Hot off the presses! May 01 Biol Psychiatry

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Latest Articles Include:

• Editorial Board
  - Biol Psychiatry 65(9):A1 (2009)
  
• Subscribers Page
  - Biol Psychiatry 65(9):A2 (2009)
  
• Table of Contents
  - Biol Psychiatry 65(9):A3-A4 (2009)
  
• Guide for Authors
  - Biol Psychiatry 65(9):A5-A6 (2009)
  
• Manuscript Submission Form—Biological Psychiatry
  - Biol Psychiatry 65(9):A7 (2009)
  
• A brief summary of the articles appearing in this issue of Biological Psychiatry
  - Biol Psychiatry 65(9):723-724 (2009)
  
• Primary Process Affects and Brain Oxytocin
  - Biol Psychiatry 65(9):725-727 (2009)
  
• Intranasal Oxytocin Increases Positive Communication and Reduces Cortisol Levels During Couple Conflict
  - Biol Psychiatry 65(9):728-731 (2009)
  Background In nonhuman mammals, the neuropeptide oxytocin has repeatedly been shown to increase social approach behavior and pair bonding. In particular, central nervous oxytocin reduces behavioral and neuroendocrine responses to social stress and is suggested to mediate the rewarding aspects of attachment in highly social species. However, to date there have been no studies investigating the effects of central oxytocin mechanisms on behavior and physiology in human couple interaction. Methods In a double-blind placebo-controlled design, 47 heterosexual couples (total n = 94) received oxytocin or placebo intranasally before a standard instructed couple conflict discussion in the laboratory. The conflict session was videotaped and coded for verbal and nonverbal interaction behavior (e.g., eye contact, nonverbal positive behavior, and self-disclosure). Salivary cortisol was repeatedly measured during the experiment. Results Oxytocin significantly increased positive communication behavior in relation to negative behavior during the couple conflict discussion (F = 4.18, p = .047) and significantly reduced salivary cortisol levels after the conflict compared with placebo (F = 7.14, p = .011). Conclusions These results are in line with animal studies indicating that central oxytocin facilitates approach and pair bonding behavior. Our findings imply an involvement of oxytocin in couple interaction and close relationships in humans.
• Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression
  - Biol Psychiatry 65(9):732-741 (2009)
  Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a! well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition t! o behavior.
• Suppressed Neuroendocrine Stress Response in Depressed Women on Job-Stress-Related Long-Term Sick Leave: A Stable Marker Potentially Suggestive of Preexisting Vulnerability
  - Biol Psychiatry 65(9):742-747 (2009)
  Background We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed women on job-stress-related long-term sick leave (LTSL). This unexpected finding prompted the question of whether HPA axis hypofunction in this group results from stress exposure or reflects preexisting vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA axis reactivity in these subjects. Method We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA axis reactivity in 29 patients and 27 control subjects after 12 months of follow-up. Clinical status and cognitive performance was also retested. Results Despite marked clinical improvement and normalization of initially observed impairments in attention and working memory, marked HPA axis hyporeactivity persisted in patients. A high test–retest correlation was found both at the level of corticotropin (R = .85, p < .001) and cortisol (R = .76, p < .001) responses. Conclusions Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independent of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA axis hyporeactivity may reflect a preexisting vulnerability in these subjects.
• Selective Serotonin Reuptake Inhibitors Modify Physiological Gastrointestinal Motor Activities via 5-HT2c Receptor and Acyl Ghrelin
  - Biol Psychiatry 65(9):748-759 (2009)
  Background Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats. Methods The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay. Results Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III–like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III–like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities. Conclusions SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.
• Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene
  - Biol Psychiatry 65(9):760-769 (2009)
  Background Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. With a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the brain-derived neurotrophic factor (BDNF) gene in the central nervous system. Methods During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span as well as DNA methylation patterns in the next generation of infants. Results Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen. Conclusions These 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.
• What is an "Adverse" Environment? Interactions of Rearing Experiences and MAOA Genotype in Rhesus Monkeys
  - Biol Psychiatry 65(9):770-777 (2009)
  Background Studies have been inconsistent in demonstrating that early adversity and specific genotype can be joint risk factors for poor behavioral outcomes. Using a rhesus monkey model, we examined how social context and different forms of early adversity influence whether a specific genotype (polymorphism in the promoter region of monoamine oxidase A [MAOA]) affects display of aggressive, fearful, and anxious behaviors. Methods Rhesus monkey infants (n = 473) were exposed to brief social challenge at age 3–4 months. Infants were reared 1) with mothers and up to 150 other animals in large cages; 2) with mothers in smaller social groups; 3) with mother and access to, at most, one other mother–infant pair; and 4) without mother but with access to a same-age peer in a nursery. Results No effects of genotype were found for infants reared by mothers in large social cages, although several genotype by rearing environment interactions were evident. Animals reared in smaller social groups were more likely to display aggression, which was especially true of animals possessing the low-activity MAOA genotype. In addition, animals with low-activity genotypes that had experienced restricted mother rearing showed more anxious behavior (scratch, yawn). Conclusions Among mother-reared animals, broader contextual features, associated with the social environment and experience of the mother, can affect the extent to which genotype contributes to behavioral expression under conditions of challenge. Results also suggest that different forms of early adverse experience can affect the types of responses displayed by animals of different genotypes.
