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Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted.Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression.Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception.Results: Our data analysis was organized by technology – to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression.Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5‐hydroxytryptophan (5‐HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5‐HTP challenge studies in healthy volunteers were collected. Serum 5‐HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5‐HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5‐HTP could be described using a one‐compartment model with a transit compartment. The typical value for clearance was 20.40 L h−1 and showed inter‐study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5‐HTP PD effect on cortisol data with a slope of 4.16 ng mL−1 h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5‐HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5‐HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK‐PD model.

Music performance anxiety (MPA) is a specific condition for musicians. Although it can have a negative influence on their music careers, little attention is paid to this phenomenon both in the professional environment and in stress research. In the current pilot study, insight was gained into the physiology of the autonomic stress response related to anxiety in musicians when performing on stage by using a wearable biosensor patch for registration of a range of physiological parameters. Also, the validity of two different psychometric questionnaires in objectifying the stress response on stage to predict the individual stress response was explored. The autonomic physiological parameters (heart rate, respiratory rate, skin temperature) of 11 violists and violinists were collected while performing on stage and in resting state using the VitalConnect HealthPatch®. In addition, scores on validated questionnaires in research on MPA (State Anxiety Inventory, Kenny Music Performance Anxiety Inventory, Short Form Health Survey) were collected in order to try to objectify the magnitude of the subjective level of both MPA and experienced stress. The registration of the autonomic parameters showed a significant increase in heart rate, respiratory rate, and stress level from resting state measurements during stage performance. Analysis of heart rate variability showed a shift from indices of parasympathetic nervous system activity during baseline measurements towards indices of sympathetic nervous system activity during stress measurements. Surprisingly, none of the questionnaires was correlated to the physiological stress parameters on stage. In conclusion, the wearable biosensor patch proved to be an adequate tool to assess physiological stress parameters on stage. The different questionnaires did not contribute to the prediction of its occurrence in a group of musicians.

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . Aim: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. Methods: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. Results: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24–0.44), 0.15 (0.11–0.2) and 0.17 (0.12–0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all pConclusions: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.

Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments. The main aim of this meeting was to discuss scientific insights, concepts and methodologies in order to improve drug development for psychiatric disorders. The meeting was designed to bring together stakeholders from academia, pharmaceutical industry, and regulatory agencies. Here we provide a synopsis of the proceedings from the meeting entitled 'New approaches to psychiatric drug development'. New views on psychiatric drug development were presented to address the challenges and pitfalls as identified by the different stakeholders. The general conclusion of the meeting was that drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and 'drugable' processes. To achieve these goals, a closer collaboration between all stakeholders in early stages of development is essential to define the research criteria together and to reach consensus on new quantitative biological methodologies and etiology-directed treatments.

Background: Following remission of an anxiety disorder or a depressive disorder, antidepressants are frequently discontinued and in the case of symptom occurrence reinstated. Reinstatement of antidepressants seems less effective in some patients, but an overview is lacking. This systematic review aimed to provide insight into the magnitude and risk factors of response failure after reinstatement of antidepressants in patients with anxiety disorders, depressive disorders, obsessive-compulsive disorder (OCD), or posttraumatic stress disorder (PTSD). Method: PubMed, Embase, and trial registers were systematically searched for studies in which patients: (1) had an anxiety disorder, a depressive disorder, OCD, or PTSD and (2) experienced failure to respond after reinstatement of a previously effective antidepressant. Results: Ten studies reported failure to respond following antidepressant reinstatement. The phenomenon was observed in 16.5% of patients with a depressive disorder, OCD, and social phobia and occurred in all common classes of antidepressants. The range of response failure was broad, varying between 3.8 and 42.9% across studies. No risk factors for failure to respond were investigated. The overall study quality was limited. Conclusion: Research investigating response failure is scarce and the study quality limited. Response failure occurred in a substantial minority of patients. Contributors to the relevance of this phenomenon are the prevalence of the investigated disorders, the number of patients being treated with antidepressants, and the occurrence of response failure for all common classes of antidepressants. This systematic review highlights the need for studies systematically investigating this phenomenon and associated risk factors.

Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.0%, 19.8%, and 32.8%, respectively), suggesting that the α2 and/or α3 receptor subtypes are involved in GABAergic modulation of prolactin secretion, although possible roles of the α1 and α5 receptor subtypes are not excluded. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.

Background Delirium is a frequently occurring syndrome in patients admitted to the intensive care unit (ICU) or medium care unit (MCU), yet the pathophysiology remains poorly understood. An excess of central serotonin can lead to an altered mental status, associated with autonomic hyperactivity, and neuromuscular excitation. Drugs with serotonergic properties are frequently and for prolonged periods administered to ICU/MCU patients. Therefore, central serotonergic toxicity may constitute a predisposing, contributing or precipitating factor in the emergence of delirium. The purpose of the present study is to determine the number of patients admitted to the ICU or MCU who are diagnosed with delirium and who show characteristics of serotonin toxicity in association with the administration of serotonergic drugs. Methods During a 10-week prospective observational cohort study in the ICU and MCU, patients aged 18 or older, diagnosed with delirium in the ICU or MCU, were included. Patients were considered as delirious in case of a positive CAM-ICU and/or at the start of haloperidol prescription on suspicion of delirium. Once included, patients were screened for recent administered serotonergic drugs and screened for physical signs associated with serotonin toxicity by a standardized physical examination by a specifically trained physician. Results A total of 61 patients diagnosed with delirium were enrolled. In 44 out of 61 patients (72 %), the use of drugs potentially contributing to serotonergic toxicity was recorded. Out of 44 patients, seven (16 %) patients showed physical signs of serotonin toxicity and in addition met the Hunter serotonin toxicity criteria, suggesting the presence of serotonergic toxicity. None of these patients were recognized as such by the treating physicians. Conclusions A significant proportion of delirious patients in the ICU might in fact be classified as suffering from central serotonin toxicity. The awareness of potential serotonin toxicity is low among physicians.

Arginine-vasopressin (AVP) is a physiological co-activator of the hypothalamus–pituitary–adrenal (HPA) axis, together with corticotrophin releasing hormone (CRH). A synthetic analogue of AVP, desmopressin (dDAVP), is often used as a pharmacological tool to assess co-activation in health and disease. The relation between dDAVP’s neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic and non-specific stress effects has not been studied. A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers (6 : 6). dDAVP was administered intravenously as a 10 μg bolus (over 1 min) or a 30 μg incremental infusion (over 60 min). Neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic effects and adverse events (AEs) were recorded, and autonomic nervous system (ANS) activation evaluated. The incremental infusion reached 1.8-fold higher dDAVP concentrations than the bolus. Neuroendocrine effects were similar for the 10 μg dDAVP bolus and the 30 μg incremental infusion, while cardiovascular and coagulatory effects were greater with the 30 µg dose. Osmolality and ANS activity remained uninfluenced. AEs corresponded to dDAVP’s side-effect profile. In conclusion, the neuroendocrine effects of a 10 μg dDAVP bolus administered over 1 min are similar to those of a 30 μg incremental infusion administered over one hour, despite higher dDAVP concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10 μg dDAVP bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen.

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus pituitary adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis. (C) 2010 Elsevier B.V. and ECNP. All rights reserved.

