A network view on psychiatric disorders: network clusters of symptoms as elementary syndromes of psychopathology.

INTRODUCTION: The vast number of psychopathological syndromes that can be observed in clinical practice can be described in terms of a limited number of elementary syndromes that are differentially expressed. Previous attempts to identify elementary syndromes have shown limitations that have slowed progress in the taxonomy of psychiatric disorders. AIM: To examine the ability of network community detection (NCD) to identify elementary syndromes of psychopathology and move beyond the limitations of current classification methods in psychiatry. METHODS: 192 patients with unselected mental disorders were tested on the Comprehensive Psychopathological Rating Scale (CPRS). Principal component analysis (PCA) was performed on the bootstrapped correlation matrix of symptom scores to extract the principal component structure (PCS). An undirected and weighted network graph was constructed from the same matrix. Network community structure (NCS) was optimized using a previously published technique. RESULTS: In the optimal network structure, network clusters showed a 89% match with principal components of psychopathology. Some 6 network clusters were found, including "Depression", "Mania", "Anxiety", "Psychosis", "Retardation", and "Behavioral Disorganization". Network metrics were used to quantify the continuities between the elementary syndromes. CONCLUSION: We present the first comprehensive network graph of psychopathology that is free from the biases of previous classifications: a 'Psychopathology Web'. Clusters within this network represent elementary syndromes that are connected via a limited number of bridge symptoms. Many problems of previous classifications can be overcome by using a network approach to psychopathology.

The network structure of human personality according to the NEO-PI-R: matching network community structure to factor structure.

INTRODUCTION: Human personality is described preferentially in terms of factors (dimensions) found using factor analysis. An alternative and highly related method is network analysis, which may have several advantages over factor analytic methods. AIM: To directly compare the ability of network community detection (NCD) and principal component factor analysis (PCA) to examine modularity in multidimensional datasets such as the neuroticism-extraversion-openness personality inventory revised (NEO-PI-R). METHODS: 434 healthy subjects were tested on the NEO-PI-R. PCA was performed to extract factor structures (FS) of the current dataset using both item scores and facet scores. Correlational network graphs were constructed from univariate correlation matrices of interactions between both items and facets. These networks were pruned in a link-by-link fashion while calculating the network community structure (NCS) of each resulting network using the Wakita Tsurumi clustering algorithm. NCSs were matched against FS and networks of best matches were kept for further analysis. RESULTS: At facet level, NCS showed a best match (96.2%) with a 'confirmatory' 5-FS. At item level, NCS showed a best match (80%) with the standard 5-FS and involved a total of 6 network clusters. Lesser matches were found with 'confirmatory' 5-FS and 'exploratory' 6-FS of the current dataset. Network analysis did not identify facets as a separate level of organization in between items and clusters. A small-world network structure was found in both item- and facet level networks. CONCLUSION: We present the first optimized network graph of personality traits according to the NEO-PI-R: a 'Personality Web'. Such a web may represent the possible routes that subjects can take during personality development. NCD outperforms PCA by producing plausible modularity at item level in non-standard datasets, and can identify the key roles of individual items and clusters in the network.

Increased plasma norepinephrine concentration in psychotic depression.

OBJECTIVE: We previously found psychotic depression (PSDEP) to have positively correlating plasma norepinephrine (NE) and vasopressin (AVP) concentrations. Since central noradrenergic activity and plasma NE concentration are highly correlated, this suggests an increased noradrenergic activation of the hypothalamus-pituitary-adrenal axis. We hypothesize the increased release of NE in PSDEP to be an associated mechanism. METHODS: To test this hypothesis we analyzed the relation between plasma NE and PSDEP in a comparison with non-psychotically depressed patients. Potentially confounding variables were, among others, melancholia and two better validated subcategories in the field of melancholia and endogenous depression, three global dimensions of psychopathology - Emotional Dysregulation, Retardation and Anxiety - smoking habit, and different types of psychotropic and particularly antidepressant treatment. The data from nine patients with PSDEP and 69 patients with non-PSDEP were reanalysed. RESULTS: Analysis of covariance controlling for the effects of tricyclic antidepressant treatment (≥100 mg) and smoking habit showed that PSDEP had an increased concentration of plasma NE. The previously found correlation between plasma NE and AVP was still present after correcting for the effects of confounding variables. CONCLUSIONS: The results suggest an increased activity of the sympathetic nervous system in PSDEP that may act as a specific mechanism for increased vasopressinergic activation. This supports the view of PSDEP as a distinct subcategory of major depression.

