First-person reports of Major Depressive Disorder reveal that when an individual becomes depressed a profound change or ‘shift’ to one’s conscious experience occurs. The depressed person reports that something fundamental to their experience has been disturbed or shifted; a change associated with the common but elusive claim that when depressed one finds oneself in a ‘different world’ detached from reality and other people. Existing attempts to utilise these phenomenological observations in a psychiatric context are challenged by the fact that (...) this experiential ‘shift’ characteristic of depression appears mysterious and resists analysis in scientific terms. This paper offers a way out of this predicament. The hypothesis proposed is that when an individual becomes depressed, the individual departs from a state of ordinary wakeful consciousness and enters a distinctive global state of consciousness akin to dreaming and the psychedelic state. After unpacking and motivating this hypothesis in the context of research in consciousness science, I outline two of its important implications for the neurobiology of depression and psychedelic psychiatry. The upshot is a promising and conceptually well-motivated hypothesis about depression which is apt for empirical uptake and development. (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)

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)

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)

We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further (...) compounds gut dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. (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)

According to several researchers, core affect lies at the foundation of our affective lives and may be characterized as a consciously accessible state combining arousal (activated-deactivated) and valence (pleasure-displeasure). The interaction between these two dimensions is still a matter of debate. In this paper we provide a novel hypothesis concerning their interaction, by arguing that subjective arousal levels modulate the experience of a stimulus’ affective quality. All things being equal, the higher the arousal, the more a given stimulus would (...) be experienced as pleasant (or unpleasant). While marshaling some preliminary evidence in favor of this hypothesis, we also show how it might be relevant in reframing our conception of depressive disorders (i.e., major and bipolar depression). (shrink)

Autistic-spectrum conditions and psychotic-spectrum conditions (mainly schizophrenia, bipolar disorder, and major depression) represent two major suites of disorders of human cognition, affect, and behavior that involve altered development and function of the social brain. We describe evidence that a large set of phenotypic traits exhibit diametrically opposite phenotypes in autistic-spectrum versus psychotic-spectrum conditions, with a focus on schizophrenia. This suite of traits is inter-correlated, in that autism involves a general pattern of constrained overgrowth, whereas schizophrenia involves undergrowth. (...) These disorders also exhibit diametric patterns for traits related to social brain development, including aspects of gaze, agency, social cognition, local versus global processing, language, and behavior. Social cognition is thus underdeveloped in autistic-spectrum conditions and hyper-developed on the psychotic spectrum.;>We propose and evaluate a novel hypothesis that may help to explain these diametric phenotypes: that the development of these two sets of conditions is mediated in part by alterations of genomic imprinting. Evidence regarding the genetic, physiological, neurological, and psychological underpinnings of psychotic-spectrum conditions supports the hypothesis that the etiologies of these conditions involve biases towards increased relative effects from imprinted genes with maternal expression, which engender a general pattern of undergrowth. By contrast, autistic-spectrum conditions appear to involve increased relative bias towards effects of paternally expressed genes, which mediate overgrowth. This hypothesis provides a simple yet comprehensive theory, grounded in evolutionary biology and genetics, for understanding the causes and phenotypes of autistic-spectrum and psychotic-spectrum conditions. (shrink)

Time is an essential feature in bipolar disorder (BP). Manic and depressed BP patients perceive the speed of time as either too fast or too slow. The present article combines theoretical and empirical approaches to integrate phenomenological, psychological, and neuroscientific accounts of abnormal time perception in BP. Phenomenology distinguishes between perception of inner time, ie, self-time, and outer time, ie, world-time, that desynchronize or dissociate from each other in BP: inner time speed is abnormally slow (as in depression) or (...) fast (as in mania) and, by taking on the role as default-mode function, impacts and modulates the perception of outer time speed in an opposite way, ie, as too fast in depression and too slow in mania. Complementing, psychological investigation show opposite results in time perception, ie, time estimation and reproduction, in manic and depressed BP. Neuronally, time speed can be indexed by neuronal variability, ie, SD. Our own empirical data show opposite changes in manic and depressed BP (and major depressive disorder [MDD]) with abnormal SD balance, ie, SD ratio, between somatomotor and sensory networks that can be associated with inner and outer time. Taken together, our combined theoretical-empirical approach demonstrates that desynchronization or dissociation between inner and outer time in BP can be traced to opposite neuronal variability patterns in somatomotor and sensory networks. This opens the door for individualized therapeutic “normalization” of neuronal variability pattern in somatomotor and sensory networks by stimulation with TMS and/or tDCS. (shrink)

