The boon and bane of nitrous oxide.

Nitrous oxide (N2O) has been known since the end of the eighteenth century. Today, N2O plays a huge role as a greenhouse gas and an ozone-depleting stratospheric molecule. The main sources of anthropogenic N2O emissions are agriculture, fuel combustion, wastewater treatment, and various industrial processes. By contrast, the contribution of medical N2O to the greenhouse effect appears to be small. The recreational and medical uses of N2O gradually diverged over time. N2O has analgesic and anesthetic effects, making it widely used in modern dentistry and surgery. New research has also begun studying N2O's antidepressant actions. N-methyl-D-aspartate (NMDA) antagonism and opioid effects are believed to be the main underlying biochemical mechanisms. At this point, numerous questions remain open and, in particular, the conduct of larger clinical trials will be essential to confirm N2O's use as a rapid-acting antidepressant. The N2O concentration delivered, the duration of a single inhalation, as well as the number of inhalations ultimately required, deserve to be better understood. Finally, the non-medical use of N2O has gained significant attention in recent years. Sudden deaths directly attributed to N2O are primarily due to asphyxia. Heavy, chronic N2O use may result in vitamin B12 deficiency, which, among other things, may cause megaloblastic anemia, venous thrombosis, myeloneuropathy, and skin pigmentation. Helpful biochemical tests include homocysteine and methylmalonic acid. The centerpiece of treatment is complete cessation of N2O use together with parenteral administration of vitamin B12.

EEG-vigilance regulation is associated with and predicts ketamine response in major depressive disorder.

Ketamine offers promising new therapeutic options for difficult-to-treat depression. The efficacy of treatment response, including ketamine, has been intricately linked to EEG measures of vigilance. This research investigated the interplay between intravenous ketamine and alterations in brain arousal, quantified through EEG vigilance assessments in two distinct cohorts of depressed patients (original dataset: n = 24; testing dataset: n = 24). Clinical response was defined as a decrease from baseline of >33% on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after infusion. EEG recordings were obtained pre-, start-, end- and 24 h post- infusion, and the resting EEG was automatically scored using the Vigilance Algorithm Leipzig (VIGALL). Relative to placebo (sodium chloride 0.9%), ketamine increased the amount of low-vigilance stage B1 at end-infusion. This increase in B1 was positively related to serum concentrations of ketamine, but not to norketamine, and was independent of clinical response. In contrast, treatment responders showed a distinct EEG pattern characterized by a decrease in high-vigilance stage A1 and an increase in low-vigilance B2/3, regardless of whether placebo or ketamine had been given. Furthermore, pretreatment EEG differed between responders and non-responders with responders showing a higher percentage of stage A1 (53% vs. 21%). The logistic regression fitted on the percent of A1 stages was able to predict treatment outcomes in the testing dataset with an area under the ROC curve of 0.7. Ketamine affects EEG vigilance in a distinct pattern observed only in responders. Consequently, the percentage of pretreatment stage A1 shows significant potential as a predictive biomarker of treatment response.Clinical Trials Registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000952-17/CZ Registration number: EudraCT Number: 2013-000952-17.

Uncovering Emotions: A Pilot Study on Classifying Moods in the Valence-Arousal Space using In-the-Wild Passive Data.

Mood classification from passive data promises to provide an unobtrusive way to track a person's emotions over time. In this exploratory study, we collected phone sensor data and physiological signals from 8 individuals, including 5 healthy participants and 3 depressed patients, for a maximum of 35 days. Participants were asked to answer a digital questionnaire three times daily, resulting in a total of 334 self-reported mood state samples. Gradient-boosting classification was applied to the collected passive data to categorize 4 mood states in the Valence-Energetic Arousal space. The cross-validation results showed better classification performance compared to a baseline model, which always predicts the majority class. The classifier using passive data had an area under the precision-recall curve of 0.39 (SD = 0.1) while the baseline had 0.26 (SD = 0.03), suggesting the presence of information in the collected features that support the classification process. The model identified the entropy of the heart rate and the average physical activity in the preceding 8 hours, along with the max normal-to-normal (NN) sinus beat interval and the NN low frequency-high frequency ratio during the questionnaire completion, as the most important features in its analysis. Additionally, the time range of data collection was considered a contextual factor.

The atypical antidepressant tianeptine confers neuroprotection against oxygen-glucose deprivation.

Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 µM) significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 µM) and FLU (1 µM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 µM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGD demonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, and that TIA pretreatment counteracted these effects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.

Human Derived Dermal Fibroblasts as in Vitro Research Tool to Study Circadian Rhythmicity in Psychiatric Disorders.

