Showing papers in "Frontiers in Psychiatry in 2019"

Systematic Review of Gut Microbiota and Major Depression.

Abstract: Background: Recently discovered relationships between the gastrointestinal microbiome and the brain have implications for psychiatric disorders, including major depressive disorder (MDD). Bacterial transplantation from MDD patients to rodents produces depression-like behaviors. In humans, case-control studies have examined the gut microbiome in healthy and affected individuals. We systematically reviewed existing studies comparing gut microbial composition in MDD and healthy volunteers. Methods: A PubMed literature search combined the terms “depression,” “depressive disorder,” “stool,” “fecal,” “gut,” and “microbiome” to identify human case-control studies that investigated relationships between MDD and microbiota quantified from stool. We evaluated the resulting studies, focusing on bacterial taxa that were different between MDD and healthy controls. Results: Six eligible studies were found in which 50 taxa exhibited differences (p<0.05) between patients with MDD and controls. Patient characteristics and methodologies varied widely between studies. Five phyla—Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria and Protobacteria—were represented; however, divergent results occurred across studies for all phyla. The largest number of differentiating taxa were within phylum Firmicutes, in which nine families and twelve genera differentiated the diagnostic groups. The majority of these families and genera were found to be statistically different between the two groups in two studies identified. Family Lachnospiraceae differentiated the diagnostic groups in four studies (with an even split in directionality). Across all five phyla, nine genera were higher in MDD (Anaerostipes, Blautia, Clostridium, Klebsiella, Lachnospiraceae incertae sedis, Parabacteroides, Parasuterella, Phascolarctobacterium, and Streptococcus), six were lower (Bifidobacterium, Dialister, Escherichia/Shigella, Faecalibacterium, and Ruminococcus), and six were divergent (Alistipes, Bacteroides, Megamonas, Oscillibacter, Prevotella, and Roseburia). We highlight mechanisms and products of bacterial metabolism as they may relate to the etiology of depression. Conclusions: No consensus has emerged from existing human studies of depression and gut microbiome concerning which bacterial taxa are most relevant to depression. This may in part be due to differences in study design. Given that bacterial functions are conserved across taxonomic groups, we propose that studying microbial functioning may be more productive than a purely taxonomic approach to understanding the gut microbiome in depression.

White Noise Speech Illusions : A Trait-Dependent Risk Marker for Psychotic Disorder?

Abstract: Introduction: White noise speech illusions index liability for psychotic disorder in case– control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. Methods: The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control-> sibling-> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. Results: While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls-> siblings-> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02–1.21, p = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79–1.09, p = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher (p interaction = 0.003; ORlow CAPE positive scale 0.96, 95% CI 0.85–1.07; ORhigh CAPE positive scale 1.26, 95% CI 1.09–1.46); cognitive ability was lower (p interaction < 0.001; ORhigh cognitive ability 0.94, 95% CI 0.84–1.05; ORlow cognitive ability 1.43, 95% CI 1.23–1.68); and exposure to childhood adversity was higher (p interaction < 0.001; ORlow adversity 0.92, 95% CI 0.82–1.04; ORhigh adversity 1.31, 95% CI 1.13–1.52). A similar, although less marked, pattern was seen for categorical patient– control and sibling–control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk (p interaction = 0.232). Conclusion: The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker.

Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation

Abstract: Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment.

Resilience in Cancer Patients.

Abstract: Background: Being diagnosed with cancer and undergoing its treatment are associated with substantial distress that can cause long-lasting negative psychological outcomes. Resilience is an individual's ability to maintain or restore relatively stable psychological and physical functioning when confronted with stressful life events and adversities. Posttraumatic growth (PTG) can be defined as positive life changes that result from major life crises or stressful events. Objectives: The aims of this study were to 1) investigate which factors can strengthen or weaken resilience and PTG in cancer patients and survivors; 2) explore the relationship between resilience and PTG, and mental health outcomes; and 3) discuss the impact and clinical implications of resilience and PTG on the process of recovery from cancer. Methods: A literature search was conducted, restricted to PubMed from inception until May 2018, utilizing the following key words: cancer, cancer patients, cancer survivors, resilience, posttraumatic growth, coping, social support, and distress. Results: Biological, personal, and most importantly social factors contribute to cancer patients' resilience and, consequently, to favorable psychological and treatment-related outcomes. PTG is an important phenomenon in the adjustment to cancer. From the literature included in this review, a model of resilience and PTG in cancer patients and survivors was developed. Conclusions: The cancer experience is associated with positive and negative life changes. Resilience and PTG are quantifiable and can be modified through psychological and pharmacological interventions. Promoting resilience and PTG should be a critical component of cancer care.

