Polypharmacy in psychiatry and weight gain: longitudinal study of 832 patients hospitalized for depression or schizophrenia, along with data of 3180 students from Europe, the U.S., South America, and China.

Epidemiologic data indicate that overweight and obesity are on the rise worldwide. Psychiatric patients are particularly vulnerable in this respect as they have an increased prevalence of overweight and obesity, and often experience rapid, highly undesirable weight gain under psychotropic drug treatment. Current treatment strategies in psychiatry are oriented towards polypharmacy, so that the information on drug-induced weight gain from earlier monotherapy studies is of very limited validity. We have analyzed the longitudinal data of 832 inpatients with ICD-10 diagnoses of either F2 (schizophrenia; n = 282) or F3 (major depression; n = 550) with the goal of ranking treatment regimens in terms of weight gain, side effects, and response to treatment. The patient data were complemented by the data of 3180 students aged 18-22 years, with which we aimed to identify factors that enable the early detection and prevention of obesity and mental health problems. After 3 weeks of treatment, 47.7% of F2 patients and 54.9% of F3 patients showed a weight gain of 2 kg and more. Major predictive factors were "starting weight" (r = 0.115), "concurrent medications" (r = 0.176), and "increased appetite"(r = 0.275). Between 11 and 30% of the observed variance in weight gain could be explained by these factors, complemented by sex and age. The comparison between monotherapy (n = 409) and polypharmacy (n = 399) revealed significant drawbacks for polypharmacy: higher weight gain (p = 0.0005), more severe side effects (p = 0.0011), and lower response rates (F2: p = 0.0008); F3: p = 0.0101). The data of 3180 students made it clear that overweight and obesity often begin early in life among those affected, and are interconnected with personality traits, while increasing the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. Although the available data did not readily lead to a comprehensive, clinically applicable model of unwanted weight gain, our results have nevertheless demonstrated that there are ways to successfully counteract such weight gain at early stages of treatment.

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results.

INTRODUCTION: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. MATERIAL AND METHODS: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. RESULTS: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (-5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DISCUSSION: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs).

BACKGROUND: This study analyzed the extent to which irregularities in genetic diversity separate psychiatric patients from healthy controls. METHODS: Genetic diversity was quantified through multidimensional "gene vectors" assembled from 4 to 8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene's "diversity index". RESULTS: The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5 % explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from "normal" diversity values were found for (1) major depression; (2) Alzheimer's disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245. The central finding of this study was the discovery of "singular genes" characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Neural Nets yielded nonlinear classifiers that correctly identified up to 90 % of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities. CONCLUSION: Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level.

Brain-derived neurotrophic factor protects serotonergic neurons against 3,4-methylenedioxymethamphetamine ("Ecstasy") induced cytoskeletal damage.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") use has been linked to persistent alterations of the brain serotonergic (5-HT) system in animal and human studies, but the molecular underpinnings are still unclear. Cytoskeletal structures such as neurofilament light chain (NfL) are promising markers of drug-induced brain toxicity and may be involved in MDMA neurotoxicity. The brain-derived neurotrophic factor (BDNF) promotes the growth and sprouting of 5-HT neurons and its differential response to MDMA administration was suggested to mediate dose- and region-dependent 5-HT damage by MDMA. However, the role of BDNF pre-treatment in preventing MDMA neurotoxicity and the potential effects of MDMA on NfL are still elusive. Therefore, a differentiated 5-HT neuronal cell line obtained from rat raphe nucleus (RN46A) was treated in vitro with either MDMA, BDNF, MDMA + BDNF, or vehicle. Cell viability (measured by MTT) and intracellular NfL levels (immunocytochemistry assay) were reduced by MDMA, but partially rescued by BDNF co-treatment. Our findings confirmed that BDNF levels can influence MDMA-induced 5-HT damage, and support BDNF to be a crucial target for neuroprotective interventions of the 5-HT system. We also provide evidence on the sensitivity of NfL to MDMA neurotoxicity, with potential implications for in-vivo monitoring of drug-induced neurotoxicity.

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia.

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history¼ and «severity at baseline¼ played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy.

Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.

Depression is associated with hyperconnectivity of an introspective socio-affective network during the recall of formative relationship episodes.

