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.

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.

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.

Major depression subtypes are differentially associated with migraine subtype, prevalence and severity.

OBJECTIVE: Migraine and major depressive disorder show a high rate of comorbidity, but little is known about the associations between the subtypes of major depressive disorder and migraine. In this cross-sectional study we aimed at investigating a) the lifetime associations between the atypical, melancholic, combined and unspecified subtype of major depressive disorder and migraine with and without aura and b) the associations between major depressive disorder and its subtypes and the severity of migraine. METHODS: A total of 446 subjects with migraine (migraine without aura: n = 294; migraine with aura: n = 152) and 2511 controls from the population-based CoLaus/PsyCoLaus study, Switzerland, were included. Associations between major depressive disorder subtypes and migraine characteristics were tested using binary logistic or linear regression. RESULTS: Melancholic, combined and unspecified major depressive disorder were associated with increased frequency of migraine with aura, whereas only melancholic major depressive disorder was associated with increased frequency of migraine without aura. Lifetime and unspecified major depressive disorder were associated with severe migraine intensity among subjects with migraine with aura but not migraine without aura, while combined major depressive disorder was associated with higher migraine frequency independently from migraine subtype. CONCLUSION: This study suggests that melancholic but not atypical major depressive disorder is associated with migraine and migraine subtypes. Future studies exploring pathophysiological mechanisms shared between melancholic depression and migraine are warranted.

The effects of ketamine on typical and atypical depressive symptoms.

OBJECTIVE: Ketamine's effects on different dimensions of depressive symptomatology, including typical/melancholic and atypical depression, remain largely unknown. This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). METHODS: Data from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar depression were pooled from three separate, double-blind, placebo-controlled, crossover studies investigating ketamine's efficacy in depression. MDD participants were unmedicated; bipolar participants received therapeutic-dose lithium or valproate. Clinical symptoms were collected preinfusion and up to 14 days postinfusion. Effect sizes were calculated for days 1 and 3 postinfusion. The primary measures of interest for this exploratory analysis were total MADRS, MADRS5, and SAS scores. Individual symptoms were also analyzed in an exploratory manner. RESULTS: Scores improved significantly at Day 1 postinfusion (MADRS: Cohen's d = 0.64; MADRS5: Cohen's d = 0.61; SAS: Cohen's d = 0.41) and continued to be significantly improved over placebo at Day 3 (MADRS: Cohen's d = 0.49; MADRS5: Cohen's d = 0.43; SAS: Cohen's d = 0.39). Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. CONCLUSION: Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former.

Characterological depression in patients with narcissistic personality disorder.

Background: Depressive symptoms often occur in patients with personality disorders. Along the lines of the precious concepts of reactive and melancholic forms of depression, two different patterns of depressive symptoms can be identified. Reactive forms of depression is considered to be related to dysfunction of emotional regulation and social functioning, and to personality disorders. This study aimed at exploring the pattern of depressive symptoms in patients with Narcissistic Personality Disorder (NPD) compared to a group of depressed patients without Personality Disorder (PD). The Newcastle Diagnostic Depression Scale (NDDS) is a clinical instrument designed to differentiate reactive depression from melancholic depression. Method: The study investigated patterns of depressive symptoms in 117 out-patients, divided into two groups. One group containing 56 patients with depressive symptoms by no PD and the other group comprised of 61 patients with depressive symptoms and NPD. The participants were interviewed using the Newcastle Diagnostic Depression Scale. Results: There was a significant difference between the groups, as the NPD group suffered from reactive forms of depression. The NPD group showed a pattern of depressive symptoms characterized by fluctuation of the depressive state, without time demarcation of depressive episode, ruminations preoccupied with hostility and accusatory feelings towards other, but not self-accusatory feelings, fluctuation suicidal ideation triggered by external events accompanied by parasuicidal behavior, lack of neuro-vegetative symptoms such as insomnia with early wakening, loss of appetite and weight loss. The No PD group showed the opposite pattern. Conclusion: Based on these results NDDS is considered to be an applicable instrument for identifying personality pathology in patients with depressive symptoms, by recognizing the specific pattern. This is thought to be important for adequate treatment planning.

