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Anxiety and anhedonia in depression: Associations with neuroticism and cognitive control.
Liao, A, Walker, R, Carmody, TJ, Cooper, C, Shaw, MA, Grannemann, BD, Adams, P, Bruder, GE, McInnis, MG, Webb, CA, et al
Journal of affective disorders. 2019;:1070-1078
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Abstract
BACKGROUND Despite the fact that higher levels of anxiety and anhedonia in Major Depressive Disorder (MDD) are linked to poorer treatment outcomes, mechanisms contributing to these clinical presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning may be critical processes involved in MDD and may help to explain symptoms of anxiety and anhedonia. METHODS Using baseline data from patients with early-onset MDD (N = 296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, we conducted a path analysis to model relationships between neuroticism, cognitive control, and reward learning to levels of anxiety and anhedonia. RESULTS Neuroticism was positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001). Cognitive control was negatively associated with anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with either anxiety or anhedonia. LIMITATIONS Extraneous variables not included in the model may have even more influence in explaining symptoms of anxiety and anhedonia. Restricted range in these variables may have attenuated some of the hypothesized relationships. Most important, because this was a cross-sectional analysis in a currently depressed sample, we cannot draw any causal conclusions without experimental and longitudinal data. CONCLUSIONS These cross-sectional findings suggest that neuroticism may contribute to anxiety and anhedonia in patients with early onset and either chronic or recurrent MDD, while enhanced cognitive control may protect against anxiety.
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Novel Pathways in the Treatment of Major Depression: Focus on the Glutamatergic System.
Tomasetti, C, Montemitro, C, Fiengo, ALC, Santone, C, Orsolini, L, Valchera, A, Carano, A, Pompili, M, Serafini, G, Perna, G, et al
Current pharmaceutical design. 2019;(4):381-387
Abstract
Depressive disorders represent protean psychiatric illnesses with heterogeneous clinical manifestations and a multitude of comorbidities leading to severe disability. In spite of decades of research on the pathophysiogenesis of these disorders, the wide variety of pharmacotherapies currently used to treat them is based on the modulation of monoamines, whose alteration has been considered the neurobiological foundation of depression, and consequently of its treatment. However, approximately one third to a half of patients respond partially or become refractory to monoamine-based therapies, thereby jeopardizing the therapeutic effectiveness in the real world of clinical practice. Recent scientific evidence has been pointing out the essential role of other biological systems beyond monoamines in the pathophysiology of depressive disorders, in particular, the glutamatergic neurotransmission. In the present review, we will discuss the most advanced knowledge on the involvement of glutamatergic system in the molecular mechanisms at the basis of depression pathophysiology, as well as the glutamate-based therapeutic strategies currently suggested to optimize depression treatment (e.g., ketamine). Finally, we will mention further "neurobiological targeted" approaches, based on glutamate system, with the purpose of promoting new avenues of investigation aiming at developing interventions that overstep the monoaminergic boundaries to improve depressive disorders therapy.
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Complementary therapies for clinical depression: an overview of systematic reviews.
Haller, H, Anheyer, D, Cramer, H, Dobos, G
BMJ open. 2019;(8):e028527
Abstract
OBJECTIVES As clinical practice guidelines vary widely in their search strategies and recommendations of complementary and alternative medicine (CAM) for depression, this overview aimed at systematically summarising the level 1 evidence on CAM for patients with a clinical diagnosis of depression. METHODS PubMed, PsycInfo and Central were searched for meta-analyses of randomised controlled clinical trials (RCTs) until 30 June 2018. Outcomes included depression severity, response, remission, relapse and adverse events. The quality of evidence was assessed according to Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) considering the methodological quality of the RCTs and meta-analyses, inconsistency, indirectness, imprecision of the evidence and the potential risk of publication bias. RESULTS The literature search revealed 26 meta-analyses conducted between 2002 and 2018 on 1-49 RCTs in major, minor and seasonal depression. In patients with mild to moderate major depression, moderate quality evidence suggested the efficacy of St. John's wort towards placebo and its comparative effectiveness towards standard antidepressants for the treatment for depression severity and response rates, while St. John's wort caused significant less adverse events. In patients with recurrent major depression, moderate quality evidence showed that mindfulness-based cognitive therapy was superior to standard antidepressant drug treatment for the prevention of depression relapse. Other CAM evidence was considered as having low or very low quality. CONCLUSIONS The effects of all but two CAM treatments found in studies on clinical depressed patients based on low to very low quality of evidence. The evidence has to be downgraded mostly due to avoidable methodological flaws of both the original RCTs and meta-analyses not following the Consolidated Standards of Reporting Trials and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Further research is needed.