A Literature Overview of Virtual Reality (VR) in Treatment of Psychiatric Disorders: Recent Advances and Limitations.

Abstract: In this paper, we conduct a literature survey on various virtual reality (VR) treatments in psychiatry. We collected 36 studies that used VR to provide clinical trials or therapies for patients with psychiatric disorders. In order to gain a better understanding of the management of pain and stress, we first investigate VR applications for patients to alleviate pain and stress during immersive activities in a virtual environment. VR exposure therapies are particularly effective for anxiety, provoking realistic reactions to feared stimuli. On top of that, exposure therapies with simulated images are beneficial for patients with psychiatric disorders such as phobia and posttraumatic stress disorder (PTSD). Moreover, VR environments have shown the possibility of changing depression, cognition, even social functions. We review empirical evidence from VR-based treatments on psychiatric illnesses such as dementia, mild cognitive impairment (MCI), schizophrenia and autism. Through cognitive training and social skill training, rehabilitation through VR therapies helps patients to improve their quality of life. Recent advances in VR technology also demonstrate potential abilities to address cognitive and functional impairments in dementia. In terms of the different types of VR systems, we discuss the feasibility of the technology within different stages of dementia as well as the methodological limitations. Although there is room for improvement, its widespread adoption in psychiatry is yet to occur due to technical drawbacks such as motion sickness and dry eyes, as well as user issues such as preoccupation and addiction. However, it is worth mentioning that VR systems relatively easily deliver virtual environments with well-controlled sensory stimuli. In the future, VR systems may become an innovative clinical tool for patients with specific psychiatric symptoms.

The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment.

Abstract: Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials.

Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

Abstract: Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interactions. Gastrointestinal (GI) dysfunction is an ASD-associated comorbidity, implying a potential role of the gut microbiota in ASD GI pathophysiology. Several recent studies found that autistic individuals harbor an altered bacterial gut microbiota. In some cases, remodeling the gut microbiota by antibiotic administration and microbiota transfer therapy reportedly alleviated the symptoms of ASD. However, there is little consensus on specific bacterial species that are similarly altered across individual studies. The aim of this study is to summarize previously published data and analyze the alteration of the relative abundance of bacterial genera in the gut microbiota in controls and individuals with ASD using meta-analysis. We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls. In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus. This meta-analysis suggests an association between ASD and alteration of microbiota composition and warrants additional prospective cohort studies to evaluate the association of bacterial changes with ASD symptoms, which would provide further evidence for the precise microbiological treatment of ASD.

Body Dissatisfaction, Importance of Appearance, and Body Appreciation in Men and Women Over the Lifespan.

Abstract: Body image disturbance is associated with several mental disorders. Previous research on body image has focused mostly on women, largely neglecting body image in men. Moreover, only a small number of studies have conducted gender comparisons of body image over the lifespan and included participants aged 50 years and older. With regard to measurement, body image has often been assessed only in terms of body dissatisfaction, disregarding further aspects such as body appreciation or the importance of appearance. The aim of this cross-sectional study was to explore different aspects of body image in the general German-speaking population and to compare men and women of various ages. Participants completed an online survey comprising questionnaires about body image. Body dissatisfaction, importance of appearance, the number of hours per day participants would invest and the number of years they would sacrifice to achieve their ideal appearance, and body appreciation were assessed and analyzed with respect to gender and age differences. We hypothesized that body dissatisfaction and importance of appearance would be higher in women than in men, that body dissatisfaction would remain stable across age in women, and that importance of appearance would be lower in older women compared to younger women. Body appreciation was predicted to be higher in men than in women. General and generalized linear models were used to examine the impact of age and gender. In line with our hypotheses, body dissatisfaction was higher in women than in men and was unaffected by age in women, and importance of appearance was higher in women than in men. However, only in men did age predict a lower level of the importance of appearance. Compared to men, women stated that they would invest more hours of their lives to achieve their ideal appearance. For both genders, age was a predictor of the number of years participants would sacrifice to achieve their ideal appearance. Contrary to our assumption, body appreciation improved and was higher in women across all ages than in men. The results seem to suggest that men's and women's body image are dissimilar and appear to vary across different ages.