Lower levels of brain-derived neurotrophic factor are associated with melancholic psychomotor retardation among depressed inpatients.

OBJECTIVES: Melancholic depression is a type of depression which is closely related to biological variables than are other types of depression. Its clinical features can be assessed using six items on the Hamilton Depression Rating Scale (HAM-D6 ). Previous studies have shown, using item response theory, that the symptom depressed mood is the least severe melancholic feature; work and activities, somatic symptoms and psychic anxiety are of moderate severity; and feelings of guilt and psychomotor retardation are the most severe. We aimed to evaluate whether the more severe melancholic signs or symptoms were associated with decreases in brain-derived neurotrophic factor (BDNF) levels. METHODS: A total of 151 severely depressed inpatients had their BDNF levels analyzed by comparing those who presented with each HAM-D6 melancholic feature to those for whom the HAM-D6 feature was absent, using multiple linear regressions. The levels of BDNF of patients who presented with each melancholic feature were also compared with those of 100 healthy controls. RESULTS: Depressed patients' median BDNF level was 44.06 ng/mL (interquartile range [IQR]: 33.99-62.4 ng/mL), and controls' median BDNF level was 65.22 ng/mL (IQR: 49.87-76.08 ng/mL) (P < .001). The presence of depressed mood, work and activities, somatic symptoms, psychic anxiety, and guilty feelings was not associated with BDNF levels. However, the presence of psychomotor retardation was associated with reduced BDNF (median reduction -10.07 ng/mL; 95% confidence interval [CI]: -19.43 to -0.71; P = .03). CONCLUSIONS: To the best of our knowledge, this study is the first to associate BDNF levels with melancholic features in a sample of severely depressed inpatients. The main finding of this study was that severely depressed inpatients who presented the most severe melancholic feature, psychomotor retardation, had significantly reduced BDNF levels in the blood.

Big Five personality characteristics are associated with depression subtypes and symptom dimensions of depression in older adults.

OBJECTIVE: This study examined the associations of personality characteristics with both subtypes and symptom dimensions of depression in older adults. METHODS: Three hundred and seventy-eight depressed older adults participated in the Netherlands Study of Depression in Older Persons. Personality characteristics were assessed by the NEO-Five Factor Inventory. Subtypes and symptom dimensions of depression were determined using the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology (IDS). Multinomial logistic regression analyses were performed to examine the associations between personality and atypical, melancholic, and unspecified subtypes of major depression. Linear regression analyses examined the associations between personality and the IDS mood, somatic, and motivation symptom dimensions. The analyses were adjusted for confounders and additionally adjusted for depression severity. RESULTS: Neuroticism, Extraversion, Conscientiousness, and Agreeableness were associated with specified (atypical or melancholic) major depression compared with unspecified major depression in the bivariate analyses but lost their significance after adjustments for functional limitations and severity of depression. Neuroticism was positively associated with the IDS mood and motivation symptom dimensions, also in the adjusted models. Further, Extraversion and Agreeableness were negatively associated with the IDS mood symptom dimension, and Extraversion and Conscientiousness were negatively associated with the IDS motivation symptom dimension. None was associated with the IDS somatic symptom dimension. CONCLUSIONS: This study demonstrated the association of personality characteristics with mood and motivational symptoms of late-life depression. The lacking ability of personality to differentiate between melancholic and atypical depression seems to be largely explained by severity of depressive symptoms. Copyright © 2017 John Wiley & Sons, Ltd.

