Transdiagnostic analysis of adverse childhood experiences and their association with psychopathology-A TRANS-D conform study.

Transdiagnostic approaches challenge traditional psychiatric classification systems. Adverse childhood experiences (ACE) represent a transdiagnostic risk factor for psychopathology with dose dependency. As different qualities of ACE typically co-occur, we identified ACE patterns to assess their power for predicting psychopathology compared to traditional diagnoses. Following TRANS-D guidelines, we categorized participants (N=360) with persistent depressive disorder (PDD), borderline personality disorder (BPD), or healthy control status (HC) into subcategories defined by ACE pattern, using the Childhood Trauma Questionnaire (CTQ). Improvement of the transdiagnostic vs. diagnostic approach in predicting psychopathology was evaluated in a cross-validated predictive modeling framework focusing on the clinical sample of PDD and BPD patients. Results were externally validated in another transdiagnostic sample (N=138). Seven pattern-based subcategories with distinct ACE profiles were identified in the primary sample and replicated in the validation sample. Patterns cut across diagnostic groups. Predictive modeling showed that diagnoses could not predict depressive symptoms and loneliness. Transdiagnostic constructs systematically predicted all measures. This study showcases ACE as a promising construct for transdiagnostic research. Our data-driven framework identified robust ACE subcategories mapping onto general and interpersonal psychopathology. Patterns of CTQ-based information may provide an approach to integrating information on co-occurring ACE to inform diagnostics and treatment.

Distinct trajectories of response to prefrontal tDCS in major depression: results from a 3-arm randomized controlled trial.

Transcranial direct current stimulation (tDCS) is a safe, effective treatment for major depressive disorder (MDD). While antidepressant effects are heterogeneous, no studies have investigated trajectories of tDCS response. We characterized distinct improvement trajectories and associated baseline characteristics for patients treated with prefrontal tDCS, an active pharmacotherapy (escitalopram), and placebo. This is a secondary analysis of a randomized, non-inferiority, double-blinded trial (ELECT-TDCS, N = 245). Participants were diagnosed with an acute unipolar, nonpsychotic, depressive episode, and presented Hamilton Depression Rating Scale (17-items, HAM-D) scores ≥17. Latent trajectory modeling was used to identify HAM-D response trajectories over a 10-week treatment. Top-down (hypothesis-driven) and bottom-up (data-driven) methods were employed to explore potential predictive features using, respectively, conservatively corrected regression models and a cross-validated stability ranking procedure combined with elastic net regularization. Three trajectory classes that were distinct in response speed and intensity (rapid, slow, and no/minimal improvement) were identified for escitalopram, tDCS, and placebo. Differences in response and remission rates were significant early for all groups. Depression severity, use of benzodiazepines, and age were associated with no/minimal improvement. No significant differences in trajectory assignment were found in tDCS vs. placebo comparisons (38.3, 34, and 27.6%; vs. 23.3, 43.3, and 33.3% for rapid, slow, and no/minimal trajectories, respectively). Additional features are suggested in bottom-up analyses. Summarily, groups treated with tDCS, escitalopram, and placebo differed in trajectory class distributions and baseline predictors of response. Our results might be relevant for designing further studies.

The cytokine IL-17A as a marker of treatment resistance in major depressive disorder?

Major depression is a complex disease and-among others, inflammation appears to play an important role in its pathophysiology. In this study, we investigated a broad range of cytokines in depressed patients. Plasma levels of interleukin (IL)-12/ IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-7, tumor necrosis factorß and vascular endothelial growth factor were compared in 48 patients suffering from major depression before, after one and after six weeks of antidepressive treatment in relation to therapy response. Interestingly, the level of IL-17A turned out to rise significantly in the non-responder group compared to responder during antidepressive treatment. IL-17A is a pro-inflammatory cytokine that initiates the production of other cytokines, thereby inducing and mediating immune response. It is also involved in allergic and autoimmune-related diseases. The database investigating the role of IL-17A in major depressive disorder has grown within the last few years comparing levels of this cytokine in depressed patients versus healthy subjects. However, little is known about the expression of IL-17A during the course of antidepressive treatment. In summary, our study provides valuable evidence that this cytokine might serve as a marker of therapy resistance to antidepressants.