What Works and What Doesn't Work? A Systematic Review of Digital Mental Health Interventions for Depression and Anxiety in Young People.

Abstract: Background: A major challenge in providing mental health interventions for young people is making such interventions accessible and appealing to those most in need. Online and app-based forms of therapy for mental health are burgeoning. It is therefore crucial to identify features that are most effective and engaging for young users. Objectives: This study reports a systematic review and meta-analysis of digital mental health interventions and their effectiveness in addressing anxiety and depression in young people to determine factors that relate to outcomes, adherence, and engagement with such interventions. Methods: A mixed methods approach was taken, including a meta-analysis of 9 randomized controlled trials that compared use of a digital intervention for depression in young people to a no-intervention control group, and 6 comparing the intervention to an active control condition. A thematic analysis and narrative synthesis of 41 studies was also performed. Results: The pooled effect size of digital mental health interventions on depression in comparison to a no-intervention control was small (Cohen's d = 0.33, 95% CI 0.11 to 0.55), while the pooled effect size of studies comparing an intervention group to an active control showed no significant differences (Cohen's d = 0.14, 95% CI -.04 to 0.31). Pooled effect sizes were higher when supervision was involved (studies with no-intervention controls: Cohen's d = 0.52, 95% CI 0.23 to 0.80; studies with active control: Cohen's d = 0.49, 95% CI -0.11, 1.01). Engagement and adherence rates were low. Qualitative analysis revealed that users liked interventions with a game-like feel and relatable, interactive content. Educational materials were perceived as boring, and users were put off by non-appealing interfaces and technical glitches. Conclusions: Digital interventions work better than no intervention to improve depression in young people when results of different studies are pooled together. However, these interventions may only be of clinical significance when use is highly supervised. Digital interventions do not work better than active alternatives regardless of the level of support. Future interventions need to move beyond the use of digital educational materials, considering other ways to attract and engage young people and to ensure relevance and appeal.

Cytokine Research in Depression: Principles, Challenges, and Open Questions.

Abstract: Cytokines have been implicated in the pathology of depression. Currently, the evidence is based on cross-sectional studies and meta-analytic research comparing blood concentrations of T helper type 1 (TH1), T helper type 2 (TH2), pro-inflammatory or anti-inflammatory cytokines of patients with a depressive disorder to those of healthy controls. Additionally, multiple longitudinal studies have investigated cytokine levels during antidepressant treatment. According to the current literature, it seems that peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated and that interferon (IFN)-γ levels are lower in patients with depression compared to healthy controls. However, the overlap of cytokine values between acutely depressed patients, remitted and recovered patients and healthy controls is considerable. Thus, the discriminative power of cytokine concentrations between depressed and non-depressed people is likely weak. Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α. However, weight gain-inducing psychopharmacological substances, such as the antidepressant mirtazapine, have been reported to potentially increase the production of pro-inflammatory cytokines. Even though cytokines are often discussed as biomarkers for depression, they have also been shown to be altered in other psychiatric disorders. Moreover, many environmental, social, psychological, biological, and medical factors are also associated with cytokine changes. Thus, cytokine alterations seem extremely unspecific. The interpretation of the results of these studies remains a challenge because it is unknown which type of cells are most responsible for cytokine changes measured in the blood nor have the main target cells or target tissues been identified. The same cytokine can be produced by multiple cell types, and the same cell can produce various cytokines. Additionally, redundancy, synergy, antagonism, and signaling cascades of cytokine signaling must be considered. Cytokines might not be associated with the diagnosis of depression according to the currently used diagnostic manuals, but rather with specific subtypes of depression, or with depressive symptoms across different psychiatric diagnoses. Therefore, the currently available diagnostic systems may not be the ideal starting point for psychiatric cytokine research.