Metabolomic biosignature differentiates melancholic depressive patients from healthy controls.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous disease at the level of clinical symptoms, and this heterogeneity is likely reflected at the level of biology. Two clinical subtypes within MDD that have garnered interest are "melancholic depression" and "anxious depression". Metabolomics enables us to characterize hundreds of small molecules that comprise the metabolome, and recent work suggests the blood metabolome may be able to inform treatment decisions for MDD, however work is at an early stage. Here we examine a metabolomics data set to (1) test whether clinically homogenous MDD subtypes are also more biologically homogeneous, and hence more predictiable, (2) devise a robust machine learning framework that preserves biological meaning, and (3) describe the metabolomic biosignature for melancholic depression. RESULTS: With the proposed computational system we achieves around 80 % classification accuracy, sensitivity and specificity for melancholic depression, but only ~72 % for anxious depression or MDD, suggesting the blood metabolome contains more information about melancholic depression.. We develop an ensemble feature selection framework (EFSF) in which features are first clustered, and learning then takes place on the cluster centroids, retaining information about correlated features during the feature selection process rather than discarding them as most machine learning methods will do. Analysis of the most discriminative feature clusters revealed differences in metabolic classes such as amino acids and lipids as well as pathways studied extensively in MDD such as the activation of cortisol in chronic stress. CONCLUSIONS: We find the greater clinical homogeneity does indeed lead to better prediction based on biological measurements in the case of melancholic depression. Melancholic depression is shown to be associated with changes in amino acids, catecholamines, lipids, stress hormones, and immune-related metabolites. The proposed computational framework can be adapted to analyze data from many other biomedical applications where the data has similar characteristics.

Feelings of worthlessness during a single complicated major depressive episode predict postremission suicide attempt.

OBJECTIVE: To establish which symptoms of major depressive episode (MDE) predict postremission suicide attempts in complicated single-episode cases. METHOD: Using the nationally representative two-wave National Epidemiologic Survey on Alcohol and Related Conditions data set, we identified wave 1 lifetime single-episode MDE cases in which the episode remitted by the beginning of the wave 2 three-year follow-up period (N = 2791). The analytic sample was further limited to 'complicated' cases (N = 1872) known to have elevated suicide attempt rates, defined as having two or more of the following: suicidal ideation, marked role impairment, feeling worthless, psychomotor retardation, and prolonged (>6 months) duration. RESULTS: Logistic regression analyses showed that, after controlling for wave 1 suicide attempt which significantly predicted postremission suicide attempt (OR = 10.0), the additional complicated symptom 'feelings of worthlessness' during the wave 1 index episode significantly and very substantially predicted postremission suicide attempt (OR = 6.96). Neither wave 1 psychomotor retardation nor wave 1 suicidal ideation nor any of the other wave 1 depressive symptoms were significant predictors of wave 2 suicide attempt. CONCLUSION: Among depressive symptoms during an MDE, feelings of worthlessness is the only significant indicator of elevated risk of suicide attempt after the episode has remitted, beyond previous suicide attempts.

[Typus melancholicus and melancholia: Theoretical synthesis using a clinical case]. / Typus melancholicus et mélancolie : synthèse théorique à partir d'un cas clinique.

OBJECTIVE: The aim of this paper is to propose, starting from the description of a clinical emblematic case, a theoretical synthesis of the work of phenomenological psychopathology dedicated to melancholia and typus melancholicus (TM), a clinical concept that describes the premorbid personality vulnerable to major depression ("melancholia" for the psychopathological tradition). METHOD: This is a phenomenological analysis of a case study of melancholia, of its premorbid personality and pathogenic triggering situation. We adopt two main phenomenological keys to understand the development of melancholia: a role-identity theory and desynchronization theory. The former understands melancholia as a disorder of identity triggered by the loss of the social role with which one has previously over-identified. The latter sees melancholia as the effect of the desynchronization from the social environment that further develops into an inhibition of the cognative-affective dynamics of life. We present the case of Jonas (64 years old), whose mother (94 years old) recently died. Before his mother's death, Jonas' life was entirely orchestrated by the caring for his mother and synchronized in time with this (e.g., he used to go to her house every 4 hours, had all his meals with her, etc.). Jonas, in addition to being hyper-synchronized and hyper-syntonic, fulfills all diagnostic criteria for TM, including "orderliness", "conscientiousness", "hyper/heteronomia" and "intolerance of ambiguity". TMs attach a disproportioned importance to their social roles (or external representations of identity) at the expense of their own ego-identity. RESULTS: The passage from premorbid personality to melancholia is triggered by the death of Jonas' mother that entails a profound depersonalization. Desynchronization and role loss cause Jonas' fall into this severe depersonalization, the core feature of which is the feeling of the loss of feeling. CONCLUSIONS: This original contribution demonstrates that a clinical case can contribute to the construction and refinement of theoretical and conceptual frameworks (like princeps Tellenbach's studies). Over-synchronized tempo and over-identification with social role are emblematically in this case the two sides of the same coin. A parallelism can be established between synchronization (with the mother) and respect for the role at the expense of own identity. The clinical case of Jonas highlights a conceptual bridge between the model of melancholia as loss of social role and the model of melancholia as desynchronization.