Major depressive disorder (MDD) is a severe mental illness that affects 5 to 20% of the general population. Current antidepressant drugs exerts only a partial clinical efficacy because approximately 30% of depressed patients failed to respond to these drugs and antidepressants produce remission only in 30% of patients. This can be explained by the fact that the complex pathophysiology of depression has not been completely elucidated, and treatments have been mainly developed following the “monoaminergic hypothesis” of depression without (...) considering the key role of other factors involved in the pathogenesis of MDD, such as the role of chronic stress and neuroinflammation. Chronic stress acts as a risk factor for the development of MDD through the impairment of neurotrophins signaling such as brain-derived neurotrophic factor (BDNF) and transforming-growth-factor-β1 (TGF-β1). Stress-induced depressive pathology contributes to altered BDNF level and function in MDD patients and, thereby, an impairment of neuroplasticity at the regional and circuit level. Recent studies demonstrate that aerobic exercise strongly increases BDNF production and it may contribute as a non-pharmacological strategy to improve the treatment of cognitive and affective symptoms in MDD. Here we will provide a general overview on the possible synergism between physical activity and antidepressants in MDD. Physical activity can synergize with antidepressant treatment by rescuing neurotrophin signaling in MDD patients, promoting neuronal health and recovery of function in MDD-related circuits, finally enhancing pharmacotherapeutic response. This synergism might be particularly relevant in elderly patients with late-life depression, a clinical subgroup with an increased risk to develop dementia. (shrink)

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to (...) investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex. All-night polysomnography data was acquired at four time points: Adaptation, Baseline, Post-1, and Post-2. Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II–IV at four electrode sites: F3, F4, P3, and P4. Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation. (shrink)

Long-term potentiation is one of the most extensively studied forms of neuroplasticity and is considered the strongest candidate mechanism for memory and learning. The use of event-related potentials and sensory stimulation paradigms has allowed for the translation from animal studies to non-invasive studies of LTP-like synaptic plasticity in humans. Accumulating evidence suggests that synaptic plasticity as measured by stimulus-specific response modulation is reduced in neuropsychiatric disorders such as major depressive disorder, bipolar disorders and schizophrenia, suggesting that impaired synaptic (...) plasticity plays a part in the underlying pathophysiology of these disorders. This is in line with the neuroplasticity hypothesis of depression, which postulate that deficits in neuroplasticity might be a common pathway underlying depressive disorders. The current study aims to replicate and confirm earlier reports that visual stimulus-specific response modulation is a viable probe into LTP-like synaptic plasticity in a large sample of healthy adults. Further, this study explores whether impairments in LTP-like synaptic plasticity is associated with self-reported subclinical depressive symptoms and stress in a healthy population. Consistent with prior research, the current study replicated and confirmed reports demonstrating significant modulation of visual evoked potentials following visual high-frequency stimulation. Current results further indicate that reduced LTP-like synaptic plasticity is associated with higher levels of self-reported symptoms of depression and perceived stress. This indicate that LTP-like plasticity is sensitive to sub-clinical levels of psychological distress, and might represent a vulnerability marker for the development of depressive symptoms. (shrink)

