Reduced gray matter volume of the hippocampal tail in melancholic depression: evidence from an MRI study.

BACKGROUND: Melancholic depression (MD) is one of the most prevalent and severe subtypes of major depressive disorder (MDD). Previous studies have revealed inconsistent results regarding alterations in grey matter volume (GMV) of the hippocampus and amygdala of MD patients, possibly due to overlooking the complexity of their internal structure. The hippocampus and amygdala consist of multiple and functionally distinct subregions, and these subregions may play different roles in MD. This study aims to investigate the volumetric alterations of each subregion of the hippocampus and amygdala in patients with MD and non-melancholic depression (NMD). METHODS: A total of 146 drug-naïve, first-episode MDD patients (72 with MD and 74 with NMD) and 81 gender-, age-, and education-matched healthy controls (HCs) were included in the study. All participants underwent magnetic resonance imaging (MRI) scans. The subregional segmentation of hippocampus and amygdala was performed using the FreeSurfer 6.0 software. The multivariate analysis of covariance (MANCOVA) was used to detect GMV differences of the hippocampal and amygdala subregions between three groups. Partial correlation analysis was conducted to explore the relationship between hippocampus or amygdala subfields and clinical characteristics in the MD group. Age, gender, years of education and intracranial volume (ICV) were included as covariates in both MANCOVA and partial correlation analyses. RESULTS: Patients with MD exhibited a significantly lower GMV of the right hippocampal tail compared to HCs, which was uncorrelated with clinical characteristics of MD. No significant differences were observed among the three groups in overall and subregional GMV of amygdala. CONCLUSIONS: Our findings suggest that specific hippocampal subregions in MD patients are more susceptible to volumetric alterations than the entire hippocampus. The reduced right hippocampal tail may underlie the unique neuropathology of MD. Future longitudinal studies are required to better investigate the associations between reduced right hippocampal tail and the onset and progression of MD.

Affective disorders and the loudness dependence of the auditory evoked potential: Serotonin and beyond.

Identifying additional noninvasive biomarkers for affective disorders, such as unipolar major depressive disorder (MDD) and bipolar disorder (BD), could aid in the diagnosis and treatment of these prevalent and debilitating neuropsychiatric conditions. One such candidate biomarker is the loudness dependence of the auditory evoked potential (LDAEP), an event-related potential that measures responsiveness of the auditory cortex to different intensities of sound. The LDAEP has been associated with MDD and BD, including therapeutic response to particular classes of antidepressant drugs, while also correlating with several other neuropsychiatric disorders. It has been suggested that increased values of the LDAEP indicate low central serotonergic neurotransmission, further implicating this EEG measure in depression. Here, we briefly review the literature on the LDAEP in affective disorders, including its association with serotonergic signaling, as well as with that of other neurotransmitters such as dopamine. We summarize key findings on the LDAEP and the genetics of these neurotransmitters, as well as prediction of response to particular classes of antidepressants in MDD, including SSRIs versus noradrenergic agents. The possible relationship between this EEG measure and suicidality is addressed. We also briefly analyze acute pharmacologic studies of serotonin and/or dopamine precursor depletion and the LDAEP. In conclusion, the existing literature suggests that serotonin and norepinephrine may modulate the LDAEP in an opposing manner, and that this event-related marker may be of use in predicting response to chronic treatment with particular pharmacologic agents in the context of affective disorders, such as MDD and BD, including in the presence of suicidality.

Affective Prosody and Its Impact on the Neurology of Language, Depression, Memory and Emotions.

Based on the seminal publications of Paul Broca and Carl Wernicke who established that aphasic syndromes (disorders of the verbal-linguistic aspects of communication) were predominantly the result of focal left-hemisphere lesions, "language" is traditionally viewed as a lateralized function of the left hemisphere. This, in turn, has diminished and delayed the acceptance that the right hemisphere also has a vital role in language, specifically in modulating affective prosody, which is essential for communication competency and psychosocial well-being. Focal lesions of the right hemisphere may result in disorders of affective prosody (aprosodic syndromes) that are functionally and anatomically analogous to the aphasic syndromes that occur following focal left-hemisphere lesions. This paper will review the deductive research published over the last four decades that has elucidated the neurology of affective prosody which, in turn, has led to a more complete and nuanced understanding of the neurology of language, depression, emotions and memory. In addition, the paper will also present the serendipitous clinical observations (inductive research) and fortuitous inter-disciplinary collaborations that were crucial in guiding and developing the deductive research processes that culminated in the concept that primary emotions and related display behaviors are a lateralized function of the right hemisphere and social emotions, and related display behaviors are a lateralized function of the left hemisphere.