Association of Chemokine (C-C Motif) Receptor 5 and Ligand 5 with Recovery from Major Depressive Disorder and Related Neurocognitive Impairment.

INTRODUCTION: Inflammatory processes play an important role in the pathophysiology of major depressive disorder (MDD), but their relevance for specific symptoms such as neurocognitive impairment is rarely investigated. METHODS: In this observational study, we investigated the changes of leukocyte chemokine (C-C motif) receptor 5 (CCR5) and ligand 5 (CCL5) mRNA levels and inflammatory cytokines in 60 MDD patients before (PRE) and after 5 weeks (W5) of antidepressive treatment in relation to therapy response and alterations in cognitive functions by means of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We hypothesized that elevated CCR5 and CCL5 levels in depressed patients would decrease upon treatment and could differ with regard to cognitive impairment associated with MDD. RESULTS: Both CCR5 and CCL5 levels were significantly decreased in the responder group compared to nonresponders even before treatment. The cytokine IL-6 as a marker of inflammation in depression did not show a difference before treatment in future responders versus nonresponders, but decreased significantly upon antidepressive therapy. Regarding neurocognitive impairment in MDD patients, an increased misperception of the emotion "anger" after 5 weeks of treatment proved to be associated with a more pronounced change in CCR5, and the perception of the emotion "disgust" became faster along with a stronger decrease in CCL5 over the same time. Executive functions typically impaired in MDD patients were not markedly associated with alterations in CCR5/CCL5. DISCUSSION: CCR5 and CCL5 are important in the targeting of immune cells by HIV. This is the first study providing valuable hints that both CCR5 and CCL5 might also serve as markers of therapy response prediction in MDD. Regarding neurocognitive impairment in depression, CCR5 and CCL5 did not reveal characteristic changes upon MDD treatment such as executive functions, which are probably delayed. However, changes of emotional perception appear to be an earlier responding feature.

Self-esteem fully mediates positive life events and depressive symptoms in a sample of 173 patients with affective disorders.

OBJECTIVES: Previous research showed that positive and negative life events influence the development of depression. However, it is less clear how life events interact with depressive symptoms and self-esteem. DESIGN AND METHODS: The present study aimed to investigate the mediating effects of self-esteem on the relationship between life events and depressive symptoms in adulthood. The Traumatic Antecedent Questionnaire, Multidimensional Self-esteem Scale (MSWS), and Becks Depression Inventory were administered in 173 psychiatric inpatients (mean age 39.69 ± 14.56 years, ranging from 18 to 76 years). At the time of assessment, all patients suffered from depressive symptoms caused by an affective disorder (major depression, bipolar I, dysthymia). RESULTS: Path analyses showed that the individual level of self-esteem (measured by MSWS) fully mediated the association between positive life events and depressive symptoms. CONCLUSIONS: The current study indicates that future therapy programmes for patients with depressive symptoms could include interventions focusing on the improvement of self-esteem, as increasing self-esteem may be beneficial for recovery. PRACTITIONER POINTS: To date, this is the first study exploring the pathways from positive/negative life events to depressive symptoms. The relationship between positive life experiences and depressive symptoms was fully mediated by self-esteem. Strengthening self-esteem in therapy might lower the vulnerability for depression.

Predicting instructed simulation and dissimulation when screening for depressive symptoms.

