Circadian rhythms in the sleep/wake cycle, along with a range of physiological measures, are severely disrupted in individuals with major depressive disorder (MDD). Moreover, several central circadian genes have been implicated as potential genetic factors underlying the illness through candidate gene studies and some genome wide association studies. However, investigations into the molecular underpinnings of circadian disturbances in the human brain have been quite challenging. In their recent publication, Li and colleagues have used a novel approach to determine (...) the rhythmic patterns of circadian gene expression in several regions of the human brain, and how these patterns are disrupted in MDD. Their findings demonstrate that in healthy subjects, several brain regions outside the suprachiasmatic nucleus (the master clock) exhibit diurnal gene expression patterns that are disrupted in the brains of MDD subjects. These findings will provide the foundation for future studies of gene‐specific drug targets, and biomarkers for the disease. (shrink)

Major depression is a prevalent mental disorder that leads to persistent negative mood and tremendous suffering in affected individuals. However, the biological realization of this disorder and associated symptom clusters remain poorly understood. Recently, phenomenological accounts of major depressive disorder and contributions to the emerging predictive processing account have provided valuable insights into the phenomenological and neuro-functional components that lead to manifestations of major depressive episodes. The purpose of this paper is to weave together these (...) different strands of research to develop a predictive processing account of major depressive disorder. In doing so, I will relate personal-level descriptions of associated phenomenal experiences to a sub-personal-level predictive processing account of the functional realization of major depression. I will argue that pervasive symptoms of the disorder, which include a diminished sense of agency, fatigue, social withdrawal, and rumination, are integrated by existential feelings of loss and impossibility. These phenomenal experiences, I will argue, are associated with dysfunctional processes of prediction error minimization, which are characterized by an overall decrease of the causal contributions of active inference and by distorted precision estimates. The emerging account promises to contribute to a better understanding of the complex processes that give rise to depressive experiences. (shrink)

Based on previous studies implicating increased functional connectivity within the self-referential brain network in major depressive disorder (MDD), and considering the functional roles of three distinct modules of such brain net (responsible for three-dimensional components of Selfhood) together with the documented abnormalities of self-related processing in MDD, we tested the hypothesis that patients with depression would exhibit increased connectivity within each module of the self-referential brain network and that the strength of these connections would correlate positively with depression (...) severity. Applying the electroencephalogram (EEG) operational synchrony analysis to extract three modules of the self-referential brain network in 12 medication-free depressive outpatients and 10 control subjects we have found an increase in the strength of EEG synchrony within all three modules in depressive patients (though non-significant for the right module). Furthermore, multiple regression analysis that used 3 factors (values of synchrony strength for all three modules) as input indicated that combined increase in the strength of synchrony in all three modules was positively associated with severity of depression. Taken together the findings of this study suggest that depression is primarily associated with hypersynchrony in all three modules of the brain self-referential network (the anterior module been responsible for “witnessing observation and first–person perspective”, the left posterior module been responsible for “reflective agency and narration” and the right posterior module been responsible for “bodily representational-emotional agency”), thus contributing to excessive self-focus, rumination, and body tension. (shrink)

Immediately before the release of DSM-5, a group of psychiatric thought leaders published the results of field tests of DSM-5 diagnostic criteria. They characterized the interrater reliability for diagnosing major depressive disorder by two trained mental health practitioners as of “questionable agreement.” These field tests confirmed an open secret among psychiatrists that our current diagnostic criteria for diagnosing major depressive disorder are unreliable and neglect essential experiences of persons in depressive episodes. Alternative diagnostic criteria exist, (...) but psychiatrists rarely encounter them, forestalling the discipline’s epistemological crisis. In Alsadair MacIntyre’s classic essay, such crises occur in science when a person encounters a rival schemata that is incompatible with their current schemata and subsequently constructs a narrative that allows them to reconstruct their own tradition. In search of rival schemata that are in conversation with their own tradition, psychiatric practitioners can utilize alternative diagnostic criteria like the Cultural Formulation Interview, embrace an epistemologically humble psychiatry, and attend to the narrative experience of a person experiencing a depressive episode. (shrink)

