The Psychobiology of Authentic and Simulated Dissociative Personality States: The Full Monty.

The etiology of dissociative identity disorder (DID) remains a topic of debate. Proponents of the fantasy model and the trauma model of DID have both called for more empirical research. To this end, the current study presents new and extended data analyses of a previously published H2O positron emission tomography imaging study. This study included 29 subjects: 11 patients with DID and 10 high- and 8 low-fantasy-prone DID-simulating mentally healthy control subjects. All subjects underwent an autobiographical memory script-driven (neutral and trauma related) imagery paradigm in 2 (simulated) dissociative personality states (neutral and trauma related). Psychobiological and psychophysiological data were obtained. Results of the new post-hoc tests on the psychophysiological responses support the trauma model. New results of the brain imaging data did not support the fantasy model. This study extends previously published results by offering important new supporting data for the trauma model of DID.

Acute social defeat does not alter cerebral 5-HT2A receptor binding in male Wistar rats.

It has been hypothesized that effects of uncontrollable stress on serotonin receptor expression contribute to the etiology of stress-related disorders like depression. While the serotonin-2A receptors (5-HT2A R) are thought to be important in this context, only few studies examined effects of stress on this receptor subtype. In this study, we therefore assessed acute and long-term changes in 5HT2A R binding after social defeat stress in rats. Male Wistar rats were subjected to social defeat by placing them in the home cage of an aggressive, dominant Long Evans rat. Acute social defeat suppressed growth, but did not affect anxiety-like behavior in an open field test. A positron emission tomography scan with the 5-HT2A R tracer [11C]MDL 100907 1 day and 3 weeks after defeat did not show significant changes in receptor binding. To verify these results, [3H]MDL 100907 binding assays were performed in homogenates of prefrontal cortex and hippocampus, which also did not indicate any changes in Bmax or Kd . These findings do not support the hypothesis that changes in 5-HT2A R function are a vital mechanism through which uncontrollable stress contributes to stress-related pathologies such as depression. It remains to be determined whether effects of stress on 5HT2A R binding depend on the nature of the stressor or on the characteristics of the rat strain.

Reduced spontaneous but relatively normal deliberate vicarious representations in psychopathy.

Psychopathy is a personality disorder associated with a profound lack of empathy. Neuroscientists have associated empathy and its interindividual variation with how strongly participants activate brain regions involved in their own actions, emotions and sensations while viewing those of others. Here we compared brain activity of 18 psychopathic offenders with 26 control subjects while viewing video clips of emotional hand interactions and while experiencing similar interactions. Brain regions involved in experiencing these interactions were not spontaneously activated as strongly in the patient group while viewing the video clips. However, this group difference was markedly reduced when we specifically instructed participants to feel with the actors in the videos. Our results suggest that psychopathy is not a simple incapacity for vicarious activations but rather reduced spontaneous vicarious activations co-existing with relatively normal deliberate counterparts.

Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease.

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to ß-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males.

INTRODUCTION: Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels. OBJECTIVES: This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement. METHODS: Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics. RESULTS: Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths. CONCLUSIONS: Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.

Fighting stigma of mental illness in midsize European countries.

PURPOSE: Stigma is the most powerful obstacle to the development of mental health care. Numerous activities aiming to reduce the stigma of mental illness and the consequent negative discrimination of the mentally ill and their families have been conducted in Europe. Descriptions of many of these activities are not easily available, either because there are no publications that describe them, or because descriptions exist only in local languages. This supplement aims to help in overcoming this imbalance by providing a description of anti-stigma activities in 14 countries in Europe regardless of the language in which they were published and regardless whether they were previously published. METHODS: The review was undertaken by experts who were invited to describe anti-stigma activities in the countries in which they reside. It was suggested that they use all the available evidence and that they consult others in their country to obtain a description of anti-stigma activities that is as complete as possible. RESULTS: The anti-stigma activities undertaken in the countries involved are presented in a tabular form. The texts contributed by the authors focus on their perception of the stigma of mental illness and of activities undertaken to combat it in their country. CONCLUSIONS: Although much has been done against the stigmatization and discrimination of the mentally ill, fighting stigma remains an essential task for mental health programs and for society. The descriptions summarized in this volume might serve as an inspiration for anti-stigma work and as an indication of potential collaborators in anti-stigma programs.

