Abstract Background Major depressive disorder (MDD) is a heterogeneous disease. More homogeneous psycho(patho)logical dimensions would facilitate MDD research as well as clinical practice. The first ...aim of this study was to find potential dimensions within a broad psychopathological assessment in depressed patients. Second, we aimed at examining how these dimensions predicted course in MDD. Methods Ten psychopathological variables were assessed in 75 MDD inpatients. Factor and regression analyses assessed putative relations between psychopathological factors and depression severity and outcome after 8 weeks of treatment. Results A 3-factor model (eigenvalue: 54.4%) was found, representing a psychomotor change, anhedonia and negative affect factor. Anhedonia and negative affect predicted depression severity ( R2 =0.37, F =20.86, p <0.0001). Anhedonia predicted non-response (OR 6.00, CI 1.46–24.59) and both negative affect (OR 5.69, CI 1.19–27.20) and anhedonia predicted non-remission (OR 9.28, CI 1.85–46.51). Limitations The sample size of the study was relatively modest, limiting the number of variables included in the analysis. Conclusions Results confirm that psychomotor change, anhedonia and negative affect are key MDD dimensions, two of which are related to treatment outcome.
Purpose: Generation Z (Gen Z) will account for a growing proportion of the global workforce in the coming years. Therefore, it is vitally important to understand this generation's unique perspectives ...and preferences regarding work. This exploratory study aims to examine the prioritisation and desirability of Gen Z work values according to respondents' nationality. Design/methodology/approach: Data for this study were collected through a survey among 1,188 undergraduate students enrolled in one university each in China, Germany, the Netherlands and Thailand. ANOVA test and Tukey post hoc analysis were used to find out the difference between the groups based on nationality. Findings: Findings indicate that nationality serves as a key differentiator in work value preferences. The findings challenge the concept of a global Gen Z as only two of the measured values, learning and visible results, were found to have universal appeal across the nationality groups. In spite of increased levels of global interconnectedness and accompanying crossvergence of values, the results show significant statistical differences in work values based on the respondents' nationality. Research limitations/implications: Because of the scope and explorative design of the present study, it cannot be certain that the findings are exclusively from Gen Z characteristics or influenced by other, non-cultural, variables. Practical implications: This study suggests there is a need for study programmes at a tertiary level to embed experiential learning components and individual study pathways in their curricula to enable students to develop realistic expectations about the workplace and their place in it. In turn, these programmes will be able to develop a competitive advantage in higher education landscape. Originality/value: The insights gained can be leveraged by internationally oriented study programmes, such as International Business (IB), to better address Gen Z needs and expectations.
In resting‐state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a ...steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting‐state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine‐induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double‐blind, placebo‐controlled crossover study with subanesthetic S‐Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting‐state fMRI and EEG data. We conducted seed‐based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine‐induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009‐012399‐28).
Purpose
To demonstrate that mapping pelvis conductivity at 3T with deep learning (DL) is feasible.
Methods
210 dielectric pelvic models were generated based on CT scans of 42 cervical cancer ...patients. For all dielectric models, electromagnetic and MR simulations with realistic accuracy and precision were performed to obtain
B1+ and transceive phase (ϕ±). Simulated
B1+ and ϕ± served as input to a 3D patch‐based convolutional neural network, which was trained in a supervised fashion to retrieve the conductivity. The same network architecture was retrained using only ϕ± in input. Both network configurations were tested on simulated MR data and their conductivity reconstruction accuracy and precision were assessed. Furthermore, both network configurations were used to reconstruct conductivity maps from a healthy volunteer and two cervical cancer patients. DL‐based conductivity was compared in vivo and in silico to Helmholtz‐based (H‐EPT) conductivity.
Results
Conductivity maps obtained from both network configurations were comparable. Accuracy was assessed by mean error (ME) with respect to ground truth conductivity. On average, ME < 0.1 Sm−1 for all tissues. Maximum MEs were 0.2 Sm−1 for muscle and tumour, and 0.4 Sm−1 for bladder. Precision was indicated with the difference between 90th and 10th conductivity percentiles, and was below 0.1 Sm−1 for fat, bone and muscle, 0.2 Sm−1 for tumour and 0.3 Sm−1 for bladder. In vivo, DL‐based conductivity had median values in agreement with H‐EPT values, but a higher precision.
Conclusion
Anatomically detailed, noise‐robust 3D conductivity maps with good sensitivity to tissue conductivity variations were reconstructed in the pelvis with DL.
The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, ...are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
Background:
Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1β.
Aims:
This ...first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants.
Methods:
The study had three parts: an ascending-dose study in fasted participants (0.5–300 mg JNJ-54175446); an ascending-dose study in fed participants (50–600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC)50 (105 ng/mL) and EC90 (900 ng/mL) values for central nervous system P2X7 receptor binding.
Results:
Seventy-seven participants received a single oral dose of JNJ-54175446 (n=59) or placebo (n=18). Area under the curve of concentration time extrapolated to infinity (AUC∞) increased dose-proportionally; maximum concentration (Cmax) of plasma (Cmax,plasma) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest Cmax,plasma reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 Cmax in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound Cmax,plasma and Cmax,CSF were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3′-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1β release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC)50:82 ng/mL; 95% confidence interval: 48–94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%).
Conclusion:
Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.
Background:
This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an ...adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood–brain barrier penetration and a clear dose–receptor occupancy relationship was demonstrated using positron emission tomography.
Aims:
The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge.
Methods:
Subjects (N = 64) were randomised to either JNJ-54175446 (50–450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge.
Results:
At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy.
Conclusion:
Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.
Background Reduced reward learning might contribute to the onset and maintenance of major depressive disorder (MDD). In particular, the inability to utilize rewards to guide behavior is hypothesized ...to be associated with anhedonia, a core feature and potential trait marker of MDD. Few studies have investigated whether reduced reward learning normalizes with treatment and/or reward learning predicts clinical outcome. Our goal was to test whether MDD is characterized by reduced reward learning, especially in the presence of anhedonic symptoms, and to investigate the relationship between reward learning and MDD diagnosis after 8 weeks of treatment. Methods Seventy-nine inpatients and 63 healthy control subjects performed a probabilistic reward task yielding an objective measure of participants’ ability to modulate behavior as a function of reward. We compared reward responsiveness between depressed patients and control subjects, as well as high- versus low-anhedonic MDD patients. We also evaluated whether reward-learning deficits predicted persistence of MDD after 8 weeks of treatment. Results Relative to control subjects, MDD patients showed reduced reward learning. Moreover, patients with high anhedonia showed diminished reward learning compared with patients with low anhedonia. Reduced reward learning at study entry increased the odds of a persisting diagnosis of MDD after 8 weeks of treatment (odds ratio 7.84). Conclusions Our findings indicate that depressed patients, especially those with anhedonic features, are characterized by an impaired ability to modulate behavior as a function of reward. Moreover, reduced reward learning increased the odds for the diagnosis of MDD to persist after 8 weeks of treatment.
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 p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group.
Conclusions:
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.
Objectives
Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause ...neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood.
Methods
Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers cytokines, C‐reactive protein and kynurenine metabolites tryptophan (TRP), kynurenine (KYN), 3‐hydroxykynurenine (3‐HK), quinolinic acid (QA), kynurenic acid (KYNA) were measured on 6 time points during 8 months follow‐up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis.
Results
Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor‐α and KYN, KYN/TRP, 3‐HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3‐HK, P = .0004) and a strong association between interferon‐y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow‐up (P = .0008).
Conclusions
Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.
PDF
