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).

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.

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.

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.

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.

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.

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).

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.

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.

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects.

BACKGROUND: Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression. RESULTS: TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04-1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001-1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers. CONCLUSIONS: This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

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.

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.

Measuring pathology using the PANSS across diagnoses: Inconsistency of the positive symptom domain across schizophrenia, schizoaffective, and bipolar disorder.

Although the Positive and Negative Syndrome Scale (PANSS) was developed for use in schizophrenia (SZ), antipsychotic drug trials use the PANSS to measure symptom change also for bipolar (BP) and schizoaffective (SA) disorder, extending beyond its original indications. If the dimensions measured by the PANSS are different across diagnoses, then the same score change for the same drug condition may have different meanings depending on which group is being studied. Here, we evaluated whether the factor structure in the PANSS was consistent across schizophrenia (n = 3647), bipolar disorder (n = 858), and schizoaffective disorder (n = 592). Along with congruency coefficients, Hancock's H, and Jaccard indices, we used target rotations and statistical tests of invariance based on confirmatory factor models. We found the five symptom dimensions measured by the 30-item PANSS did not generalize well to schizoaffective and bipolar disorders. A model based on an 18-item version of the PANSS generalized better across SZ and BP groups, but significant problems remained in generalizing some of the factors to the SA sample. Schizophrenia and bipolar disorder showed greater similarity in factor structure than did schizophrenia and schizoaffective disorder. The Anxiety/Depression factor was the most consistent across disorders, while the Positive factor was the least consistent.

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.

Sirukumab: A Potential Treatment for Mood Disorders?

Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab's effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.

The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine's mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.

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.