• Theta Burst Stimulation of the Prefrontal Cortex: Safety and Impact on Cognition, Mood, and Resting Electroencephalogram
  - Biol Psychiatry 65(9):778-784 (2009)
  Background Because standard repetitive transcranial magnetic stimulation (rTMS) protocols exhibit post-stimulus effects of short duration, novel protocols such as theta burst stimulation (TBS), are promising approaches to enhance the effectiveness of rTMS. However, little is known about the side effect profile of such protocols. Thus, the present study explores whether TBS is safe particularly in terms of effects on cognition, mood, and electroencephalogram (EEG) measures in healthy subjects. Methods Twenty-four healthy volunteers participated in 2 randomized, placebo-controlled, cross-over experiments and underwent continuous TBS (cTBS), intermittent TBS (iTBS), and shamTBS either over the left dorsolateral prefrontal cortex (DLPFC, n = 12) or the medial prefrontal cortices (mPFC, n = 12). Clinical side effects, performance in a neuropsychological battery, mood changes, and resting EEG were recorded. Results Neither a seizure nor epileptiform EEG activity was observed. The most prominent side effect was the occurrence of vagal reactions during TBS; otherwise no serious side effects were found. Standardized low-resolution brain electromagnetic tomography showed current density changes in the α2 band after iTBS of the DLPFC, which remained detectable up to 50 min after stimulation. The few changes in neuropsychological performance were concordant with stimulation site. No impact on mood was detected. Conclusions Although TBS protocols of the human prefrontal cortex seem to be safe in healthy subjects, future studies need to address the occurrence of vagal reactions. Excitatory and inhibitory properties of motor cortex TBS might not be transferable to prefrontal sites, and the action of specific TBS protocols needs to be further investigated prior to clinical application.
• Variation in Catechol-O-Methyltransferase Is Associated with Duloxetine Response in a Clinical Trial for Major Depressive Disorder
  - Biol Psychiatry 65(9):785-791 (2009)
  Background The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD). Methods We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action. Primary analysis examined baseline to end point reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score, using a set-based test for association for each gene. Follow-up analyses examined individual SNPs within any significant gene for association with reduction in HAMD17 and 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C-30). Results After correction for multiple comparisons, only COMT was associated with change in HAMD17 (experimentwide p = .018). Peak association was detected with rs165599 (p = .006), which accounted for approximately 3% of variance in HAMD17 change and >4% of variance in IDS-C-30 change (p = .001). The least-squared mean change (SE) in HAMD17 score by rs165599 genotype was −10.8 (1.2), −8.7 (.6), and −6.5 (.7) for patients with GG, GA, and AA genotypes, respectively. For SNPs in serotonin 2A receptor (HTR2A) previously associated with citalopram response, including rs7997012, no significant evidence of association with duloxetine response was identified. Conclusions Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance.
• Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder
  - Biol Psychiatry 65(9):792-800 (2009)
  Background Significant alterations in γ-aminobutyric acid (GABA) and glutamate levels have been previously reported in major depressive disorder (MDD); however, no studies to date have investigated associations between these amino acid neurotransmitters and treatment resistance. Methods The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (Glx) levels measured by proton magnetic resonance spectroscopy (1H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 nontreatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs). Results Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared with both HV (20.2% mean reduction; p = .001; Cohen's d = 1.3) and nTRD subjects (16.4% mean reduction; p = .007; Cohen's d = 1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p = .047; Cohen's d = .76) with TRD patients exhibiting reduced GABA in comparison with the other two groups (22.4% to 24.5% mean reductions). Group differences in Glx/W were not significant in either brain region. Only GABA results in OCC survived correction for multiple comparisons. Conclusions Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.
• Depressive Symptoms Are Associated with Soluble P-Selectin Reactivity to Acute Exercise in Heart Failure
  - Biol Psychiatry 65(9):801-807 (2009)