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Psychological therapies for preventing seasonal affective disorder.
Forneris, CA, Nussbaumer-Streit, B, Morgan, LC, Greenblatt, A, Van Noord, MG, Gaynes, BN, Wipplinger, J, Lux, LJ, Winkler, D, Gartlehner, G
The Cochrane database of systematic reviews. 2019;(5):CD011270
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Abstract
BACKGROUND Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This is one of four reviews on the efficacy and safety of interventions to prevent SAD; we focus on psychological therapies as preventive interventions. OBJECTIVES To assess the efficacy and safety of psychological therapies (in comparison with no treatment, other types of psychological therapy, second-generation antidepressants, light therapy, melatonin or agomelatine or lifestyle interventions) in preventing SAD and improving person-centred outcomes among adults with a history of SAD. SEARCH METHODS We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 August 2015). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to 19 June 2018). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles. SELECTION CRITERIA To examine efficacy, we included randomised controlled trials (RCTs) on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. To examine adverse events, we intended to include non-randomised studies. We planned to include studies that compared psychological therapy versus no treatment, or any other type of psychological therapy, light therapy, second-generation antidepressants, melatonin, agomelatine or lifestyle changes. We also planned to compare psychological therapy in combination with any of the comparator interventions listed above versus no treatment or the same comparator intervention as monotherapy. DATA COLLECTION AND ANALYSIS Two review authors screened abstracts and full-text publications against the inclusion criteria, independently extracted data, assessed risk of bias, and graded the certainty of evidence. MAIN RESULTS We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 articles at full-text review for eligibility. We included one controlled study enrolling 46 participants. We rated this RCT at high risk for performance and detection bias due to a lack of blinding.The included RCT compared preventive use of mindfulness-based cognitive therapy (MBCT) with treatment as usual (TAU) in participants with a history of SAD. MBCT was administered in spring in eight weekly individual 45- to 60-minute sessions. In the TAU group participants did not receive any preventive treatment but were invited to start light therapy as first depressive symptoms occurred. Both groups were assessed weekly for occurrence of a new depressive episode measured with the Inventory of Depressive Syptomatology-Self-Report (IDS-SR, range 0-90) from September 2011 to mid-April 2012. The incidence of a new depressive episode in the upcoming winter was similar in both groups. In the MBCT group 65% of 23 participants developed depression (IDS-SR ≥ 20), compared to 74% of 23 people in the TAU group (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.30; 46 participants; very low quality-evidence).For participants with depressive episodes, severity of depression was comparable between groups. Participants in the MBCT group had a mean score of 26.5 (SD 7.0) on the IDS-SR, and TAU participants a mean score of 25.3 (SD 6.3) (mean difference (MD) 1.20, 95% CI -3.44 to 5.84; 32 participants; very low quality-evidence).The overall discontinuation rate was similar too, with 17% discontinuing in the MBCT group and 13% in the TAU group (RR 1.33, 95% CI 0.34 to 5.30; 46 participants; very low quality-evidence).Reasons for downgrading the quality of evidence included high risk of bias of the included study and imprecision.Investigators provided no information on adverse events. We could not find any studies that compared psychological therapy with other interventions of interest such as second-generation antidepressants, light therapy, melatonin or agomelatine. AUTHORS' CONCLUSIONS The evidence on psychological therapies to prevent the onset of a new depressive episode in people with a history of SAD is inconclusive. We identified only one study including 46 participants focusing on one type of psychological therapy. Methodological limitations and the small sample size preclude us from drawing a conclusion on benefits and harms of MBCT as a preventive intervention for SAD. Given that there is no comparative evidence for psychological therapy versus other preventive options, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences and other preventive interventions that are supported by evidence.