A number of psychiatric disorders are defined by persistent or recurrent sleep-wake disturbances alongside disruptions in circadian rhythm and altered clock gene expression. Circadian rhythms are present not only in the hypothalamic suprachiasmatic nucleus but also in peripheral tissues. In this respect, cultures of human derived dermal fibroblasts may serve as a promising new tool to investigate cellular and molecular mechanisms underlying the pathophysiology of mental illness. In this article, we discuss the advantages of fibroblast cultures to study psychiatric disease. More specifically, we provide an update on recent advances in modeling circadian rhythm disorders using human fibroblasts.

The switching process from buprenorphine sublingual tablets to the monthly buprenorphine subcutaneous depot injection in opioid dependent patients.

The 2018 European Union (EU) approved weekly and monthly subcutaneous buprenorphine depot injection (BUP-XR), for opioid substitution medication proved to offer some specific treatment benefits. The present study examines the process of switching from buprenorphine sublingual tablets (BUP-SL) to BUP-XR from a patient's point of view. In total, nine patients were surveyed by means of an open-answer questionnaire regarding course and side effects of the medication switch. Six of these patients were surveyed in more detail under BUP-SL, as well as 4 and 16 weeks after the switch to BUP-XR by means of a test battery of questions on socio-demography, withdrawal symptoms, craving, physical well-being, treatment satisfaction and concomitant use of illegal substances. Patients reported significant worse physical well-being and lower treatment satisfaction in 4 weeks compared with 16 weeks after the medication switch to the BUP-XR. Furthermore, they reported significant more frequent co-use of illicit drugs, worse physical well-being, lower treatment satisfaction and more craving experience 4 weeks after the switch compared with the treatment under BUP-SL. Patients 16 weeks under BUP-XR reported significant more illicit co-use and lower treatment satisfaction compared with patients under BUP-SL. Connections between therapy dissatisfaction, physical discomfort, experienced craving and drug co-consumption were discovered. In the first weeks after the medication switch, patients experience potentially distressing symptoms, which, however, seem to diminish over time. Close supervision and comprehensive patient education on possible burdens of the medication switch to the BUP-XR might prevent unfavourable treatment courses and premature therapy dropouts.

Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia.

Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-γ, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3ßS9 phosphorylation and reducing STAT1S727 and STAT3Y705 phosphorylation levels in IFN-γ treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1S727 and P-STAT3Y705 . Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain.

Investigating the association between depression and cerebral haemodynamics-A systematic review and meta-analysis.

BACKGROUND: Vascular mechanisms may play a role in depression. The aim of this review is to summarise the evidence on alterations in cerebral haemodynamics in depression. METHODS: MEDLINE (1946- present), Embase (1947-present), Web of Science (1970-present), PsycINFO (1984-present), CINAHL (1976-present) and CENTRAL were searched using a predefined search strategy. A meta-analysis was conducted in four groups: 1) global cerebral blood flow (CBF) in ml/min/100 g, 2) CBF velocity (CBFv) in cm/s (maximum flow of left middle cerebral artery, 3) combined CBF and CBFv, 4) Ratio of uptake of Tc 99 m HMPAO (region of interest compared to whole brain). Data are presented as mean difference or standardised mean difference and 95% confidence interval (95% CI). A narrative synthesis of the remaining studies was performed. RESULTS: 87 studies were included. CBF was significantly reduced in depressed patients compared to HC [15 studies, 538 patients, 416 HC, MD: -2.24 (95% CI -4.12, -0.36), p = 0.02, I2 = 64%]. There were no statistically significant differences in other parameters. The narrative synthesis revealed variable changes in CBF in depressed patients, particularly affecting the anterior cingulate and prefrontal cortices. LIMITATIONS: There were various sources of heterogeneity including the severity of depression, use of antidepressant medication, imaging modality used and reporting of outcomes. All of these factors made direct comparisons between studies difficult. CONCLUSIONS: The reduction in CBF in depressed patients compared to HCs may indicate a role for assessment and CBF altering interventions in high-risk groups. However, results were inconsistent across studies, warranting further work to investigate specific subgroups.

Novel Insights Into the Neurobiology of the Antidepressant Response From Ketamine Research: A Mini Review.