Internet Addiction, Smartphone Addiction, and Hikikomori Trait in Japanese Young Adult: Social Isolation and Social Network

Abstract: Background: As the number of internet users becomes higher, problems related to internet overuse are becoming more and more serious. Adolescents and youth may particularly be attracted to and preoccupied with various online activities. In this study, we investigated the relationship of internet addiction, smartphone addiction and the risk of hikikomori, severe social withdrawal, in Japanese young adult. Methods: The subjects were 478 college/university students in Japan. They were requested to complete the study questionnaire, which consisted of questions about demographics, internet use, the Internet Addiction Test (IAT), the Smartphone Addiction Scale (SAS)-Short Version (SV), and the 25-item Hikikomori Questionnaire (HQ-25), etc. We investigated the difference and correlation of the results between two groups based on the purpose of internet use or the total score of each self-rating scale, such as screened positive or negative for the risk of internet addiction, smartphone addiction or hikikomori. Results: There was a trend that males favored gaming in their internet use while females used the internet mainly for social networking via smartphone, and the mean SAS-SV score was higher in females. Two-group comparisons between gamers and social media users, according to the main purpose of internet use, showed that gamers used the internet longer and had significantly higher mean IAT and HQ-25 scores. Regarding hikikomori trait, the subjects at high risk for hikikomori on HQ-25, had longer internet usage time and higher scores on both IAT and SAS-SV. Correlation analyses revealed that HQ-25 and IAT scores had a relatively strong relation, although HQ-25 and SAS-SV had a moderately weak one. Discussion: Internet technology has changed our daily lives dramatically and altered the way we communicate as well. As social media applications are becoming more popular, users are connected more tightly to the internet and their time spent with others in the real world continues to decrease. Males often isolate themselves from the social community in order to engage in online gaming while females use the internet as to not be excluded from their communications online. Mental health providers should be aware of the seriousness of internet addictions and hikikomori.

Cytokine Alterations in Schizophrenia: An Updated Review.

Abstract: Schizophrenia, a multisystem disorder with an unknown etiology, is associated with several immune dysfunctions, including abnormal levels of circulating cytokines. In this review, we investigated the changes of cytokines in schizophrenic patients, their connection with behavioral symptoms severity and their potential clinical implications. We also assessed the possible causative role of abnormal cytokine levels in schizophrenia pathogenesis. Based on meta-analyses, we categorized cytokines according to their changes in schizophrenic patients into four groups: (1) increased cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-12, and transforming growth factor (TGF)-β, (2) non-altered cytokines, including IL-2, IL-4, and IL-17, (3) increased or non-altered cytokines, including IL-8 and interferon (IFN)-γ, and (4) IL-10 with increased, decreased, and non-altered levels. Notably, alterations in cytokines may be variable in four different categories of SP, including first-episode and drug-naive, first-episode and non-drug-naive, stable chronic, and chronic in acute relapse. Furthermore, disease duration, symptoms severity, incidence of aggression, and cognitive abilities are correlated with levels of certain cytokines. Clinical implications of investigating the levels of cytokine in schizophrenic patients include early diagnosis, novel therapeutic targets development, patient stratification for choosing the best therapeutic protocol, and predicting the prognosis and treatment response. The levels of IL-6, IL-8, IFN-γ, IL-2 are related to the treatment response. The available evidence shows a potential causative role for cytokines in schizophrenia development. There is a substantial need for studies investigating the levels of cytokines before disease development and delineating the therapeutic implications of the disrupted cytokine levels in schizophrenia.

Is the HPA Axis as Target for Depression Outdated, or Is There a New Hope?

Abstract: Major depressive disorder (MDD) is a very common stress-related mental disorder that carries a huge burden for affected patients and the society. It is associated with a high mortality that derives from suicidality and the development of serious medical conditions such as heart diseases, diabetes, and stroke. Although a range of effective antidepressants are available, more than 50% of the patients do not respond to the first treatment they are prescribed and around 30% fail to respond even after several treatment attempts. The heterogeneous condition of MDD, the lack of biomarkers matching patients with the right treatments and the situation that almost all available drugs are only targeting the serotonin, norepinephrine, or dopamine signaling, without regulating other potentially dysregulated systems may explain the insufficient treatment status. The hypothalamic-pituitary-adrenal (HPA) axis is one of these other systems, there is numerous and robust evidence that it is implicated in MDD and other stress-related conditions, but up to date there is no specific drug targeting HPA axis components that is approved and no test that is routinely used in the clinical setting identifying patients for such a specific treatment. Is there still hope after these many years for a breakthrough of agents targeting the HPA axis? This review will cover tests detecting altered HPA axis function and the specific treatment options such as glucocorticoid receptor (GR) antagonists, corticotropin-releasing hormone 1 (CRH1) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.