Role of Brain Imaging in Drug Development for Psychiatry.

BACKGROUND: Over the last decades, many brain imaging studies have contributed to new insights in the pathogenesis of psychiatric disease. However, in spite of these developments, progress in the development of novel therapeutic drugs for prevalent psychiatric health conditions has been limited. OBJECTIVE: In this review, we discuss translational, diagnostic and methodological issues that have hampered drug development in CNS disorders with a particular focus on psychiatry. The role of preclinical models is critically reviewed and opportunities for brain imaging in early stages of drug development using PET and fMRI are discussed. The role of PET and fMRI in drug development is reviewed emphasizing the need to engage in collaborations between industry, academia and phase I units. RESULTS: Brain imaging technology has revolutionized the study of psychiatric illnesses, and during the last decade, neuroimaging has provided valuable insights at different levels of analysis and brain organization, such as effective connectivity (anatomical), functional connectivity patterns and neurochemical information that may support both preclinical and clinical drug development. CONCLUSION: Since there is no unifying pathophysiological theory of individual psychiatric syndromes and since many symptoms cut across diagnostic boundaries, a new theoretical framework has been proposed that may help in defining new targets for treatment and thus enhance drug development in CNS diseases. In addition, it is argued that new proposals for data-mining and mathematical modelling as well as freely available databanks for neural network and neurochemical models of rodents combined with revised psychiatric classification will lead to new validated targets for drug development.

Chronic stress and antidepressant agomelatine induce region-specific changes in synapsin I expression in the rat brain.

The antidepressant agomelatine acts as a melatonergic receptor (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity-associated molecules. Recently, we showed that agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in the stress-compromised brain. To characterize further the effects of this antidepressant in the stressed brain, here we investigated whether it induces changes in the expression of synapsin I (SynI), a regulator of synaptic transmission and plasticity. Adult male rats were subjected to daily footshock stress and agomelatine treatment for 3 weeks. Their brains were subsequently stained for total and phosphorylated SynI. Chronic footshock and agomelatine induced region-specific changes in SynI expression. Whereas chronic stress increased total SynI expression in all layers of the medial prefrontal cortex, agomelatine treatment abolished some of these effects. Furthermore, chronic agomelatine administration decreased total SynI expression in the hippocampal subregions of both stressed and nonstressed rats. Importantly, chronic stress decreased the fraction of phosphorylated SynI in all layers of the medial prefrontal cortex as well as selectively in the outer and middle molecular layers of the hippocampal dentate gyrus. These stress effects were at least partially abolished by agomelatine. Altogether, our data show that chronic stress and agomelatine treatment induce region-specific changes in SynI expression and its phosphorylation. Moreover, agomelatine partially counteracts the stress effects on SynI, suggesting a modulation of synaptic function by this antidepressant.

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications.

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[(11)C]methyltryptophan ([(11)C]AMT) and 5-hydroxy-L-[ß-(11)C]tryptophan ([(11)C]5-HTP). Both tracers have advantages and disadvantages. [(11)C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [(11)C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain.

Latent class analysis of the Yale-Brown Obsessive-Compulsive Scale symptoms in obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous, and findings of underlying structure classification based on symptom grouping have been ambiguous to date. Variable-centered approaches, primarily factor analysis, have been used to identify homogeneous groups of symptoms; but person-centered latent methods have seen little use. This study was designed to uncover sets of homogeneous groupings within 1611 individuals with OCD based on symptoms. METHOD: Latent class analysis models using 61 obsessive-compulsive symptoms collected from the Yale-Brown Obsessive-Compulsive Scale were fit. Relationships between latent class membership and treatment response, sex, symptom severity, and comorbid tic disorders were tested for relationship to class membership. RESULTS: Latent class analysis models of best fit yielded 3 classes. Classes differed only in frequency of symptom endorsement. Classes with higher symptom endorsement were associated with earlier age of onset, being male, higher Yale-Brown Obsessive-Compulsive Scale symptom severity scores, and comorbid tic disorders. There were no differences in treatment response between classes. CONCLUSIONS: These results provide support for the validity of a single underlying latent OCD construct, in addition to the distinct symptom factors identified previously via factor analyses.