The intentional distortion of test results presents a fundamental problem to self-report-based psychiatric assessment, such as screening for depressive symptoms. The first objective of the study was to clarify whether depressed patients like healthy controls possess both the cognitive ability and motivation to deliberately influence results of commonly used screening measures. The second objective was the construction of a method derived directly from within the test takers' responses to systematically detect faking behavior. Supervised machine learning algorithms posit the potential to empirically learn the implicit interconnections between responses, which shape detectable faking patterns. In a standardized design, faking bad and faking good were experimentally induced in a matched sample of 150 depressed and 150 healthy subjects. Participants completed commonly used questionnaires to detect depressive and associated symptoms. Group differences throughout experimental conditions were evaluated using linear mixed-models. Machine learning algorithms were trained on the test results and compared regarding their capacity to systematically predict distortions in response behavior in two scenarios: (1) differentiation of authentic patient responses from simulated responses of healthy participants; (2) differentiation of authentic patient responses from dissimulated patient responses. Statistically significant convergence of the test scores in both faking conditions suggests that both depressive patients and healthy controls have the cognitive ability as well as the motivational compliance to alter their test results. Evaluation of the algorithmic capability to detect faking behavior yielded ideal predictive accuracies of up to 89%. Implications of the findings, as well as future research objectives are discussed. Trial Registration The study was pre-registered at the German registry for clinical trials (Deutsches Register klinischer Studien, DRKS; DRKS00007708).

The Role of Self-Esteem in Depression: A Longitudinal Study.

BACKGROUND: Based on the vulnerability model, several studies indicate that low self-esteem seems to contribute to depressive symptoms. AIMS: The aim of this study was to treat depressive symptoms in a cognitive behavioural group therapy, focusing on the enhancement of self-esteem, and to explore co-variation in depressive symptoms and the level of self-esteem. METHOD: The Multidimensional Self-esteem Scale (MSWS) and the Beck Depression Inventory (BDI) were administered to 147 psychiatric in-patients with current depressive symptoms due to an affective disorder (major depression, bipolar I, dysthymia). Self-esteem was measured pre-treatment (t0) and post-treatment (t4, after 5 weeks of eight group sessions); the BDI was applied weekly. A linear mixed growth analysis was conducted to estimate the change in depressive symptoms including interactions with self-esteem. RESULTS: Within the 5 weeks of group therapy, depressive symptoms showed a linear decline, which was stronger for patients with higher gains in self-esteem between t0 and t4. Self-esteem at t0 was unrelated to the change in depression but predicted self-esteem at t4. CONCLUSIONS: Treating depressive symptoms in a cognitive behavioural group therapy in a naturalistic setting might have a positive effect on the process of recovery. Moreover, depressive symptoms and level of self-esteem seemed to co-vary.

Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression?

INTRODUCTION: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. METHODS: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1ß, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. RESULTS: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. DISCUSSION: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.

The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men.

Genetic variations in the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) have been associated with maladaptive stress responses and major depressive disorder (MDD). In a case-control study design, we examined whether single nucleotide polymorphisms (SNPs) and haploid genotype (haplotype) associations of MR gene NR3C2, GR gene NR3C1 and genes of GR chaperone molecules FK506 binding protein 5 (FKBP5) and corticotrophin-releasing hormone receptor 1 (CRHR1) differed between healthy subjects (n = 634) and inpatients with major depressive disorder (n = 412). All analyses were conducted for women and men separately. After conservative correction of Type-I-error to obtain reliable p values, one SNP in the NR3C1 gene, namely rs6195, showed a significant association with the presence of a major depression (p = 0.048) in females. In contrast, NR3C2, FKBP5 and CRHR1 polymorphisms were not significantly associated with MDD. No haplotype effects could be identified. Our results support the notion of an association between variants of GR-related genes in women and the pathophysiology of depression: females suffering from MDD showed a more than three times higher frequency of the T/C polymorphism compared to controls, which thus seems to increase the vulnerability to depression in females.

Lower Oxytocin Plasma Levels in Borderline Patients with Unresolved Attachment Representations.