Effects of Seclusion and Restraint in Adult Psychiatry: A Systematic Review.

Abstract: Background: Determining the clinical effects of coercion is a difficult challenge, raising ethical, legal, and methodological questions. Despite limited scientific evidence on effectiveness, coercive measures are frequently used, especially in psychiatry. This systematic review aims to search for effects of seclusion and restraint on psychiatric inpatients with wider inclusion of outcomes and study designs than former reviews. Methods: A systematic search was conducted following PRISMA guidelines, primarily through Pubmed, Embase, and CENTRAL. Interventional and prospective observational studies on effects of seclusion and restraint on psychiatric inpatients were included. Main search keywords were restraint, seclusion, psychiatry, effect, harm, efficiency, efficacy, effectiveness, and quality of life. Results: Thirty-five articles were included, out of 6,854 records. Studies on the effects of seclusion and restraint in adult psychiatry comprise a wide range of outcomes and designs. The identified literature provides some evidence that seclusion and restraint have deleterious physical or psychological consequences. Estimation of post-traumatic stress disorder incidence after intervention varies from 25% to 47% and, thus, is not negligible, especially for patients with past traumatic experiences. Subjective perception has high interindividual variability, mostly associated with negative emotions. Effectiveness and adverse effects of seclusion and restraint seem to be similar. Compared to other coercive measures (notably forced medication), seclusion seems to be better accepted, while restraint seems to be less tolerated, possibly because of the perception of seclusion as "non-invasive." Therapeutic interaction appears to have a positive influence on coercion perception. Conclusion: Heterogeneity of the included studies limited drawing clear conclusions, but the main results identified show negative effects of seclusion and restraint. These interventions should be used with caution and as a last resort. Patients' preferences should be taken into account when deciding to apply these measures. The therapeutic relationship could be a focus for improvement of effects and subjective perception of coercion. In terms of methodology, studying coercive measures remains difficult but, in the context of current research on coercion reduction, is needed to provide workable baseline data and potential targets for interventions. Well-conducted prospective cohort studies could be more feasible than randomized controlled trials for interventional studies.

Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop

Abstract: Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association. Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for "sleep-wake circadian rhythms" OR "circadian sleep disorders" OR "sleep-wake pattern" OR "sleep disorders" OR "melatonin" AND "autism spectrum disorder" OR "autism". Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD. Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual's vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and "research gaps" are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.

State of the Field: Differentiating Intellectual Disability From Autism Spectrum Disorder.

Abstract: The topic of this special issue on secondary versus idiopathic autism allows for discussion of how different groups may come to manifest autism spectrum disorder (ASD) or ASD-like symptoms despite important etiological differences. A related issue is that, because many of the social communication deficits that define ASD represent a failure to acquire developmentally expected skills, these same deficits would be expected to occur to some extent in all individuals with intellectual disability (ID). Thus, regardless of etiology, ASD symptoms may appear across groups of individuals with vastly different profiles of underlying deficits and strengths. In this focused review, we consider the impact of ID on the diagnosis of ASD. We discuss behavioral distinctions between ID and ASD, in light of the diagnostic criterion mandating that ASD should not be diagnosed if symptoms are accounted for by ID or general developmental delay. We review the evolution of the autism diagnosis and ASD diagnostic tools to understand how this distinction has been conceptualized previously. We then consider ways that operationalized criteria may be beneficial for making the clinical distinction between ID with and without ASD. Finally, we consider the impact of the blurred diagnostic boundaries between ID and ASD on the study of secondary versus idiopathic ASD. Especially pertinent to this discussion are findings that a diagnosis of ID in the context of an ASD diagnosis may be one of the strongest indicators that an associated condition or specific etiological factor is present (i.e., secondary autism).

Physical Exercise in Major Depression: Reducing the Mortality Gap While Improving Clinical Outcomes

Abstract: Major depression shortens life while the effectiveness of frontline treatments remains modest. Exercise has been shown to be effective both in reducing mortality and in treating symptoms of major depression, but it is still underutilized in clinical practice, possibly due to prevalent misperceptions. For instance, a common misperception is that exercise is beneficial for depression mostly because of its positive effects on the body ("from the neck down"), whereas its effectiveness in treating core features of depression ("from the neck up") is underappreciated. Other long-held misperceptions are that patients suffering from depression will not engage in exercise even if physicians prescribe it, and that only vigorous exercise is effective. Lastly, a false assumption is that exercise may be more harmful than beneficial in old age, and therefore should only be recommended to younger patients. This narrative review summarizes relevant literature to address the aforementioned misperceptions and to provide practical recommendations for prescribing exercise to individuals with major depression.

