Disorder specificity despite comorbidity: Resting EEG alpha asymmetry in major depressive disorder and post-traumatic stress disorder

The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N = 15) and post-traumatic stress disorder (PTSD) (N = 14) relative to healthy controls (N = 15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups.     

Sex- and age-related differences in major depressive disorder with comorbid anxiety treated with fluoxetine

Summary Objective: To examine sex- and age-related differences of treatment outcome in a cohort of outpatients with major depressive disorder (MDD), with and without comorbid anxiety, treated with fluoxetine.Methods: Outpatients with a SCID-diagnosis of MDD aged 18 to 65 years were treated openly with fluoxetine (20mg/day) for 8 weeks. The 17-item Hamilton Depression Rating Scale (HAM-D-17) was administered at baseline, and at weeks 2, 4, 6 and 8. Remission of MDD was defined as a HAM-D-17 score 7 at week 8. Rates of remission and change of depressive symptoms of MDD were compared among women aged <45 years and 45 years. The analyses were then repeated in men. The presence of comorbid anxiety disorders was included in the prediction model for change of depressive symptoms of MDD across age and sex.Results: 176 women and 153 men were included in this analysis. Remission of MDD occurred in 57.1% and 50% of younger and older women respectively. Similar rates were present in men (57.2% and 49.1%, respectively). Age did not predict remission of depression or change of depressive symptoms of MDD, in both women and men. Anxious and non-anxious subtypes of depression did not present sex- or age-related differences in treatment outcome.Conclusion: In this cohort of outpatients with MDD, we observed no sex- or age-related differences in response to an 8-week treatment with the SSRI fluoxetine. Similarly, there were no age-related differences among women with anxious and non-anxious subtype of depression.     

Serum brain-derived neurotrophic factor (BDNF) concentrations in pregnant women with post-traumatic stress disorder and comorbid depression

There is accumulating evidence for the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression. However, the role of BDNF in the pathophysiology of post-traumatic stress disorder (PTSD) remains controversial, and no study has assessed BDNF concentrations among pregnant women with PTSD. We examined early-pregnancy BDNF concentrations among women with PTSD with and without depression. A total of 2928 women attending prenatal care clinics in Lima, Peru, were recruited. Antepartum PTSD and depression were evaluated using PTSD Checklist—Civilian Version (PCL-C) and Patient Health Questionnaire-9 (PHQ-9) scales, respectively. BDNF concentrations were measured in a subset of the cohort (N?=?944) using a competitive enzyme-linked immunosorbent assay (ELISA). Logistic regression procedures were used to estimate odds ratios (OR) and 95 % confidence intervals (95 % CI). Antepartum PTSD (37.4 %) and depression (27.6 %) were prevalent in this cohort of low-income pregnant Peruvian women. Approximately 19.9 % of participants had comorbid PTSD-depression. Median serum BDNF concentrations were lower among women with comorbid PTSD-depression as compared with women without either condition (median [interquartile range], 20.44 [16.97–24.30] vs. 21.35 [17.33–26.01]?ng/ml; P?=?0.06). Compared to the referent group (those without PTSD and depression), women with comorbid PTSD-depression were 1.52-fold more likely to have low (<25.38 ng/ml) BDNF concentrations (OR?=?1.52; 95 % CI 1.00–2.31). We observed no evidence of reduced BDNF concentrations among women with isolated PTSD. BDNF concentrations in early pregnancy were only minimally and non-significantly reduced among women with antepartum PTSD. Reductions in BDNF concentrations were more pronounced among women with comorbid PTSD-depression.     

A longitudinal examination of peritraumatic emotional responses and their association with posttraumatic stress disorder and major depressive disorder among veterans

Research has revealed a significant association between several peritraumatic emotional responses and posttraumatic stress disorder (PTSD). Preliminary research has also linked peritraumatic emotional responses with a diagnosis of major depressive disorder (MDD). The majority of this research has been cross-sectional, thereby making it difficult to determine the extent to which the various peritraumatic emotional responses may increase risk for, or serve as a premorbid marker of, PTSD and MDD. This study examined the longitudinal role of peritraumatic emotional responses on the subsequent development of PTSD and MDD in a sample of US military veterans. Whereas a number of peritraumatic emotional responses were concurrently associated with PTSD, only peritraumatic numbness maintained the association with this diagnosis longitudinally. For MDD, peritraumatic numbness was the only emotional response related to the diagnosis both concurrently and longitudinally. Study findings are a preliminary proof of concept that peritraumatic numbness may serve as a premorbid marker for the development of PTSD and MDD following a traumatic event. Implications of these findings for the diagnosis, assessment, and treatment of both PTSD and MDD are discussed.     

Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia

STUDY OBJECTIVE: Insomnia impacts the course of major depressive disorder (MDD), hinders response to treatment, and increases risk for depressive relapse. This study is an initial evaluation of adding cognitive behavioral therapy for insomnia (CBTI) to the antidepressant medication escitalopram (EsCIT) in individuals with both disorders. DESIGN AND SETTING: A randomized, controlled, pilot study in a single academic medical center. PARTICIPANTS: 30 individuals (61% female, mean age 35 +/- 18) with MDD and insomnia. INTERVENTIONS: EsCIT and 7 individual therapy sessions of CBTI or CTRL (quasi-desensitization). Measurements and results: Depression was assessed with the HRSD17 and the depression portion of the SCID, administered by raters masked to treatment assignment, at baseline and after 2, 4, 6, 8, and 12 weeks of treatment. The primary outcome was remission of MDD at study exit, which required both an HRSD17 score < or =7 and absence of the 2 core symptoms of MDD. Sleep was assessed with the insomnia severity index (ISI), daily sleep diaries, and actigraphy. EsCIT + CBTI resulted in a higher rate of remission of depression (61.5%) than EsCIT + CTRL (33.3%). EsCIT + CBTI was also associated with a greater remission from insomnia (50.0%) than EsCIT + CTRL (7.7%) and larger improvement in all diary and actigraphy measures of sleep, except for total sleep time. CONCLUSIONS: This pilot study provides evidence that augmenting an antidepressant medication with a brief, symptom focused, cognitive-behavioral therapy for insomnia is promising for individuals with MDD and comorbid insomnia in terms of alleviating both depression and insomnia.     

Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder

Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.     

重性抑郁症首发未用药患者的枕叶GABA波谱研究

在中枢神经系统中,γ-氨基丁酸(GABA)是主要的抑制性神经递质。由于GABA在普通磁共振波谱(MRS)上为低谱峰信号,且与其他物质的波峰重叠,因此难以准确得出其在脑内感兴趣区的含量。为观察抑制性神经递质GABA在首发未用药重性抑郁症(MDD)患者枕叶的含量改变,本研究采用了J-耦合编辑点分辨波谱(MEGA-PRESS)技术检测18例首发未用药重性MDD(17项HAMD评分>18分)患者和23名健康对照被试枕叶皮层的GABA含量。采用双样本t检验及相关分析进行统计学处理。结果表明,病例组枕叶GABA含量(11.35±3.26)显著低于对照组(27.30±8.87),P<0.001。病例组枕叶GABA含量与汉密尔顿抑郁量表及贝克抑郁自评量表相关性均不显著。首发未用药重性MDD患者的枕叶GABA含量降低,可能导致其视觉功能下降。     

Stressful events, stress perception and treatment outcomes in patients with depressive disorders: the CRESCEND study

Background

Investigations of associations between stressful events and depression treatment outcomes have led to conflicting findings. In a prospective naturalistic study of depression treatment we sought to investigate perceived stress as a predictor of 12-week antidepressant treatment outcome.

Methods

A nationwide sample of 580 people with depressive disorders was recruited from 18 hospitals in Korea. Number of stressful events in the last 12 months and subjective perception of stress were ascertained, and were dichotomized by median values. Participants commenced on antidepressant treatment were re-evaluated at 1, 2, 4, 8, and 12 weeks later. Assessment scales for evaluating depression (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and at every follow-up visit. Covariates included pre-treatment socio-demographic and clinical characteristics, and treatment-related characteristics.

Results

Higher baseline perceived stress was significantly associated with worse 12-week antidepressant treatment outcomes in terms of depression, anxiety, and global severity after adjustment for all covariates. However, baseline number of stressful events was not associated with any treatment outcomes.

Limitations

The study was observational, and the treatment modality was naturalistic.

Conclusions

Depressive patients with higher level of perceived stress at the time of commencing treatment had less favorable outcomes after antidepressant treatment. This may represent a group requiring more specific assessment and more intensive management in order to improve treatment response.     