Dysfunctional beliefs in the process of change of cognitive treatment in obsessive compulsive checkers.

Cognitive behaviour therapy (CBT) is considered to be effective in the reduction of obsessive compulsive symptoms. However, questions remain as to how CBT works. Cognitive-behavioural models postulate that negative appraisals of intrusive thoughts and dysfunctional beliefs that give rise to them underlie the development and maintenance of obsessive-compulsive disorder (OCD). The current study aimed to study this hypothesis by investigating the processes of change over the course of cognitive treatment for OCD. Furthermore, a new theoretical approach and method for studying processes of change was presented. The participants were seven patients suffering from OCD with predominantly checking symptoms. Process variables (beliefs, anxiety and compulsions) were measured using idiosyncratic diaries and were analysed on an intra- and inter-individual level using dynamic systems methods. Results showed significant decreases in credibility of dysfunctional beliefs in six out of the seven participants, which is in line with the cognitive-behavioural model. Associations between process variables were in general medium to high. However, the actual patterns of change showed important intra- and interpersonal differences. Results indicated that different paths can lead to clinical recovery, and it was concluded that process studies that focus on individual trajectories of change can contribute to our understanding of OCD and its treatment. Furthermore, dynamic systems methods provide insight into intra-individual processes and shed a new light on variability.

Symptom dimensions in OCD: item-level factor analysis and heritability estimates.

To reduce the phenotypic heterogeneity of obsessive-compulsive disorder (OCD) for genetic, clinical and translational studies, numerous factor analyses of the Yale-Brown Obsessive Compulsive Scale checklist (YBOCS-CL) have been conducted. Results of these analyses have been inconsistent, likely as a consequence of small sample sizes and variable methodologies. Furthermore, data concerning the heritability of the factors are limited. Item and category-level factor analyses of YBOCS-CL items from 1224 OCD subjects were followed by heritability analyses in 52 OCD-affected multigenerational families. Item-level analyses indicated that a five factor model: (1) taboo, (2) contamination/cleaning, (3) doubts, (4) superstitions/rituals, and (5) symmetry/hoarding provided the best fit, followed by a one-factor solution. All 5 factors as well as the one-factor solution were found to be heritable. Bivariate analyses indicated that the taboo and doubts factor, and the contamination and symmetry/hoarding factor share genetic influences. Contamination and symmetry/hoarding show shared genetic variance with symptom severity. Nearly all factors showed shared environmental variance with each other and with symptom severity. These results support the utility of both OCD diagnosis and symptom dimensions in genetic research and clinical contexts. Both shared and unique genetic influences underlie susceptibility to OCD and its symptom dimensions.

Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia: a PET study with [(11)C]verapamil as a probe for P-glycoprotein function.

P-glycoprotein (P-gp), a major efflux pump in the blood-brain barrier (BBB) has a profound effect on entry of drugs, peptides and other substances into the central nervous system (CNS). The brain's permeability can be negatively influenced by modulation of the transport function of P-gp. Inflammatory mediators play a role in schizophrenia, and may be able to influence the integrity of the BBB, via P-gp modulation. We hypothesized that P-gp function in the BBB is changed in patients with schizophrenia. Positron-emission tomography was used to measure brain uptake of [(11)C]verapamil, which is normally extruded from the brain by P-gp. We found that patients with chronic schizophrenia under treatment with antipsychotic drugs compared with healthy controls showed a significant decrease in [(11)C]verapamil uptake in the temporal cortex, the basal ganglia, and the amygdala, and amygdalae, and a trend towards a significant decrease was seen throughout the brain. The decrease of [(11)C]verapamil uptake correlates with an increased activity of the P-gp pump. Increased P-gp activity may be a factor in drug resistance in schizophrenia, induced by the use of antipsychotic agents.

