This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-& Aring;sberg Depression Rating Scale [MADRS] >= 25) despite an adequate course with ongoing antidepressant for >= 6 weeks to <= 12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.

The antidepressant efficacy and safety of seltorexant monotherapy in major depressive disorder (MDD) was investigated in a placebo-controlled, placebo lead-in, randomized, double-blind, phase 1b study. Participants were randomized to receive seltorexant (20 mg or 40 mg) or placebo. The treatment effect was assessed by changes in the Hamilton Rating Scale for Depression-17 item (HDRS17) from treatment-period baseline to week 5 in lead-in placebo non-responders ("enriched" intent-to-treat analysis set). As a secondary outcome, the effect of seltorexant on HDRS17 was assessed in patients with and without subjective insomnia. Seltorexant's effects on polysomnography, serum cortisol, and cortisol waking response were also measured. In total, 128 participants were enrolled, including 86 in the enriched sample (lead-in placebo non-responders). The mean changes from baseline (SD) in HDRS17 score at week 5 differed significantly across arms: -7.0 (5.04) for seltorexant 20 mg, -5.5 (4.34) for seltorexant 40 mg, and -4.4 (3.67) for placebo (p = 0.0456), which was attributable to the difference between the 20 mg and placebo arms (p = 0.0049). Improvement in depression severity at week 5 for seltorexant 20 mg was greater in patients with higher baseline insomnia severity (nominal p = 0.0059). The treatment benefit in the 20 mg arm remained significant when HDRS scores were adjusted by removing the sleep items (nominal p = 0.0289). The mean HDRS17 change versus placebo was numerically larger in the 20 mg than the 40 mg arm, consistent with data from a previous study in which seltorexant was administered adjunctively to conventional antidepressants. In secondary analyses, the waking cortisol response decreased in the 20 mg arm but not the 40 mg or placebo arms, and while total sleep increased more in the 40 mg arm, this arm also showed reduced REM onset latency and increased stage N1 sleep, which were not evident in the 20 mg arm. These biomarker data suggest mechanistic hypotheses that may account for the apparent curvilinear dose-response relationship of seltorexant. Trial Registration: ClinicalTrials.gov, NCT03374475.

Background: Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. Objective: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. Methods: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1–73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42, T-tau, and P-tau181 were analyzed using commercial ELISA assays. Results: Preoperative L-CSF Aβ42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ= 0.34–0.55, p < 0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aβ42: 0.77–0.88, T-tau: 0.91–0.94, P-tau181: 0.94–0.96, p < 0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ42: V-CSF = 185+0.34*L-CSF, T-tau: Ln(V-CSF) = 3.11+0.49*Ln(L-CSF), P-tau181: V-CSF = 8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ42: V-CSF = 86.7+0.75*L-CSF, T-tau: V-CSF = 86.9+0.62*L-CSF, P-tau181: V-CSF = 2.6+0.74*L-CSF). Conclusion: Aβ42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.

JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) ( N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1–3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

Introduction: The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing.

The core Alzheimer’s Disease cerebrospinal fluid (CSF) biomarkers, amyloid β 1-42 (Aβ 42 ), total tau (T-tau) and phosphorylated tau 181 (P-tau 181 ), have presented added value for differential diagnostics in the field of neurodegenerative diseases. Moreover, the concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar region CSF (L-CSF) has been partly established for idiopathic normal pressure hydrocephalus (iNPH) patients. In this study, we aim to provide conversion factors between V-CSF and L-CSF. Altogether 138 patients were diagnosed for possible iNPH and received ventriculoperitoneal shunt. Lumbar CSF samples were obtained 3-months prior shunt surgery. Additional intraoperative interventricular CSF samples were obtained from 97 patients. Furthermore, follow-up samples of 41 patients were obtained 0-, 3-, 6- and 18-months (0M, 3M, 6M, 18M) postoperatively by shunt valve and lumbar punctures. Aβ 42 , T-tau and P-tau 181 CSF concentrations of samples collected were analyzed using Elecsys (Cohort of 97 patients) and Innotest (Cohort of 41 patients) assays. Preoperative L-CSF Aβ 42 , T-tau and P-tau 181 associated to intraoperative V-CSF (Sprearman ρ=0.54 Aβ 42, r=0.34 T-tau, r=0.55 P-tau, all p<0.001). Strong associations were seen between postoperative L- and V-CSF for all biomarkers in the every follow-up sampling point (Spearman ρ Aβ 42 : 0M=.77, 3M=.88, 6M=.83, 18M=.84) (T-tau: 0M=.92, 3M=.91, 6M=.92, 18M=.94) (P-tau 181 : 0M=.96, 3M=.95, 6M=.94, 18M=.94) (all p<0.0001). Regression equations were determined for intraoperative V-CSF and preoperative L-CSF (Aβ 42 : V-CSF=185+0.34 * L-CSF, T-tau: Ln(V-CSF)=3.11+0.49 * Ln(L-CSF) and P-tau 181 : V-CSF=8.2+0.51 * L-CSF, all p<0.01), and for postoperative V-CSF and L-CSF (Aβ 42 : V-CSF=86.7+0.75 * L-CSF, T-tau: V-CSF=86.9+0.62 * L-CSF and P-tau 181 : V-CSF=1.9+0.75 * L-CSF all p<0.0001). The Aβ 42 , T-tau and P-tau 181 showed linear dependency between ventricular and lumbar CSF for preoperative L-CSF and intraoperative V-CSF as well as for postoperatively collected L-CSF and V-CSF. The regression equations based on these findings provide a novel tool to use V-CSF for diagnostics and prognostics entities that rely on the lumbar CSF concentrations.

