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Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

Introduction: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. Methods: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. Results: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. Conclusions: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.

In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

Background. Placebo response, drug response, and drug–placebo differences appear to vary among psychiatric conditions. Method. We evaluated the Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports to compare the magnitude of placebo response, magnitude of psychotopic drug response, and drug–placebo differences among various diagnostic groups such as depression, anxiety, and psychotic disorders. Results. Six diagnostic groups (psychosis, obsessive–compulsive disorder (OCD), generalized anxiety disorder (GAD), depression, post-traumatic stress disorder, panic) varied in response to both placebo and active drug treatments. Response to placebo was high among patients participating in GAD, depression, and panic disorder clinical trials. Conversely, patients participating in psychotic disorder and OCD trials experienced low response to placebo. Conclusion. Our findings indicate that the magnitude of placebo response and drug response were heterogeneous and were statistically significantly different among various psychiatric disorders. Although a noticeable degree of heterogeneity was detected in the drug–placebo ratio among various disorders, the differences did not reach statistical significance. This finding suggests that placebo use should be continued for newer agents being tested for all of the psychiatric disorders. These findings may help in the development of psychopharmacology trial designs and in the deliberations of ethics committees.

Insomnia is a common symptom in the clinical course of schizophrenia. There is a robust association between insomnia and suicidality in other psychiatric disorders. Two previous studies found associations between insomnia and suicide attempt or completed suicide in patients with schizophrenia. We hypothesized that greater insomnia would be associated with greater levels of suicidal ideation in patients with schizophrenia and other nonaffective psychoses. We recruited 108 inpatients and outpatients age 18-65 between July 2010 and July 2016 with DSM-IV nonaffective psychosis (schizophrenia, schizoaffective disorder, or schizophreniform disorder). We investigated relationships between current insomnia (Insomnia Severity Index [ISI]), suicidal ideation over the past week, and lifetime history of suicide attempt (Beck Scale for Suicide Ideation [BSS]) in regression analyses. After controlling for potential confounders, insomnia was a significant indicator of suicidal ideation (β = 0.27, p = 0.032). Insomnia was also a significant indicator of a high BSS score (≥16; OR = 1.14, 95% CI: 1.01-1.28, p = 0.029). Furthermore, participants with severe insomnia were almost 15 times more likely to have a lifetime history suicide attempt than participants without current insomnia (OR = 14.8, 95% CI: 1.4-157, p = 0.025). Insomnia was also an indicator of greater PANSS total (β = 0.33, p = 0.001), positive subscale (β = 0.32, p = 0.002), and general subscale (β = 0.40, p < 0.001) scores. Insomnia is associated with suicidal ideation, lifetime suicide attempt, and greater psychopathology in patients with schizophrenia. Our findings suggest that formal assessment of insomnia may be germane to the clinical care of patients with schizophrenia as a marker of suicide risk and symptom severity.

Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants. The inclusion of polygenic risk scores does not improve the performance of standard-of-care predictive models of disease outcomes in patients with psychosis.

Although there is great interest in the improving the ability to track patients’ change over time in routine clinical care settings, no standardized transdiagnostic measure is currently available for busy clinicians to apply. The Clinical Global Impression (CGI) scales are simple measures widely used as outcomes in psychiatric clinical trials. However, the CGI suffers from poorly defined scoring anchors. Efforts to improve the anchors by enhancing the anchor descriptions have proven useful but are limited by being disease-specific, thereby acting as a barrier to the routine clinical adoption of the CGI. To inform the development of more broadly applicable CGI scoring anchors, we surveyed 24 clinical trial investigators, asking them to rank-order seven elements that inform their CGI-Severity (CGI-S) scoring. Symptom severity emerged as the most important element in determining CGI-S scores; the functional status of the patient emerged as a second element. Less importance was given to self-report symptom scores, staff observations, or side effects. Relative rankings of the elements’ importance did not differ by investigators’ experience nor time usually spent with patients. We integrated these results with published illness-specific CGI anchors to develop the Transdiagnostic CGI (T-CGI), which employs standardized scoring anchors applicable across psychiatric illnesses. Pending validity and reliability evaluations, the T-CGI may prove well-suited for inclusion in routine clinical settings and for incorporation into electronic medical records as a simple and useful measure of treatment efficacy.

[...]modern neuropsychobiological models for FND are incorporating Bayesian inference to account for abnormal sensorimotor experiences in patients (Edwards, Adams, Brown, Parees, & Friston, 2012), formulations initially applied to conceptualize auditory hallucinations or alien-hand delusions. A greater investment in neuropsychiatric disorders will be advantageous for psychiatry to expand its clinical neuroscience skills. [...]by taking a greater interest in FND and seeing this condition as part of their professional mandate, psychiatry has the opportunity to extend its influence by bringing mind-body discussions to the center of the general hospital – advocating for a biopsychosocial conceptualization across a range of medical conditions. Stigma can be overcome, in part, if the psychiatrist, psychologist, and/or other mental health clinician is seen as an integral part of the FND team. [...]new clinical pathways are needed to enhance collaboration between psychiatrists, neurologists, and allied health professionals in the assessment and management of FND – including imbedding psychiatrists within neurology clinics and developing specialized care models where patients are jointly evaluated by neurologists and psychiatrists.

There is evidence suggesting that some patients with schizophrenia have increased circulating pro-inflammatory markers present in their serum. We hypothesize that serum soluble interleukin-2 receptor (sIL-2r) levels may serve as a biomarker for a subset of patients with schizophrenia. Serum sIL-2r levels were serially sampled from 59 medically stabilized subjects with schizophrenia and 57 control subjects. Serum sIL-2r levels were consistently elevated for subjects with schizophrenia when compared to controls. This finding was driven by a subgroup of patients (16/59) who had serum sIL-2r levels two standard deviations beyond the mean of the control sample. Elevated serum sIL-2r levels were associated with increased Positive and Negative Syndrome Scale total scores, negative symptom and general psychopathology subscale scores. These results suggest that a subset of patients with schizophrenia have an elevation in a marker of immune activation that is stable over time and is associated with increased levels of psychopathology.

Aberrant activation of the immune system has been implicated in an increasingly large number of disease states and can influence cognition, mood, and memory. There is a long and controversial history of reports of immune activation associated with schizophrenia. In this study, we measured mitogen-stimulated cytokine levels serially in 100 medication-stabilized continuously ill subjects with schizophrenia and compared and contrasted them with mitogen-stimulated cytokine levels from 51 normal volunteers. The subjects with schizophrenia had consistently higher mitogen-stimulated IL-2 levels and lower IL-6 levels than the normal volunteers. These effects could not be explained by medications, smoking, or other clinical variables. We conclude that continuously symptomatic medication-stabilized subjects with schizophrenia have a mitogen-stimulated cytokine expression pattern that is suggestive of ongoing immune activation.