Is melancholia a distinct syndrome? Recurrence, chronicity, and severity give evidence in the 50 year follow-up of the Lundby Study.

Introduction: Whether melancholia is a distinct syndrome has long been debated. One aspect of a valid syndrome is whether it allows for determination of a prognosis. The aim of this study is to investigate the course of melancholic depression versus non-melancholic depression with a focus on: (i) time to and probability of recovery from the first depressive episode, (ii) time to and risk of the first recurrence, (iii) rate of recurrence, (iv) time with depression or antidepressant medication, and (v) suicide risk. Methods: The Lundby Study is a longitudinal community study on mental health that followed a geographically defined population (N = 3,563) for up to 50 years, 1947-1997. Subjects with first onset depression were assessed as melancholic (N = 46) or non-melancholic (N = 381) using the DSM-IV melancholic specifier. These diagnoses were made in retrospect using all available information from semi-structured interviews by psychiatrists, key informants, registers, and patient records. Results: We found no significant difference between melancholic- and non-melancholic depression in time to and probability of recovery from the first depressive episode. The time to first recurrence was shorter in melancholic than in non-melancholic depression and the risk of first recurrence for the melancholic group was 2.77 (95% confidence interval [CI] 1.83-4.20) times the risk in the non-melancholic group. The median rate of recurrence was higher in the melancholic group, at 0.19 recurrences per year at risk (interquartile range [IQR] 0.08-0.47), compared to the non-melancholic group, at 0.10 recurrences per year at risk (IQR 0.05-0.21) (p < 0.03). The median percentage of time being depressed or on antidepressant medication was higher in the melancholic group, 17% (IQR 3-20%), compared to the non-melancholic group, 8% (IQR 7-33%) (p < 0.001). The risk of suicide was higher in the melancholic group, hazard ratio 4.13 (95% CI 1.49-11.48, p < 0.01). Discussion: To conclude, melancholic depression had a more recurrent, chronic, and severe course with a higher suicide risk than did non-melancholic depression in the Lundby population. Although our use of retrospective diagnosis might limit interpretation of results, the findings indicate that melancholia may be useful in determining prognosis and may be a valid psychopathological syndrome.

Changes of cortical thickness in the first episode, drug-naive depression patients with and without melancholic features.

Melancholic depression (MD) is a more severe type of major depressive disorder (MDD) with a core feature of anhedonia. However, its pathophysiology remains unclear. The current study aims to investigate whether there is a significant difference in cortical thickness (CT) that can be used to differentiate MD patients from non-melancholic depression (NMD) patients. We recruited 137 first-episode drug-naive MDD patients and 75 healthy controls (HCs) for structural magnetic resonance imaging, analyzed using the Surface-based morphometry approach. Meanwhile, the MDD patients were divided into the MD and NMD subgroups according to their scores on the Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale. No significant CT differences among the three groups were found. We also did not find significant CT changes between the NMD and the HCs groups or between the MD and NMD groups. However, the CT of the left postcentral gyrus and right precuneus among MD patients were larger than HCs. Moreover, the CT of the left postcentral gyrus and right precuneus were not correlated with the severity of the disease and illness duration. The findings suggest that the CT alterations of the left postcentral gyrus and the right precuneus are distinct pathological mechanisms for MD.

Apathy in melancholic depression and abnormal neural activity within the reward-related circuit.

