A web-based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes.

AIMS: To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. METHODS: Eligible patients in Japan (aged 18-59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self-reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5-Dimension 5-Levels questionnaire (EQ-5D-5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. RESULTS: In total, 3376 patients were included in the analysis (56% male; 48% aged 50-59 years). Overall, 67.1% of patients self-reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ-9, GAD-7, WSAS, and EQ-5D-5L scores (correlation coefficients: 0.67, 0.55, 0.56, -0.51, respectively; all p < 0.0001). Descriptive analyses showed that one-third of patients reporting EB symptoms did not tell their physician, with two-thirds finding these symptoms distressing and likely to affect recovery. CONCLUSION: EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD.

Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Goal Attainment Scaling for Depression: Validation of the Japanese GAS-D Tool in Patients with Major Depressive Disorder.

Purpose: Goal attainment scaling (GAS) has been proposed as a person-centric, semi-quantitative measure that assimilates achievement of individually set goals into a single standardized "goal attainment score" that can be compared at the population level. We aimed to examine the reliability and validity of the Japanese version of the GAS for depression (GAS-D) tool in assessing goal attainment in people living with major depressive disorder (MDD). Patients and Methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the GAS-D and other clinical rating scales at baseline and Weeks 8, 12 and 24. Results: Goal attainment was significantly associated with symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) scale, confirming convergent validity. In particular, GAS-D scores were significantly related to MADRS total score at Weeks 12 and 24, indicating that improvements in overall symptom severity with vortioxetine treatment were likely to be reflected in the achievement of individualized treatment goals. With an intraclass correlation coefficient of 0.67 (95% CI 0.45-0.82), the GAS-D also showed moderate test-retest reliability between Weeks 8 and 12 while proving independent of demographic characteristics. Conclusion: The results of this open-label study support the use of the GAS-D as a valid and sensitive outcome measure in the assessment of treatment response in MDD.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Assessing Reliability and Validity of the Oxford Depression Questionnaire (ODQ) in a Japanese Clinical Population.

Purpose: Originally developed in English, the Oxford Depression Questionnaire (ODQ) is a patient-reported scale specifically developed for assessing emotional blunting in people with major depressive disorder (MDD). We aimed to examine the reliability and validity of the Japanese version of the ODQ. Patients and methods: This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the ODQ and other clinical rating scales at baseline and Weeks 8, 12 and 24. Results: One hundred and sixteen patients initiated vortioxetine and had ≥1 post-baseline visit. Directionally, the associations between ODQ scores and other clinical measures were as expected and demonstrated good concurrent validity. Factor analysis shows that the scale has a good fit for three factors. The Cronbach's α coefficient was 0.912, and the scale also showed good test-retest reliability with intraclass correlation coefficients for the ODQ total score and domains ranging between 0.69 and 0.82. ODQ scores had strong positive correlations with symptom severity assessed using the Montgomery and Åsberg Depression Rating Scale and were moderately correlated with work productivity, overall functioning, and quality of life scales. Conclusion: Data from this prospective analysis confirm that the Japanese version of the ODQ retains the good validity and reliability of the original English scale and is suitable for use in prospective studies wanting to capture treatment effects on emotional blunting in MDD.

Blunted diurnal interleukin-6 rhythm is associated with amygdala emotional hyporeactivity and depression: a modulating role of gene-stressor interactions.

Background: The immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions. Methods: One hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored. Results: The blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (t = 3.67, FWE-corrected p = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (F = 19.71, p < 0.001). When considered in a comprehensive model, the diminished diurnal pattern predicted greater depressive symptoms (ß = -0.40), modulated by the amygdala hypoactivity (ß = 0.36) and rs1800796-stressor interactions (ß = -0.41; all p < 0.001). Conclusion: Here we show that the blunted interleukin-6 diurnal rhythm predicts depressive symptoms, modulated by amygdala emotional hyporeactivity and gene-stressor interactions. These findings indicate a potential mechanism underlying vulnerability to depressive disorders, suggesting their early detection, prevention, and treatment through the understanding of immune system dysregulation.