Pharmacological function tests consisting of 100 µg hCRH (corticorelin) and 10 µg dDAVP (desmopressin) mimic endogenous hypothalamus–pituitary–adrenal (HPA) axis activation. However, physiological CRH concentrations preclude informative vasopressinergic co-activation (using dDAVP) and independent quantification of both corticotrophinergic (using hCRH) and vasopressinergic (using dDAVP) activation is limited due to administration on separate occasions. This randomized, double-blind, placebo-controlled, partial five-way crossover study in healthy males and females (six : six) examined whether (1) concomitant administration of dDAVP and hCRH provides more informative vasopressinergic co-activation than dDAVP alone; and (2) whether the administration of dDAVP followed two hours later by hCRH can quantify both vasopressinergic and corticotrophinergic activation on a single test day. Combining 10 µg dDAVP with 10 µg and 30 µg hCRH caused dose-related ACTH and cortisol release which was larger than with 10 µg dDAVP alone and respectively comparable to and greater than that induced by 100 µg hCRH. Using 10 µg dDAVP alone demonstrated limited ACTH release while the effects of 100 µg hCRH two hours later were three times as large. ACTH and cortisol released by 10 µg dDAVP returned to baseline prior to 100 µg hCRH administration and dDAVP did not influence the response to subsequent hCRH administration. Dose-related vasopressinergic co-activation of the HPA axis was induced by combining 10 µg dDAVP with 10 µg and 30 µg hCRH. Combining 10 µg dDAVP with 10 µg hCRH induced the potentially most informative vasopressinergic co-activation since it is not restricted by ceiling or flooring effects. The hCRH response was not affected by prior dDAVP, allowing for a practical function test examining both HPA activation routes on the same day.

5-hydroxytryptophan (5-HTP) is a direct 5-hydroxytryptamine (5-HT) precursor used to assess central serotonergic function. Its use has been limited by a narrow window between neuroendocrine changes and side effects, and variable kinetics related to inconsistent administration modes. By combining 5-HTP with carbidopa (CBD), increased bioavailability for brain penetration and decreased peripheral side effects would be expected, due to reduced peripheral decarboxylation of 5-HTP to 5-HT. A doubleblind, placebo-controlled, single rising dose, four-way crossover trial with placebo randomisation was performed in 15 healthy male volunteers to investigate the neuroendocrine dose–response relationship at various 5-HTP levels; the tolerability and subjective effects of oral 5-HTP at 100, 200 and 300mg combined with CBD and the pharmacokinetic properties of the 5-HTP/CBD-challenge. Dose-dependent increases in average cortisol concentrations were observed. Mean response (area-under-the-curve) over the first 4 hours (SD): 172.0 nmol/L (22.3) for placebo, 258.3nmol/L (72.6) for 100mg, 328.47nmol/L (84.6) for 200mg and 387.3nmol/L (82.4) for 300mg 5-HTP. Similar dose-dependent increases for prolactin were seen while adreno-corticotrophic hormone response was more variable. 5-HTP kinetics were adequately described using a one-compartment model with first-order absorption and a lag time (mean oral clearance 28 L/h interindividual coefficient of variation 31%). Nausea and vomiting occurred dose-dependently as most frequent side effects, resulting in dose-related dropout of 6.6% at 100mg and 45.5% at 300mg 5-HTP. Orally administered 5-HTP combined with CBD is an effective serotonergic challenge test, exhibiting dose-related plasma concentrations and neuroendocrine responsiveness. Frequent occurrence of nausea and vomiting limits the applicability of this challenge at 5-HTP doses above 100mg

Introduction and purpose: Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HIP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NM) and creatine using 7-Tesla (7 T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers. Methods: A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7 day wash-out period. After administration of the oral 5-HTP function test. ACTH and cortisol were measured over 4 h and MRS scans at 71 were performed every 30 min over 3 h measuring Glx: Creatine, Chol:Creatine and NAA:Creatine ratios. Results: In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NM levels over 180 min but induced a significant decrease of Glx at 60 min on post-hoc analysis. 5-Hip-induced significant ACTH release reaching an E-max of 60.2 ng/L at 80 min followed by cortisol with an E-max, of 246.4 ng/mL at 110 min. Conclusions: The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area. (C) 2010 Elsevier Inc. All rights reserved.