Treatment response to esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior without evidence of early response: a pooled post hoc analysis of ASPIRE.

OBJECTIVE: To assess the likelihood of attaining response/remission of depressive symptoms with esketamine nasal spray (ESK) plus standard of care (SoC) vs placebo nasal spray (PBO) plus SoC at 4 weeks in patients with major depressive disorder and active suicidal ideation with intent (MDSI) without early response. METHODS: A post hoc analysis of pooled data from ASPIRE I and ASPIRE II evaluated ESK plus SoC vs PBO plus SoC in adults with MDSI without response (≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] score) at 24 hours after the first dose or at week 1 after the first two doses (ie, 24-hour and week 1 nonresponders). Response and remission (MADRS score ≤ 12) rates were assessed on day 25. RESULTS: The analysis included 362 patients (n = 182, ESK plus SoC; n = 180, PBO plus SoC). Among 24-hour nonresponders, more patients receiving ESK plus SoC vs PBO plus SoC achieved response (63.9% vs 48.0%, P = .010) and remission (35.1% vs 24.4%, P = .074) at day 25. Odds of response/remission were higher with ESK plus SoC vs PBO plus SoC (response: 1.89, 95% CI, 1.17-3.05; remission: 1.48, 95% CI, 0.93-2.35). Similar findings were observed among week 1 nonresponders for response (48.4% vs 34.5%, P = .075), remission (25.0% vs 13.1%, P = .060), and odds of response/remission (response: 2.03, 95% CI, 1.22-3.40; remission: 1.63, 95% CI, 1.01-2.62). CONCLUSIONS: Patients with MDSI not responding within the first week of treatment with ESK plus SoC may still benefit from a full 4-week treatment course.

The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder.

BACKGROUND: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. METHODS: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. RESULTS: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. CONCLUSION: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

Default mode network connectivity change corresponds to ketamine's delayed glutamatergic effects.

Ketamine exerts rapid antidepressant effects peaking 24 h after a single infusion, which have been suggested to be reflected by both reduced functional connectivity (FC) within default mode network (DMN) and altered glutamatergic levels in the perigenual anterior cingulate cortex (pgACC) at 24 h. Understanding the interrelation and time point specificity of ketamine-induced changes of brain circuitry and metabolism is thus key to future therapeutic developments. We investigated the correlation of late glutamatergic changes with FC changes seeded from the posterior cingulate cortex (PCC) and tested the prediction of the latter by acute fractional amplitude of low-frequency fluctuations (fALFF). In a double-blind, randomized, placebo-controlled study of 61 healthy subjects, we compared effects of subanesthetic ketamine infusion (0.5 mg/kg over 40 min) on resting-state fMRI and MR-Spectroscopy at 7 T 1 h and 24 h post-infusion. FC decrease between PCC and dorsomedial prefrontal cortex (dmPFC) was found at 24 h post-infusion (but not 1 h) and this FC decrease correlated with glutamatergic changes at 24 h in pgACC. Acute increase in fALFF was found in ventral PCC at 1 h which was not observed at 24 h and inversely correlated with the reduced dPCC FC towards the dmPFC at 24 h. The correlation of metabolic and functional markers of delayed ketamine effects and their temporal specificity suggest a potential mechanistic relationship between glutamatergic modulation and reconfiguration of brain regions belonging to the DMN.

The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease.

Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo-controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements.

Computational meta-analysis of statistical parametric maps in major depression.

OBJECTIVE: Several neuroimaging meta-analyses have summarized structural brain changes in major depression using coordinate-based methods. These methods might be biased toward brain regions where significant differences were found in the original studies. In this study, a novel voxel-based technique is implemented that estimates and meta-analyses between-group differences in grey matter from individual MRI studies, which are then applied to the study of major depression. METHODS: A systematic review and meta-analysis of voxel-based morphometry studies were conducted comparing participants with major depression and healthy controls by using statistical parametric maps. Summary effect sizes were computed correcting for multiple comparisons at the voxel level. Publication bias and heterogeneity were also estimated and the excess of heterogeneity was investigated with metaregression analyses. RESULTS: Patients with major depression were characterized by diffuse bilateral grey matter loss in ventrolateral and ventromedial frontal systems extending into temporal gyri compared to healthy controls. Grey matter reduction was also detected in the right parahippocampal and fusiform gyri, hippocampus, and bilateral thalamus. Other areas included parietal lobes and cerebellum. There was no evidence of statistically significant publication bias or heterogeneity. CONCLUSIONS: The novel computational meta-analytic approach used in this study identified extensive grey matter loss in key brain regions implicated in emotion generation and regulation. Results are not biased toward the findings of the original studies because they include all available imaging data, irrespective of statistically significant regions, resulting in enhanced detection of additional areas of grey matter loss.