Exploring the role of empathy in prolonged grief reactions to bereavement.

Grief reactions to the bereavement of a close individual could involve empathy for pain, which is fundamental to social interaction. To explore whether grief symptoms interact with social relatedness to a person to whom one directs empathy to modulate the expression of empathy, we administered an empathy task to 28 bereaved adults during functional magnetic resonance imaging, in which participants were subliminally primed with facial stimuli (e.g., faces of their deceased or living relative, or a stranger), each immediately followed by a visual pain stimulus. Individuals' grief severity promoted empathy for the pain stimulus primed with the deceased's face, while it diminished the neural response to the pain stimulus primed with the face of either their living relative or a stranger in the medial frontal cortex (e.g., the right dorsal anterior cingulate cortex). Moreover, preliminary analyses showed that while the behavioral empathic response was promoted by the component of "longing" in the deceased priming condition, the neural empathic response was diminished by the component of "avoidance" in the stranger priming condition. Our results suggest an association between grief reactions to bereavement and empathy, in which grief symptoms interact with interpersonal factors to promote or diminish empathic responses to others' pain.

Effects of integrated hospital treatment on the default mode, salience, and frontal-parietal networks in anorexia nervosa: A longitudinal resting-state functional magnetic resonance imaging study.

The psychopathology of patients with anorexia nervosa has been hypothesized to involve inappropriate self-referential processing, disturbed interoceptive awareness, and excessive cognitive control, including distorted self-concern, disregard of their own starvation state, and extreme weight-control behavior. We hypothesized that the resting-state brain networks, including the default mode, salience and frontal-parietal networks, might be altered in such patients, and that treatment might normalize neural functional connectivity, with improvement of inappropriate self-cognition. We measured resting-state functional magnetic resonance images from 18 patients with anorexia nervosa and 18 healthy subjects before and after integrated hospital treatment (nourishment and psychological therapy). The default mode, salience, and frontal-parietal networks were examined using independent component analysis. Body mass index and psychometric measurements significantly improved after treatment. Before treatment, default mode network functional connectivity in the retrosplenial cortex and salience network functional connectivity in the ventral anterior insula and rostral anterior cingulate cortex were decreased in anorexia nervosa patients compared with those in controls. Interpersonal distrust was negatively correlated with salience network functional connectivity in the rostral anterior cingulate cortex. Default mode network functional connectivity in the posterior insula and frontal-parietal network functional connectivity in the angular gyrus were increased in anorexia nervosa patients compared with those in controls. Comparison between pre- and post-treatment images from patients with anorexia nervosa exhibited significant increases in default mode network functional connectivity in the hippocampus and retrosplenial cortex, and salience network functional connectivity in the dorsal anterior insula following treatment. Frontal-parietal network functional connectivity in the angular cortex showed no significant changes. The findings revealed that treatment altered the functional connectivity in several parts of default mode and salience networks in patients with anorexia nervosa. These alterations of neural function might be associated with improvement of self-referential processing and coping with sensations of discomfort following treatment for anorexia nervosa.

Validation and Functional Relevance of the Short Form of the Perceived Deficits Questionnaire for Depression for Japanese Patients with Major Depressive Disorder.