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Cognitive-Behavioral Therapy Plus Healthy Lifestyle Enhancement for Depressed, Overweight/Obese Adolescents: Results of a Pilot Trial.
Jelalian, E, Jandasek, B, Wolff, JC, Seaboyer, LM, Jones, RN, Spirito, A
Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53. 2019;(sup1):S24-S33
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Abstract
The objective of this article was to conduct a treatment development study to examine the feasibility, acceptability, and preliminary efficacy of treating depressed, overweight/obese adolescents using both an exercise regimen and a Cognitive Behavioral Therapy (CBT) protocol modified to address aspects of healthy living and nutrition (CBT plus healthy lifestyle; CBT-HL). A randomized controlled repeated measures design was used to test the hypothesis that CBT-HL would lead to greater reductions in depressed mood and weight compared to CBT for Depression Only (CBT). Participants (n=33; 24 in CBT-HL condition) included 33 adolescents (median age 15, 73% female, 61% white, 36% Hispanic) who met DSM-IV criteria for Current Major Depressive Episode (MDE) and had BMI ≥ 85th percentile. CBT-HL was found to be feasible to implement with most adolescents. Both conditions resulted in improvement in depressed mood. The CBT-HL protocol was more effective in stabilizing weight status as assessed by BMI. Percent time spent in MVPA was increased at 12 weeks for adolescents in CBT-HL compared to those in CBT. The CBT-HL protocol was acceptable to most, but not all, adolescents, and resulted in an improvement in depressed mood as well as stabilization of weight status. A larger study to test efficacy and moderators of treatment outcome is necessary to better understand which adolescents would benefit most from the increased demands of exercise and adhering to nutrition recommendations in addition to standard CBT for depression. Revisions to the treatment protocol to support weight loss, not just stabilization, are also suggested.
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The UKB envirome of depression: from interactions to synergistic effects.
Hullam, G, Antal, P, Petschner, P, Gonda, X, Bagdy, G, Deakin, B, Juhasz, G
Scientific reports. 2019;(1):9723
Abstract
Major depressive disorder is a result of the complex interplay between a large number of environmental and genetic factors but the comprehensive analysis of contributing environmental factors is still an open challenge. The primary aim of this work was to create a Bayesian dependency map of environmental factors of depression, including life stress, social and lifestyle factors, using the UK Biobank data to determine direct dependencies and to characterize mediating or interacting effects of other mental health, metabolic or pain conditions. As a complementary approach, we also investigated the non-linear, synergistic multi-factorial risk of the UKB envirome on depression using deep neural network architectures. Our results showed that a surprisingly small number of core factors mediate the effects of the envirome on lifetime depression: neuroticism, current depressive symptoms, parental depression, body fat, while life stress and household income have weak direct effects. Current depressive symptom showed strong or moderate direct relationships with life stress, pain conditions, falls, age, insomnia, weight change, satisfaction, confiding in someone, exercise, sports and Townsend index. In conclusion, the majority of envirome exerts their effects in a dynamic network via transitive, interactive and synergistic relationships explaining why environmental effects may be obscured in studies which consider them individually.
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Nutraceuticals for major depressive disorder- more is not merrier: An 8-week double-blind, randomised, controlled trial.