Major depressive disorder is a heterogeneous syndrome, of which the most common subtype is melancholic depression (MEL). Previous studies have indicated that anhedonia is frequently a cardinal feature in MEL. As a common syndrome of motivational deficit, anhedonia is closely associated with dysfunction in reward-related networks. However, little is currently known about apathy, another syndrome of motivational deficits, and the underlying neural mechanisms in MEL and non-melancholic depression (NMEL). Herein, the Apathy Evaluation Scale (AES) was used to compare apathy between MEL and NMEL. On the basis of resting-state functional magnetic resonance imaging, functional connectivity strength (FCS) and seed-based functional connectivity (FC) were calculated within reward-related networks and compared among 43 patients with MEL, 30 patients with NMEL, and 35 healthy controls. Patients with MEL had higher AES scores than those with NMEL (t = -2.20, P = 0.03). Relative to NMEL, MEL was associated with greater FCS (t = 4.27, P < 0.001) in the left ventral striatum (VS), and greater FC of the VS with the ventral medial prefrontal cortex (t = 5.03, P < 0.001) and dorsolateral prefrontal cortex (t = 3.18, P = 0.005). Taken together the results indicate that reward-related networks may play diverse pathophysiological roles in MEL and NMEL, thus providing potential directions for future interventions in the treatment of various depression subtypes.

Abnormal dynamic functional connectivity of hippocampal subregions associated with working memory impairment in melancholic depression.

BACKGROUND: Previous studies have demonstrated structural and functional changes of the hippocampus in patients with major depressive disorder (MDD). However, no studies have analyzed the dynamic functional connectivity (dFC) of hippocampal subregions in melancholic MDD. We aimed to reveal the patterns for dFC variability in hippocampus subregions - including the bilateral rostral and caudal areas and its associations with cognitive impairment in melancholic MDD. METHODS: Forty-two treatment-naive MDD patients with melancholic features and 55 demographically matched healthy controls were included. The sliding-window analysis was used to evaluate whole-brain dFC for each hippocampal subregions seed. We assessed between-group differences in the dFC variability values of each hippocampal subregion in the whole brain and cognitive performance on the MATRICS Consensus Cognitive Battery (MCCB). Finally, association analysis was conducted to investigate their relationships. RESULTS: Patients with melancholic MDD showed decreased dFC variability between the left rostral hippocampus and left anterior lobe of cerebellum compared with healthy controls (voxel p < 0.005, cluster p < 0.0125, GRF corrected), and poorer cognitive scores in working memory, verbal learning, visual learning, and social cognition (all p < 0.05). Association analysis showed that working memory was positively correlated with the dFC variability values of the left rostral hippocampus-left anterior lobe of the cerebellum (r = 0.338, p = 0.029) in melancholic MDD. CONCLUSIONS: These findings confirmed the distinct dynamic functional pathway of hippocampal subregions in patients with melancholic MDD, and suggested that the dysfunction of hippocampus-cerebellum connectivity may be underlying the neural substrate of working memory impairment in melancholic MDD.

Melancholic features and typical neurovegetative symptoms of major depressive disorder show specific polygenic patterns.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterised by a heterogeneous clinical presentation and an estimated twin-based heritability of ~40-50 %. Different clinical MDD subtypes might partly reflect distinctive underlying genetics. This study aims to investigate if polygenic risk scores (PRSs) for different psychiatric disorders, personality traits, and substance use-related traits may be associated with different clinical subtypes of MDD (i.e., MDD with melancholic or psychotic features), higher symptom severity, or different clusters of depressive symptoms (i.e., sadness symptoms, typical neurovegetative symptoms, detachment symptoms, and negative thoughts). METHODS: The target sample included 1149 patients with MDD, recruited by the European Group for the Study of Resistant Depression. PRSs for 25 psychiatric disorders and traits were computed based on the most recent publicly available summary statistics of the largest genome-wide association studies. PRSs were then used as predictors in regression models, adjusting for age, sex, population stratification, and recruitment sites. RESULTS: Patients with MDD having higher PRS for MDD and loneliness were more likely to exhibit melancholic features of MDD (p = 0.0009 and p = 0.005, respectively). Moreover, patients with higher PRS for alcohol intake and post-traumatic stress disorder were more likely to experience greater typical neurovegetative symptoms (p = 0.0012 and p = 0.0045, respectively). LIMITATIONS: The proportion of phenotypic variance explained by the PRSs was limited. CONCLUSIONS: This study suggests that melancholic features and typical neurovegetative symptoms of MDD may show distinctive underlying genetics. Our findings provide a new contribution to the understanding of the genetic heterogeneity of MDD.

Abnormal long- and short-range functional connectivity in patients with first-episode drug-naïve melancholic and non-melancholic major depressive disorder.