Alcoholism Identification Based on an AlexNet Transfer Learning Model.

Abstract: (Aim) This paper proposed a novel alcoholism identification approach that can assist radiologists to make diagnosis. (Method) AlexNet was used as the basic transfer learning model. Global learning rate was small at 10-4, and the iteration epoch number as 10. The learning rate factor of replaced layers as 10 times larger than that of transferred layers. We tested five different replacement configurations of transfer learning. (Results) The experiment shows replacing the final fully connected layer achieved the best performance. Our method yielded a sensitivity of 97.44%± 1.15%, a specificity of 97.41%± 1.51%, a precision of 97.34%± 1.49%, an accuracy of 97.42%± 0.95%, and an F1 score of 97.37%± 0.97% on the test set. (Conclusion) This method can assist radiologists in their routine alcoholism screening of brain magnetic resonance images.

Dysconnectivity of Multiple Brain Networks in Schizophrenia: A Meta-Analysis of Resting-State Functional Connectivity

Abstract: Background: Seed-based studies on resting-state functional connectivity (rsFC) in schizophrenia have shown disrupted connectivity involving a number of brain networks; however, the results have been controversial. Methods: We conducted a meta-analysis based on independent component analysis (ICA) brain templates to evaluate dysconnectivity within resting-state brain networks in patients with schizophrenia. Seventy-six rsFC studies from 70 publications with 2,588 schizophrenia patients and 2,567 healthy controls (HCs) were included in the present meta-analysis. The locations and activation effects of significant intergroup comparisons were extracted and classified based on the ICA templates. Then, multilevel kernel density analysis was used to integrate the results and control bias. Results: Compared with HCs, significant hypoconnectivities were observed between the seed regions and the areas in the auditory network (left insula), core network (right superior temporal cortex), default mode network (right medial prefrontal cortex, and left precuneus and anterior cingulate cortices), self-referential network (right superior temporal cortex), and somatomotor network (right precentral gyrus) in schizophrenia patients. No hyperconnectivity between the seed regions and any other areas within the networks was detected in patients, compared with the connectivity in HCs. Conclusions: Decreased rsFC within the self-referential network and default mode network might play fundamental roles in the malfunction of information processing, while the core network might act as a dysfunctional hub of regulation. Our meta-analysis is consistent with diffuse hypoconnectivities as a dysregulated brain network model of schizophrenia.

Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma.

Abstract: Adverse childhood experiences (ACEs) may be referred to by other terms (e.g., early life adversity or stress and childhood trauma) and have a lifelong impact on mental and physical health. For example, childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. The heritability of ACE-related phenotypes such as PTSD, depression, and resilience is low to moderate, and, moreover, is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Currently, there is increasing interest in the investigation of epigenetic contributions to ACE-induced differential health outcomes. Although there are a number of studies in this field, there are still research gaps. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with ACE-induced differential health outcomes are provided. Limitations in this field, e.g., uncertain clinical diagnosis, conceptual inconsistencies, and technical drawbacks, are reviewed, with suggestions for advances using new technologies and novel research directions. We thereby provide a platform on which the field of ACE-induced phenotypes in mental health may build.

Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies.

Abstract: Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an N-methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.

Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults

Abstract: Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions.

Heart Rate Variability as Indicator of Clinical State in Depression.

