Neural correlates of sleepiness induced by catecholamine depletion

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

Reduced olfactory bulb volume in adults with a history of childhood maltreatment

The human olfactory bulb (OB) is the first relay station of the olfactory pathway and may have the potential for postnatal neurogenesis in early childhood. In animals, chronic stress affects the OB and olfactory functioning. For humans, it has been shown that major depressive disorder is accompanied by reduced OB volume and reduced olfactory function. However, it is not clear if major stress in childhood development also affects olfactory functioning and OB volume in humans. OB volume was measured and olfactory function was tested in 17 depressive patients with and 10 without a history of severe childhood maltreatment (CM). CM patients exhibited a significantly reduced olfactory threshold and identification ability. The OB volume of the CM patients was significantly reduced to 80% of the non-CM patients. In conclusion, postnatal neurogenesis might be by reduced in CM, which may affect olfactory function of the brain in later life. Alternatively, a reduced OB volume may enhance psychological vulnerability in the presence of adverse childhood conditions although other areas not analyzed in this study may also be involved.

Physician perceptions of risk regarding mood disorders and pharmacological management during pregnancy: What is current practice?

Mood disorders are the most common form of mental illness and one of the leading causes of morbidity worldwide. Major depressive disorder and bipolar disorder have a lifetime prevalence of 16.2% and 4.4%, respectively. Women comprise a substantial proportion of this population, and an estimated 500,000 pregnancies each year involve women with a psychiatric condition. Management with psychotropic medications is considered standard of care for most patients with mood disorders. However, many of these medications are known human teratogens. Because pregnant women with mood disorders face a high risk of relapse if unmanaged, the obstetrician faces a unique challenge in providing the best care to both mother and baby. It has been suggested that many obstetricians overestimate the teratogenic risks associated with psychotropic medications, while concurrently underestimating the risks associated with unmanaged mood disorders. This may be due a knowledge gap regarding the most current teratogen information, and lack of official management guidelines. Therefore, the purpose of this study is to determine the current knowledge base of obstetricians regarding the teratogenic effects of common psychotropic medications, as wells as to capture current management practices for pregnant women with mood disorders. A total of 117 Texas obstetricians responded to a survey regarding teratogen knowledge and management practice. It was common for respondents to encounter women who disclose both having a mood disorder and taking a psychotropic medication during pregnancy. Many respondents did not utilize up-to-date drug counseling resources, and were unaware of or over-estimated the teratogenic risks of common medications used to treat mood disorders. Finally, many respondents reported wanting to refer pregnant patients with mood disorders to psychiatrists for co-management, but are reportedly restricted in doing so due to accessibility or insurance issues. This study demonstrates that there is a knowledge gap among obstetricians regarding the teratogenicity of common psychotropic medications utilized to manage a patient population they frequently encounter. Further, obstetricians have vastly different risk perceptions of these medications, resulting in various management approaches and recommendations. Future research should focus on establishing standard practice guidelines, as well as better accessibility to psychiatric services for pregnant women.

Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial

BACKGROUND: Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence.Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. DESIGN: A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). METHOD: Participants are patients aged over 18 years meeting diagnostic criteria for major depressive disorder or dysthymic disorder, with a score of 19 or above on the Beck depression inventory, second edition (BDI-II) and presenting at least one cognitive conflict (implicative dilemma or dilemmatic construct) as assessed using the RGT. The BDI-II is the primary outcome measure, collected at baseline, at the end of therapy, and at 3- and 12-month follow-up; other secondary measures are also used. DISCUSSION: We expect that adding a dilemma-focused intervention to CBT will increase the efficacy of one of the more prestigious therapies for depression, thus resulting in a significant contribution to the psychological treatment of depression. TRIAL REGISTRATION: ISRCTN92443999; ClinicalTrials.gov Identifier: NCT01542957.

[A psychocardiology update on depression and coronary heart disease].

The prevalence of a major depressive disorder in patients after myocardial infarction is 20%. Depression is a risk factor for incident coronary heart disease and poor prognosis after myocardial infarction. Poor lifestyle habits and adherence to cardiac therapy as well as metabolic and pathophysiologic changes may partially explain this link. The threatening experience of an acute coronary event and immune and inflammatory changes may be unique features contributing to incident depression after myocardial infarction. While psychotherapy, antidepressants, and physical exercise may alleviate depressive symptoms in patients with coronary heart disease, cardiac rehabilitation additionally reduces mortality risk. Attempts are being undertaken to identify the cardiotoxic characteristics of depression to develop even more effective therapies in the future.

Associations between mood, anxiety or substance use disorders and inflammatory markers after adjustment for multiple covariates in a population-based study.