BACKGROUND: We attempted to explore the common and distinct long- and short-range functional connectivity (FC) patterns of melancholic and non-melancholic major depressive disorder (MDD) and their associations with clinical characteristics. METHODS: Fifty-nine patients with first-episode drug-naïve MDD, including 31 patients with melancholic features and 28 patients with non-melancholic features, underwent resting-state functional magnetic resonance imaging (fMRI) scanning to examine long- and short-range FC. Thirty-two healthy volunteers were recruited as controls. The support vector machines (SVM) was applied to distinguish the melancholic patients from the non-melancholic patients by using the FC of abnormal brain regions. RESULTS: Compared to healthy volunteers, patients with MDD showed increased long-range positive FC (lpFC) in the right insula/inferior frontal gyrus and left insula. Relative to non-melancholic patients, melancholic patients displayed decreased lpFC in the right lingual gyrus, decreased short-range positive FC (spFC) in the right middle temporal gyrus and right superior parietal lobule, increased lpFC in the left inferior parietal lobule, and increased spFC in the left middle occipital gyrus/inferior occipital gyrus, left cerebellum VII/IX, and bilateral cerebellum CrusII. Increased lpFC in the left inferior parietal lobule in melancholic patients was correlated with the TEPS abstract anticipatory scores. SVM results showed that FCs of five combinations within different brain regions could distinguish melancholic patients from non-melancholic patients. CONCLUSIONS: FC abnormalities in the default mode network and parietal-occipital brain regions may underlie the neurobiology of melancholic MDD. An increased lpFC in the left inferior parietal lobule correlated with anhedonia may be a distinctive neurobiological feature of melancholic MDD.

The aberrant dynamic amplitude of low-frequency fluctuations in melancholic major depressive disorder with insomnia.

Background: Insomnia is considered one of the manifestations of sleep disorders, and its intensity is linked to the treatment effect or suicidal thoughts. Major depressive disorder (MDD) is classified into various subtypes due to heterogeneous symptoms. Melancholic MDD has been considered one of the most common subtypes with special sleep features. However, the brain functional mechanisms in melancholic MDD with insomnia remain unclear. Materials and methods: Melancholic MDD and healthy controls (HCs, n = 46) were recruited for the study. Patients were divided into patients with melancholic MDD with low insomnia (mMDD-LI, n = 23) and patients with melancholic MDD with high insomnia (mMDD-HI, n = 30), according to the sleep disturbance subscale of the 17-item Hamilton Depression Rating Scale. The dynamic amplitude of low-frequency fluctuation was employed to investigate the alterations of brain activity among the three groups. Then, the correlations between abnormal dALFF values of brain regions and the severity of symptoms were investigated. Results: Lower dALFF values were found in the mMDD-HI group in the right middle temporal gyrus (MTG)/superior temporal gyrus (STG) than in the mMDD-LI (p = 0.014) and HC groups (p < 0.001). Melancholic MDD groups showed decreased dALFF values than HC in the right middle occipital gyri (MOG)/superior occipital gyri (SOG), the right cuneus, the bilateral lingual gyrus, and the bilateral calcarine (p < 0.05). Lower dALFF values than HC in the left MOG/SOG and the left cuneus in melancholic MDD groups were found, but no significant difference was found between the mMDD-LI group and HC group (p = 0.079). Positive correlations between the dALFF values in the right MTG/STG and HAMD-SD scores (the sleep disturbance subscale of the HAMD-17) in the mMDD-HI group (r = 0.41, p = 0.042) were found. In the pooled melancholic MDD, the dALFF values in the right MOG/SOG and the right cuneus (r = 0.338, p = 0.019), the left MOG/SOG and the left cuneus (r = 0.299, p = 0.039), and the bilateral lingual gyrus and the bilateral calcarine (r = 0.288, p = 0.047) were positively correlated with adjusted HAMD scores. Conclusion: The occipital cortex may be related to depressive symptoms in melancholic MDD. Importantly, the right MTG/STG may play a critical role in patients with melancholic MDD with more severe insomnia.

Overlapping and segregated changes of functional hubs in melancholic depression and non-melancholic depression.