JNJ-42165279 is a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of fatty acid amides (FAA) including anandamide (AEA), palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA). We assessed the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with JNJ-42165279 in subjects with social anxiety disorder (SAD). This was a multicenter, double-blind, placebo-controlled study randomizing subjects to 12 weeks of treatment with either JNJ-42165279 (25 mg daily) or placebo (PBO). The primary endpoint was the change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to end of study. Secondary endpoints included the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating Scale (HDRS 17 ), and the Clinical Global Impression-Improvement (CGI-I). Samples were collected for plasma concentration of AEA, PEA, OEA, and JNJ-42165279. A total of 149 subjects were enrolled with a mean baseline LSAS total score of 102.6 (SD 16.84). The mean change from baseline (SD) in LSAS total score at week 12 was numerically greater for JNJ-42165279: −29.4 (27.47) compared to PBO: −22.4 (23.57) but not significant. The percentage of subjects with ≥30% improvement from baseline in the LSAS total score was significantly higher for JNJ-42165279 (42.4%) compared to PBO (23.6%) ( p value = 0.04). The percentage of subjects with a CGI-I score of much or very much improved was also significantly higher for JNJ-42165279 (44.1%) than for PBO (23.6%) ( p value = 0.02). The drug was well tolerated. JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703.

In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.

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.

Total and phosphorylated tau (T-tau, P-T181-tau) in CSF are considered biomarkers of neurodegeneration and disease progression in Alzheimer's disease (AD). Cytoskeletal protein neurofilament light (NFL) would be a universal biomarker of neurodegeneration. Pre-synaptic protein neurogranin (Ng) seems to measure early synaptic degeneration. Our objective was to evaluate biomarker stability prospectively after CSF shunt surgery in iNPH and compare lumbar (L-) and ventricular (V-) CSF. CSF was collected prior to CSF shunt by lumbar puncture. In addition, simultaneous lumbar (L-CSF) and shunt valve puncture (V-CSF) at 0 (1-73 months after CSF shunt placement), 3, 6 and 18 months in 39 patients shunted due to iNPH (26 with confirmed amyloid-β (Aβ) plaques and 13 patients without Aβ pathology in right frontal cortical brain biopsy) at the KUH in Finland. CSF samples were analyzed with commercial ELISAs. Absolute levels of all four biomarkers correlated highly between V-CSF and L-CSF (T-tau: R = 0.83, P-T181-tau: R = 0.92, NFL: R = 0.94, Ng: R = 0.9; all P < 0.0001) but were systematically lower in V-CSF (T-tau: 22%, P-tau: 20%, NFL: 32%, Ng: 21%). No significant difference was seen in the levels of T-tau, P-T181-tau and Ng over 18 months either in L-CSF or V-CSF. However, the NFL levels showed an overall decrease of 6% per month. The levels of measured biomarkers were 20-30% lower in intraventricular CSF compared with lumbar. Longitudinal follow up of 18 months shows that after initial upregulation post-surgery, T-tau, P-tau and Ng are stable in iNPH patients irrespective of the brain biopsy Aβ pathology, while NFL normalized towards its pre-shunt levels.

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 (HDRS 17 ). 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:Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo.OBJECTIVE:Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy.METHODS:Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging.RESULTS:Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau.CONCLUSIONS:S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

Background: Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects. Methods: Five consecutive cohorts of healthy subjects were enrolled and received doses of 5–60 mg orally once daily over 10 days of JNJ-42847922 (n=6) or placebo (n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale. Results: JNJ-42847922 was rapidly absorbed after the morning dose administration. The median tmax ranged from 0.5–1.5 h and mean t1/2 values from 2–3 h. At JNJ-42847922 dose levels ⩾20 mg, mean Cmax and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.

Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ-42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ-42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study. A positron emission tomography study with the FAAH tracer [11 C]MK3168 was conducted to determine brain FAAH occupancy after single and multiple doses of JNJ-42165279. JNJ-42165279 administration resulted in an increase in plasma and CSF FAA. Significant blocking of brain FAAH binding of [11 C]MK3168 was observed after pretreatment with JNJ-42165279. JNJ-42165279 produces potent central and peripheral FAAH inhibition. Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ-42165279. No safety concerns were identified.