Inflammation is one possible mechanism underlying the associations between mental disorders and cardiovascular diseases (CVD). However, studies on mental disorders and inflammation have yielded inconsistent results and the majority did not adjust for potential confounding factors. We examined the associations of several pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and high sensitive C-reactive protein (hsCRP) with lifetime and current mood, anxiety and substance use disorders (SUD), while adjusting for multiple covariates. The sample included 3719 subjects, randomly selected from the general population, who underwent thorough somatic and psychiatric evaluations. Psychiatric diagnoses were made with a semi-structured interview. Major depressive disorder was subtyped into "atypical", "melancholic", "combined atypical-melancholic" and "unspecified". Associations between inflammatory markers and psychiatric diagnoses were assessed using multiple linear and logistic regression models. Lifetime bipolar disorders and atypical depression were associated with increased levels of hsCRP, but not after multivariate adjustment. After multivariate adjustment, SUD remained associated with increased hsCRP levels in men (β = 0.13 (95% CI: 0.03,0.23)) but not in women. After multivariate adjustment, lifetime combined and unspecified depression were associated with decreased levels of IL-6 (β = -0.27 (-0.51,-0.02); β = -0.19 (-0.34,-0.05), respectively) and TNF-α (β = -0.16 (-0.30,-0.01); β = -0.10 (-0.19,-0.02), respectively), whereas current combined and unspecified depression were associated with decreased levels of hsCRP (β = -0.20 (-0.39,-0.02); β = -0.12 (-0.24,-0.01), respectively). Our data suggest that the significant associations between increased hsCRP levels and mood disorders are mainly attributable to the effects of comorbid disorders, medication as well as behavioral and physical CVRFs.

Symptom-based subtypes of depression and their psychosocial correlates: A person-centered approach focusing on the influence of sex

BACKGROUND: Reducing the complexity of major depressive disorder by symptom-based subtypes constitutes the basis of more specific treatments. To date, few studies have empirically derived symptom subtypes separated by sex, although the impact of sex has been widely accepted in depression research. METHODS: The community-based sample included 373 males and 443 females from the Zurich Program for Sustainable Development of Mental Health Services (ZInEP) manifesting depressive symptoms in the past 12 months. Latent Class Analysis (LCA) was performed separately by sex to extract sex-related depression subtypes. The subtypes were characterized by psychosocial characteristics. RESULTS: Three similar subtypes were found in both sexes: a severe typical subtype (males: 22.8%; females: 35.7%), a severe atypical subtype (males: 17.4%; females: 22.6%), and a moderate subtype (males: 25.2%; females: 41.8%). In males, two additional subgroups were identified: a severe irritable/angry-rejection sensitive (IARS) subtype (30%) comprising the largest group, and a small psychomotor retarded subtype (4%). Males belonging to the severe typical subtype exhibited the lowest masculine gender role orientation, while females of the typical subtype showed more anxiety disorders. The severe atypical subtype was associated with eating disorders in both sexes and with alcohol/drug abuse/dependence in females. In contrast, alcohol/drug abuse/dependence was associated with the severe IARS subtype in males. LIMITATIONS:The study had a cross-sectional design, allowing for no causal inferences. CONCLUSIONS:This study contributes to a better understanding of sex-related depression subtypes, which can be well distinguished on the basis of symptom profiles. This provides the base for future research investigating the etiopathogenesis and effective treatment of the heterogeneous depression disorder.

Preliminary Evidence for a Nexus between Rumination, Behavioural Avoidance, Motive Satisfaction and Depression

The present study tested a theoretically derived link between rumination and depressive symptoms through behavioural avoidance and reduced motive satisfaction as a key aspect of positive reinforcement. Rumination, behavioural avoidance, motive satisfaction and levels of depression were assessed via self-report measures in a clinical sample of 160 patients with major depressive disorder. Path analysis-based mediation analysis was used to estimate the direct and indirect effects as proposed by the theoretical model. Operating in serial, behavioural avoidance and motive satisfaction partially mediated the association between rumination and depressive symptoms, irrespective of gender, medication and co-morbid anxiety disorders. This is the first study investigating the associations between behavioural avoidance, rumination and depression in a clinical sample of depressed patients. The findings are in line with an understanding of rumination in depression as also serving an avoidance function. Copyright © 2014 John Wiley & Sons, Ltd.

BDNF Val66Met polymorphism influence on striatal blood-level-dependent response to monetary feedback depends on valence and agency

Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of the striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether BDNF Val66Met polymorphism predicts VS activity. We found that BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.