BACKGROUND: Previous research found associations between neuropsychiatric disorders and patterns of highly connected "hub" nodes, which are crucial in coordinating brain functions. Melancholic depression is considered a relatively distinct and homogenous subtype of major depressive disorder (MDD), which responds better to pharmacological treatments than placebos or psychotherapies. Accordingly, melancholic depression probably has distinct neuropathological underpinnings. This study aims to examine the overlapping and segregated changes of functional hubs in melancholic and non-melancholic MDD. METHODS: Thirty-one melancholic patients, 28 non-melancholic patients, and 32 healthy controls were included. Resting-state functional imaging data were analyzed using global functional connectivity. RESULTS: Both melancholic and non-melancholic patients had increased GFC in the bilateral insula and decreased GFC in the PCC/precuneus compared to HCs. The distinction was that melancholic patients showed increased GFC in the bilateral thalamus, right inferior parietal lobule (IPL), and left cerebellum Crus I and decreased GFC in the left temporal lobe, whereas non-melancholic patients showed increased GFC in the left superior parietal lobe. Additionally, compared with non-melancholic patients, melancholic individuals displayed significant increases of GFC in the left IPL and cerebellum. CONCLUSION: Increased GFC of the insula and decreased GFC of the PCC and precuneus are the common abnormalities of melancholic and non-melancholic MDD. Hyperconnectivity of the IPL and cerebellum might be distinctive neuropathological features of melancholic MDD.

White Matter Network Disruption Is Associated With Melancholic Features in Major Depressive Disorder.

Background: The efficacy and prognosis of major depressive disorder (MDD) are limited by its heterogeneity. MDD with melancholic features is an important subtype of MDD. The present study aimed to reveal the white matter (WM) network changes in melancholic depression. Materials and Methods: Twenty-three first-onset, untreated melancholic MDD, 59 non-melancholic MDD patients and 63 health controls underwent diffusion tensor imaging (DTI) scans. WM network analysis based on graph theory and support vector machine (SVM) were used for image data analysis. Results: Compared with HC, small-worldness was reduced and abnormal node attributes were in the right orbital inferior frontal gyrus, left orbital superior frontal gyrus, right caudate nucleus, right orbital superior frontal gyrus, right orbital middle frontal gyrus, left rectus gyrus, and left median cingulate and paracingulate gyrus of MDD patients. Compared with non-melancholic MDD, small-worldness was reduced and abnormal node attributes were in right orbital inferior frontal gyrus, left orbital superior frontal gyrus and right caudate nucleus of melancholic MDD. For correlation analysis, the 7th item score of the HRSD-17 (work and interest) was positively associated with increased node betweenness centrality (aBC) values in right orbital inferior frontal gyrus, while negatively associated with the decreased aBC in left orbital superior frontal gyrus. SVM analysis results showed that abnormal aBC in right orbital inferior frontal gyrus and left orbital superior frontal gyrus showed the highest accuracy of 81.0% (69/83), the sensitivity of 66.3%, and specificity of 85.2% for discriminating MDD patients with or without melancholic features. Conclusion: There is a significant difference in WM network changes between MDD patients with and without melancholic features.

Associations of major depressive disorder and related clinical characteristics with 25-hydroxyvitamin D levels in middle-aged adults.

Background: Vitamin D deficiency has been suggested to contribute to the onset of depression, but published results are inconsistent. The aims of this study were 1) to compare serum 25-hydroxyvitamin D (25(OH)D) levels in patients with depression and non-depressed controls and 2) to examine whether distinct subtypes and symptom severity of depression may vary in their association with 25(OH)D.Methods: The study involved cross-sectional data of n=1169 participants from the BiDirect Study (n=639 patients with clinically diagnosed major depressive disorder (MDD), n=530 controls). Serum 25(OH)D was measured via LS-MS/MS. We performed analysis of covariance to evaluate adjusted means of 25(OH)D levels and multinomial logistic regression to assess the association of depression and its clinical characteristics, namely distinct subtypes and symptom severity, with 25(OH)D status (adjusted for age, sex, education, season of blood sample collection, and lifestyle factors).Results: In total, 45.0% of the participants had adequate 25(OH)D levels (≥20 ng/ml), whereas 24.9% had a deficiency (<12 ng/ml). Patients with MDD had lower 25(OH)D levels than controls (16.7 vs. 19.6 ng/ml, p<0.001). Patients with atypical depression had the lowest levels (14.6 ng/ml). Symptom severity was inversely related to 25(OH)D. Moreover, patients with MDD had a more than 2-times higher odds of 25(OH)D deficiency than controls. Atypical depression showed the highest odds of deficiency.Conclusions: The results support that patients with depression have lower 25(OH)D concentrations than non-depressed individuals. Distinct subtypes, particularly the atypical subtype, may play a special role in this context. Therefore, depression heterogeneity should be considered in future research.