Purpose: To validate the five-item version of the Perceived Deficits Questionnaire for Depression (PDQ-D-5) for assessing subjective cognitive function in Japanese patients with major depressive disorder (MDD) using data from the PERFORM-J study. Patients and Methods: A total of 518 Japanese outpatients diagnosed with MDD were assessed on severity of depressive symptoms, cognitive function, social and work function, and quality of life (QoL) over 6 months following initiation of antidepressant therapy. This post hoc analysis evaluated the internal consistency and convergent validity of the PDQ-D-5 in relation to the original PDQ-D-20. Correlations of scores on these measures were examined at each time point and over time. The same set of analyses was explored between PDQ-D-5 and the Patient Health Questionnaire-nine-item (PHQ-9), Montgomery-Asberg Depression Rating Scale (MADRS), Digit Symbol Substitution Test (DSST), five-level version of EQ-5D (EQ-5D-5L), Sheehan Disability Scale (SDS), and Work Productivity and Activity Impairment (WPAI) questionnaire. Results: PDQ-D-5 scores showed good internal consistency. Strong positive correlations were observed between PDQ-D-5 and PDQ-D-20 at each time point (correlation coefficient: baseline, 0.94; month 1, 0.94; month 2, 0.96; month 6, 0.96) and over time (0.92) (all p < 0.0001). Longitudinally, there were positive correlations between PDQ-D-5 scores versus those on the PHQ-9, MADRS, and SDS. Similarly, negative correlations were noted between PDQ-D-5 scores and EQ-5D-5L and DSST scores to a variable degree. There were moderate positive correlations over time between PDQ-D-5 and all WPAI subscale scores except those on absenteeism. Conclusion: PDQ-D-5 scores rated in Japanese patients with MDD were found to adequately represent scores on the PDQ-D-20. The short version also showed associations with several measures of functional outcome, depression severity and QoL. This validates the PDQ-D-5 as a feasible and clinically reliable tool to assess subjective experience on cognition, which is applicable to time-limited consultations. UMIN Clinical Trials Registry for Primary Study: UMIN000024320.

Association between baseline cognitive symptoms and the subsequent presenteeism and global function in patients with major depressive disorder.

Cognitive symptoms in major depressive disorder (MDD) contribute to impaired functional abilities and work productivity, particularly presenteeism. We investigated the association between baseline cognitive symptoms and subsequent presenteeism, and global functional impairment in Japanese patients with MDD from PERFORM-J (Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder in Japan) - a 6-month, multicenter, epidemiological study data. A total of 518 patients initiating antidepressant monotherapy (first-line or switched from another drug) were enrolled. Assessments include Perceived Deficits Questionnaire - Depression (PDQ-D) for cognitive complaints, Sheehan Disability Scale (SDS) for global function (analysed n = 318), and Work Productivity and Activity Impairment Questionnaire for presenteeism (analysed n = 122). A strong association between changes in presenteeism and changes in SDS scores (r: total = 0.636; work/school = 0.686) was observed. After adjusting for sociodemographic and MDD-related factors, patients without cognitive complaints at baseline showed lower odds of impaired presenteeism at 6 months versus patients with cognitive complaints (0.243, 95% CI: 0.079 to 0.747, p = 0.014) and also in patients with first episode of MDD against with recurrent MDD (0.327 (95% CI: 0.136 to 0.787). Similarly, patients without cognitive complaints had healthier global functioning (lower mean SDS total score) than patients with cognitive complaints (8.3 vs 11.2; 95% CI, -5.189 to -0.578; p = 0.014). First depressive episode (lower risk of presenteeism), being male, and low baseline SDS total score (better global functioning) were also associated with improved outcomes. These results highlight the potential value of baseline PDQ-D scores in predicting subsequent workplace and global functioning in patients undergoing treatment for MDD.

Health-Related Quality of Life Over 6 Months in Patients With Major Depressive Disorder Who Started Antidepressant Monotherapy.

OBJECTIVES: Major depressive disorder (MDD) is increasing worldwide and is associated with impaired quality of life (QOL). This study aimed to assess the QOL and its association with cognitive symptoms in patients with MDD who started antidepressant monotherapy. METHODS: Data from the PERFORM (Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder) study were analyzed. A descriptive epidemiological analysis on EQ-5D-5L utility score, the level of each dimension, and the EuroQoL visual analog scale value was conducted at 4 visits during 6 months' follow-up. The association between cognitive complaints and changes in QOL measures was analyzed using multivariate linear regression analysis. RESULTS: The median EQ-5D-5L utility score improved from 0.67 at baseline to 0.82 at month 6. Although the proportion of patients reporting level 1 (no problem) in every dimension of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression increased over time, less than half of the patients achieved level 1 in pain/discomfort and depression/anxiety, which were closely related to depression and usual activities at month 6. Patients with no cognitive complaints or no history of MDD at baseline showed greater improvement in EQ-5D-5L utility scores and EuroQoL visual analog scale value for measuring QOL than those with these characteristics. CONCLUSIONS: Treatment over 6 months improved QOL in patients with MDD although there remained room for improvement in dimensions of usual activities, pain/discomfort, and depression/anxiety. Cognitive complaints or history of MDD at baseline predicted less improvement in QOL at 6 months. Any history of MDD might delay improvement in QOL after treatment.