Processes of change in cognitive-behavioural treatment of obsessive-compulsive disorder: Current status and some future directions.

The present paper discusses theoretical and methodological issues involved in the processes of change in cognitive-behavioural treatment (CBT) of obsessive-compulsive disorder (OCD). Treatment outcome studies showed that CBT is effective in reducing obsessive-compulsive symptoms. However, why and how CBT works cannot be corroborated by comparing pre- and post-assessment. Recently, there has been a resurgence of interest in theory driven process studies. By showing patterns of change over time, process studies can contribute to our insight into the actual mechanisms of change during treatment. We review process research in the field of OCD and discuss methodological issues involved in process studies for this particular disorder. It is concluded that studying the processes of change harbours promising possibilities for bridging the gap between theory and clinical practice.

The role of the COMT Val(158)Met polymorphism in the phenotypic expression of obsessive-compulsive disorder.

Obsessive-Compulsive Disorder (OCD) is characterized by the presence of obsessions and compulsions, and shows considerable phenotypic variability. Family and twin studies have indicated a genetic component in the etiology of OCD, and the catechol-O-methyl transferase (COMT) gene is an important candidate gene for OCD. This study investigates the influence of the functional COMT Val158Met polymorphism on the phenotypic expression of OCD, using an item-level factor-analytic approach in a large sample. The COMT Val158Met variant was genotyped in 373 patients and 462 controls. It was tested whether there was an association between the COMT Val158Met polymorphism and OCD or dimensional phenotypes such as YBOCS severity score, age of onset of obsessive-compulsive symptoms and six symptom dimensions recently found in a large item-level factor-analytic study [Katerberg et al., submitted]. We further investigated possible sex-specific associations between the COMT Val158Met polymorphism and OCD or dimensional phenotypes. There was a trend for an association of the COMT 158Met allele with OCD in males, and an interaction between the COMT Val158Met genotype and sex on the somatic and sensory phenomena symptom dimension, with females showing lower scores. In conclusion, a dimensional approach seems fruitful in detecting genes of importance for OCD.

Antagonism of 5-HT(1A) receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT(7) receptors.

Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT(1A) autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5-HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5-HT(7) receptors. Experiments were performed with the specific 5-HT(7) antagonist SB 258741 and the putative 5-HT(7) agonist AS19. In this study WAY 100.635 was used to block 5-HT(1A) receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5-HT in the ventral hippocampus as well as 5-HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co-administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5-HT in ventral hippocampus, hinting at opposed 5-HT(7) receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell-shaped dose-effect curve: moderately increasing 5-HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5-HT(7) receptors and moderate affinity for 5-HT(1A) receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5-HT neuronal activity mediated by 5-HT(7) receptors. It can be speculated, that the restoration of 5-HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5-HT(1A) receptors alone, in fact results from a shift in balance between 5-HT(1A) and 5-HT(7) receptor function.

Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood-brain barrier.

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography was used to measure brain uptake of [11C]verapamil, which is normally expelled from the brain by P-gp. Cerebral volume of distribution (V(T)) of [11C]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to healthy controls showed a significant decrease of [11C]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [11C]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs. Our results may explain why treatment-resistant depression can develop.

Circulating cerebral S100B protein is associated with depressive symptoms following myocardial infarction.