Interpersonal problems and affective dysregulation are core characteristics of borderline personality disorder (BPD). BPD patients predominantly show unresolved attachment representations. The oxytocin (OT) system is associated with human social attachment and affiliative behavior, and OT dysregulation may be related to distinct attachment characteristics. Here, we investigated whether attachment representations are related to peripheral OT levels in BPD patients. Twenty-one female BPD patients and 20 age-, gender-, and education-matched healthy controls (HCs) were assessed with clinical scales and measures of interpersonal and attachment-related characteristics, including the Adult Attachment Projective Picture System (AAP). Plasma OT concentrations were measured prior to and during social exclusion in a virtual ball tossing game (Cyberball). The majority of BPD patients (63.2%) but no HCs showed unresolved (disorganized) attachment representations. In this subgroup of patients, baseline OT plasma levels were significantly lower than in BPD patients with organized attachment representations. This pilot study extends previous findings of altered OT regulation in BPD as a putative key mechanism underlying interpersonal dysregulation. Our results provide first evidence that altered OT plasma levels are related to disorganized attachment representations in BPD patients.

Prefrontal Transcranial Direct Current Stimulation for Treatment of Schizophrenia With Predominant Negative Symptoms: A Double-Blind, Sham-Controlled Proof-of-Concept Study.

Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (-36.1%) than after sham tDCS (-0.7%). PANSS sum scores decreased significantly more with active (-23.4%) than with sham stimulation (-2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia.

Effects of social exclusion on emotions and oxytocin and cortisol levels in patients with chronic depression.

OBJECTIVE: Patients with chronic depression (CD) experience a high burden of disease, severe co-morbidity, and increased mortality. Although interpersonal dysfunction is a hallmark of CD, the underlying mechanisms are largely unexplored. Oxytocin (OT) has been proposed to play a crucial role in the social deficits of mental disorders and has been found to be dysregulated after social exclusion (ostracism) in patients with borderline personality disorder. This study investigated how social exclusion affects emotions, OT levels, and cortisol (CT) levels in CD patients. METHOD: Twenty-one patients diagnosed with CD and 21 healthy controls (HC) matched for gender, age, and education underwent repeated neuroendocrine measurements in a standardized laboratory setting while playing Cyberball, a virtual ball-tossing game that mimics a social exclusion situation. Emotional reactions, plasma OT and cortisol levels were assessed at baseline and 5, 15, and 40 min after Cyberball. RESULTS: At baseline, there were no group differences in OT levels. Immediately after playing Cyberball, plasma OT levels showed divergent changes in CD patients and HC; the difference in direction of change was significant with a reduction in CD patients compared to HC (p = .035*); CT levels did not differ between groups at any time point, but decreased over time. Patients showed more threatened emotional needs and increased negative emotions, especially anger and resentment, and showed higher sensitivity to ambiguous threat of social exclusion than healthy controls. CONCLUSIONS: CD patients react to ostracism with pronounced negative emotions. The reduction in OT levels in CD patients after social exclusion may contribute to their interpersonal dysfunction and their difficulty in coping adequately with aversive social cues.

The influence of Hatha yoga as an add-on treatment in major depression on hypothalamic-pituitary-adrenal-axis activity: a randomized trial.

OBJECTIVES: The impact of Hatha yoga as add-on treatment to quetiapine fumarate extended release (QXR) or escitalopram (ESC) in depressed patients on hypothalamic-pituitary-adrenal (HPA) axis activity was assessed. METHODS: 60 inpatients suffering from major depressive disorder (MDD) according to DSM-IV were randomized for a 5 week treatment with Yoga or not (control group) and with either QXR (300 mg/day) or ESC (10 mg/day). Serial dexamethasone/corticotropin releasing hormone (DEX/CRH) tests were performed to assess HPA axis function. The Hamilton Depression Rating Scale (21-HAMD) was used weekly. RESULTS: A more pronounced down regulation of the HPA axis activity due to yoga could not be detected. The stepwise long term cortisol reduction was seen in both medication groups, irrespectively of yoga add-on treatment. In addition, cortisol improvers in week 1 of therapy (reduction in cortisol peak value within the DEX/CRH test) reached significant greater amelioration of depressive symptoms after 5 weeks. CONCLUSIONS: Our results suggest that antidepressant agents down regulate HPA axis function to a greater extent than additional Hatha yoga treatment. Moreover, an early reduction of HPA system hyperactivity after one week of pharmacological treatment seems to raise the possibility of a favorable treatment response.

Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness.

The hypothalamic-pituitary-adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.