Abstract: Background: Depression is a severe disease with great burdens for the affected individuals and public health care systems. Autonomic nervous system (ANS) dysfunction indexed by measures of heart rate variability (HRV) has repeatedly been associated with depression. However, HRV parameters are subject to a wide range of multi-factorial influences and underlying mechanisms in depression are still unclear. HRV parameters have been proposed to be promising candidates for diagnostic or predictive bio-markers for depression but necessary longitudinal design studies investigating the relationship between HRV and depression are scarce. Methods: The sample in this study consisted of 62 depressive individuals without antidepressant medication prior to assessment and 65 healthy controls. Fifteen minute blocks of resting ECGs were recorded 1-2 days before onset of antidepressant treatment and 2 weeks thereafter. The ECGs were pre-processed to extract inter-beat-intervals. Linear and non-linear methods were used to extract HRV parameters. ANOVAS were performed to investigate group differences between depressive patients and healthy controls. Associations between the change in severity of depression and HRV parameters were assessed in a repeated measurements design. Results: Analyses revealed HRV parameter differences between the groups of depressive patients and healthy controls at baseline. Further results show differences in HRV parameters within subjects after 2 weeks of antidepressant treatment. Change in HRV parameter values correlated with changes in symptom severity of depression. Discussion: The current results provide further insight into the relationship between HRV parameters and depression. This may help to underpin utilization of HRV parameters are bio-maker for disease state in depression. Results are discussed within a theoretical framework to link arousal and ANS regulation in depression.

Low Self-Esteem and Its Association With Anxiety, Depression, and Suicidal Ideation in Vietnamese Secondary School Students: A Cross-Sectional Study.

Abstract: Background: There is a correlation between self-esteem in adolescents and risks and protective factors for their health and welfare. The study was conducted to determine the prevalence of low self-esteem and sociodemographic features related to anxiety, depression, educational stress, and suicidal ideation in secondary school students in Vietnam. Methods: A cross-sectional design was employed for this study with participation of 1,149 students in Cantho City in Vietnam. A structured questionnaire was applied to ask about self-esteem, depression, anxiety, educational stress, and suicidal ideation. Results: Students with low self-esteem were detected at a prevalence of 19.4%. High educational stress and physical and emotional abuse by parents or other adults in the household were major risk factors correlated to low self-esteem, while a protective factor for low self-esteem was attending supplementary classes. An association among lower self-esteem and increased anxiety, depression, and suicidal ideation was detected. Conclusions: Self-esteem is associated with anxiety, depression, and academic stress, which significantly affect students' quality of life and links to suicidal ideation. These results therefore suggested the need for a school-based or web-based provision aimed at proactively increasing students' self-esteem and skills for dealing with academic stress.

The Endocannabinoid System and Cannabidiol's Promise for the Treatment of Substance Use Disorder.

Abstract: Substance use disorder is characterized by repeated use of a substance, leading to clinically significant distress, making it a serious public health concern. The endocannabinoid system plays an important role in common neurobiological processes underlying substance use disorder, in particular by mediating the rewarding and motivational effects of substances and substance-related cues. In turn, a number of cannabinoid drugs (e.g., rimonabant, nabiximols) have been suggested for potential pharmacological treatment for substance dependence. Recently, cannabidiol (CBD), a non-psychoactive phytocannabinoid found in the cannabis plant, has also been proposed as a potentially effective treatment for the management of substance use disorder. Animal and human studies suggest that these cannabinoids have the potential to reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, salience of drug cues, and inhibiting the reward-facilitating effect of drugs. Such functions likely arise through the targeting of the endocannabinoid and serotonergic systems, although the exact mechanism is yet to be elucidated. This article seeks to review the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs' therapeutic potential in addictions, with a focus on CBD. Subsequently, this article will evaluate the underlying evidence for CBD as a potential treatment for substance use disorder, across a range of substances including nicotine, alcohol, psychostimulants, opioids, and cannabis. While early research supports CBD's promise, further investigation and validation of CBD's efficacy, across preclinical and clinical trials will be necessary.

The Reliability and Validity of the Center for Epidemiologic Studies Depression Scale (CES-D) for Chinese University Students.