Melancholic-Like behaviors and circadian neurobiological abnormalities in melatonin MT1 receptor knockout mice.

BACKGROUND: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. METHODS: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. RESULTS: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. CONCLUSIONS: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition.

Aberrant high-beta band functional connectivity during reward processing in melancholic major depressive disorder: An MEG study.

OBJECTIVE: To identify the spatial-temporal pattern variation of whole-brain functional connectivity (FC) during reward processing in melancholic major depressive disorder (MDD) patients, and to determine the clinical correlates of connectomic differences. METHODS: 61 MDD patients and 32 healthy controls were enrolled into the study. During magnetoencephalography (MEG) scanning, all participants completed the facial emotion recognition task. The MDD patients were further divided into two groups: melancholic (n = 31) and non-melancholic (n = 30), based on the Mini International Neuropsychiatric Interview (M.I.N.I.) assessment. Melancholic symptoms were examined by using the 6-item melancholia subscale from the Hamilton Depression Rating Scale (HAM-D6). The whole-brain orthogonalized power envelope connections in the high-beta band (20-35 Hz) were constructed in each period after the happy emotional stimuli (0-200 ms, 100-300 ms, 200-400 ms, 300-500 ms, and 400-600 ms). Then, the network-based statistic (NBS) was used to determine the specific abnormal connection patterns in melancholic MDD patients. RESULTS: The NBS identified a sub-network difference at the mid-late period (300-500 ms) in response to happy faces among the three groups (corrected P = 0.035). Then, the post hoc and correlation analyses found five FCs were decreased in melancholic MDD patients and were related to HAM-D6 score, including FCs of left fusiform gyrus-right orbital inferior frontal gyrus (r = -0.52, P < 0.001), left fusiform gyrus-left amygdala (r = -0.26, P = 0.049), left posterior cingulate gyrus-right precuneus (r = -0.32, P = 0.025), left precuneus-right precuneus (r = -0.27, P = 0.049), and left precuneus-left inferior occipital gyrus (r = -0.32, P = 0.025). CONCLUSION: In response to happy faces, melancholic MDD patients demonstrated a disrupted functional connective pattern (20-35 Hz, 300-500 ms), which involved brain regions in visual information processing and the limbic system. The aberrant functional connective pattern in reward processing might be a biomarker of melancholic MDD.

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.

Neural substrates of predicting anhedonia symptoms in major depressive disorder via connectome-based modeling.

MAIN PROBLEM: Anhedonia is a critical diagnostic symptom of major depressive disorder (MDD), being associated with poor prognosis. Understanding the neural mechanisms underlying anhedonia is of great significance for individuals with MDD, and it encourages the search for objective indicators that can reliably identify anhedonia. METHODS: A predictive model used connectome-based predictive modeling (CPM) for anhedonia symptoms was developed by utilizing pre-treatment functional connectivity (FC) data from 59 patients with MDD. Node-based FC analysis was employed to compare differences in FC patterns between melancholic and non-melancholic MDD patients. The support vector machines (SVM) method was then applied for classifying these two subtypes of MDD patients. RESULTS: CPM could successfully predict anhedonia symptoms in MDD patients (positive network: r = 0.4719, p < 0.0020, mean squared error = 23.5125, 5000 iterations). Compared to non-melancholic MDD patients, melancholic MDD patients showed decreased FC between the left cingulate gyrus and the right parahippocampus gyrus (p_bonferroni = 0.0303). This distinct FC pattern effectively discriminated between melancholic and non-melancholic MDD patients, achieving a sensitivity of 93.54%, specificity of 67.86%, and an overall accuracy of 81.36% using the SVM method. CONCLUSIONS: This study successfully established a network model for predicting anhedonia symptoms in MDD based on FC, as well as a classification model to differentiate between melancholic and non-melancholic MDD patients. These findings provide guidance for clinical treatment.

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.

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.

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.

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.

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.