BACKGROUND: Prevalence of depressive symptoms in the post-myocardial infarction (MI) period varies from 8 to 30%. Cerebral damage after MI, caused by transient ischemia, an inflammatory response or both, may contribute to development of post-MI depression. S100B is an established protein marker of cerebral damage. In a pilot study, the authors assessed whether S100B serum levels are: (1) increased during the week after MI, and (2) related to depressive symptoms during index hospital admission and the year following MI. METHODS: This pilot study is a substudy of the Myocardial Infarction and Depression Intervention Trial (MIND-IT). In 48 patients, serum levels of S100B were available at 1, 2, 3, 4 and 8 days following MI. Subsequently, in 27 patients, depressive symptoms were measured at 0, 3, 6, 9 and 12 months following MI with the Beck Depression Inventory (BDI). In 21 of the initial 48 patients, BDI data were lacking due to refusals to fill out BDI forms or missing data. RESULTS: Significant and transient increases in serum S100B were observed in 81.3% of the 48 patients: 37.5% reached S100B serum levels comparable to serum levels found in acute brain injury (>0.20 microg/l) and 43.8% reached mildly elevated S100B serum levels comparable to serum levels found in depressive disorder (0.10-0.20 microg/l). In 18.7%, no S100B was detected in serum. Using non-parametric Spearman rank correlation tests, a trend towards an association was found between serum S100B and depressive symptoms during the post-MI year (rho values between 0.16 and 0.53) in 27 patients who completed both the S100B serum study and the BDI study. CONCLUSION: Transiently elevated levels of S100B are suggestive of minor acute cerebral damage in the first days following MI and associated with depressive symptoms in the year following MI. Cerebral damage could be an important mechanism in the pathogenesis in a subtype of post-MI depression.

Major depressive disorder is associated with changes in a cluster of serum and urine biomarkers.

Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers). All participants were of Caucasian origin. We developed an algorithm to combine the heterogeneity at biomarker level. This method enabled the identification of correlating biomarkers based on differences in variation and distribution between groups, combined the outcome of the selected biomarkers, and calculated depression probability scores (the "bio depression score"). Phenotype permutation analysis showed a significant discrimination between MDD and euthymic (control) subjects for biomarkers in urine (P < .001), in serum (P = .02) and in the combined serum plus urine result (P < .001). Based on this algorithm, a combination of 8 urine biomarkers and 9 serum biomarkers were identified to correlate with MDD, enabling an area under the curve (AUC) of 0.955 in a Receiver Operating Characteristic (ROC) analysis. Selection of either urine biomarkers or serum biomarkers resulted in AUC values of 0.907 and 0.853, respectively. Internal cross-validation (5-fold) confirmed the association of this set of biomarkers with MDD.

Chronically restricted sleep leads to depression-like changes in neurotransmitter receptor sensitivity and neuroendocrine stress reactivity in rats.

STUDY OBJECTIVES: Frequently disrupted and restricted sleep is a common problem for many people in our Western society. In the long run, insufficient sleep may have repercussions for health and may sensitize individuals to psychiatric diseases. In this context, we applied an animal model of chronic sleep restriction to study effects of sleep loss on neurobiological and neuroendocrine systems that have been implied in the pathophysiology of depression, particularly the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: Adult rats were exposed to a schedule of chronic partial sleep deprivation allowing them only 4 h of sleep per day. Sleep restriction was achieved by placing the animals in slowly rotating drums. To examine the regulation and reactivity of the HPA axis, blood samples were collected to measure adrenocorticotropin (ACTH) and corticosterone (CORT) responses. MEASUREMENTS AND RESULTS: While one day of restricted sleep had no significant effect on HPA axis stress reactivity, sleep restriction for a week caused a blunted pituitary ACTH response in a conditioned fear paradigm. Despite this lower ACTH response, adrenal CORT release was normal. The blunted pituitary response may be related to reduced sensitivity of serotonin-1A receptors and/or receptors for corticotropin-releasing hormone (CRH), since sleep restricted rats showed similar reductions in ACTH release to direct pharmacological stimulation with a serotonin-1A agonist or CRH. CONCLUSIONS: Chronic sleep restriction may lead to changes in neurotransmitter receptor systems and neuroendocrine reactivity in a manner similar to that seen in depression. This experimental study thus supports the hypothesis that disrupted and restricted sleep may contribute to the symptomatology of psychiatric disorders.