The serendipitous discovery of ketamine's antidepressant effects represents one of the major landmarks in neuropsychopharmacological research of the last 50 years. Ketamine provides an exciting challenge to traditional concepts of antidepressant drug therapy, producing rapid antidepressant effects seemingly without targeting monoaminergic pathways in the conventional way. In consequence, the advent of ketamine has spawned a plethora of neurobiological research into its putative mechanisms. Here, we provide a brief overview of current theories of antidepressant drug action including monoaminergic signaling, disinhibition of glutamatergic neurotransmission, neurotrophic and neuroplastic effects, and how these might relate to ketamine. Given that research into ketamine has not yet yielded new therapies beyond ketamine itself, current knowledge gaps and limitations of available studies are also discussed.

Enduring Effects of Conditional Brain Serotonin Knockdown, Followed by Recovery, on Adult Rat Neurogenesis and Behavior.

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.

Quality of Life in Opioid Replacement Therapy: A Naturalistic Cross-Sectional Comparison of Methadone/Levomethadone, Buprenorphine, and Diamorphine Patients.

BACKGROUND: Research on quality of life (QoL) of chronically ill patients provides an opportunity to evaluate the efficacy of long-term treatments. Although it is established that opioid replacement therapy is an effective treatment for opioid-dependent patients, there is little knowledge about physical and psychological functioning of QoL for different treatment options. OBJECTIVES: Altogether, 248 opioid-dependent patients receiving substitution treatment with either methadone/levomethadone (n = 126), diamorphine (n = 85), or buprenorphine (n = 37) were recruited in 6 German therapy centers. METHODS: Sociodemographic data were collected. QoL - physical and psychological functioning - for different substitutes was assessed using the Profile of the Quality of Life in the Chronically Ill (PLC) questionnaire. RESULTS: Patient groups were similar regarding age and duration of opioid dependence. Employment rate was significantly higher (p < 0.005, φ = 0.22) in the buprenorphine group (46%) compared to methadone (18%). Dosage adjustments were more frequent (p < 0.001, φ = 0.29) in diamorphine (55%) than in methadone (30%) or buprenorphine (19%) patients. Buprenorphine and diamorphine patients rated their physical functioning substantially higher than methadone patients (p < 0.001, η2 = 0.141). Diamorphine patients reported a higher psychological functioning (p < 0.001, η2 = 0.078) and overall life improvement (p < 0.001, η2 = 0.060) compared to methadone, but not compared to buprenorphine patients (both p > 0.25). CONCLUSION: Measurement of important QoL aspects indicates significant differences for physical and psychological functioning in patients receiving the substitutes methadone/levomethadone, diamorphine, and buprenorphine. This could be relevant for the differential therapy of opioid addiction.

BDNF serum concentrations in 2053 participants of the Berlin Aging Study II.

Serum BDNF concentrations in 2053 participants of the Berlin Aging Study II (BASE-II; 1572 individuals from the older age group [60-85 years], 481 individuals from the younger-age reference group [22-37 years]) were studied. There was no effect of age, sex, body mass index, self-reported depression, or BDNF Val66Met variant on serum BDNF concentrations. Multiple linear regression analysis failed to detect significant relationships of Digit Symbol Substitution Test score and Consortium to Establish a Registry for Alzheimer's Disease memory score to BDNF levels. However, we detected a positive correlation between platelet counts and BDNF levels (r = 0.303, p < 0.001). Our findings do not support an effect of aging, self-reported depression, or the Val66Met variant on serum BDNF concentrations. The role of thrombocytes in the biology of serum BDNF merits further study.

Robustly High Hippocampal BDNF levels under Acute Stress in Mice Lacking the Full-length p75 Neurotrophin Receptor.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation. METHOD: We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTRExIII-/-) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 (Il6) was assessed with RT-PCR. RESULTS: Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain Il6 mRNA expression irrespective of genotype; however, p75NTRExIII-/- mice showed elevated baseline Il6 expression and thus a lower relative increase. CONCLUSIONS: Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related Il6 gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.

COVID-19 and neurocognitive disorders.

PURPOSE OF REVIEW: The COVID-19 infection results in various viral-related physical and mental health problems, joined with the long-term psychological impact of the pandemic in general. However, the accompanying neurocognitive changes remain poorly understood. RECENT FINDINGS: We synthetize the current knowledge of viral (SARS-CoV-2) induced inflammation, mechanisms to viral entry into the central nervous system and altered neurotransmitter systems to provide an informed neurobiological explanation for the rise of neurocognitive disorders (defined as per the DSM-5 criteria). SUMMARY: The mild and major neurocognitive disorder symptoms due to the COVID-19 pandemic provide a unique opportunity to address the early changes underlying neurocognitive impairment at both clinical and molecular level. We discuss the utilization of the available evidence for their management and future novel therapeutic opportunities.

The Early Impact of the COVID-19 Pandemic on Acute Care Mental Health Services.