Electroencephalographic Parameters Differentiating Melancholic Depression, Non-melancholic Depression, and Healthy Controls. A Systematic Review.

Introduction: The objective of this systematic review was to investigate whether electroencephalographic parameters can serve as a tool to distinguish between melancholic depression, non-melancholic depression, and healthy controls in adults. Methods: A systematic review comprising an extensive literature search conducted in PubMed, Embase, Google Scholar, and PsycINFO in August 2020 with monthly updates until November 1st, 2020. In addition, we performed a citation search and scanned reference lists. Clinical trials that performed an EEG-based examination on an adult patient group diagnosed with melancholic unipolar depression and compared with a control group of non-melancholic unipolar depression and/or healthy controls were eligible. Risk of bias was assessed by the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) checklist. Results: A total of 24 studies, all case-control design, met the inclusion criteria and could be divided into three subgroups: Resting state studies (n = 5), sleep EEG studies (n = 10), and event-related potentials (ERP) studies (n = 9). Within each subgroup, studies were characterized by marked variability on almost all levels, preventing pooling of data, and many studies were subject to weighty methodological problems. However, the main part of the studies identified one or several EEG parameters that differentiated the groups. Conclusions: Multiple EEG modalities showed an ability to distinguish melancholic patients from non-melancholic patients and/or healthy controls. The considerable heterogeneity across studies and the frequent methodological difficulties at the individual study level were the main limitations to this work. Also, the underlying premise of shifting diagnostic paradigms may have resulted in an inhomogeneous patient population. Systematic Review Registration: Registered in the PROSPERO registry on August 8th, 2020, registration number CRD42020197472.

A Preliminary Randomized Controlled Trial of Different Treatment Regimens for Melancholic Depression.

BACKGROUND: Fluoxetine, bupropion, cognitive behavioral therapy (CBT), and physical therapies (modified electroconvulsive treatment or repetitive transcranial magnetic stimulation) can be used to manage melancholic depression. OBJECTIVE: To compare the efficacy and safety of various treatments in patients with melancholic depression. METHODS: This was a preliminary multicenter randomized controlled trial that included patients with depression in their first or recurrent acute episode between September 2016 and June 2019, and randomized to fluoxetine, fluoxetine+CBT, fluoxetine+bupropion, and fluoxetine+bupropion+brain stimulation. The primary endpoint was the decrease in the 17-item Hamilton Depression Rating Scale (17-HDRS). The secondary endpoint included the scores from the Quick Inventory of Depressive Symptomatology (QIDS-SR), QOL-6, and safety. Adverse events (AEs) were monitored. The follow-ups were performed at the end of the 0th, 2nd, 4th, 6th, 8th, and 12th weeks of treatment. RESULTS: Finally, 113 patients were included in the analyses: fluoxetine (n=37), fluoxetine+CBT (n=27), fluoxetine+bupropion (n=34), and fluoxetine+bupropion+brain stimulation (n=15). The 17-HDRS and QIDS-SR scores decreased in all four groups (all P<0.05). There were no differences in the 17-HDRS scores among the four groups at the end of treatment (P=0.779), except for fluoxetine alone showing a better response regarding self-consciousness than fluoxetine+bupropion. The QOL-6 scores increased in all four groups. The occurrence of AEs among the four groups showed no significant difference (P=0.053). CONCLUSION: This preliminary trial suggests that all four interventions (fluoxetine, fluoxetine+CBT, fluoxetine+bupropion, and fluoxetine+bupropion+brain stimulation) achieved similar response and remission rates in patients with melancholic depression, but that fluoxetine had a better effect on self-consciousness than fluoxetine+bupropion. The safety profile was manageable.

An electrophysiological model of major depression: Relevance to clinical subtyping and pharmacological management.