While previous research has suggested that adults with a history of childhood sexual abuse may be more prone to produce false memories, little is known about the consequences of childhood neglect on basic memory processes. For this reason, the authors investigated how a group of women with a history of childhood emotional neglect and diagnosed with recurrent Major Depressive Disorder performed on the Deese–Roediger–McDermott paradigm in comparison to control groups. The results indicated that women with MDD and CEN were (...) actually less prone to produce false memories relative to both women with MDD but no CEN and healthy women without MDD and any form of childhood maltreatment. These findings were explained in terms of the inability to extract/retrieve gist memories that support false recognition of critical lures, an explanation that seems to fit well with emerging MRI findings linking childhood neglect to reduced volume of brain regions associated to memory function. (shrink)

BackgroundRecurrent Major Depressive Disorder is one of the most disabling mental disorders in modern society. Prior research has shown that self-compassion protects against ruminative tendencies, a key feature of recurrent MDD. In addition, self-compassion has been found to be positively related to higher psychophysiological flexibility in young, healthy adults. To our knowledge, there is a lack of studies on how self-compassion relates to vmHRV in patients with recurrent MDD. The aim of the current study was to investigate whether higher (...) self-compassion would associate with lower ruminative tendencies and higher vmHRV in a sample of adults with recurrent MDD.MethodsWe included a sample of 63 patients between 20 and 71 years old with a history of three or more depressive episodes. They filled out the Self-Compassion Scale, Beck Depression Inventory, and Rumination Rating Scale. ECG was acquired while resting and the square root of the mean squared differences of successive RR interval values was calculated as measure of vmHRV.ResultsAs hypothesized, self-compassion was associated with lower ruminative tendencies. However, self-compassion was not associated with level of vmHRV. Several confounding variables were controlled for in the statistical analyses, and higher age predicted lower vmHRV across all statistical analyses.ConclusionThe results confirmed our hypothesis that higher self-compassion would be associated with lower ruminative tendencies in recurrent MDD. Contrary to our expectation, we did not find that the tendency to be more self-compassionate was associated with higher vmHRV. As such, higher self-compassion seems to relate with a lower tendency to ruminate about past mistakes and events but does not seem to relate to a flexible autonomic stress response. Other potential explanatory factors for lower vmHRV in recurrent MDD is suggested as focus for exploration in future studies. (shrink)

Understanding the biological basis of consciousness is one of the central challenges for modern science. Is a mature scientific explanation really possible, and if so, how should consciousness science be organized so as to achieve this? This thesis is a collection of four papers which approach these questions via an account of the natural categories or ‘kinds’, drawn from philosophy of science, to which paradigmatic mental phenomena like consciousness belong. The central claims defended in the thesis are twofold. Firstly, that (...) to facilitate a mature science of consciousness it is crucial to explicitly introduce a new organizing concept of consciousness modelled on the kinds of concepts which underpin previous successful explanations of other natural phenomena – that of a natural kind concept of consciousness. This draws on the general observation that some concepts are better suited to scientific theorizing about the world than others, and thus that progress in scientific and philosophical domains can be (and indeed, has often been) made by working to refine our existing conceptual schemes to reflect this. Secondly, that a mature science of consciousness will be one which recognizes the reality and explanatory importance of a particular category of mental phenomena called ‘global states of consciousness’ which includes dreaming and wakefulness. Examination of this latter claim leads to a third idea explored and motivated in the thesis which brings consciousness science into closer connection with psychiatry. This is the hypothesis that Major Depressive Disorder involves a change to a subject’s global state of consciousness, marking a change from a state of ordinary wakeful consciousness to an altered ‘depressive state’ of consciousness akin to a dream or psychedelic state. (shrink)

Objective Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition. -/- Method In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) (...) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients. -/- Results (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets. -/- Conclusions These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations. (shrink)

