Subjective sleep characteristics in primary insomnia versus insomnia with comorbid anxiety or mood disorder

Sleep and Biological Rhythms - We assessed subjective sleep measures in a cohort of 146 patients with chronic insomnia and hypothesized that these measures may differ depending on the presence as...     

Treatment-resistant residual insomnia in patients with recurrent major depressive episodes

Residual symptoms are common in depression, and their presence is associated with poorer clinical outcomes of depression. We conducted a case series study of first-onset major depression to elucidate the clinical course of residual insomnia and examine the relationship between residual insomnia and recurrence of depression. Subjects were 128 patients (57 males; mean age 52.8 years) with first-onset major depression. For all patients, we continuously assessed the number and breakdown of residual symptoms listed on the 17-item Hamilton Rating Scale for Depression and quantities of prescribed psychotropic medications during the depressive and remission phases. Even during the first remission phase, 85.9% of the patients with first-onset major depression experienced an average of 2.95 residual symptoms. The most common residual symptom was insomnia (65.4%), followed by reduced work and interests (43.3%) and fatigue (39.4%). Each additional recurrence resulted in a significantly shorter remission phase as well as significant increases in antidepressant and hypnotics dosages. Hypnotics dosage during the first remission phase for patients with three or more recurrent episodes was significantly higher than that for those with only a single episode. Our findings suggest a possible link between treatment-resistant residual insomnia during the first remission phase and recurrence risk of depression. In particular, it is possible that presence of treatment-resistant insomnia during the first remission phase is related to later recurrence of depressive episodes. It is important to see patients with treatment-resistant insomnia of early stage carefully, with special attention to treatment adherence.

     

Effect of ramelteon coadministered with antidepressant in patients with insomnia and major depressive disorder: an exploratory study

Sleep and Biological Rhythms - The purpose is to evaluate the effect and safety of ramelteon 8 mg/day for 8 weeks in the treatment of insomnia in patients with concurrent...     

Treatment of a depressive disorder patient with EEG-driven photic stimulation

This study examined the effects of electroencephalographic-(EEG-) driven photic stimulation on a case of depressive disorder, as measured by a psychometric test of mood states, EEG parameters, and several autonomic indices. The EEG-driven photic stimulation enhances the alpha rhythm of brain waves using photic signals, the brightness of which is modulated by a subject's own alpha rhythm. The patient was a 37-year-old businessman, who was treated for depression with medication during the 13 months prior to his first visit to our hospital. He underwent two sets of inpatient treatment sessions, comprising first 16 and then 18 treatment sessions. The treatments brought about the following changes: an improvement in general mood state, alpha rhythm increase, cardiac parasympathetic suppression, and increased skin conductance level. In addition, significant correlations between alpha rhythm increase and cardiac parasympathetic suppression or cardiac sympathetic predominance were observed with each inpatient treatment. Significant correlations between alpha rhythm increase, cardiac parasympathetic suppression, or cardiac sympathetic predominance and the improvement of general mood state were also observed. Thus, from these observations, it was concluded that the alpha enhancement induced by EEG-driven photic stimulation produced an improvement in the patient's depressive symptomatology connected with cardiac parasympathetic suppression and sympathetic predominance.     

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized,double-blind,placebo-controlled study

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness–Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.     

Chipping away at major depressive disorder

An intriguing recent study examines the role of miR-1202, a glutamate receptor regulating microRNA, in regulating major depressive disorder.     

Genome-wide DNA methylation scan in major depressive disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.     

Dysregulation of brain dopamine systems in major depressive disorder

Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression—no established mechanism can explain all aspects of the disease. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. This mini-review focuses on dysregulation of brain dopamine (DA) systems in the pathophysiology of MDD and describing new cellular targets for potential medication development focused on DA-modulated micro-circuits. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through dopaminergic substrates in the brain.     

Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder

Background

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).

Methodology/Principal Findings

We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.

Conclusions/Significance

These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.     

Plasma metabonomics as a novel diagnostic approach for major depressive disorder

Major depressive disorder (MDD) is a socially detrimental psychiatric disorder, contributing to increased healthcare expenditures and suicide rates. However, no empirical laboratory-based tests are available to support the diagnosis of MDD. In this study, a NMR-based plasma metabonomic method for the diagnosis of MDD was tested. Proton nuclear magnetic resonance ((1)H NMR) spectra of plasma sampled from first-episode drug-na??ve depressed patients (n = 58) and healthy controls (n = 42) were recorded and analyzed by orthogonal partial least-squares discriminant analysis (OPLS-DA). The OPLS-DA score plots of the spectra demonstrated that the depressed patient group was significantly distinguishable from the healthy control group. Moreover, the method accurately diagnosed blinded samples (n = 26) in an independent replication cohort with a sensitivity and specificity of 92.8% and 83.3%, respectively. Taken together, NMR-based plasma metabonomics may offer an accurate empirical laboratory-based method applicable to the diagnosis of MDD.     