BACKGROUND: Depression and the experience of early adversity are associated with impairments in interpersonal and social cognitive functioning. The neural mechanisms involved in these impairments remain insufficiently understood. METHODS: In a sample of 48 depressed and 50 healthy participants, we explored seed-to-voxel functional connectivity (FC) during the recall of formative relationship episodes using functional magnetic resonance imaging. RESULTS: While depressive symptoms were associated with increased FC of brain regions that form an introspective socio-affective network, such as the precuneus, bilateral anterior insula, dorsal anterior cingulate cortex, left amygdala, and medial prefrontal cortex, early adversity linked to decreased FC of brain regions mediating emotion processing such as the bilateral anterior insula and increased FC of the bilateral parahippocampal gyrus. LIMITATIONS: We report both results that are corrected for the number of seeds tested in FC analyses using strict Bonferroni adjustments and unadjusted results as part of an exploratory analysis. DISCUSSION: Our findings suggest that depression and early adversity are associated with differential FC patterns in the brain during the recall of formative relationship episodes. Hyperconnectivity of an introspective socio-affective network associated with depressive symptoms may link to enhanced self-focus and emotional reactivity. Patterns of neural activation associated with early adversity may underpin numbed affective states or enhanced affective memory regulation. Overall, these findings inform about the neural underpinnings of a reflective ability that is predictive of the adaptation to depression and to early adversity and relevant for psychotherapy outcomes.

Nocturnal Gamma-Hydroxybutyrate Reduces Cortisol-Awakening Response and Morning Kynurenine Pathway Metabolites in Healthy Volunteers.

BACKGROUND: Gamma-hydroxybutyrate (GHB; or sodium oxybate) is an endogenous GHB-/gamma-aminobutyric acid B receptor agonist. It is approved for application in narcolepsy and has been proposed for the potential treatment of Alzheimer's disease, Parkinson's disease, fibromyalgia, and depression, all of which involve neuro-immunological processes. Tryptophan catabolites (TRYCATs), the cortisol-awakening response (CAR), and brain-derived neurotrophic factor (BDNF) have been suggested as peripheral biomarkers of neuropsychiatric disorders. GHB has been shown to induce a delayed reduction of T helper and natural killer cell counts and alter basal cortisol levels, but GHB's effects on TRYCATs, CAR, and BDNF are unknown. METHODS: Therefore, TRYCAT and BDNF serum levels, as well as CAR and the affective state (Positive and Negative Affect Schedule [PANAS]) were measured in the morning after a single nocturnal dose of GHB (50 mg/kg body weight) in 20 healthy male volunteers in a placebo-controlled, balanced, randomized, double-blind, cross-over design. RESULTS: In the morning after nocturnal GHB administration, the TRYCATs indolelactic acid, kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid; the 3-hydroxykynurenine to kynurenic acid ratio; and the CAR were significantly reduced (P < 0.05-0.001, Benjamini-Hochberg corrected). The quinolinic acid to kynurenic acid ratio was reduced by trend. Serotonin, tryptophan, and BDNF levels, as well as PANAS scores in the morning, remained unchanged after a nocturnal GHB challenge. CONCLUSIONS: GHB has post-acute effects on peripheral biomarkers of neuropsychiatric disorders, which might be a model to explain some of its therapeutic effects in disorders involving neuro-immunological pathologies. This study was registered at ClinicalTrials.gov as NCT02342366.

Thinking about the past to shape the present: neural activation during the recall of relationship episodes.

Reflecting on oneself and others in relationships is an ability that is central to our social existence. Specifically, considering formative autobiographical experiences in relationships may contribute to more flexibility in perceiving, as well as in shaping present relationships. Reflecting on such experiences mobilizes different social cognitive and affective processes. We aim to explore the neural basis of these processes. With a newly developed functional magnetic imaging (fMRI) task, we investigated brain activation in 35 healthy individuals during recall of relationship episodes involving themselves or others. We found that recalling formative episodes involving themselves modulated brain activity in the right parahippocampus, left precuneus, bilateral fusiform gyrus, bilateral insula, and left presupplementary motor area. These areas are involved in memory processes, self-generated thought, and affective experience. The recall of relationship episodes involving others led to similar activation patterns. Our results underscore the close link between self-reflection, understanding others, and memory processes and emphasize the role of affective dimensions for self-relevant experiences. They contribute to a growing body of research on neural mechanisms involved in complex social cognitive processes decisive for our capacity to navigate our social environment.

Training emotion regulation through real-time fMRI neurofeedback of amygdala activity.

