exposed peri-conceptionally to SST showed reduced social interactions, with a decrease of about half in time spent in social interactions compared to controls, reduced exploration of the open arm by 20% in the elevated plus maze test indicating increased anxiety and altered sensorimotor gating, with a 1.5–2-fold decrease in startle inhibition. Conclusion Maternal periconceptional exposure to SST provokes alterations in offspring behavior in the absence of maternal infection. Because we administered SST, a non-absorbable antibiotic, only to the dam, we conclude that these neurobehavioral alterations in the offspring are related to maternal gut microbiota alterations.

Transcranial direct current stimulation in treatment-resistant obsessive-compulsive disorder: An open-label pilot study.

Abstract: Background Obsessive–compulsive disorder (OCD) is a severe mental illness. OCD symptoms are often resistant to available treatments. Abnormalities within the orbitofronto-striato-pallido-thalamic circuitry, especially orbitofrontal cortex (OFC) hyperactivity and cerebellar hypoactivity have been observed in patients. Non-invasive brain stimulation studies have indicated that transcranial direct current stimulation (tDCS) may be a useful alternative to alleviate treatment-resistant symptoms in various neuropsychiatric conditions. Methods In an open-label pilot study, 8 patients with treatment-resistant OCD received 10 sessions (twice a day) of 2 mA tDCS applied with the cathode over the left OFC and the anode over the right cerebellum. OCD (Y-BOCS and OCD-VAS) as well as depressive (MADRS) symptoms were measured 4 times: one time before tDCS and 3 times after (immediately after, 1 and 3 months after the 10th tDCS session). Results We reported a significant 26.4% (± 15.8) decrease of Y-BOCS score (p = 0.002). The beneficial effect lasted during the 3 month follow-up. No effect of tDCS was observed on depressive symptoms. At end point, 5 out of 8 patients had a decrease of ≥ 25%; and 3 out of 8 patients had a decrease of ≥ 35% in Y-BOCS score. tDCS was well tolerated. Conclusion tDCS with the cathode placed over the left OFC combined with the anode placed over the right cerebellum is a suitable and safe approach to decrease OCD symptoms in patients with treatment-resistant OCD. Large scale randomized controlled studies are needed to confirm this promising result.

MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults.

Abstract: The first study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults commenced in the spring of 2014. The search for psychotherapeutic options for autistic individuals is imperative considering the lack of effective conventional treatments for mental health diagnoses that are common in this population. Serious Adverse Events (SAEs) involving the administration of MDMA in clinical trials have been rare and non-life threatening. To date, MDMA has been administered to over 1133 individuals for research purposes without the occurrence of unexpected drug-related SAEs that require expedited reporting per FDA regulations. Now that safety parameters for limited use of MDMA in clinical settings have been established, a case can be made to further develop MDMA-assisted therapeutic interventions that could support autistic adults in increasing social adaptability among the typically developing population. As in the case with classic hallucinogens and other psychedelic drugs, MDMA catalyzes shifts toward openness and introspection that do not require ongoing administration to achieve lasting benefits. This infrequent dosing mitigates adverse event frequency and improves the risk/benefit ratio of MDMA, which may provide a significant advantage over medications that require daily dosing. Consequently, clinicians could employ new treatment models for social anxiety or similar types of distress administering MDMA on one to several occasions within the context of a supportive and integrative psychotherapy protocol.

Neural and psychological underpinnings of gambling disorder: A review.

Abstract: Gambling disorder affects 0.4 to 1.6% of adults worldwide, and is highly comorbid with other mental health disorders. This article provides a concise primer on the neural and psychological underpinnings of gambling disorder based on a selective review of the literature. Gambling disorder is associated with dysfunction across multiple cognitive domains which can be considered in terms of impulsivity and compulsivity. Neuroimaging data suggest structural and functional abnormalities of networks involved in reward processing and top-down control. Gambling disorder shows 50-60% heritability and it is likely that various neurochemical systems are implicated in the pathophysiology (including dopaminergic, glutamatergic, serotonergic, noradrenergic, and opioidergic). Elevated rates of certain personality traits (e.g. negative urgency, disinhibition), and personality disorders, are found. More research is required to evaluate whether cognitive dysfunction and personality aspects influence the longitudinal course and treatment outcome for gambling disorder. It is hoped that improved understanding of the biological and psychological components of gambling disorder, and their interactions, may lead to improved treatment approaches and raise the profile of this neglected condition.