Background: The vascular depression hypothesis emphasizes the significance of vascular lesions in late-life depression. At present, no meta-analytic model has investigated whether a difference in hyperintensity burden compared to controls between late-life and late-onset depression is evident. By including a substantial number of studies, focusing on a meaningful outcome measure, and considering several moderating and control variables, the present meta-analysis investigates the severity of hyperintensity burden in major depressive disorder (MDD) and bipolar disorder (BD). A major focus (...) of the present meta-analysis refers to the role of age at illness onset. It is analyzed whether late-onset rather than late-life depression characterizes vascular depression. Method: In total, 68 studies were included in the meta-analysis and a multilevel random effects model was calculated using Hedges’ g as the effect size measure. Results: The severity of hyperintensity burden was significantly greater in the patient group compared to the control group. This effect was evident regarding the whole patient group (g = 0.229) as well as both depression subgroups, with a significantly greater effect in BD (g = 0.374) compared to MDD (g = 0.189). Hyperintensity burden was more pronounced in late-onset depression than in early-onset depression or late-life depression. A considerable heterogeneity between the included studies was observed, which is reflected by the large variability in effects sizes. Conclusion: In conclusion, the present meta-analysis underscores the association of hyperintensities with MDD and BD. Especially late-onset depression is associated with an increased hyperintensity burden, which is in line with the vascular depression hypothesis. The results suggest that it might be more feasible to confine the concept of vascular depression specifically to late-onset depression as opposed to late-life depression. Further research is needed to understand the causal mechanisms that might underlie the relation between hyperintensity burden and depression. (shrink)

Anxious major depressive disorder is a common subtype of major depressive disorder; however, its unique neural mechanism is not well-understood currently. Using multimodal MRI data, this study examined common and specific alterations of amygdala subregions between patients with and without anxiety. No alterations were observed in the gray matter volume or intra-region functional integration in either patient group. Compared with the controls, both patient groups showed decreased functional connectivity between the left superficial amygdala and the left (...) putamen, and between the right superficial amygdala and the bilateral anterior cingulate cortex and medial orbitofrontal cortex, while only patients with anxiety exhibited decreased activity in the bilateral laterobasal and superficial amygdala. Moreover, the decreased activity correlated negatively with the Hamilton depression scale scores in the patients with anxiety. These findings provided insights into the pathophysiologic processes of anxious major depressive disorder and may help to develop new and effective treatment programs. (shrink)

Background: Frailty is a common syndrome among older adults and patients with several comorbidities. Grip strength is a representative parameter of frailty because it is a valid indicator of current and long-term physical conditions in the general population and patients with severe mental illnesses. Physical and cognitive capacities of people with SMIs are usually impaired; however, their relationship with frailty or social functioning have not been studied to date. The current study aimed to determine if GS is a valid predictor (...) of changes in cognitive performance and social functioning in patients with type-2 diabetes mellitus and SMIs. Methods: Assessments of social functioning, cognitive performance, and GS were conducted in 30 outpatients with type 2 diabetes mellitus, 35 with major depressive disorder, 42 with bipolar disorder, 30 with schizophrenia, and 28 healthy controls, twice during 1-year, follow-up period. Descriptive analyses were conducted using a one-way analysis of variance for continuous variables and the chi-squared test for categorical variables. Differences between groups for the motor, cognitive, and social variables at T1 and T2 were assessed using a one-way analysis of covariance, with sex and age as co-variates. To test the predictive capacity of GS at baseline to explain the variance in cognitive performance and social functioning at T2, a linear regression analysis was performed. Results: Predictive relationships were found among GS when implicated with clinical, cognitive, and social variables. These relationships explained changes in cognitive performance after one year of follow-up; the variability percentage was 67.7%, in patients with type-2 diabetes mellitus and 89.1% in patients with schizophrenia. Baseline GS along with other variables, also predicted changes in social functioning in major depressive disorder, bipolar disorder, and schizophrenia, with variability percentages of 67.3, 36, and 59%, respectively. Conclusion: GS combined with other variables significantly predicted changes in cognitive performance and social functioning in people with SMIs or type-2 diabetes mellitus. Interventions aimed to improve the overall physical conditions of patients who have poor GS could be a therapeutic option that confers positive effects on cognitive performance and social functioning. (shrink)