Temperament and character in psychotic depression compared with other subcategories of depression and normal controls.

Background. Support has been found for high harm avoidance as general vulnerability trait for depression and decreased self-directedness (SD) as central state-related personality change. Additional personality characteristics could be present in psychotic depression (PD). Increased noradrenergic activation in PD predicts the involvement of reward dependence (RD). Methods. The data during the acute episode and after full remission from the same subjects, that we used before, were reanalyzed. The dependence of the 7 dimensions of the Temperament and Character Inventory version 9 on PD, three other subcategories of depression, and a group of normal controls was tested by MANCOVA. Results. Low RD at both time points, and low Cooperativeness during the acute episode, were found as additional characteristics of PD. Conclusion. The combination of two premorbid temperaments, high HA and low RD, and the development of a state-related reduction of two character functions, SD and CO, may be the precondition for the development of combined depressive and psychotic psychopathology.

An Increase of the Character Function of Self-Directedness Is Centrally Involved in Symptom Reduction during Remission from Major Depression.

Background. Studies with the Temperament and Character Inventory (TCI) in depressive disorders have shown changes (Δ) of the character of Self-Directedness (SD) and the temperament of Harm Avoidance (HA). The central question of this study is which of these two changes is most proximally related to the production of depressive symptoms. Methods. The start and endpoint data from a two-year followup of 58 depressed patients were reanalyzed. We used the ΔHA and ΔSD scores as well as the Δ scores on three dimensions of psychopathology, called Emotional Dysregulation (ED), Retardation (RET), and Anxiety (ANX). The presence of the main relation between personality and psychopathology was tested in all patients and in four subcategories. The data were analyzed by MANCOVA and Structural Equation Modelling (SEM). Results. ΔHA and ΔSD correlated negatively, and only ΔSD was related (negatively) to ΔED. This pattern was found in all subcategories. SEM showed ΔHA and ΔSD had an ambiguous causal interrelationship, while ΔSD, ΔRET, and ΔANX had unidirectional effects on ΔED. Conclusion. The results correspond with a central pathogenetic role for a state-related deficit at the character level in depression. This may have important consequences for investigations of endophenotypes and clinical treatment.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features.

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.

Character and temperament in major depressive disorder and a highly anxious-retarded subtype derived from melancholia.

BACKGROUND: An anxious-retarded subtype of major depressive disorder, defined by high scores for both anxiety and retardation, has been derived from melancholia and appeared to have higher external validity in terms of poor outcome and vasopressinergic stress hormone regulation. A specific personality could enhance the validity of this subtype, and the association with melancholia suggested the absence of a personality disorder. As 2 character dimensions of the Temperament and Character Inventory (TCI), self-directedness (SD) and cooperativeness, parsimoniously predict the presence of a personality disorder, the primary aim was to test whether patients with the highly anxious-retarded subtype of depression have both normal SD and normal cooperativeness. A secondary aim was to optimally account for the general personality characteristics of patients with a major depressive disorder. METHODS: Eighty-six patients with major depressive disorder and matched healthy controls were selected. Seventy patients were eventually recruited for a 2-year follow-up encompassing 5 assessments of personality (TCI) and psychopathology (Comprehensive Psychopathological Rating Scale). Full remission of depression was defined by the presence of less than 3 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition items of depression during 2 weeks. RESULTS: State-dependent changes of SD and harm avoidance (HA) scores were found in all depressed patients. Fully remitted patients had only high HA compared with healthy controls. Unexpectedly, fully remitted patients with the highly anxious-retarded subtype, in addition, had low SD. CONCLUSION: The temperament of high HA may be the predisposing TCI trait for major depressive disorder in general. Low SD may be a specific presumably premorbid character trait for the highly anxious-retarded subtype derived from melancholia.

Four-dimensional structure underlying scales for depression anxiety and retardation: emergence of trapped anger and scale improvements.