Being in control of one's emotions is not only desirable in many everyday situations but is also a great challenge in a variety of mental disorders. Successful intentional emotion regulation is related to down-regulation of amygdala activity. Training mental interventions supported by neurofeedback of one's own amygdala activity using real-time (rt-)fMRI might be beneficial for mental health and well-being. Rt-fMRI guided amygdala-downregulation using cognitive interventions such as a "reality check", however, have not been well-investigated. Fifteen healthy subjects underwent four rt-fMRI sessions with neurofeedback of their own amygdala activity while applying a reality check as an emotion regulation strategy in order to down-regulate their amygdala signal during a stimulation with emotional pictures. The Control group comprised of eleven subjects also trained emotion regulation but without obtaining feedback. We hypothesized more prominent down-regulation of amygdala activity at the end of the training in the Feedback group. We investigated effects over time and between groups and further task specific connectivity of the amygdala by using psychophysiological interaction analyses. Four weekly amygdala-based feedback sessions resulted in significantly decreased amygdala activity (p = 0.003, d = 0.93), also compared to the Control group (p = 0.014, d = 1.12). Task specific connectivity of the amygdala with the anterior cingulate cortex, hippocampus and distinct prefrontal areas was increased in the Feedback group. Training of emotion regulation supported by rt-fMRI neurofeedback resulted in a prominent amygdala down-regulation compared to training without feedback. The finding implicates successful emotion regulation, compliant with emotion control models, through an easily applicable reality check strategy. Rt-fMRI neurofeedback may support emotion regulation learning and bears clinical potential for psychotherapy.

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice.

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/- ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/- mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/- and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.

Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination.

Recent studies suggest that the antidepressant effects of the psychedelic 5-HT2A receptor agonist psilocybin are mediated through its modulatory properties on prefrontal and limbic brain regions including the amygdala. To further investigate the effects of psilocybin on emotion processing networks, we studied for the first-time psilocybin's acute effects on amygdala seed-to-voxel connectivity in an event-related face discrimination task in 18 healthy volunteers who received psilocybin and placebo in a double-blind balanced cross-over design. The amygdala has been implicated as a salience detector especially involved in the immediate response to emotional face content. We used beta-series amygdala seed-to-voxel connectivity during an emotional face discrimination task to elucidate the connectivity pattern of the amygdala over the entire brain. When we compared psilocybin to placebo, an increase in reaction time for all three categories of affective stimuli was found. Psilocybin decreased the connectivity between amygdala and the striatum during angry face discrimination. During happy face discrimination, the connectivity between the amygdala and the frontal pole was decreased. No effect was seen during discrimination of fearful faces. Thus, we show psilocybin's effect as a modulator of major connectivity hubs of the amygdala. Psilocybin decreases the connectivity between important nodes linked to emotion processing like the frontal pole or the striatum. Future studies are needed to clarify whether connectivity changes predict therapeutic effects in psychiatric patients.

Adaptive Value Normalization in the Prefrontal Cortex Is Reduced by Memory Load.

Adaptation facilitates neural representation of a wide range of diverse inputs, including reward values. Adaptive value coding typically relies on contextual information either obtained from the environment or retrieved from and maintained in memory. However, it is unknown whether having to retrieve and maintain context information modulates the brain's capacity for value adaptation. To address this issue, we measured hemodynamic responses of the prefrontal cortex (PFC) in two studies on risky decision-making. In each trial, healthy human subjects chose between a risky and a safe alternative; half of the participants had to remember the risky alternatives, whereas for the other half they were presented visually. The value of safe alternatives varied across trials. PFC responses adapted to contextual risk information, with steeper coding of safe alternative value in lower-risk contexts. Importantly, this adaptation depended on working memory load, such that response functions relating PFC activity to safe values were steeper with presented versus remembered risk. An independent second study replicated the findings of the first study and showed that similar slope reductions also arose when memory maintenance demands were increased with a secondary working memory task. Formal model comparison showed that a divisive normalization model fitted effects of both risk context and working memory demands on PFC activity better than alternative models of value adaptation, and revealed that reduced suppression of background activity was the critical parameter impairing normalization with increased memory maintenance demand. Our findings suggest that mnemonic processes can constrain normalization of neural value representations.

Prefrontal hemodynamic after-effects caused by rebreathing may predict affective states - A multimodal functional near-infrared spectroscopy study.