Predictors of response and remission in patients with treatment-resistant depression: A post hoc pooled analysis of two acute trials of esketamine nasal spray.

This exploratory post hoc analysis of two pooled 4-week, phase 3, double-blind, placebo- and active-controlled studies that compared esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD; n = 310) with a newly initiated oral AD plus placebo nasal spray (AD+PBO; n = 208) in patients with treatment-resistant depression (TRD) examined baseline patient demographic and psychiatric characteristics as potential predictors of response (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) and remission (MADRS total score ≤12) at day 28. Overall, younger age, any employment, fewer failed ADs in the current depressive episode, and reduction in Clinical Global Impression-Severity (CGI-S) score at day 8 were significant positive predictors of response and remission at day 28. Treatment assignment was an important predictor of both response and remission. Patients treated with ESK+AD had 68% and 55% increased odds of achieving response and remission, respectively, versus those treated with AD+PBO. In the ESK+AD group, attainment of response and remission was more likely in patients who were employed, without significant anxiety at baseline, and who experienced a reduction in CGI-S score at day 8. Identification of predictors of response and remission may facilitate identification of those patients with TRD most likely to benefit from ESK+AD. Trial Registration: ClinicalTrials.gov: NCT02417064 (clinicaltrials.gov/ct2/show/NCT02417064) and NCT02418585 (clinicaltrials.gov/ct2/show/NCT02418585).

An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.

Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder.

Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently depressed MDD subjects extend to or persist in patients who experience prolonged remission. The aim of the present study was to investigate gray matter (GM) differences in unmedicated, currently-depressed participants (dMDD) and unmedicated, currently-remitted (rMDD) participants with MDD compared to healthy controls (HC). The GM density and volume were compared across groups using voxel-based morphometry, a quantitative neuroanatomical technique, and high-resolution MRI images from 107 HC, 58 dMDD and 27 rMDD subjects. Relative to the HC group the dMDD group had reduced GM in the dorsal anterolateral (DALPFC), the dorsomedial (DMPFC) and the ventrolateral prefrontal cortex (VLPFC). Relative to the rMDD group the dMDD group showed reduced GM in the DALPFC, the VLPFC, the anterior cingulate cortex (ACC), the precuneus and the inferior parietal lobule. No regions were identified in which the rMDD group showed significantly lower GM compared to the HC group after p-values were corrected for the number of comparisons performed. In unmedicated patients in the depressed phase of MDD, we found evidence of morphometric abnormalities in DALPFC and in medial prefrontal cortical regions belonging to the visceromotor network. These findings, along with the absence of GM abnormalities in the remitted sample imply a possible link between greater GM tissue and better clinical outcome. Consistent with other neuroimaging and post-mortem neuropathological studies of MDD, we also found evidence of decreased white matter in patients with dMDD and rMDD.

Association of Hippocampal Subfields, CSF Biomarkers, and Cognition in Patients With Parkinson Disease Without Dementia.