Impact on cortisol and antidepressant efficacy of quetiapine and escitalopram in depression.

BACKGROUND: In this study, the impact of quetiapine fumarate extended release (QXR) and escitalopram (ESC) on HPA axis activity was investigated in depressed patients in relationship to antidepressant efficacy. METHODS: In a randomized, open-label 5-week trial 60 inpatients suffering from major depression (DSM-IV criteria) were treated for 5 weeks with either QXR (300 mg/day) or ESC (10mg/day). The dexamethasone/CRH (DEX/CRH) test was performed before treatment, after 1, and after 5 weeks of treatment. Cortisol (COR) AUC values were used to assess HPA axis function. The Hamilton Depression Rating Scale was used weekly to estimate antidepressant efficacy. RESULTS: QXR and ESC showed comparable antidepressant effects but strongly differed in their impact on HPA axis activity. In the QXR group, a marked inhibition of COR AUC levels was observed which was most pronounced after one week of treatment but showed a partial re-increase after 5 weeks of treatment. In contrast, ESC transiently stimulated COR AUC values (week 1) whereas COR AUC levels at week 0 and week 5 were comparable. COR improvement at week 1 (defined as COR peak value reduction between DEX/CRH test 1 and 2) was significantly associated with better clinical outcome. CONCLUSION: Apparently, different effects on HPA axis activity reflect distinct pharmacoendocrinological properties of psychotropic drugs.

[Risk factors for inpatient suicide]. / Risikofaktoren für Suizide und Suizidversuche an einem Universitätsklinikum.

OBJECTIVE: The study aimed to examine suicidal behaviour during in-patient care in a psychiatric university hospital. METHOD: Based upon a psychiatric basic documentation system prevalence and risk factors of in-patient suicides and suicide attempts were investigated (1995 - 2010). RESULTS: A total of 42 in-patient suicides and 166 attempts were found among 16 251 patients. According to the multivariate logistic regression analysis the risk of suicide during hospitalization increases significantly for male patients, with more previous psychiatric hospitalizations and suicidality according to clinical impression at admission or suicide attempt before admission. Patients with affective or schizophrenic disorders were at highest risk. The following risk factors are associated with suicide attempt during stay: female gender, borderline personality disorder (F60.3), more previous psychiatric hospitalizations, shorter duration of disorder, earlier age of onset, suicidality according to clinical impression at admission or suicide attempt before admission. CONCLUSION: As depressive and schizophrenic patients represent the high-risk group of in-patient suicide, suicide prevention should be a major goal in their treatment. More frequent suicide risk assessment is recommended particularly before granting a leave or an outing.

Pharmacological challenge with naloxone and cue exposure in alcohol dependence: results of a randomized, double-blind placebo-controlled trial.

OBJECTIVES: Animal and clinical studies implicated opioid dysfunction in the pathogenesis of alcohol abuse and dependence. The π-opioid antagonist naltrexone reduces craving, eventually modulated by hypothalamic-pituitary-adrenal axis. Altered cortisol response to opioid receptor blockade not only in alcohol dependent persons, but also in persons with a family history of alcohol dependency was reported. METHODS: Twenty patients with alcohol dependence who had undergone detoxification were recruited. Naloxone (3.2 mg/70 kg body weight) having a very similar receptor profile to naltrexone and placebo were administered in cross-over fashion on two separate days 48 h apart. Mood and craving was assessed with well-established instruments (Alcohol Craving Questionnaire (ACQ), Profile of Mood Scale (POMS)). Both patients and raters were blind to all treatments. Twelve patients were first treated with naloxone, eight were first treated with placebo. RESULTS: No significant differences were found between the placebo and naloxone groups according to ACQ and POMS. Cortisol levels were significantly higher in naloxone group. CONCLUSIONS: We could not replicate the result, that blocking of the endogenous opioid system leads to reduced craving in alcohol-dependent individuals, while increase of cortisol after naloxone challenge is the expected biological effect of opioid receptor blockade on the hypothalamic-pituitary-adrenal (HPA) axis.