Brain activity has been shown to be influenced by respiratory behavior. Here, we evaluated whether respiration-induced hypo- or hypercapnia may support differentiation between physiological versus pathological respiratory behavior. In particular, we investigated whether systemic physiological measures could predict the brain's time-frequency hemodynamics after three respiratory challenges (i.e., breath-holding, rebreathing, and hyperventilation) compared to resting-state. Prefrontal hemodynamics were assessed in healthy subjects (N = 27) using functional near-infrared spectroscopy (fNIRS). Systemic physiological measures were assessed in form of heart rate, partial end-tidal carbon dioxide, respiration rate, and saturation of peripheral oxygen. Time-frequency dynamics were quantified using the wavelet transform coherence (i.e., defined here as cortical-systemic coherence). We found that the three respiratory challenges modulated cortical-systemic coherence differently: (1) After rebreathing, cortical-systemic coherence could be predicted from the amplitude of the heart rate (strong negative correlation). (2) After breath-holding, the same observation was made (moderate negative correlation). (3) After hyperventilation, no significant effect was observed. (4) These effects were found only in the frequency range of very low-frequency oscillations. The presented findings highlight a distinct role of rebreathing in predicting cortical-systemic coupling based on heart rate changes, which may represents a measure of affective states in the brain. The applied multimodal assessment of hemodynamic and systemic physiological measures during respiratory challenges may therefore have potential applications in the differentiation between physiological and pathological respiratory behavior.

Increased pregenual anterior cingulate glucose and lactate concentrations in major depressive disorder.

There is ample evidence that glucose metabolism in the pregenual anterior cingulate cortex (PACC) is increased in major depressive disorder (MDD), whereas it is still unknown whether glucose levels per se are also elevated. Elevated cerebrospinal fluid (CSF) lactate concentrations in MDD patients might indicate that increased glycolytical metabolization of glucose to lactate in astrocytes either alone or in conjunction with mitochondrial dysfunction results in an accumulation of lactate and contributes to pathophysiological mechanisms of MDD. However, until now, no study investigated in vivo PACC glucose and lactate levels in MDD. Proton magnetic resonance spectroscopy was therefore used to test the hypothesis that patients with MDD have increased PACC glucose and lactate levels. In 40 healthy and depressed participants, spectra were acquired from the PACC using a maximum echo J-resolved spectroscopy protocol. Results show significant increases of glucose and lactate in patients, which are also associated with depression severity. These findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate. Targeting these metabolic disturbances might affect the balance of metabolic pathways regulating neuronal energetics and result in an attenuation of the elevated basal activity of brain regions within the neural circuitry of depression.

Predicting relapse after antidepressant withdrawal - a systematic review.

A substantial proportion of the burden of depression arises from its recurrent nature. The risk of relapse after antidepressant medication (ADM) discontinuation is high but not uniform. Predictors of individual relapse risk after antidepressant discontinuation could help to guide treatment and mitigate the long-term course of depression. We conducted a systematic literature search in PubMed to identify relapse predictors using the search terms '(depress* OR MDD*) AND (relapse* OR recurren*) AND (predict* OR risk) AND (discontinu* OR withdraw* OR maintenance OR maintain or continu*) AND (antidepress* OR medication OR drug)' for published studies until November 2014. Studies investigating predictors of relapse in patients aged between 18 and 65 years with a main diagnosis of major depressive disorder (MDD), who remitted from a depressive episode while treated with ADM and were followed up for at least 6 months to assess relapse after part of the sample discontinued their ADM, were included in the review. Although relevant information is present in many studies, only 13 studies based on nine separate samples investigated predictors for relapse after ADM discontinuation. There are multiple promising predictors, including markers of true treatment response and the number of prior episodes. However, the existing evidence is weak and there are no established, validated markers of individual relapse risk after antidepressant cessation. There is little evidence to guide discontinuation decisions in an individualized manner beyond overall recurrence risk. Thus, there is a pressing need to investigate neurobiological markers of individual relapse risk, focusing on treatment discontinuation.

Time-frequency dynamics of the sum of intra- and extracerebral hemodynamic functional connectivity during resting-state and respiratory challenges assessed by multimodal functional near-infrared spectroscopy.