OBJECTIVE: To examine whether hippocampal volume loss is primarily associated with cognitive status or pathologic ß-amyloid 1-42 (Aß42) levels, this study compared hippocampal subfield volumes between patients with Parkinson disease (PD) with mild cognitive impairment (PD-MCI) and without cognitive impairment (PD-CN) and between patients with low and high Aß42 levels, in addition exploring the relationship among hippocampal subfield volumes, CSF biomarkers (Aß42, phosphorylated and total tau), neuropsychological tests, and activities of daily living. METHODS: Forty-five patients with PD without dementia underwent CSF analyses and MRI as well as comprehensive motor and neuropsychological examinations. Hippocampal segmentation was conducted using FreeSurfer image analysis suite 6.0. Regression models were used to compare hippocampal subfield volumes between groups, and partial correlations defined the association between variables while controlling for intracranial volume (ICV). RESULTS: Linear regressions revealed cognitive group as a statistically significant predictor of both the hippocampal-amygdaloid transition area (HATA; ß = -0.23, 95% CI -0.44 to -0.02) and the cornu ammonis 1 region (CA1; ß = -0.28, 95% confidence interval [CI] -0.56 to -0.02), independent of disease duration and ICV, with patients with PD-MCI showing significantly smaller volumes than PD-CN. In contrast, no subfields were predicted by Aß42 levels. Smaller hippocampal volumes were associated with worse performance on memory, language, spatial working memory, and executive functioning tests. The subiculum was negatively correlated with total tau levels (r = -0.37, 95% CI -0.60 to -0.09). CONCLUSION: Cognitive status, but not CSF Aß42, predicted hippocampal volumes, specifically the CA1 and HATA. Hippocampal subfields were associated with various cognitive domains, as well as with tau pathology.

Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Synaptopathy including alterations of synaptic plasticity (long-term potentiation, LTP) may precede neurodegeneration in Alzheimer's disease (AD). We studied LTP-like corticospinal plasticity induced by paired-associative stimulation (PASLTP) in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI). METHODS: 15 AD and 15 aMCI patients, and 23 demographically matched healthy controls (HC) were included. Resting motor threshold (RMT) and stimulus intensity needed to evoke motor evoked potentials (MEP) of 1 mV (SI1mV) were obtained as single-pulse transcranial magnetic stimulation (TMS) measures of corticospinal excitability in a hand muscle at baseline, followed by PASLTP using standard methodology. MEP amplitude change after PASLTP normalized to baseline was defined as plasticity effect. All measures were repeated in two visits for examining test-retest reliability. RESULTS: SI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test-retest reliability in all groups. PASLTP indiscriminately did not induce LTP-like plasticity in any of the groups, and expressed poor test-retest reliability. CONCLUSIONS: aMCI shows corticospinal hyperexcitability, consistent with glutamatergic excitotoxicity in early-stage AD. Possible abnormalities of LTP-like plasticity could not be reliably tested with the standard PASLTP protocol due to massive inter-subject variability even in HC, and poor test-retest reliability. SIGNIFICANCE: Findings indicate corticospinal hyperexcitability in prodromal AD, and reliability of single-pulse TMS measures for identifying such abnormality. In contrast, the standard PASLTP protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test-retest reliability.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies.

Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment.Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria.Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO.Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray.Trial Registration: ClinicalTrials.gov identifiers NCT02417064 and NCT02418585.

New therapeutic targets for mood disorders.

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

Executive Function Is Related to the Urinary Urgency in Non-demented Patients With Parkinson's Disease.

Introduction: Evidence suggests urinary urgency is associated with cognitive impairment in a subtype of Parkinson's disease (PD) patients. This study investigates if cognitive impairment independently predicts the presence of urinary dysfunction. Methods: We report data of 189 idiopathic PD patients, excluding those with concomitant diseases or medication interacting with bladder function. A standardized questionnaire was used to define the presence of urinary urgency. All patients underwent a comprehensive motor, cognitive non-motor and health-related quality of life (HRQoL) assessment. Multivariable linear regression analysis was performed to identify independent variables characterizing urinary urgency in PD (PD-UU), which were assigned as discriminant features to estimate their individual contribution to the phenotype of the PD-UU group. Results: Of 189 PD patients, 115 (60.8%) reported PD-UU. The linear regression analysis showed that among cognitive domains, executive function (EF; p = 0.04) had a significant negative association with PD-UU. In a second model, scores of the Montreal Cognitive Assessment (MoCA) significantly differentiated between study groups (p = 0.007) and also non-motor symptom (NMS) burden (p < 0.001). The third model consisted of reports of HRQoL, of which stigma was the only subscale of the Parkinson's Disease Questionnaire (PDQ-39) differentiating between patients with and without PD-UU (p = 0.02). The linear discriminant analysis provided evidence that the combination of EF, NMS burden, nocturia, and stigma discriminated between groups with 72.4% accuracy. Conclusion: In our large, non-demented PD cohort, urinary urgency was associated with executive dysfunction (EF), supporting a possible causative link between both symptoms. A combination of neuropsychological and non-motor aspects identified patients with PD-UU with high discriminative accuracy.