Therapeutic Potential of Vortioxetine for Anhedonia-Like Symptoms in Depression: A Post Hoc Analysis of Data from a Clinical Trial Conducted in Japan.

AIM: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder. METHODS: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0-17 or ≥18). RESULTS: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was -1.34 for vortioxetine 10 mg (P = 0.0300) and -1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was -3.11 (10 mg dose) and -3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥18), and -2.08 (10 mg) and -2.61 (20 mg) for patients with a lower baseline score (0-17). CONCLUSION: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.

Implicit and explicit emotional memory recall in anxiety and depression: Role of basolateral amygdala and cortisol-norepinephrine interaction.

Anxiety and depression are linked to both explicit and implicit memory biases, which are defined as the tendency to preferentially recall emotionally negative information at conscious and subconscious levels, respectively. Functional connectivity (FC) of the basolateral amygdala (BLA) and related stress hormones (i.e., cortisol and norepinephrine) are purportedly implicated in these biases. However, previous findings on memory biases in anxiety and depression have been inconsistent, likely due to their symptomatic complications. Therefore, the underlying neurobiological mechanism remains unclear. We thus investigated whether anxiety and depression as premorbid predispositions are related to the memory biases, and whether FC of BLA, cortisol, and 3-methoxy-4-hydroxyphenylglycol (MHPG: a major metabolite of norepinephrine) would affect the anxiety/depression-related biased memory recall in 100 participants without psychiatric symptomatology. Psycho-behavioral assessment, resting-state fMRI scans, and saliva collection at 10-points-in-time across two days were conducted. Correlations of memory biases with anxiety/depression and neurobiological markers were explored. As a result, neither anxiety nor depression were correlated with explicit memory bias to negative (vs. positive) information, although depression was associated with better recall of the negative stimuli only when they were perceived as self-relevant. In contrast, both anxiety and depression were correlated with implicit memory bias; however, the effects were solely explained by anxiety. Furthermore, FC of the BLA with subgenual anterior cingulate cortex (sgACC) and the synergetic effect of cortisol and MHPG uniquely affected the implicit memory bias. These findings suggest that anxiety facilitates an initial snapshot of negative information and can be accompanied by depression when the information creates negative semantic associations with the self. The BLA-sgACC neural connectivity and cortisol-norepinephrine interaction that are associated with the implicit memory bias might be one of the important neurobiological targets in the prevention and treatment for comorbid anxiety and depressive disorders.

Prediction of residual cognitive disturbances by early response of depressive symptoms to antidepressant treatments in patients with major depressive disorder.

BACKGROUND: Patients with major depressive disorder (MDD) frequently retain cognitive disturbances after recovery from mood symptoms. We investigated the relationship between early response of mood symptoms and/or remission, and residual cognitive disturbances after 6 months of antidepressant treatment. METHODS: 518 patients with MDD were followed up for 6 months after antidepressant treatment initiation (first-line or switch from a previous drug). Subjective and objective cognitive disturbances were assessed by the Perceived Deficits Questionnaire - Depression (PDQ-D) and digit symbol substitution test (DSST), respectively. Depressive symptoms, as well as remission and early response to treatment, were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Multivariable linear and logistic regression models were used to adjust for confounders. RESULTS: Early response of depressive mood (≥50% reduction in MADRS score at month 1) was related with fewer residual subjective cognitive symptoms, as evaluated by the PDQ-D at month 6 (p<0.001). Likewise, early remission status at month 2 was inversely associated with PDQ-D scores at month 6 (p<0.001). Among patients with baseline DSST scores of ≥1 standard deviation below the norm, early response/remission was associated with better performance on the DSST at month 6 (p<0.05). LIMITATIONS: The cohort may not be representative of the general MDD patient population, and the possible influence of concomitant medications was not evaluated. CONCLUSIONS: These findings suggest that early improvements in depressive symptoms predict better cognitive outcomes in patients with MDD. Grouping of patients by mood and cognition status in early stages of antidepressant treatments may facilitate efforts to improve long-term functional outcomes.