Major Depressive Disorder (MDD) is a serious condition with a large disease burden. It is often claimed that MDD is a “brain disease.” What would it mean for MDD to be a brain disease? I argue that the best interpretation of this claim is as offering a substantive empirical hypothesis about the causes of the syndrome of depression. This syndrome-causal conception of disease, combined with the idea that MDD is a disease of the brain, commits the brain disease (...) conception of MDD to the claim that brain dysfunction causes the symptoms of MDD. I argue that this consequence of the brain disease conception of MDD is false. It incorrectly rules out genuine instances of content-sensitive causation between adverse conditions in the world and the characteristic symptoms of MDD. Empirical evidence shows that the major causes of depression are genuinely psychological causes of the symptoms of MDD. This rules out, in many cases, the “brute” causation required by the brain disease conception. The existence of cases of MDD with non-brute causes supports the reinstatement of the old nosological distinction between endogenous and exogenous depression. (shrink)

In this paper we discuss the two-system framework, examine its strengths, point out a fundamental weakness concerning the unity of conscious experience, and then propose a new hypothesis that avoids that weakness and other related concerns. According to our strong emergence hypothesis, what emerges are not merely mental properties in specialized, distributed neural areas, but also a new, irreducibly singular entity that functions in a recurrent manner to integrate its mental properties and to rewire its brain. We argue (...) that the former function is suggested, in part, by the effects of anesthetics on sensory integration, and that the latter function is suggested by evidence garnered from the neuroscience of mindfulness, constraint-induced movement therapy for stroke, and neuroimaging data surrounding mental illness. We then discuss how our strong emergence hypothesis relates to the description and treatment of neuropsychiatric disorders. Finally, potential objections are addressed. (shrink)

Mood disorders, including major depressive disorder and bipolar disorder, are highly prevalent, frequently disabling, and sometimes deadly. Additional research and more effective medications are desperately needed, but clinical trials research in mood disorders is fraught with ethical issues. Although many authors have discussed these issues, most do so from a theoretical viewpoint. This manuscript uses available empirical data to inform a discussion of the primary ethical issues raised in mood disorders research. These include issues of consent and decision-making (...) capacity, including patients’ motivations for participating in research. We also address drug withdrawals, placebo controls, and the overall safety of research. Finally, we examine the extant literature for studies discussing potential indirect benefits of clinical trials research to participants. Taken together, the evidence suggests that clinical trials research incorporating drug withdrawals and placebo controls can be conducted safely and ethically, even in patients with severe or treatment-resistant mood disorders. In fact, given the dearth of effective treatment options for this population, it is our opinion that a moral imperative exists to extend the offer of research participation to severely ill or treatment-resistant groups. (shrink)

The field of narrative medicine holds that personal narratives about illness have the potential to give illness meaning and to create order out of disparate facets of experience, thereby aiding a patient’s treatment and resisting universalizing medical discourse. Two narratives of bipolar disorder, Kay Redfield Jamison’s prose memoir An Unquiet Mind and Ellen Forney’s graphic memoir Marbles challenge these ideas. These writers demonstrate that one result of bipolar disorder is a rupture to their sense of identity, making straightforward (...) and verbal forms of narrative impossible. During periods of relative mood stability, reliable memories of mania or depression are equally impossible. As a result, these memoirists seek to develop sources of self-knowledge other than memory and introspection, long the foundations of personal narrative. Finally, An Unquiet Mind and Marbles return attention to questions of selfhood at a time when scholarship on memoir rejects interpretations of life stories as clear and reliable expressions of identity. (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)

The global signal, which was once regarded as a nuisance of functional magnetic resonance imaging, has been proven to convey valuable neural information. This raised the following question: what is a GS represented in local brain regions? In order to answer this question, the GS topography was developed to measure the correlation between global and local signals. It was observed that the GS topography has an intrinsic structure characterized by higher GS correlation in sensory cortices and lower GS correlation in (...) higher-order cortices. The GS topography could be modulated by individual factors, attention-demanding tasks, and conscious states. Furthermore, abnormal GS topography has been uncovered in patients with schizophrenia, major depressive disorder, bipolar disorder, and epilepsy. These findings provide a novel insight into understanding how the GS and local brain signals coactivate to organize information in the human brain under various brain states. Future directions were further discussed, including the local-global confusion embedded in the GS correlation, the integration of spatial information conveyed by the GS, and temporal information recruited by the connection analysis. Overall, a unified psychopathological framework is needed for understanding the GS topography. (shrink)