Hypermethylation in the ZBTB20 gene is associated with major depressive disorder

Background

Although genetic variation is believed to contribute to an individual’s susceptibility to major depressive disorder, genome-wide association studies have not yet identified associations that could explain the full etiology of the disease. Epigenetics is increasingly believed to play a major role in the development of common clinical phenotypes, including major depressive disorder.

Results

Genome-wide MeDIP-Sequencing was carried out on a total of 50 monozygotic twin pairs from the UK and Australia that are discordant for depression. We show that major depressive disorder is associated with significant hypermethylation within the coding region of ZBTB20, and is replicated in an independent cohort of 356 unrelated case-control individuals. The twins with major depressive disorder also show increased global variation in methylation in comparison with their unaffected co-twins. ZBTB20 plays an essential role in the specification of the Cornu Ammonis-1 field identity in the developing hippocampus, a region previously implicated in the development of major depressive disorder.

Conclusions

Our results suggest that aberrant methylation profiles affecting the hippocampus are associated with major depressive disorder and show the potential of the epigenetic twin model in neuro-psychiatric disease.     

Advanced melatonin onset relative to sleep in women with unmedicated major depressive disorder

ABSTRACT

Studies on circadian timing in depression have produced variable results, with some investigations suggesting phase advances and others phase delays. This variability may be attributable to differences in participant diagnosis, medication use, and methodology between studies. This study examined circadian timing in a sample of unmedicated women with and without unipolar major depressive disorder. Participants were aged 18–28 years, had no comorbid medical conditions, and were not taking medications. Eight women were experiencing a major depressive episode, nine had previously experienced an episode, and 31 were control participants with no history of mental illness. Following at least one week of actigraphic sleep monitoring, timing of salivary dim light melatonin onset (DLMO) was assessed in light of <1 lux. In currently depressed participants, melatonin onset occurred significantly earlier relative to sleep than in controls, with a large effect size. Earlier melatonin onset relative to sleep was also correlated with poorer mood for all participants. Our results indicate that during a unipolar major depressive episode, endogenous circadian phase is advanced relative to sleep time. This is consistent with the early-morning awakenings often seen in depression. Circadian misalignment may represent a precipitating or perpetuating factor that could be targeted for personalized treatment of major depression.     

Social rhythm regularity moderates the relationship between sleep disruption and depressive symptoms in veterans with post-traumatic stress disorder and major depressive disorder

ABSTRACT

Approximately 50% to 80% of individuals with posttraumatic stress disorder (PTSD) also meet criteria for major depressive disorder (MDD). Sleep disturbance is a major concern in both PTSD and MDD, and is associated with poor treatment response, poor functional outcome and increased suicide risk. Social rhythm regularity, or the consistency of daily habitual behaviors, is theoretically linked to circadian rhythms and may be disturbed in both PTSD and MDD. The present study examined the relationship between social rhythm regularity, sleep disruption and MDD and PTSD symptoms in a sample of veterans with comorbid PTSD and MDD. Baseline data were obtained from 56 male veterans who met DSM-IV criteria for PTSD and MDD. Veterans completed the Social Rhythm Metric (SRM), a self-report questionnaire that assesses the regularity of routines by determining how regularly individuals completed 17 different types of activities. In a linear regression model, increased minutes awake after sleep onset (WASO) was a significant predictor of increased depression scores on the Hamilton Rating Scale for Depression (p < .05). SRM scores did not significantly predict depressive symptoms, however the interaction of WASO and SRM significantly predicted depressive symptoms (p = <.05), with significant relationships found at SRM scores less than 3.62. Neither minutes awake after sleep onset, SRM scores, nor their interaction was associated with PTSD symptom severity. Social and possibly circadian rhythm regularity may represent a risk or resilience factor for individuals with comorbid PTSD and MDD. Findings highlight the importance of exploring the interactions of sleep and social/circadian rhythms in depression in order to inform continued treatment development.     

Impairment of endothelial protection by ischemic postconditioning in patients with major depressive disorder

This study used a model of ischemia-reperfusion injury to the brachial artery endothelium to investigate whether the protective role of ischemic postconditioning (IPostC) is impaired in patients with major depressive episode. Flow-mediated dilation (FMD) was measured before and after ischemia-reperfusion in the absence or presence of IPostC in 24 patients with major depressive disorder and 20 healthy controls. In addition, the severity of the depression, as assessed by the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores, and plasma nitrogen dioxide (NO(x)) levels were also determined. Ischemia-reperfusion resulted in a significant decrease in FMD in both patients with a major depressive episode and healthy controls. IPostC effectively prevented this decrease in FMD in healthy controls, but not in patients with a major depressive episode. HDRS and BDI scores were markedly increased, but plasma NO(x) levels decreased, in patients with a major depressive episode compared with those in healthy controls. Correlation analysis showed that HDRS and BDI scores and plasma NO(x) levels were significantly associated with post-ischemia-reperfusion FMD. These results suggest that endothelial protection by IPostC is impaired in patients with major depressive disorder, which may be related to the decrease in endothelial nitric oxide production and the severity of the depression.     

Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.