Electroencephalography (EEG) is a non-invasive method to identify markers of treatment response in major depressive disorder (MDD). In this review, existing literature was assessed to determine how EEG markers change with different modalities of MDD treatments, and to synthesize the breadth of EEG markers used in conjunction with MDD treatments. PubMed and EMBASE were searched from 2000 to 2021 for studies reporting resting EEG (rEEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG) measures in patients undergoing MDD treatments. (...) The search yielded 966 articles, 204 underwent full-text screening, and 51 studies were included for a narrative synthesis of findings along with confidence in the evidence. In rEEG studies, non-linear quantitative algorithms such as theta cordance and theta current density show higher predictive value than traditional linear metrics. Although less abundant, TMS-EEG measures show promise for predictive markers of brain stimulation treatment response. Future focus on TMS-EEG measures may prove fruitful, given its ability to target cortical regions of interest related to MDD. (shrink)

Several decades of research converge on the formulation that individuals diagnosed with major depressive disorder exhibit negative biases in their processing of emotional information. It is becoming increasingly clear, however, that traditional between-group comparisons have obscured the substantial heterogeneity of cognitive and affective dysfunction that is associated with depressive symptomatology. In this article, we review the findings of research examining attention to and memory for negative emotional information using a more dimensional perspective on depression. Specifically, we explore (...) studies that assess cognitive biases along a continuum of depressive symptom severity and consider the influence of co-occurring dimensions of functioning, in particular the severity of anxiety symptoms. Finally, we identify critical empirical questions and issues in this growing literature. (shrink)

Schuklenk and van de Vathorst's paper is a very welcome addition to the literature on the assisted dying debate and will be of great interest to clinicians working in the field of mental health.1 Many psychiatrists will have had patients who have asked them to allow them to die, to desist in their efforts to prevent their suicide, and one of us has had personal experience, outside of professional life, of being asked to aid in someone's attempt to end their (...) life in the context of an episode of mood disorder. The person with depression asking professionals, friends and family members to aid them in ending their life is a very real phenomenon. In their discussion, Schuklenk and van de Vathorst's paper uses two principles that we endorse and add weight to their argument: namely, the reality of suffering in depression and the parity of mental and physical illness. Indeed, the case Schuklenk and van de Vathorst make is a strong one and our commentary will focus on the premise of the argument around choosing death and some empirical clarification about competence in depression and the nature of treatment-resistant depression (TRD) and its prognosis. The conceptual concern we wish to discuss in relation to assisted dying, endorsed by the state and legislature, is not linked to any moral or religious concern, or even on grounds related to ‘slippery slope’ or ‘abuse’ arguments. Rather the worry is how one could operationalise decisions around assisted dying as based on competence and capacity and view such decisions as rational. I think this concern is not limited to depressive illness, but to all decisions regarding choosing non-existence. Schuklenk and van de Vathorst offer the following useful criteria to regulate assisted suicide:1. (shrink)

Nowadays, the major depressive disorder is a common disease that negatively affects the life quality of many people around the world. As MDD symptoms are closely related with the changes in food and eating, the relation between patients’ emotional responses and food tastes could be used as criteria for diagnostic. Until now, studies on the emotional response to different food tastes for patients affected by MDD have been poorly described in literature. Therefore, the aim of this study was (...) to evaluate the emotional response of patients suffering from MDD to the imagined different food tastes and to compare the results with a control group. Emotional responses in tested participants were induced by using cards with words of basic food tastes such as “sweet,” “salty,” “bitter,” “sour,” and “neutral.” The assessment of emotional response was performed with FaceReader 6 software. The outcome of this study showed that participants with MDD expressed lower “happy” and “contempt” and higher “surprised” emotions, along with a higher negative valence mean, in comparison with controls for all tested basic tastes of food. When Likert scale was used, significant differences in response were only found for “sour” and “salty” imaginary tastes between healthy group and patients with MDD. The findings of this study provide the additional data on food–associated emotion analysis of MDD patients and could be useful for the further development of the contactless method for early diagnosis of MDD. (shrink)