Early Improvement with Vortioxetine Predicts Response and Remission: A Post Hoc Analysis of Data from a Clinical Trial Conducted in Japan.

AIM: Several weeks of treatment with an antidepressive agent may be required before efficacy is demonstrated in patients with major depressive disorder. This study investigated the predictive value of early partial improvement with vortioxetine for treatment response and remission. METHODS: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 26. The key outcomes were the predictive value of early partial improvement (reduction in MADRS total score of ≥20% from baseline to week 2) with vortioxetine for MADRS response (≥50% decrease in score from baseline) and remission (decrease in score to ≤10) at week 8. RESULTS: Relevant data were available for 478 patients; 62/158 patients receiving placebo, 71/162 receiving vortioxetine 10 mg, and 66/158 receiving vortioxetine 20 mg were early improvers. Early improvers receiving vortioxetine (10 mg or 20 mg) were more likely than non-early improvers to achieve a week 8 response (71.2-73.2% vs 29.7-38.0%) or remission (50.7-51.5% vs 17.4-18.7%). Positive predictive values for response and remission with vortioxetine were ~70% and ~50%, respectively; negative predictive values were ~70% and ~80%, respectively. CONCLUSION: Improvement with vortioxetine may be predicted by early partial improvement in MADRS score. Some patients may benefit from longer-term treatment even without early improvement, another finding that may aid clinical decision-making. ClinicalTrials.gov registration for primary study: NCT02389816.

Paradoxical somatic information processing for interoception and anxiety in alexithymia.

The concept of alexithymia has garnered much attention in an attempt to understand the psychological mechanisms underlying the experience of feeling an emotion. In this study, we aimed to understand how the interoceptive processing in an emotional context relates to problems of alexithymia in recognizing self-emotions. Therefore, we prepared experimental conditions to induce emotional awareness based on interoceptive information. As such, we asked participants to be aware of interoception under an anxiety-generating situation anticipating pain, having them evaluate their subjective anxiety levels in this context. High alexithymia participants showed attenuated functional connectivity within their 'interoception network', particularly between the insula and the somatosensory areas when they focused on interoception. In contrast, they had enhanced functional connectivity between these regions when they focused on their anxiety about pain. Although access to somatic information is supposed to be more strongly activated while attending to interoception in the context of primary sensory processing, high alexithymia individuals were biased as this process was activated when they felt emotions, suggesting they recognize primitive and unprocessed bodily sensations as emotions. The paradoxical somatic information processing may reflect their brain function pathology for feeling emotions and their difficulty with context-dependent emotional control.

Patient and Physician Perspectives of Depressive Symptoms and Expectations for Treatment Outcome: Results from a Web-Based Survey.