Improvement of rating scales for anxiety and depression has insufficiently been based on their underlying multidimensional structure. The aim of this study was to detect the underlying symptom structure of 3 scales for anxiety, depression, and retardation from the Comprehensive Psychopathological Rating Scale (CPRS), to test its validity, and to investigate whether the scales developed from this structure have lower item overlap than the original scales. All items (N = 21) of the 3 subscales (Brief Anxiety Scale [BAS], Montgomery Asberg Depression Rating Scale [MADRS], and Motivational Inhibition) were selected. Principal components analysis was performed on the scores of 334 outpatients. Correlations between factor-regression scores on the CPRS components and scores on the Mood and Anxiety Symptom Questionnaire dimensions were analyzed. New rating scales based on the CPRS components were developed and compared with the original scales. Four CPRS components were found: depression, retardation, anxiety, and trapped anger. Each had a specific correlational pattern with the Mood and Anxiety Symptom Questionnaire dimensions. Overlap between the 4 new scales was lower than that between the original scales. A 4-dimensional symptom structure underlies CPRS scales for anxiety, depression, and retardation. This structure results in the detection of a scale for trapped anger and improvement of the 3 original scales.

Plasma cortisol and norepinephrine in Alzheimer's disease: opposite relations with recall performance and stage of progression.

OBJECTIVE: Alzheimer's disease (AD) is characterized by effortful retrieval memory impairments, loss of hippocampal neurons and elevated plasma cortisol (CORT) concentrations. The latter could induce further memory decline. AD is also characterized by increased central and peripheral noradrenergic activity. Since noradrenergic function is involved in memory formation, this upregulated function could counteract memory decline. The aim of the present study was to test these hypotheses using plasma norepinephrine (NE) as a noradrenergic parameter, and recall of the prerecency part of neutral valence word lists as a measure of effortful retrieval. METHODS: Area under the curve (AUC) of morning, midday and afternoon plasma CORT and plasma NE concentrations was related to two measures of recall performance, ie summated recall scores of the prerecency and recency parts of three word lists, and to the stage of the Clinical Dementia Rating (CDR). RESULTS: Partial correlation between each hormone AUC value and prerecency recall performance, controlling for the effect of the other hormone, showed opposite relations between recall and either plasma CORT or NE. Similar stronger correlations were found with the CDR score. CONCLUSIONS: Plasma CORT and NE are oppositely related with effortful retrieval and the stage of progression in AD.

Depression with above-normal plasma vasopressin: validation by relations with family history of depression and mixed anxiety and retardation.

An anxious-retarded subtype of depression has been derived from the DSM-IV category of melancholia. It is defined by combined high scores for anxiety and retardation, and is related to family history of depression and increased plasma vasopressin (AVP) levels. Central problems concerning this hypothesized subcategory are whether elevated plasma AVP is related to family history, whether it would be better operationalized by a cut-off level for plasma AVP than as continuous variable, and whether the anxious-retarded phenotype would be better described in terms that account for full variability of mixed anxiety and retardation. A previous study suggested that above-normal plasma AVP was a more useful endophenotypic parameter than plasma AVP as a continuous variable. To answer these and related questions, 81 patients were investigated. Receiver Operating Characteristic analyses yielded a cut-off value of 5.56 pg/ml for above-normal plasma AVP, log-transformed plasma AVP (ln (AVP)) was used as continuous variable, and the correlation between anxiety and retardation was used to account for full variability of the anxious-retarded phenotype. Family history was related to above-normal plasma AVP (n = 16) and non-significantly to ln (AVP). Depression with above-normal plasma AVP, as well as familial depression with above-normal plasma AVP, showed a high correlation between anxiety and retardation, and this correlation was significantly higher than that found in the depressed patient control groups. The data support the delimitation of a largely familial depression with above-normal plasma AVP, vasopressinergic activation of the hypothalamus-pituitary-adrenal axis and a variable anxious-retarded phenotype.

Anxious-retarded depression: relation to family history of depression.

Anxious-retarded depression is a two-dimensionally defined subcategory of depression based on high scores for both anxiety and retardation. The anxious-retarded subcategory is related to melancholia as defined by DSM-IV. Patients with this diagnosis exhibit elevated plasma arginine vasopressin (AVP) and a high correlation between plasma vasopressin and cortisol, which suggests vasopressinergic overactivation of the hypothalamus-pituitary-adrenal (HPA) axis. In this report, we present the multidimensional derivation of the anxious-retarded subcategory from DSM-IV melancholia, and a second step in the validation of this anxious-retarded subcategory by exploring its relation to family history of depression. The patient sample comprised 89 patients with major depression and encompassed 66 patients investigated previously regarding plasma AVP and cortisol. All patients were rated for the following three dimensions of psychopathology: autonomic dysregulation (anxiety), motivational inhibition (retardation), and emotional dysregulation, as well as for family history of depression. The dependence of DSM-IV melancholia on the sum scores and the dichotomized scores on the three dimensions was investigated by multiple logistic regression. Thereafter, the dependence of the family history for depression on the same parameters was also investigated. The melancholic subcategory depended on the interaction between the sum scores, as well as on the interaction between the dichotomized scores for anxiety and retardation that constitute the anxious-retarded subcategory. Family history for depression depended only on the interaction of the dichotomized scores, and thus on the anxious-retarded subcategory.