OBJECTIVE: This study aimed to explore the effects of COVID-19 and the lockdown measures adopted in England on patients with acute mental illness. METHODS: The authors analyzed referrals to the crisis resolution and home treatment (CRHT) team and inpatient admissions to acute adult wards, at Leicestershire Partnership National Health Service Trust, an integrated community and mental health trust in the United Kingdom. Number of CRHT referrals and inpatient admissions during a 4-week period starting March 16, 2020 ("COVID-19 period"), was studied and compared with the same period in 2018 and 2019 ("control periods"). Demographic and clinical characteristics of patients admitted during the COVID-19 period were compared with those admitted during the 2019 control period. RESULTS: The number of CRHT referrals and inpatient admissions were lower during the COVID-19 period, compared with the control periods, by approximately 12% and 20%, respectively. Patients admitted during the COVID-19 period were significantly more often detained under the Mental Health Act and were considered to pose a risk of aggression. The pattern of diagnoses differed significantly between 2020 and 2019. A higher percentage of patients admitted during the COVID-19 period were diagnosed as having nonaffective psychotic disorders (52% versus 35%) or bipolar disorder (25% versus 15%), and fewer received a diagnosis of depression (8% versus 16%), anxiety disorder (0% versus 3%), adjustment disorder (0% versus 8%), emotionally unstable personality disorder (6% versus 15%), or any other personality disorder (0% versus 5%) (p=0.01). CONCLUSIONS: These findings suggest that the pandemic has profoundly affected care by acute mental health services.

Deletion of muscarinic acetylcholine receptor 3 in microglia impacts brain ischemic injury.

Microglia are the immune cells of the brain and become activated during any type of brain injury. In the middle cerebral artery occlusion (MCAo) model, a mouse model for ischemic stroke, we have previously shown that microglia and invaded monocytes upregulate the expression of the muscarinic acetylcholine receptor 3 (M3R) in the ischemic lesion. Here we tested whether this upregulation has an impact on the pathogenesis of MCAo. We depleted the m3R receptor in microglia, but not in circulating monocytes by giving tamoxifen to CX3CR1-CreERT+/+M3Rflox/flox (M3RKOmi) animals 3 weeks prior to MCAo. We found that M3RKOmi male mice had bigger lesions, more pronounced motor deficits after one week and cognitive deficits after about one month compared to control males. The density of Iba1+ cells was lower in the lesions of M3RKO male mice in the early, but not in the late disease phase. In females, these differences were not significant. By giving tamoxifen 1 week prior to MCAo, we depleted m3R in microglia and in circulating monocytes (M3RKOmi/mo). Male M3RKOmi/mo did not differ in lesion size, but had a lower survival rate, showed motor deficits and a reduced accumulation of Iba1+ positive cells into the lesion site. In conclusion, our data suggest that the upregulation of m3R in microglia and monocytes in stroke has a beneficial effect on the clinical outcome in male mice.

The importance of previous lifetime trauma in stroke-induced PTSD symptoms and mental health outcomes.

The 'Stroke Complications after Traumatic Experiences and Stress' (SATURN) study was designed to investigate the effects of a prior traumatic event on PTSD symptoms triggered by a subsequent stroke. First-ever ischemic stroke patients were surveyed 9-13 months after hospitalization at the Charité University Medical Center. Stroke-induced PTSD symptoms were measured using the Impact of Event Scale-revised (IES-R). Prior traumatization together with past PTSD symptoms was assessed retrospectively with the Brief Trauma Questionnaire (BTQ) and the 7-item Short Screening Scale for PTSD. Depressive symptoms were assessed with the Beck Depression Inventory (BDI-II). The Short Form (SF)-36 was used to evaluate physical and mental health outcomes. We received 258 responses from 636 eligible patients (~41%). Based on respondents' scores on the IES-R, the prevalence of probable PTSD due to the stroke event was 11% in our sample. Female sex and younger age were associated with more severe PTSD symptoms. Psychological endpoints did not differ between patients who denied prior trauma exposure and those who reported earlier trauma exposure but denied subsequent PTSD symptoms. However, a history of trauma exposure in tandem with endorsing subsequent PTSD symptoms was linked with significantly increased post-stroke PTSD and depressive symptoms together with decreased psychological well-being. Self-reported physical health did not differ across groups. Younger age, being a woman, and having developed PTSD symptoms in the aftermath of a prior trauma were associated with adverse psychological outcomes after stroke.

Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 -/- mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus. METHODS: Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs. RESULTS: Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 -/- mice, adult neurogenesis was consistently increased. Furthermore, Tph2 -/- mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT. DISCUSSION: We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.