Review: Major Depression as an Inflammatory Disease
In their review, Miller et al. (pages 732–741) discuss recent data which indicate that inflammation may play a role in the development of major depression. Inflammatory cytokines enter the brain and interact with virtually every pathophysiologic domain relevant to depression including effects on neurotransmitter metabolism, neuroendocrine function and neural plasticity. In addition, evidence indicates that inflammatory biomarkers may identify patients who are less likely to respond to conventional antidepressant therapy, and preliminary studies suggest that immune-targeted therapies may improve depressive symptoms.
Mechanisms of Stress
The neuropeptide oxytocin increases social approach behavior and pair bonding in animals, but these mechanisms have not been investigated in human couple interaction. Ditzen et al. (pages 728–731) administered oxytocin or placebo intranasally to couples before a standard couple conflict discussion in the laboratory. Oxytocin increased positive communication behavior in relation to negative behavior and reduced salivary cortisol compared to placebo. Oxytocinergic mechanisms might therefore be involved in human couple interaction and mediate stress-reducing effects of close relationships.
Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, but there may be situations where HPA activation promotes resilience. Wahlberg et al. (pages 742–747) previously found that HPA activity is reduced in depressed women on long-term sick leave. They now show that this pattern of HPA activity is quite stable over a 1 year period of follow-up. Their findings suggest that HPA function may be a trait related to vulnerability to stress-related disorders.
Selective serotonin reuptake inhibitors (SSRIs) can cause upper gastrointestinal (GI) symptoms that can lead to their discontinuation. Fujitsuka et al. (pages 748–759) administered SSRIs to freely-moving, food-deprived rats and found that SSRIs have inhibitory effects on ghrelin and GI motor activities through the serotonin 2c receptor (5-HT2cR). This indicates a functional divergence of central 5-HT2cR pathways that regulate GI motor activities and feeding/energy metabolism.
Impact of Infant Adversity: Genetic Risk Factors and Epigenetic Consequences
Using a rodent model of infant maltreatment, Roth et al. (pages 760–769) found that a stressful caregiving environment leaves lasting epigenetic marks on brain-derived neurotrophic factor (BDNF) DNA that is associated with reduced BDNF gene expression in both the current and next generations. They also demonstrated that these epigenetic marks and gene expression can be rescued with a DNA methylation inhibitor. Their results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.
Karere et al. (pages 770–777) studied infant monkeys from four different rearing conditions to examine how social context and different forms of early adversity interact with MAOA genotype to influence behavioral responsiveness. Animals reared in small social groups were more likely to be aggressive and anxious. This effect was most prominent among a low activity MAOA genotype. However, no genotype effects were evident in monkeys reared in larger social cages. These findings parallel the human child abuse literature in suggesting that some of the detrimental effects of the combination of vulnerable genotypes and early maternal neglect may be attenuated by exposure to a rich social environment.
Safety of Theta Burst Stimulation
Transcranial magnetic stimulation (TMS) was recently approved by the U.S. Food and Drug Administration for the treatment of depression. In their study, Grossheinrich et al. (pages 778–784) evaluate the safety of one approach to delivering TMS called theta burst stimulation (TBS). In this approach, high frequency (50–100 Hz) TMS is delivered in “bursts” with a frequency of 5 Hz, i.e., the frequency of the theta oscillations of the electroencephalography. The authors administered intermittent, continuous, and sham TBS over the dorsolateral or medial prefrontal cortex in healthy volunteers to evaluate its safety. Overall, they found this approach to be safe and well-tolerated by subjects, although one subject had a vaso-vagal reaction to the TBS.
Genetic Influence on Depression and Treatment Outcome
Perlis et al. (pages 785–791) assessed the impact of variations in 19 candidate genes on response over 6 weeks in 250 duloxetine-treated patients in a double-blind study of major depressive disorder (MDD). This study failed to replicate differences in clinical response related to variation in the serotonin-2A receptor gene, but it did find that a polymorphism in the catechol-O-methyltransferase (COMT) gene was associated with symptom change.
In 4,785 twin pairs from the Swedish Twin Registry, Kendler et al. (pages 808–811) found that early age at onset in depressed twins predicted the risk for major depression in their co-twins, while late age at onset predicted the co-twin risk for vascular disease. These results suggest that early- and late-onset depression seem to be distinct diseases.
Distinct Biological Profiles of Depression & Stress
Van Eijndhoven et al. (pages 812–818) performed a volumetric assessment of amygdala and hippocampus in a sample of unmedicated, first episode MDD patients in comparison with recovered first episode patients and healthy controls. The results show that a state-related increase of amygdala volume can be detected early in the course of MDD.
Reductions in occipital cortex gamma-aminobutyric acid (GABA) levels had been described in subgroups of depressed patients, but the relationship to antidepressant treatment response was not yet clear. Price et al. (pages 792–800) compared the cortical amino acid neurotransmitter levels of patients with treatment-resistant depression (TRD), non-treatment-resistant MDD patients, and healthy volunteers. Occipital GABA levels in TRD patients were reduced in comparison to the other groups, while non-TRD patients resembled controls. These findings provide initial evidence for a distinct neuronal amino acid profile in TRD patients.
Wirtz et al. (pages 801–807) determined the effects of depressive symptom severity on the circulating soluble adhesion molecule (sP-selectin) response to an acute exercise challenge in male patients with heart failure (HF) compared to controls. In HF patients, but not in controls, higher depression scores were associated with higher sP-selectin levels at pre- and post-exercise time points and with greater increases in sP-selectin levels over time in response to exercise.
Stress-induced analgesia is associated with posttraumatic stress disorder (PTSD). Kraus et al. (pages 819–822) now report that in borderline personality disorder (BPD) patients diagnosed with PTSD, a thermal stimulus that causes discomfort deactivated the amygdala, a brain region that contributes to the intensity of emotional responses. However, no difference in pain sensitivity was found between those with or without PTSD, and amygdala deactivation was independent of BPD symptom severity and dissociation.
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© 2009 Published by Elsevier Inc. All rights reserved.