Negative self-referential processing has fruitfully been studied in unipolar depressed patients, but remarkably less in patients with bipolar disorder (BD). This exploratory study examines the relation between task-based self-referential processing and depressive symptoms in BD and their possible importance to the working mechanism of mindfulness-based cognitive therapy (MBCT) for BD. The study population consisted of a subsample of patients with BD (n = 49) participating in an RCT of MBCT for BD, who were assigned to MBCT + TAU (n (...) = 23) or treatment as usual (TAU) (n = 26). Patients performed the self-referential encoding task (SRET), which measures (1) positive and (2) negative attributions to oneself as well as (3) negative self-referential memory bias, before and after MBCT + TAU or TAU. At baseline, all three SRET measures were significantly related to depressive symptoms in patients with BD. Moreover, repeated measures analyses of variance revealed that negative self-referential memory bias diminished over time in the MBCT + TAU group, compared with the TAU group. Given the preliminary nature of our findings, future research should explore the possibly mediating role of reducing negative self-referential memory bias in preventing and treating depressive symptoms in BD through MBCT. (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)

The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and healthy controls (...) (n = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls. (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)

The use of placebo as a control condition in clinical trials of major depressive disorder and anxiety disorders continues to be an area of ethical concern. Typically, opponents of placebo controls argue that they violate the beneficent-based, “best proven diagnostic and therapeutic method” that the original Helsinki Declaration of 1964 famously asserted participants are owed. A more consequentialist, oppositional argument is that participants receiving placebo might suffer enormously by being deprived of their usual medication(s). Nevertheless, recent findings of potential (...) for suicidality in young people treated with antidepressants, along with meta-analyses suggesting that antidepressants add no significant clinical benefit over placebos, warrant a re-evaluation of the arguments against placebo. Furthermore, the nature of placebo treatment in short-term clinical trials is often not well understood, and lack of understanding can foster opposition to it. This paper will show how scientific justifications for placebo use are morally relevant. The fundamental ethical importance of placebo controls is discussed in relation to several aspects of clinical trials, including detection of adverse events, accurate assessment of clinical benefit, advancing understanding of the heterogeneity of depression and anxiety disorders and respecting informed consent requirements. Prohibiting the use of placebo controls is morally concerning in that such prohibitions allow for the possibility of serious adverse public health consequences. Moral worries that research participants receiving placebo are being unduly jeopardised will be shown to be exaggerated, especially in relation to the net benefits for end-users to be gained from the quality of data resulting from using placebo controls. (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)

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.

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)

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)

This article explores the role of affect in the disorganized language and thought that can manifest itself in bipolar disorder. Bipolar disorder, or as it was previously known, manic-depressive illness, can produce psychotic language and thought in its more extreme forms. During the production of discourse in bipolar disorder, there is a strong correlation between the underlying affective state, i.e., depression, euthymia, hypomania, and mania, and linguistic and cognitive performance. A psycholinguistic model of the dynamics between language, (...) thought, and affect in bipolar disorder based on McNeill¿s concept of a ¿Growth Point¿ is proposed. In particular, the poetic structural phases of discourse production in bipolar disorder, which vary according to the underlying affective state, provide a phenomenological bridge between the psychotic discourse of mania and normal language production. (shrink)

A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder , showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study has (...) examined whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview that allowed for separation of episodic and non-episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups. (shrink)