Recall performance, plasma cortisol and plasma norepinephrine in normal human subjects.

This study investigated hypothalamic-pituitary-adrenal (HPA)-axis and sympathetic nervous system (SNS) correlates of recall performance in normal human subjects. Twenty-two normal human subjects were given one memory task: short-term recall of unrelated non-organizable lists of neutral words, in immediate recall conditions. Two types of memory were individualized: measures reflecting effortful processing and measures reflecting automatic processing, which were related to 3 daytime plasma cortisol (CORT) and plasma NE values, and assessed after venipuncture. It was hypothesized that plasma CORT is positively related and plasma norepinephrine (NE) is negatively related to effortful processing. Pearson correlation was computed and regression analysis was performed. Positive correlation appeared between plasma CORT values and negative correlation appeared between plasma NE values and measures reflecting effortful processing. However, stepwise multiple regression analysis showed that only morning plasma CORT values are functionally positively and afternoon plasma NE values are functionally negatively related to effortful processing. This suggests that morning HPA-axis activities enhance and afternoon SNS activities inhibit effortful processing.

Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse.

The aim of the study is to test whether fluvoxamine affects the function of the hypothalamic pituitary adrenal (HPA) axis in female borderline (borderline personality disorder, BPD) patients with and without a history of sustained childhood abuse. Special attention is given to the presence of comorbid major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The HPA axis of 30 female BPD patients with (n = 17) and without (n = 13) a history of sustained childhood abuse was challenged with a combined dexamethasone and corticotropin releasing hormone test (DEX/CRH test) before and after 6 (n = 14) and 12 (n = 16) weeks of fluvoxamine treatment (150 mg/day). Both 6- and 12-week fluvoxamine treatments were associated with a significant and robust reduction of the adrenocorticotrophic hormone (ACTH) and cortisol response to the DEX/CRH test. The magnitude of the reduction was dependent on the presence of sustained childhood abuse, but not on the presence of comorbid MDD or PTSD: patients with a history of sustained childhood abuse showed the strongest reduction in ACTH and cortisol. In conclusion, Fluvoxamine treatment reduces the hyperresponsiveness of the HPA axis in BPD patients with a history of sustained childhood abuse. This effect is likely to be obtained in the first 6 weeks of treatment.

Anxious-retarded depression: relation with plasma vasopressin and cortisol.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious-retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whether the plasma AVP level is also elevated in anxious-retarded depression, melancholic depression and anxious-retarded melancholic depression, and whether plasma AVP and cortisol levels are correlated in these subcategories. A total of 66 patients with major depression not using oral contraception were investigated. Patients with anxious-retarded depression had a highly significant AVP-cortisol correlation, while no such correlation was found in patients with nonanxious-retarded depression. Log-transformed mean plasma AVP values were higher in patients with anxious-retarded depression than in patients with nonanxious-retarded depression. Patients with anxious-retarded melancholic depression also had a significantly elevated level of plasma AVP and a highly significant correlation between plasma AVP and cortisol levels. The correlation was low in patients with melancholic depression. Anxious-retarded depression may be a useful refinement of the melancholic subcategory with regard to dysregulation of the HPA axis and plasma AVP release.

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.

Evidence for two processes underlying the serial position curve of single- and multi-trial free recall in a heterogeneous group of psychiatric patients: a confirmatory factor analytic study.

The U-shaped serial position curve (SPC) of single-trial free recall is a well-established empirical fact, and there is ample evidence that it is the result of two different memory functions. However, it is insufficiently clear whether the same holds true for the SPC of multi-trial free recall. Free recall test measurements of two large heterogeneous groups of psychiatric patients were subjected to factor extraction using Principal Components Analysis and oblique rotation in two studies. The results of these two experiments show that the SPCs of single- and multi-trial free recall arise from the same two functions i.e. one function underlies the recency part, the other the primacy and middle (prerecency) part. Possible theoretical interpretations are discussed.