Abstract: Aims: Depression is prevalent among university students worldwide, and the prevalence appears to be increasing. As an intermediate stage between being healthy and having depression, students with subthreshold depression could develop worsening depression or recover with intervention to prevent depression. The Center for Epidemiologic Studies Depression Scale (CES-D) is a useful tool to assess subthreshold depression. The primary purpose of the current study was to evaluate the psychometric characteristics of CES-D in Chinese university students. Secondly, we aimed to describe the prevalence of subthreshold depression among the student sample and examine its demographic correlates. Methods: A total of 2,068 university students participated in the study, and they were asked to respond to the Chinese CES-D, Beck Depression Inventory-II (BDI-II), and Positive and Negative Affect Schedule (PANAS). The factor structure was evaluated by conducting exploratory (EFA) and confirmatory factor analysis (CFA) using a structural equation modeling approach. The reliability was assessed by calculating Cronbach's alpha, inter-item correlation, and item-total correlation coefficients. The prevalence of subthreshold depression was calculated and demographic correlates of gender, grade, and major were examined by multiple regression. Results: The final sample included 1,920 participants. The EFA results suggested extraction of three factors (somatic symptoms, negative affect, and anhedonia) that account for 52.68% of total variance. The CFA results suggested that the newly derived model with 14 items was the best fit for our data. Six items were removed from the original scale (item 9, 10, 13, 15, 17, and 19). The Cronbach's alpha of the 14-item CES-D was 0.87. The prevalence of subthreshold depression among university students reached 32.7% for the 20-item CES-D and 31% for the 14-item CES-D, although there was no significant difference of prevalence in gender, grade, and major. Conclusions: The CES-D has good reliability and validity for assessing subthreshold depression in Chinese university students.

Executive Function in Autism Spectrum Disorder: History, Theoretical Models, Empirical Findings, and Potential as an Endophenotype

Abstract: This review presents an outline of executive function (EF) and its application to autism spectrum disorder (ASD). The development of the EF construct, theoretical models of EF, and limitations in the study of EF are outlined. The potential of EF as a cognitive endophenotype for ASD is reviewed, and the Research Domain Criteria (RDoC) framework is discussed for researching EF in ASD given the multifaceted factors that influence EF performance. A number of executive-focused cognitive models have been proposed to explain the symptom clusters observed in ASD. Empirical studies suggest a broad impairment in EF, although there is significant inter-individual variability in EF performance. The observed heterogeneity of EF performance is considered a limiting factor in establishing EF as a cognitive endophenotype in ASD. We propose, however, that this variability in EF performance presents an opportunity for subtyping within the spectrum that can contribute to targeted diagnostic and intervention strategies. Enhanced understanding of the neurobiological basis that underpins EF performance, such as the excitation/inhibition hypothesis, will likely be important. Application of the RDoC framework could provide clarity on the nature of EF impairment in ASD with potential for greater understanding of, and improved interventions for, this disorder.

Characterizing the Interplay Between Autism Spectrum Disorder and Comorbid Medical Conditions: An Integrative Review.

Abstract: Co-occurring medical disorders and associated physiological abnormalities in individuals with autism spectrum disorder (ASD) may provide insight into causal pathways or underlying biological mechanisms. Here, we review medical conditions that have been repeatedly highlighted as sharing the strongest associations with ASD – epilepsy, sleep, as well as gastrointestinal and immune functioning. We describe within each condition their prevalence, associations with behaviour, and evidence for any successful treatments. We additionally discuss research aiming to uncover potential aetiological mechanisms. We then consider the potential interaction between each group of conditions and ASD and, based on the available evidence, propose a model that integrates these medical comorbidities in relation to potential shared aetiological mechanisms. Future research should aim to systematically examine the interactions between these physiological systems, rather than considering these in isolation, using robust and sensitive biomarkers across an individual’s development. A consideration of the overlap between medical conditions and ASD may aid in defining biological subtypes within ASD and in the development of specific targeted interventions.

Placebo Effect in the Treatment of Depression and Anxiety.

Abstract: The aim of this review is to evaluate the placebo effect in the treatment of anxiety and depression. Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin or norepinephrine in the brain. However, analyses of the published and the unpublished clinical trial data are consistent in showing that most (if not all) of the benefits of antidepressants in the treatment of depression and anxiety are due to the placebo response, and the difference in improvement between drug and placebo is not clinically meaningful and may be due to breaking blind by both patients and clinicians. Although this conclusion has been the subject of intense controversy, the current article indicates that the data from all of the published meta-analyses report the same results. This is also true of recent meta-analysis of all of the antidepressant data submitted to the Food and Drug Administration (FDA) in the process of seeking drug approval. Also, contrary to previously published results, the new FDA analysis reveals that the placebo response has not increased over time. Other treatments (e.g., psychotherapy and physical exercise) produce the same benefits as antidepressants and do so without the side effects and health risks of the active drugs. Psychotherapy and placebo treatments also show a lower relapse rate than that reported for antidepressant medication.

Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium.

Abstract: Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing-next to anti-inflammatory-dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such "non-inflammatory" patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in "non-inflamed" patients.