  Background To determine the effects of depressive symptom severity on the circulating soluble adhesion molecule response to an acute exercise challenge in patients with heart failure (HF) compared with control subjects. Methods Thirty-eight male HF patients and 19 male control subjects (mean age ± SEM: 55.5 ± 1.9) completed the Beck Depression Inventory (BDI) before undergoing a moderate 20-minute bicycle exercise at approximately 65% to 70% VO2peak. Plasma levels of the soluble adhesion molecules P-selectin (sP-selectin) (sCD62P) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined immediately before and after and 10 minutes after exercise. Results Higher BDI scores moderated greater increases in sP-selectin levels in response to exercise over time in HF patients as compared with control subjects [F(1.8/84.5) = 3.25, p = .05]. Post hoc testing revealed that in HF patients, but not in control subjects, higher BDI scores were significantly associated with greater increases in sP-selectin levels over time in response to exercise [BDI by exercise interaction: F(1.6/49.6) = 5.67, p = .010]. Also, in HF patients, but not in control subjects, higher BDI scores were associated with higher sP-selectin levels at pre-exercise and postexercise time points [main effect BDI: F(1/31) = 4.86, p = .035]. Conclusions Our findings suggest that in male HF patients with increasing depressive symptom severity, levels of the adhesion molecule sP-selectin are higher before and after exercise and have greater increases in response to exercise. This could have implications for acute coronary syndromes associated with exercise and thereby may impact mortality.
• Delineation of Two Genetic Pathways to Major Depression
  - Biol Psychiatry 65(9):808-811 (2009)
  Background We sought to identify two sets of familial/genetic risk factors for major depression (MD): 1) high familial loading for MD, which we predicted would be most prominent in cases of MD with an early age at onset (AAO), and 2) high familial loading for vascular disease (VD), which should be strongest in MD cases with a late AAO. Methods We examined 4785 twin pairs from the Swedish Twin Registry, assessed at a mean age of 54.0 (SD = 7.4), where both members of the pair were evaluated by interview and at least one member reported a lifetime history of modified DSM-IV MD. Risk for VD was assessed from hospital discharge information and death certificates. Results Using Cox proportional hazard models and controlling for zygosity, age, and sex, early AAO in depressed twins predicted risk for MD in their cotwins, whereas late AAO predicted cotwin risk for VD. Using piecewise regression, the hazard ratio (HR) relating AAO per decade to risk for MD in cotwin was much stronger for AAO from 13–23 years (HR = .62) than for AAO 24–65 years (HR = 0.94). The HR relating AAO of MD in twin and risk for VD in cotwin was twice as strong for AAO from 47–65 years (HR = 1.17) as for AAO 13–46 years (1.08). Conclusions From a familial/genetic perspective, MD is etiologically heterogeneous. Early and late onset MD are indexed, respectively, by the risk for MD and VD in relatives.
• Amygdala Volume Marks the Acute State in the Early Course of Depression
  - Biol Psychiatry 65(9):812-818 (2009)
  Background The amygdala and hippocampus play a key role in the neural circuitry mediating depression. It remains unclear how much structural and functional changes of amygdala and hippocampus reflect the acute state of depression or an underlying neurobiological trait marker of depression. Methods High-resolution anatomical images were acquired in 20 medication-naïve major depressive disorder (MDD) patients with a current first episode, 20 medication-free patients recovered from a first episode of MDD, and 20 healthy control subjects that were matched for age, gender, and level of education. Manual volumetry of amygdala and hippocampus was performed on coronal images. Volumetric measurements of brain volume and intracranial volume were acquired with automatic segmentation procedures. Results Both amygdalae were significantly enlarged in currently depressed patients, whereas there was no significant difference between recovered patients and control subjects. The amygdala enlargement correlated positively with the severity of depressive state but with no other clinical or neuropsychological variable. The hippocampal volume did not differ between groups. Conclusions A state related increase of amygdala volume can be detected early in the course of MDD. Neurotoxic effects might account for the fact that state-related amygdala enlargement has not been found in recurrent depression with relative long illness duration.
• Amygdala Deactivation as a Neural Correlate of Pain Processing in Patients with Borderline Personality Disorder and Co-Occurrent Posttraumatic Stress Disorder
  - Biol Psychiatry 65(9):819-822 (2009)
  Background Previous studies have revealed altered affective pain processing in patients with borderline personality disorder (BPD) as well as in patients with posttraumatic stress disorder (PTSD). Reduced levels of activation in the amygdala might be related to antinociceptive mechanisms pertinent to both disorders. This study aimed at clarifying whether central antinoceptive mechanisms discriminate BPD patients with and without co-occurrent PTSD. Methods We investigated 29 medication-free female outpatients with BPD, 12 with and 17 without co-occurrent PTSD. Psychophysical characteristics were assessed, and functional magnetic resonance imaging was performed during heat stimulation with stimuli adjusted for equal subjective painfulness. Results No difference in pain sensitivity was found between both groups of patients. Amygdala deactivation, however, was more pronounced in BPD patients with co-occurrent PTSD compared with those without PTSD. Amygdala deactivation was independent of BPD symptom severity and dissociation. Conclusions Amygdala deactivation seems to differentiate patients who meet criteria for both BPD and PTSD from BPD patients without co-occurrent PTSD. On the basis of these preliminary findings it might be speculated that reduced pain sensitivity or at least the emotional component of it is associated with amygdala deactivation in patients with both disorders, whereas BPD patients without PTSD use different yet unknown antinociceptive mechanisms.
• The following Biological Psychiatry articles in press are now available in full text at http://www.sobp.org/journal
  - Biol Psychiatry 65(9):823 (2009)