Error-related brain activity in youth and young adults before and after treatment for generalized or social anxiety disorder

Abstract: Increased error monitoring, as measured by the error-related negativity (ERN), has been shown to persist after treatment for obsessive-compulsive disorder in youth and adults; however, no previous studies have examined the ERN following treatment for related anxiety disorders. We used a flanker task to elicit the ERN in 28 youth and young adults (8-26years old) with primary diagnoses of generalized anxiety disorder (GAD) or social anxiety disorder (SAD) and 35 healthy controls. Patients were assessed before and after treatment with cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRI), and healthy controls were assessed at a comparable interval. The ERN increased across assessments in the combined sample. Patients with SAD exhibited an enhanced ERN relative to healthy controls prior to and following treatment, even when analyses were limited to SAD patients who responded to treatment. Patients with GAD did not significantly differ from healthy controls at either assessment. Results provide preliminary evidence that enhanced error monitoring persists following treatment for SAD in youth and young adults, and support conceptualizations of increased error monitoring as a trait-like vulnerability that may contribute to risk for recurrence and impaired functioning later in life. Future work is needed to further evaluate the ERN in GAD across development, including whether an enhanced ERN develops in adulthood or is most apparent when worries focus on internal sources of threat.

The potential use of histone deacetylase inhibitors in the treatment of depression.

Abstract: Numerous preclinical studies demonstrate that changes in gene expression in the brain occur in animal models of depression using exposure to stress, such as social defeat and leaned helplessness, and that repeated administration of antidepressants ameliorates these stress-induced changes in gene expression. These findings suggest that alteration in gene transcription in the central nervous system in response to stress plays an important role in the pathophysiology of depression. Recent advances in epigenetics have led to the realization that chromatin remodeling mediated by histone deacetylase (HDAC) is closely involved in the regulation of gene transcription. In this context, we first review several preclinical studies demonstrating the antidepressant-like efficacy of HDAC inhibitors. We then suggest the efficacy of HDAC inhibitors in treatment-resistant depression based on the mechanism of action of HDAC. Finally, we discuss the possibility of using HDAC inhibitors in patients with treatment-resistant depression.

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Abstract: Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner's discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment.

The cognitive impairments and psychological wellbeing of methamphetamine dependent patients compared with health controls.

Abstract: Background and aims Chronic methamphetamine (MA) use is associated with cognitive impairment and psychopathological symptoms. This longitudinal study aims to examine the cognitive function of MA addicts during periods of abstinence. Methods Fifty-four MA dependent individuals and 58 healthy controls (HC) completed the psychological wellbeing scales and the CogState Battery that evaluated seven cognitive domains. During approximately 6-month abstinence, the subjects completed the CogState battery twice at the interval of 3 months. Results In the tasks of verbal memory, social emotional cognition, and spatial working memory, working memory, and problem solving the MA group performed worse than the HC group (P Conclusions Chronic MA addicts exhibited impairment of some CogState battery domains and poor psychological wellbeing, and that some of these subdomains were recoverable on abstinence. Therefore, improved cognitive function should be considered an important component in the treatment of MA dependence.

Mitochondrial DNA copy number is reduced in male combat veterans with PTSD.

Abstract: Introduction Mitochondrial abnormalities may be involved in PTSD, although few studies have examined this. Mitochondrial DNA copy number (mtDNAcn) in blood cells is an emerging systemic index of mitochondrial biogenesis and function. The present study assessed mtDNAcn in male combat-exposed veterans with PTSD compared to those without PTSD as well as its correlation with clinical scales. Methods mtDNAcn was assessed with a TaqMan multiplex assay in granulocytes of 43 male combat veterans with (n = 43) or without (n = 44) PTSD. Twenty of the PTSD subjects had co-morbid major depressive disorder (MDD). The Clinician Administered PTSD Scale (CAPS), the Positive and Negative Affect Schedule (PANAS), the Early Trauma Inventory (ETI) and the Beck Depression Inventory II (BDI-II) were used for the clinical assessments. All analyses were corrected for age and BMI. Results mtDNAcn was significantly lower in subjects with PTSD (p Discussion This study provides the first evidence of: (i) a significant decrease of mtDNAcn in combat PTSD, (ii) a possible “inverted-U” shaped relationship between PTSD symptom severity and mtDNAcn within PTSD subjects, and (iii) a direct correlation of mtDNAcn with positive affectivity within PTSD subjects. Altered mtDNAcn in PTSD may reflect impaired energy metabolism, which might represent a novel aspect of its pathophysiology.

Molecular aspects of monoamine oxidase B.

Abstract: Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the effect of alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.