Objective: The aim of the study was to identify clinical variables associated with changes in specific domains of self-reported depression during treatment by antidepressant and/or repetitive Transcranial Magnetic Stimulation in patients with Major Depressive Disorder.Methods: Data from a trial involving 170 patients with MDD receiving either venlafaxine, rTMS or both were re-analyzed. Depressive symptoms were assessed each week during the 2 to 6 weeks of treatment with the 13-item Beck Depression Inventory. Associations between depression changes on BDI13 (...) domains, treatment arm, time, and clinical variables were tested in a mixed linear model.Results: A significant decrease of self-reported depressive symptoms was observed over time. The main characteristics associated with persistent higher depressive symptomatology on Negative Self-Reference domain of the BDI13 were personality disorders, a past history of suicide attempt, age under 65 years old, and female sex.Conclusions: Early cognitive intervention targeting specifically negative self-referencing process could be considered during pharmacological or rTMS treatment for patients with personality disorders and past history of suicide attempt. (shrink)

The lifetime prevalence of major depressive disorder in adolescents is reported to be as high as 20%; thus, MDD constitutes a significant social and public health burden. MDD is often associated with nonsuicidal self-injury behavior, but the contributing factors including cognitive function have not been investigated in detail. To this end, the present study evaluated cognitive impairment and psychosocial factors in associated with MDD with NSSI behavior. Eighteen and 21 drug-naïve patients with first-episode MDD with or without NSSI (...) and 24 healthy control subjects were enrolled in the study. The Hamilton Anxiety Scale, Hamilton Depression Scale, Adolescent Self-injury Questionnaire, Beck Scale for Suicide Ideation–Chinese Version, Shame Scale for Middle School Students, Sensation Seeking Scale and Childhood Trauma Questionnaire were used to assess depression-related behaviors, and event-related potentials were recorded as a measure of cognitive function. The latency of the N1, N2, P3a, P3b, and P50 components of ERPs at the Cz electrode point; P50 amplitude and P50 inhibition showed significant differences between the 3 groups. CTQ scores also differed across three groups, and the NSSI– and NSSI+ groups showed significant differences in scores on the Shame Scale for Middle School Students. Thus, cognitive function was impaired in adolescents with MDD with NSSI behavior, which was mainly manifested as memory decline, attention and executive function deficits, and low anti-interference ability. We also found that childhood abuse, lack of social support, and a sense of shame contributed to NSSI behavior. These findings provide insight into the risk factors for MDD with NSSI behavior, which can help mental health workers more effectively diagnose and treat these patients. (shrink)

Research on the neurobiology and psychosocial features of Major Depressive Disorder has the ability to extend our understanding of affiliative behavior. In depression, decreased hedonic capacity and hypoactivity in dopaminergic and prefrontal circuitries may decrease the ability to experience affiliative relationships as rewarding. We suggest that neurobiological research on depression can provide a test case for theoretical models of affiliation.

ObjectiveThis study aims to investigate the effectiveness of mindfulness-based cognitive therapy combined with medication therapy in preventing the recurrence of major depressive disorder in convalescent patients.MethodsA total of 130 patients with convalescent MDD were enrolled in this prospective study. Sixty-five patients were assigned to the experimental group and received medication therapy combined with MBCT, and 65 patients were assigned to the control group and treated with medication alone. The recurrence rate and related hormonal changes were compared between the (...) two groups.ResultsAfter 1 year of MBCT intervention, eight patients experienced recurrence in the experimental group, a recurrence rate of 12.31%, and 19 patients experienced recurrence in the control group, a recurrence rate of 29.23%. The Hamilton Depression Rating Scale and the World Health Organization Quality of Life Scale scores in both the experimental and the control groups were significantly improved after treatment. The difference in the HAM-D scores before and after treatment in the experimental group was 16.74 ± 4.54; this was significantly higher than that of the control group. The WHOQOL-BREF scores in the experimental group were significantly improved compared with those of the control group. The differences in the levels of corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol before and after treatment in the experimental group and the control group were statistically significant. The difference in CRH before and after treatment in the experimental group was 16.8 ± 7.2, which was higher than that of the control group. The intervention with MBCT had a significant impact on the recurrence of MDD [β = 1.206, P = 0.039, 95% CI = 0.0790–1.229]. The difference in the HAM-D scores also had a significant impact on the recurrence of MDD.ConclusionCompared with medication therapy alone, the use of MBCT combined with medication therapy can effectively prevent the recurrence of MDD in convalescent patients. (shrink)