Sarris, J, Byrne, GJ, Stough, C, Bousman, C, Mischoulon, D, Murphy, J, Macdonald, P, Adams, L, Nazareth, S, Oliver, G, et al
Journal of affective disorders. 2019;:1007-1015
Abstract
BACKGROUND One of the most pressing questions in "Nutritional Psychiatry" is whether using combinations of different nutraceuticals with putative antidepressant activity may provide an enhanced synergistic antidepressant effect. METHODS A phase II/III, Australian multi-site, 8-week, double-blind, RCT involving 158 outpatients with a DSM-5 diagnosis of MDD. The intervention consisted of a nutraceutical combination: S-adenosyl methionine; Folinic acid; Omega-3 fatty acids; 5-HTP, Zinc picolinate, and relevant co-factors versus placebo. The primary outcome was change in MADRS score. Hypothesis-driven analyses of potential moderators of response involving key SNPs, and BDNF were also conducted. RESULTS Placebo was superior to the nutraceutical combination in reducing MADRS score (differential reduction -1.75 points), however a mixed linear model revealed a non-significant Group X Time interaction (p = 0.33). Response rates were 40% for the active intervention and 51% for the placebo; remission rates were 34% and 43% for active and placebo groups, respectively. No significant differences were found between groups on any other secondary depression, anxiety, psychosocial, or sleep outcome measures. Key SNPs and BDNF did not significantly moderate response. No significant differences occurred between groups for total adverse effects, aside from more nausea in the active group. LIMITATIONS Very high placebo response rates suggest a placebo run-in design may have been valuable. INTERPRETATION The adoption of a nutraceutical 'shotgun' approach to treating MDD was not supported, and appeared to be less effective than adding placebo to treatment as usual.
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Monoaminergic system and depression.
Perez-Caballero, L, Torres-Sanchez, S, Romero-López-Alberca, C, González-Saiz, F, Mico, JA, Berrocoso, E
Cell and tissue research. 2019;(1):107-113
Abstract
Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.
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Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome.
Postolache, TT, Del Bosque-Plata, L, Jabbour, S, Vergare, M, Wu, R, Gragnoli, C
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2019;(3):186-203
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Abstract
Schizophrenia (SCZ) and major depressive disorder (MDD) in treatment-naive patients are associated with increased risk for type 2 diabetes (T2D) and metabolic syndrome (MetS). SCZ, MDD, T2D, and MetS are often comorbid and their comorbidity increases cardiovascular risk: Some risk genes are likely co-shared by them. For instance, transcription factor 7-like 2 (TCF7L2) and proteasome 26S subunit, non-ATPase 9 (PSMD9) are two genes independently reported as contributing to T2D and SCZ, and PSMD9 to MDD as well. However, there are scarce data on the shared genetic risk among SCZ, MDD, T2D, and/or MetS. Here, we briefly describe T2D, MetS, SCZ, and MDD and their genetic architecture. Next, we report separately about the comorbidity of SCZ and MDD with T2D and MetS, and their respective genetic overlap. We propose a novel hypothesis that genes of the prolactin (PRL)-pathway may be implicated in the comorbidity of these disorders. The inherited predisposition of patients with SCZ and MDD to psychoneuroendocrine dysfunction may confer increased risk of T2D and MetS. We illustrate a strategy to identify risk variants in each disorder and in their comorbid psychoneuroendocrine and mental-metabolic dysfunctions, advocating for studies of genetically homogeneous and phenotype-rich families. The results will guide future studies of the shared predisposition and molecular genetics of new homogeneous endophenotypes of SCZ, MDD, and metabolic impairment.
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Genome-wide DNA methylomic differences between dorsolateral prefrontal and temporal pole cortices of bipolar disorder.
Ho, AM, Winham, SJ, Armasu, SM, Blacker, CJ, Millischer, V, Lavebratt, C, Overholser, JC, Jurjus, GJ, Dieter, L, Mahajan, G, et al
Journal of psychiatric research. 2019;:45-54
Abstract
Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation - an epigenetic mechanism both heritable and sensitive to the environment - may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.