Monitoring respiratory processes is important for evaluating neuroimaging data, given their influence on time-frequency dynamics of intra- and extracerebral hemodynamics. Here we investigated the time-frequency dynamics of the sum of intra- and extracerebral hemodynamic functional connectivity states during hypo- and hypercapnia by using three different respiratory challenge tasks (i.e., hyperventilation, breath-holding, and rebreathing) compared to resting-state. The sum of intra- and extracerebral hemodynamic responses were assessed using functional near-infrared spectroscopy (fNIRS) within two regions of interest (i.e., the dorsolateral and the medial prefrontal cortex). Time-frequency fNIRS analysis was performed based on wavelet transform coherence to quantify functional connectivity in terms of positive and negative phase-coupling within each region of interest. Physiological measures were assessed in the form of partial end-tidal carbon dioxide, heart rate, arterial tissue oxygen saturation, and respiration rate. We found that the three respiration challenges modulated time-frequency dynamics differently with respect to resting-state: 1) Hyperventilation and breath-holding exhibited inverse patterns of positive and negative phase-coupling. 2) In contrast, rebreathing had no significant effect. 3) Low-frequency oscillations contributed to a greater extent to time-frequency dynamics compared to high-frequency oscillations. The results highlight that there exist distinct differences in time-frequency dynamics of the sum of intra- and extracerebral functional connectivity not only between hypo- (hyperventilation) and hypercapnia but also between different states of hypercapnia (breath-holding versus rebreathing). This suggests that a multimodal assessment of intra-/extracerebral and systemic physiological changes during respiratory challenges compared to resting-state may have potential use in the differentiation between physiological and pathological respiratory behavior accompanied by the psycho-physiological state of a human.

Changes in cocaine consumption are associated with fluctuations in self-reported impulsivity and gambling decision-making.

BACKGROUND: In cross-sectional studies, cocaine users generally display elevated levels of self-reported and cognitive impulsivity. To what extent these impairments are stable v. variable markers of cocaine use disorder, and, thus, are pre-existing or drug-induced, has not yet been systematically investigated. METHOD: We conducted a longitudinal study with cocaine users who changed or maintained their consumption intensity, measuring self-reported impulsivity with the Barratt Impulsiveness Scale (BIS-11), and cognitive impulsivity with the Rapid Visual Processing task (RVP), Iowa Gambling task (IGT), and Delay Discounting task (DD) at baseline and at 1-year follow-up. We assessed 48 psychostimulant-naive controls and 19 cocaine users with decreased, 19 users with increased, and 19 users with unchanged cocaine intake after 1 year as confirmed by hair analysis. RESULTS: Results of linear multilevel modelling showed significant group × time interactions for the BIS-11 total score and the IGT total card ratio. Increasers showed a trend for elevated scores, whereas decreasers exhibited reduced self-reported impulsivity scores within 1 year. Surprisingly, increasers' IGT performance was improved after 1 year, whereas decreasers' performance deteriorated. By contrast, neither RVP response bias B" nor DD total score showed substantial group × time interactions. Importantly, BIS-11 and DD revealed strong test-retest reliabilities. CONCLUSION: Self-reported impulsivity (BIS-11) and decision-making impulsivity (IGT) covary with changing cocaine use, whereas response bias and delay discounting remain largely unaffected. Thus, self-reported impulsivity and gambling decision-making were strongly state-dependent in a stimulant-using population and may be suitable to monitor treatment success, whereas delay of gratification was confirmed as a potential endophenotype of stimulant addiction.

Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders.

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, is fundamental to brain function and implicated in the pathophysiology of several neuropsychiatric disorders. GABA activates G-protein-coupled GABAB receptors comprising principal GABAB1 and GABAB2 subunits as well as auxiliary KCTD8, 12, 12b and 16 subunits. The KCTD12 gene has been associated with bipolar disorder, major depressive disorder and schizophrenia. Here we compare Kctd12 null mutant (Kctd12(-/-)) and heterozygous (Kctd12(+/-)) with wild-type (WT) littermate mice to determine whether lack of or reduced KCTD12 expression leads to phenotypes that, extrapolating to human, could constitute endophenotypes for neuropsychiatric disorders with which KCTD12 is associated. Kctd12(-/-) mice exhibited increased fear learning but not increased memory of a discrete auditory-conditioned stimulus. Kctd12(+/-) mice showed increased activity during the inactive (light) phase of the circadian cycle relative to WT and Kctd12(-/-) mice. Electrophysiological recordings from hippocampal slices, a region of high Kctd12 expression, revealed an increased intrinsic excitability of pyramidal neurons in Kctd12(-/-) and Kctd12(+/-) mice. This is the first direct evidence for involvement of KCTD12 in determining phenotypes of emotionality, behavioral activity and neuronal excitability. This study provides empirical support for the polymorphism and expression evidence that KCTD12 confers risk for and is associated with neuropsychiatric disorders.