Several functional magnetic resonance imaging studies have demonstrated abnormalities in static intra- and interhemispheric functional connectivity among diverse brain regions in patients with major depressive disorder. However, the dynamic changes in intra- and interhemispheric functional connectivity patterns in patients with MDD remain unclear. Fifty-eight first-episode, drug-naive patients with MDD and 48 age-, sex-, and education level-matched healthy controls underwent resting-state fMRI. Whole-brain functional connectivity, analyzed using the functional connectivity density approach, was decomposed into ipsilateral and contralateral functional connectivity. (...) We computed the intra- and interhemispheric dynamic FCD using a sliding window analysis to capture the dynamic patterns of functional connectivity. The temporal variability in functional connectivity was quantified as the variance of the dFCD over time. In addition, intra- and interhemispheric static FCD patterns were calculated. Associations between the dFCD variance and sFCD in abnormal brain regions and the severity of depressive symptoms were analyzed. Compared to HCs, patients with MDD showed lower interhemispheric dFCD variability in the inferior/middle frontal gyrus and decreased sFCD in the medial prefrontal cortex/anterior cingulate cortex and posterior cingulate cortex/precuneus in both intra- and interhemispheric comparisons. No significant correlations were found between any abnormal dFCD variance or sFCD at the intra- and interhemispheric levels and the severity of depressive symptoms. Our results suggest intra- and interhemispheric functional connectivity alterations in the dorsolateral prefrontal cortex and default mode network regions involved in cognition, execution and emotion. Furthermore, our study emphasizes the essential role of altered interhemispheric communication dynamics in the DLPFC in patients with MDD. These findings contribute to our understanding of the pathophysiology of MDD. (shrink)

Background: Electroconvulsive therapy is one of the most effective treatments for major depressive disorder. Recently, there has been increasing attention to evaluate the effect of ECT on resting-state functional magnetic resonance imaging. This study aims to compare rs-fMRI of depressive disorder patients with healthy participants, investigate whether pre-ECT dynamic functional network connectivity network estimated from patients rs-fMRI is associated with an eventual ECT outcome, and explore the effect of ECT on brain network states.Method: Resting-state functional magnetic resonance (...) imaging data were collected from 119 patients with depression or depressive disorder, and 61 healthy participants, with an age mean of 52.25 years old. The pre-ECT and post-ECT Hamilton Depression Rating Scale were 25.59 ± 6.14 and 11.48 ± 9.07, respectively. Twenty-four independent components from default mode and cognitive control network were extracted, using group-independent component analysis from pre-ECT and post-ECT rs-fMRI. Then, the sliding window approach was used to estimate the pre-and post-ECT dFNC of each subject. Next, k-means clustering was separately applied to pre-ECT dFNC and post-ECT dFNC to assess three distinct states from each participant. We calculated the amount of time each subject spends in each state, which is called “occupancy rate” or OCR. Next, we compared OCR values between HC and DEP participants. We also calculated the partial correlation between pre-ECT OCRs and HDRS change while controlling for age, gender, and site. Finally, we evaluated the effectiveness of ECT by comparing pre- and post-ECT OCR of DEP and HC participants.Results: The main findings include depressive disorder patients had significantly lower OCR values than the HC group in state 2, where connectivity between cognitive control network and default mode network was relatively higher than other states, Pre-ECT OCR of state, with more negative connectivity between CCN and DMN components, is linked with the HDRS changes. This means that those DEP patients who spent less time in this state showed more HDRS change, and The post-ECT OCR analysis suggested that ECT increased the amount of time DEP patients spent in state 2.Conclusion: Our finding suggests that dynamic functional network connectivity features, estimated from CCN and DMN, show promise as a predictive biomarker of the ECT outcome of DEP patients. Also, this study identifies a possible underlying mechanism associated with the ECT effect on DEP patients. (shrink)

Heterogeneity within MDD has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP (...) biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A ([11C]WAY-100635), as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets. (shrink)