We present a neurochemical model of unipolar major depressive disorder that makes predictions for optimizing pharmacological treatment of this debilitating neuropsychiatric disorder. We suggest that there are two principal electrophysiological subtypes of depression, with the more common one involving a high excitatory/inhibitory (E/I) electrophysiological ratio, and a less common low E/I subtype. The high E/I subtype is paradoxically a variant of previous conceptions of atypical depression, whereas the low E/I subtype is a variant of melancholic depression. We focus on the ratio of norepinephrine (NE) to serotonin (5HT) as primary determinants of E/I ratio, which have opposing effects on mood regulation. We suggest that high NE/5HT (or E/I) ratio depressions should be treated with pharmacological agents that boost 5HT (such as SSRIs) and/or drugs that reduce noradrenergic transmission (such as clonidine, guanfacine, propranolol, prazosin). In contrast, low NE/5HT (or E/I) depressions should be treated with agents that boost NE (such as most tricyclics) and/or drugs that reduce serotonergic transmission. Our model predicts that the rapidly acting antidepressant ketamine (and possibly scopolamine), which has an acutely excitatory electrophysiological profile that may be followed by sustained increased inhibition, should improve the high NE/5HT subtype and worsen the low subtype.

Shared and distinct homotopic connectivity changes in melancholic and non-melancholic depression.

OBJECTIVE: Previous studies have revealed different neuroimaging features between melancholic and non-melancholic major depressive disorder (MDD). However, homotopic connectivity of melancholic and non-melancholic MDD remains unknown. The present study aimed to explore common and distinct homotopic connectivity patterns of melancholic and non-melancholic MDD and their associations with clinical characteristics. METHODS: Sixty-four patients with MDD and thirty-two healthy controls were scanned by resting-state functional magnetic resonance imaging (fMRI). Voxel-mirrored homotopic connectivity (VMHC) and pattern classification were applied to analyze the imaging data. RESULTS: Relative to healthy controls, melancholic patients displayed decreased VMHC in the fusiform gyrus, posterior cingulate cortex (PCC), superior occipital gyrus (SOG), postcentral gyrus and precentral/postcentral gyrus, and non-melancholic patients displayed decreased VMHC in the PCC. Compared with non-melancholic patients, melancholic patients displayed reduced VMHC in the precentral gyrus and precentral/postcentral gyrus. Support vector machine (SVM) results exhibited VMHC in the precentral gyrus could distinguish melancholic patients from non-melancholic patients with more than 0.6 for specificity, sensitivity and accuracy. CONCLUSION: The study demonstrated common and distinct homotopic connectivity patterns in melancholic and non-melancholic patients. Decreased VMHC in the PCC may be a state-related change for depression, and reduced VMHC in the precentral gyrus and postcentral gyrus may be a distinctive neurobiological feature for melancholic MDD. VMHC in precentral gyrus might be served as potential imaging markers to discriminate melancholic patients from non-melancholic MDD.

Disrupted Regional Homogeneity in Melancholic and Non-melancholic Major Depressive Disorder at Rest.

Background: Melancholic depression has been viewed as one severe subtype of major depressive disorder (MDD). However, it is unclear whether melancholic depression has distinct changes in brain imaging. We aimed to explore specific or distinctive alterations in melancholic MDD and whether the alterations could be used to separate melancholic MDD from non-melancholic MDD or healthy controls. Materials and Methods: Thirty-one outpatients with melancholic MDD and thirty-three outpatients with non-melancholic MDD and thirty-two age- and gender-matched healthy controls were recruited. All participants were scanned by resting-state functional magnetic resonance imaging (fMRI). Imaging data were analyzed with the regional homogeneity (ReHo) and support vector machine (SVM) methods. Results: Melancholic MDD patients exhibited lower ReHo in the right superior occipital gyrus/middle occipital gyrus than non-melancholic MDD patients and healthy controls. Merely for non-melancholic MDD patients, decreased ReHo in the right middle frontal gyrus was negatively correlated with the total HRSD-17 scores. SVM analysis results showed that a combination of abnormal ReHo in the right fusiform gyrus/cerebellum Crus I and the right superior occipital gyrus/middle occipital gyrus exhibited the highest accuracy of 83.05% (49/59), with a sensitivity of 90.32% (28/31), and a specificity of 75.00% (21/28) for discriminating patients with melancholic MDD from patients with non-melancholic MDD. And a combination of abnormal ReHo in the right fusiform gyrus/cerebellum VI and left postcentral gyrus/precentral gyrus exhibited the highest accuracy of 98.41% (62/63), with a sensitivity of 96.77% (30/31), and a specificity of 100.00%(32/32) for separating patients with melancholic MDD from healthy controls. Conclusion: Our findings showed the distinctive ReHo pattern in patients with melancholic MDD and found brain area that may be associated with the pathophysiology of non-melancholic MDD. Potential imaging markers for discriminating melancholic MDD from non-melancholic MDD or healthy controls were reported.