Association of cognitive activities of daily living (ADL) function and nonmotor burden in nondemented Parkinson's disease patients.

OBJECTIVE: In Parkinson's disease (PD), nonmotor symptoms (NMS) considerably influence disease progression and cognitive decline. Depression, anxiety, sleep disturbances, and hallucinations (DASH), may indicate a risk for dementia (PDD). Mild impairments in activities of daily living (ADL) caused by cognitive dysfunction are also present in the prodromal stage of PDD. The association of both factors has been sparsely investigated. Aim was to evaluate these specific NMS in a large nondemented PD cohort and their co-occurrence with cognitive dysfunction and ADL impairments. METHOD: Data of 226 PD patients was analyzed. Using corresponding items, two DASH scores were constructed from the NMS-Scale and Parkinson's disease Questionnaire (PDQ-39). Correlations between DASH scores and PDD risk factors were examined. PD patients with mild cognitive impairment (PD-MCI) were additionally split into patients with low and high DASH burden, the latter group additionally stratified by presence of cognitive-driven ADL impairment. RESULTS: DASH-NMS scores differed significantly between PD-MCI and cognitively normal (PD-CN) patients (p = .04), while the DASH-PDQ did not (p = .73). The only significant predictor of the DASH-NMS score was cognitive-driven ADL (p = .01). PD-MCI patients with a high DASH burden and more cognitive ADL impairment presented with worse global cognition than patients with a low burden (p = .045). CONCLUSION: Our results show that the DASH-NMS is superior to the DASH-PDQ score, related to the severity of cognitive impairment, and strongly influenced by cognitive-driven ADL impairment. Presence of DASH symptoms and cognitive-ADL in PD-MCI patients may define a risk group for PDD conversion. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Assessment of cognitive-driven activity of daily living impairment in non-demented Parkinson's patients.

The core criterion for Parkinson's disease dementia (PDD) is the impairment in activities of daily living (ADL) function primarily caused by cognitive, not motor symptoms. There is evidence to assume that mild ADL impairments in mild cognitive impairment (PD-MCI) characterize those patients at high risk for dementia. Data of 216 Parkinson's disease (PD) patients assessed with comprehensive motor and neuropsychological assessments were analysed. Based on linear regression models, subscores of the Functional Activities Questionnaire (FAQ) primarily reflecting patients' global cognitive status (FAQC ) or PD-related motor severity (FAQM ) were developed. A quotient (FAQQ ) of both scores was calculated, with values >1 indicating more cognitive- compared to motor-driven ADL impairment. Both FAQC and FAQM scores were higher in PD-MCI than cognitively normal (PD-CN) patients, indicating more severe cognitive- and motor-driven ADL impairments in this group. One third (31.6%) of the PD-MCI group had a FAQQ score >1, which was significantly different from patients with PD-CN (p = .02). PD-MCI patients with an FAQQ score >1 were more impaired on tests assessing attention (p = .019) and language (p = .033) compared to PD-MCI patients with lower FAQQ values. The differentiation between cognitive- and motor-driven ADL is important, as the loss of functional capacity is the defining factor for a diagnosis of PDD. We were able to differentiate the cognitive-driven from the motor-driven ADL impairments for the FAQ. PD-MCI patients with more cognitive- compared to motor-driven ADL impairments may pose a risk group for conversion to PDD and can be targeted for early treatments.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

Valproate activates the Notch3/c-FLIP signaling cascade: a strategy to attenuate white matter hyperintensities in bipolar disorder in late life?