PURPOSE: A previous international study suggested that perceptions of depression symptoms, social function, and treatment expectations are different between patients/physicians. We aimed to examine whether such differences exist in Japan. METHODS: A web-based survey was conducted with patients who reported that they had been diagnosed with depression, and physicians who reported that they had treated patients with depression, in Japan. Questionnaires were designed to quantify patients' perceptions of symptoms, social function, and treatment expectations. Patients were categorized into three stages of disorder based on their reported current symptoms: severe symptomatic, mild symptomatic, and remission. Physicians were assigned up to three patients, were provided with patient information from the questionnaire completed by those patients, and finally the completed questionnaire forms for each patient. Agreement between the perceptions of the patients and physicians was examined for each stage. RESULTS: Of the 2618 eligible patients, 828 were assigned to 326 eligible physicians. Overall, we found small differences in the perceptions of depression treatment between patients/physicians. Slightly fewer physicians than patients reported physical symptoms (85% vs 91%; p=0.018) in the mild symptomatic stage. Fewer physicians than patients reported cognitive symptoms in the severe (82% vs 87%; p=0.029) and mild (54% vs 66%; p=0.003) symptomatic stages. Social function was deemed to be lower by physicians than by patients, across all stages of disorder (p<0.001). Regarding treatment expectations, more physicians than patients reported "return to a normal life" in the mild symptomatic (51% vs 35%, p<0.001) and remission stages (57% vs 36%, p<0.001), and more patients than physicians reported "reduction of side effects" in the severe (10% vs 4%, p=0.004) and mild (12% vs 5%, p<0.001) symptomatic disorder stages. CONCLUSION: These results suggest small differences in patient/physician perceptions of depression treatment in Japan. Discrepancies between patients'/physicians' perceptions may vary depending on the medical environment.

The Role of the Thalamus in the Neurological Mechanism of Subjective Sleepiness: An fMRI Study.

PURPOSE: The thalamus, the region that forms the attentional network and transmits external sensory signals to the entire brain, is important for sleepiness. Herein, we examined the relationship between activity in the thalamus-seed brain network and subjective sleepiness. MATERIALS AND METHODS: Fifteen healthy male participants underwent an experiment comprising a baseline evaluation and two successive interventions, a 9-day sleep extension followed by 1-night total sleep deprivation. Pre- and post-intervention tests included the Karolinska sleepiness scale and neuroimaging for arterial spin labeling and functional connectivity. We examined the association between subjective sleepiness and the functional magnetic resonance imaging indices. RESULTS: The functional connectivity between the left or right thalamus and various brain regions displayed a significant negative association with subjective sleepiness, and the functional connectivity between the left and right thalamus displayed a significant positive association with subjective sleepiness. The graph theory analysis indicated that the number of positive functional connectivity related to the thalamus showed a strong negative association with subjective sleepiness, and conversely, the number of negative functional connectivity showed a positive association with subjective sleepiness. Arterial spin labeling analysis indicated that the blood flow in both the left and right thalami was significantly negatively associated with subjective sleepiness. Functional connectivity between the anterior cingulate cortex and salience network areas of the left insular cortex, and that between the anterior and posterior cingulate cortices showed a strong positive and negative association with subjective sleepiness, respectively. CONCLUSION: Subjective sleepiness and the thalamic-cortical network dynamics are strongly related, indicating the application of graph theory to study sleepiness and consciousness. These results also demonstrate that resting functional connectivity largely reflects the "state" of the subject, suggesting that the control of sleep and conscious states is essential when using functional magnetic resonance imaging indices as biomarkers.

Wrist and finger motor representations embedded in the cerebral and cerebellar resting-state activation.

Several functional magnetic resonance imaging (fMRI) studies have demonstrated that resting-state brain activity consists of multiple components, each corresponding to the spatial pattern of brain activity induced by performing a task. Especially in a movement task, such components have been shown to correspond to the brain activity pattern of the relevant anatomical region, meaning that the voxels of pattern that are cooperatively activated while using a body part (e.g., foot, hand, and tongue) also behave cooperatively in the resting state. However, it is unclear whether the components involved in resting-state brain activity correspond to those induced by the movement of discrete body parts. To address this issue, in the present study, we focused on wrist and finger movements in the hand, and a cross-decoding technique trained to discriminate between the multi-voxel patterns induced by wrist and finger movement was applied to the resting-state fMRI. We found that the multi-voxel pattern in resting-state brain activity corresponds to either wrist or finger movements in the motor-related areas of each hemisphere of the cerebrum and cerebellum. These results suggest that resting-state brain activity in the motor-related areas consists of the components corresponding to the elementary movements of individual body parts. Therefore, the resting-state brain activity possibly has a finer structure than considered previously.