Differentiating Melancholic and Non-melancholic Major Depressive Disorder Using Fractional Amplitude of Low-Frequency Fluctuations.

BACKGROUND: Melancholic major depressive disorder (MDD) is a network-based brain disorder. However, whether or not network-based changes can be applied to differentiate melancholic (MEL) from non-melancholic (NMEL) MDD remains unclear. METHODS: Thirty-one MEL patients, 28 NMEL patients, and 32 matched healthy controls (HCs) were scanned using resting-state functional magnetic resonance imaging. Patients were assessed by the Chinese version of Snaith-Hamilton Pleasure Scale (SHAPS-C) and Temporal Experience of Pleasure Scale (TEPS). Fractional amplitude of low-frequency fluctuations (fALFF) and correlation analysis were used to analyze the data. RESULTS: Compared with HCs, the MEL group had significantly higher fALFF values in the bilateral inferior frontal gyrus and right supplementary motor area (SMA) and significantly lower fALFF values in the right inferior occipital gyrus (IOG), right middle temporal gyrus (MTG)/left IOG, and bilateral superior occipital gyrus (SOG)/MTG. On the other hand, the NMEL group showed significantly higher fALFF values in the bilateral SMA and significantly lower fALFF values in the bilateral posterior cingulate cortex/precuneus relative to HCs. Compared with the NMEL group, the MEL group showed significantly lower fALFF values in the left anterior cingulate cortex (ACC). A correlation was found between the fALFF values of the right SMA and the SHAPS-C in the MEL group. In addition, correlations were observed between the fALFF values of the left ACC and the TEPS contextual consummatory and total scores in all patients. CONCLUSION: Our study uncovered that MDD exhibited altered brain activity in extensive brain networks, including the default-mode network, frontal-striatal network, reward system, and frontal-limbic network. Decreased fALFF in the left ACC might be applied to differentiate the two subtypes of MDD.

Depressão sem tristeza, com tristeza e melancólica / Depression without sadness, with sadness and melancholic one / Depresión sin tristeza, con tristeza y melancólica / Dépression sans tristesse, avec tristesse et mélancolique

RESUMO Este estudo psicanalítico das depressões parte do pressuposto de que esse quadro é sintoma da atividade de um núcleo inconsciente que se organiza em resposta a modos específicos de presença do objeto primário: 1) operatório, 2) em codependência, e 3) por desinvestimento ou por investimento negativo do sujeito. Essa compreensão permite reconhecer as características do campo transferencial-contratransferencial e conduzir as análises em cada caso.

ABSTRACT This psychoanalytic study on depressions assumes that this condition is a symptom of the activity of an unconscious nucleus that is organized in response to specific modes of presence of the primary object: 1) operative; 2) in codependency; and 3) by disinvestment or negative investment by the subject. This understanding allows us to recognize the characteristics of the transferential-countertransferential field, and to conduct the analyzes in each case.

RESUMEN Este estudio psicoanalítico de las depresiones parte del supuesto de que ese cuadro es un síntoma de la actividad de un núcleo inconsciente que se organiza en respuesta a modos específicos de presencia del objeto primario: 1) operatorio; 2) en codependencia; y 3) por desinversión / inversión negativa del sujeto. Esta comprensión permite reconocer las características del campo transferencial-contratransferencial, y conducir los análisis en cada caso.

RÉSUMÉ Cette étude psychanalytique des dépressions se base sur le présupposé que cette condition est un symptôme de l'activité d'un noyau inconsciente qui s'organise en réponse à des modes spécifiques de présence de l'objet primaire : 1) opératoire ; 2) dans la codépendance ; et 3) par désinvestissement ou investissement négatif du sujet. Cette compréhension permet de reconnaître les caractéristiques du champ transférentiel / contre transférentiel et de mener les analyses propres à chaque cas.