Major depressive disorder,when under treatment,may not affect functional outcomes in patients with tibial plateau fractures

BackgroundThe purpose of this study is to determine if treated psychological depression is associated with poorer functional outcomes in patients who sustain tibial plateau fractures.MethodsPatients with a tibia plateau fracture were prospectively followed. Functional status was assessed using the Short Musculoskeletal Function Assessment (SMFA) at baseline (pre-injury), 3 months, 6 months, and 1 year post injury. Clinical outcomes were recorded at each follow up visit and radiographic outcomes were obtained from follow up radiographs. Records were reviewed to identify patients who were being treated for major depressive disorder (MDD). SMFA scores and clinical outcomes were compared between the depression and no depression cohorts.Results420 patients were treated for a tibial plateau fracture and the mean age was 50.83 ± 15.60 years. Forty-two (10%) patients with 42 fractures were being treated for MDD at the time of their fracture. Patients with MDD were older (p = 0.05) and were more likely female (p < 0.01). At baseline, the clinical depression cohort had worse Total SMFA scores compared to the non-depressed cohort (5.90 ± 14.41 vs. 2.69 ± 8.35, p < 0.01). There were no differences in total SMFA score or any SMFA subscores at 3, 6, and 12 months. The incidence of wound complications, reoperations, and radiographic outcomes also did not differ between the cohorts.ConclusionDespite patients with MDD reporting higher SMFA (poorer) scores at baseline, MDD was not associated with worse injuries, diminished clinical or poorer functional outcomes following tibial plateau fractures.     

Depression impairs learning,whereas the selective serotonin reuptake inhibitor,paroxetine, impairs generalization in patients with major depressive disorder

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization.     

Pooled analysis of sustained response rates for extended release quetiapine fumarate as monotherapy or adjunct to antidepressant therapy in patients with major depressive disorder

Background

Clinical trials are not generally powered to analyze outcomes such as sustained response. We evaluated sustained response rates for patients with major depressive disorder receiving quetiapine XR as monotherapy or adjunct therapy.

Method

Post hoc analyses of pooled data from four previously reported randomized, placebo-controlled studies of quetiapine XR 150 and 300 mg/day as monotherapy or adjunct therapy to ongoing antidepressant. Sustained response rates (≥50% reduction in MADRS total score at specific timepoint and each subsequent visit until Week 6) were calculated at Weeks 1, 2, and 4; rates were compared using a Cochran–Mantel–Haenszel analysis.

Results

In the monotherapy studies, the proportion of patients experiencing sustained response was greater with quetiapine XR 150 mg/day versus placebo at Week 2 (20.0% vs. 13.3%; p<0.05) and Week 4 (33.3% vs. 23.3%; p<0.01) (observed cases [OC]). The corresponding sustained response rates for quetiapine XR 300 mg/day were 18.0% (p=0.104) and 29.7% (p=0.063), respectively (OC).The proportion of patients experiencing sustained response was greater in the adjunct studies versus placebo at Weeks 2 and 4 for quetiapine XR 150 (Week 2, 30.1% vs. 15.2%, p<0.001; Week 4, 40.1% vs. 32.0%, p<0.05) and 300 mg/day (Week 2, 29.0% vs. 15.2%, p<0.001; Week 4, 42.0% vs. 32.0%, p<0.05) (OC).

Limitations

Post hoc analyses, acute treatment period; no active comparator.

Conclusions

Quetiapine XR as monotherapy (150 mg/day at Weeks 2 and 4) or adjunct to ongoing antidepressant therapy (150 and 300 mg/day at Weeks 2 and 4) increased sustained response rates versus placebo.     

Extended-release quetiapine fumarate (quetiapine XR) monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder

Background

Patients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge.

Methods

This 6-week, randomised, open-label, rater-blinded trial evaluated once-daily extended-release quetiapine fumarate (quetiapine XR; 300 mg/day) as add-on to ongoing antidepressant and quetiapine XR monotherapy (300 mg/day) compared with add-on lithium (0.6–1.2 mmol/L) in patients with treatment-resistant MDD. Primary efficacy measure: change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomisation to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS.

Results

At week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229); least squares means (LSM) differences (97.5% CI) in MADRS total score changes were −2.32 (−4.6, −0.05) and −0.97 (−3.24, 1.31), respectively. LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; p<0.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (≥50% reduction in total score), MADRS remission (total score ≤10, add-on quetiapine XR only) and Clinical Global Impressions (‘much’/‘very much’ improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments.

Limitations

Limitations included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase.

Conclusions

Add-on quetiapine XR (300 mg/day) and quetiapine XR monotherapy (300 mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD.     

Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.