Summary Background Self-binding directives instruct clinicians to overrule treatment refusal during future severe episodes of illness. These directives are promoted as having potential to increase autonomy for individuals with severe episodic mental illness. Although lived experience is central to their creation, service users’ views on self-binding directives have not been investigated substantially. This study aimed to explore whether reasons for endorsement, ambivalence, or rejection given by service users with bipolar disorder can address concerns regarding self-binding directives, decision-making capacity, and (...) human rights. Methods This study used qualitative data from an internet-based survey distributed to the mailing list of the UK charity Bipolar UK, which contained multiple closed and open questions on advance decision-making in bipolar disorder. Quantitative analysis of a closed question about self-binding directives had already demonstrated endorsement amongst a very high proportion of participants with bipolar disorder who completed the survey. We conducted thematic analysis of responses from those participants who answered a subsequent open question about reasons for their view. Research was co-produced within a multi-disciplinary team, with clinical, legal, and ethical expertise, and lived experience of bipolar disorder. Ideas and methodologies associated with all these areas of expertise were used in the analysis of these reasons and to gain insight into the thoughts of individuals with bipolar disorder about self-binding directives and associated issues. Findings Between Oct 23 and Dec 5, 2017, 932 individuals with a self-reported clinical diagnosis of bipolar disorder completed the internet survey, with 565 (154 men; 400 women; 11 transgender or other) providing free text answers to the open question. A large majority of respondents endorsed self-binding directives, nearly all describing a determinate shift to types of distorted thinking and decision-making when unwell as their key justification. Responses indicating ambivalence were dominated by logistical concerns about the drafting and implementation of self-binding directives, while those who rejected self-binding directives also cited logistical concerns, validity of their thinking when unwell, and potential contravention of human rights. Interpretation This study is, to our knowledge, the first large study of reasons why mental health service users might endorse or reject the use of self-binding directives. The findings provide empirical support for introducing self-binding directives into mental health advance decision-making practice and policy and may help to address enduring ethical concerns surrounding possible implementation of the directive while a person retains decision-making capacity. The opinions expressed here in responses given by multiple service users with bipolar disorder challenge a prominent view within international disability rights debates that involuntary treatment and recognition of impaired mental capacity constitute inherent human rights violations. Funding The Wellcome Trust . (shrink)

This essay, the last in a series, focuses on the relationship between Nietzsche’s mental illness and his philosophical art. It is predicated upon my original diagnosis of his mental condition as bipolar affective disorder, which began in early adulthood and continued throughout his creative life. The kaleidoscopic mood shifts allowed him to see things from different perspectives and may have imbued his writings with passion rarely encountered in philosophical texts. At times hovering on the verge of psychosis, Nietzsche was (...) able to gain access to unconscious images and the music of language, usually inhibited by the conscious mind. He reached many of his linguistic, psychological and philosophical insights by willing suspension of the rational. None of these, however, could have been communicated had he not tamed the subterranean psychic forces with his impressive discipline and hard work. (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)

Sertraline is one of the most commonly prescribed antidepressants. Major depressive disorder (MDD) is characterized by spontaneous thoughts that are laden with negative affect-a "malignant sadness". Prior neuroimaging studies have identified abnormal resting-state functional connectivity (rsFC) in the spontaneous brain networks of MDD patients. But how antidepressant medication acts to relieve the experience of depression as well as adjust its associated spontaneous networks and mood-regulation circuits remains an open question. In this study, we recruited 22 drug-naïve MDD patients along (...) with 35 normal controls and investigated whether the functional integrity of cortical networks associated with spontaneous thoughts is modulated by sertraline treatment. We attempted to predict post-treatment effects based upon what we observed in the pre-treatment rsFC of drug-naïve MDD patients. In the result, we demonstrated that (1) after the sertraline treatment, the medial temporal lobe of default network (DNMTL) and mood regulation pathway-the fronto-parietal control network (FPCN), the thalamus, and the salience network (SN)-were restored to normal connectivity, relative to the pre-treatment condition; however, the altered connections of FPCN-core DN (DNCORE), FPCN-SN, and intra-FPCN among MDD patients remained impaired; (2) thalamo-prefrontal connectivity provides moderate predictive power (r2 = 0.63) for the effectiveness of sertraline treatment. In summary, our findings contribute to a body of evidence that suggests salubrious effects of sertraline treatment primarily involve the FPCN-thalamus-SN pathway. The pre-treatment rsFC in this pathway could serve as a predictor of sertraline treatment outcome. (shrink)

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)