OBJECTIVES: Increased prevalence of deep white matter hyperintensities (DWMHs) has been consistently observed in patients with geriatric depression and bipolar disorder. DMWHs are associated with chronicity, disability, and poor quality of life. They are thought to be ischemic in their etiology and may be related to the underlying pathophysiology of mood disorders in the elderly. Notably, these lesions strikingly resemble radiological findings related to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome. CADASIL arises from mutations in Notch3, resulting in impaired signaling via cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein (c-FLIP) through an extracellular signal-regulated kinase (ERK)-dependent pathway. These signaling abnormalities have been postulated to underlie the progressive degeneration of vascular smooth muscle cells (VSMC). This study investigates the possibility that the anticonvulsant valproate (VPA), which robustly activates the ERK mitogen-activated protein kinase (MAPK) cascade, may exert cytoprotective effects on VSMC through the Notch3/c-FLIP pathway. METHODS: Human VSMC were treated with therapeutic concentrations of VPA subchronically. c-FLIP was knocked down via small interfering ribonucleic acid transfection. Cell survival, apoptosis, and protein levels were measured. RESULTS: VPA increased c-FLIP levels dose- and time-dependently and promoted VSMC survival in response to Fas ligand-induced apoptosis in VSMC. The anti-apoptotic effect of VPA was abolished by c-FLIP knockdown. VPA also produced similar in vivo effects in rat brain. CONCLUSIONS: These results raise the intriguing possibility that VPA may be a novel therapeutic agent for the treatment of CADASIL and related disorders. They also suggest that VPA might decrease the liability of patients with late-life mood disorders to develop DWMHs.

Bifactor Modeling of the Positive and Negative Syndrome Scale: Generalized Psychosis Spans Schizoaffective, Bipolar, and Schizophrenia Diagnoses.

Objective: Common genetic variation spans schizophrenia, schizoaffective and bipolar disorders, but historically, these syndromes have been distinguished categorically. A symptom dimension shared across these syndromes, if such a general factor exists, might provide a clearer target for understanding and treating mental illnesses that share core biological bases. Method: We tested the hypothesis that a bifactor model of the Positive and Negative Syndrome Scale (PANSS), containing 1 general factor and 5 specific factors (positive, negative, disorganized, excited, anxiety), explains the cross-diagnostic structure of symptoms better than the traditional 5-factor model, and examined the extent to which a general factor reflects the overall severity of symptoms spanning diagnoses in 5094 total patients with a diagnosis of schizophrenia, schizoaffective, and bipolar disorder. Results: The bifactor model provided superior fit across diagnoses, and was closer to the "true" model, compared to the traditional 5-factor model (Vuong test; P < .001). The general factor included high loadings on 28 of the 30 PANSS items, omitting symptoms associated with the excitement and anxiety/depression domains. The general factor had highest total loadings on symptoms that are often associated with the positive and disorganization syndromes, but there were also substantial loadings on the negative syndrome thus leading to the interpretation of this factor as reflecting generalized psychosis. Conclusions: A bifactor model derived from the PANSS can provide a stronger framework for measuring cross-diagnostic psychopathology than a 5-factor model, and includes a generalized psychosis dimension shared at least across schizophrenia, schizoaffective, and bipolar disorder.

Validation of a novel Montreal Cognitive Assessment scoring algorithm in non-demented Parkinson's disease patients.

INTRODUCTION: The early diagnosis of mild cognitive impairment (PD-MCI) in Parkinson's disease (PD) is essential as it increases the future risk for PD dementia (PDD). Recently, a novel weighting algorithm for the Montreal Cognitive Assessment (MoCA) subtests has been reported, to best discriminate between those with and without cognitive impairment in PD. The aim of our study was to validate this scoring algorithm in a large sample of non-demented PD patients, hypothesizing that the weighted MoCA would have a higher diagnostic accuracy for PD-MCI than the original MoCA. METHODS: In 202 non-demented PD patients, we evaluated cognitive status, clinical and demographic data, as well as the MoCA with a weighted and unweighted score. Receiver operating characteristic (ROC) curve analysis was used to evaluate discriminative ability of the MoCA. Group comparisons and ROC analysis were performed for PD-MCI classifications with a cut-off ≤ 1, 1.5, and 2 standard deviation (SD) below appropriate norms. RESULTS: PD-MCI patients scored lower on the weighted than the original MoCA version (p < 0.001) compared to PD patients with normal cognitive function. Areas under the curve only differed significantly for the 2 SD cut-off, leading to an increased sensitivity of the weighted MoCA score (72.9% vs. 70.5%) and specificity compared to the original version (79.0% vs. 65.4%). CONCLUSIONS: Our results indicate better discriminant power for the weighted MoCA compared to the original for more advanced stages of PD-MCI (2 SD cut-off). Future studies are needed to evaluate the predictive value of the weighted MoCA for PDD.

Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration-QTc Analysis.

Nonclinical assays with JNJ-54861911, a ß-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (Cmax ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.