Don't forget asking the others! - The added value of significant other's reports on patient interpersonal style for the prediction of therapy process and outcome

Theory: Interpersonal factors play a major role in causing and maintaining depression. It is unclear, however, to what degree significant others of the patient need to be involved for characterizing the patient's interpersonal style. Therefore, our study sought to investigate how impact messages as perceived by the patients' significant others add to the prediction of psychotherapy process and outcome above and beyond routine assessments, and therapist factors. Method: 143 outpatients with major depressive disorder were treated by 24 therapists with CBT or Exposure-Based Cognitive Therapy. Interpersonal style was measured pre and post therapy with the informant‐based Impact Message Inventory (IMI), in addition to the self‐report Inventory of Interpersonal Problems (IIP‐32). Indicators for the patients' dominance and affiliation as well as interpersonal distress were calculated from these measures. Depressive and general symptomatology was assessed at pre, post, and at three months follow‐up, and by process measures after every session. Results: Whereas significant other's reports did not add significantly to the prediction of the early therapeutic alliance, central mechanisms of change, or post‐therapy outcome including therapist factors, the best predictor of outcome 3 months post therapy was an increase in dominance as perceived by significant others. Conclusions: The patients' significant others seem to provide important additional information about the patients' interpersonal style and therefore should be included in the diagnostic process. Moreover, practitioners should specifically target interpersonal change as a potential mechanism of change in psychotherapy for depression.

Amygdala response to self-critical stimuli and symptom improvement in psychotherapy for depression

Background: Cognitive–behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory. Aims: To better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment. Method: Functional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self-critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients. Results: Patients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association. Conclusions: Amygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition.

Stimulant medication and psychotic symptoms in offspring of parents with mental illness

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6–21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82–10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.

Evidence for chronic low-grade systemic inflammation in individuals with agoraphobia from a population-based prospective study.

BACKGROUND Anxiety disorders have been linked to an increased risk of incident coronary heart disease in which inflammation plays a key pathogenic role. To date, no studies have looked at the association between proinflammatory markers and agoraphobia. METHODS In a random Swiss population sample of 2890 persons (35-67 years, 53% women), we diagnosed a total of 124 individuals (4.3%) with agoraphobia using a validated semi-structured psychiatric interview. We also assessed socioeconomic status, traditional cardiovascular risk factors (i.e., body mass index, hypertension, blood glucose levels, total cholesterol/high-density lipoprotein-cholesterol ratio), and health behaviors (i.e., smoking, alcohol consumption, and physical activity), and other major psychiatric diseases (other anxiety disorders, major depressive disorder, drug dependence) which were treated as covariates in linear regression models. Circulating levels of inflammatory markers, statistically controlled for the baseline demographic and health-related measures, were determined at a mean follow-up of 5.5 ± 0.4 years (range 4.7 - 8.5). RESULTS Individuals with agoraphobia had significantly higher follow-up levels of C-reactive protein (p = 0.007) and tumor-necrosis-factor-α (p = 0.042) as well as lower levels of the cardioprotective marker adiponectin (p = 0.032) than their non-agoraphobic counterparts. Follow-up levels of interleukin (IL)-1β and IL-6 did not significantly differ between the two groups. CONCLUSIONS Our results suggest an increase in chronic low-grade inflammation in agoraphobia over time. Such a mechanism might link agoraphobia with an increased risk of atherosclerosis and coronary heart disease, and needs to be tested in longitudinal studies.

Evaluation of association between childhood obesity and depression: A systematic literature review

Obesity has become a major public health concern throughout the world. Both developing as well as developed countries have been facing the consequences of obesity. [1, 2] According to World Health Organization, worldwide prevalence of overweight among adults was 1.6 billion and that of obesity was 400 million by the end of year 2005. At the same time, around 20 million children of less than 5 years of age were overweight worldwide. [3] ^ From amongst the obese children, around 15% of children manifest symptoms of depression before 18 years of age as compared to non-obese children of the same age group. Approximately 3-5% of these obese individuals develop major depressive disorders (MDD). [4, 5] The incidence of depression increases markedly as the child reaches puberty. The risk of persistent depression in childhood as well as in adulthood is two to four times higher if the child is obese as compared to those depressed adult individuals who are not obese in their childhood. [6, 7] ^ This paper will review the scientific literature concerning the association between childhood obesity and depression. ^

Complexity analysis of spontaneous brain activity: effects of depression and antidepressant treatment

Magnetoencephalography (MEG) allows the real-time recording of neural activity and oscillatory activity in distributed neural networks. We applied a non-linear complexity analysis to resting-state neural activity as measured using whole-head MEG. Recordings were obtained from 20 unmedicated patients with major depressive disorder and 19 matched healthy controls. Subsequently, after 6 months of pharmacological treatment with the antidepressant mirtazapine 30 mg/day, patients received a second MEG scan. A measure of the complexity of neural signals, the Lempel–Ziv Complexity (LZC), was derived from the MEG time series. We found that depressed patients showed higher pre-treatment complexity values compared with controls, and that complexity values decreased after 6 months of effective pharmacological treatment, although this effect was statistically significant only in younger patients. The main treatment effect was to recover the tendency observed in controls of a positive correlation between age and complexity values. Importantly, the reduction of complexity with treatment correlated with the degree of clinical symptom remission. We suggest that LZC, a formal measure of neural activity complexity, is sensitive to the dynamic physiological changes observed in depression and may potentially offer an objective marker of depression and its remission after treatment.