Prevention Of Major Depressive Disorder Research Articles

Exploring causal association between functional/structural connectivity and major depression disorder: A bidirectional Mendelian randomization study

ObjectivesPrior observational studies have suggested a correlation between major depressive disorder (MDD) and communication imbalances within the resting-state brain network (RSN), but the causal relationship remains unclear. This research uses Mendelian randomization (MR) analysis to explore the potential causal effects between functional connectivity (FC), structural connectivity (SC) and MDD. MethodsTwo-sample bidirectional MR analysis was employed in this study. Inverse variance weighted (IVW) was used to explore the causal relationship between the FC/SC and MDD, with various methods such as MR-Egger to conduct sensitivity analyses. ResultsThe IVW analysis results showed that higher genetic predicted dorsal attention network FC, limbic network SC, and dorsal attention network SC were associated with an increased risk of MDD (β: 15.08, 95%CI: 5.89–24.27, p = 0.001; β: 3.79, 95%CI: −0.22-7.8, p = 0.034; β: 9.89, 95%CI: 0.88–18.90, p = 0.031). Reverse MR analysis demonstrated that a genetically predicted elevated risk of MDD was associated with reduced frontal parietal network FC (β: −0.00046, p = 0.041). ConclusionsThe study suggests a causal relationship between the FC and SC within specific RSNs and the risk of MDD. Abnormalities in the dorsal attention network FC/SC and the limbic network SC were risk factors for MDD. The FC abnormality of the frontal parietal network may be the downstream influence following the MDD onset. Further investigation is needed to determine the potential utility of these neuroimaging markers in the prevention of MDD or the evaluation of treatment efficacy.

Assessing the associations of 1,400 blood metabolites with major depressive disorder: a Mendelian randomization study.

Major Depressive Disorder (MDD) is one of the most prevalent and debilitating health conditions worldwide. Previous studies have reported a link between metabolic dysregulation and MDD. However, evidence for a causal relationship between blood metabolites and MDD is lacking. Using a two-sample bidirectional Mendelian randomization analysis (MR), we assessed the causal relationship between 1,400 serum metabolites and Major Depressive Disorder (MDD). The Inverse Variance Weighted method (IVW) was employed to estimate the causal association between exposures and outcomes. Additionally, MR-Egger regression, weighted median, simple mode, and weighted mode methods were used as supplementary approaches for a comprehensive appraisal of the causality between blood metabolites and MDD. Pleiotropy and heterogeneity tests were also conducted. Lastly, the relevant metabolites were subjected to metabolite function analysis, and a reverse MR was implemented to explore the potential influence of MDD on these metabolites. After rigorous screening, we identified 34 known metabolites, 13 unknown metabolites, and 18 metabolite ratios associated with Major Depressive Disorder (MDD). Among all metabolites, 33 were found to have positive associations, and 32 had negative associations. The top five metabolites that increased the risk of MDD were the Arachidonate (20:4n6) to linoleate (18:2n6) ratio, LysoPE(18:0/0:0), N-acetyl-beta-alanine levels, Arachidonate (20:4n6) to oleate to vaccenate (18:1) ratio, Glutaminylglutamine, and Threonine to pyruvate ratio. Conversely, the top five metabolites that decreased the risk of MDD were N6-Acetyl-L-lysine, Oleoyl-linoleoyl-glycerol (18:1 to 18:2) [2] to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) [2] ratio, Methionine to phosphate ratio, Pregnanediol 3-O-glucuronide, and 6-Oxopiperidine-2-carboxylic acid. Metabolite function enrichment was primarily concentrated in pathways such as Bile Acid Biosynthesis (FDR=0.177), Glutathione Metabolism (FDR=0.177), Threonine, and 2-Oxobutanoate Degradation (FDR=0.177). In addition, enrichment was noted in pathways like Valine, Leucine, and Isoleucine Biosynthesis (p=0.04), as well as Ascorbate and Aldarate Metabolism (p=0.04). Within a pool of 1,400 blood metabolites, we identified 34 known metabolites and 13 unknown metabolites, as well as 18 metabolite ratios associated with Major Depressive Disorder (MDD). Additionally, three functionally enriched groups and two metabolic pathways were selected. The integration of genomics and metabolomics has provided significant insights for the screening and prevention of MDD.

An individual participant data meta-analysis of psychological interventions for preventing depression relapse

AbstractMajor depressive disorder is a leading cause of disability worldwide; identifying effective strategies to prevent depression relapse is crucial. This individual participant data meta-analysis addresses whether and for whom psychological interventions can be recommended for relapse prevention of major depressive disorder. One- and two-stage individual patient data meta-analyses were conducted on 14 randomized controlled trials (N = 1,720). The relapse risk over 12 months was substantially lower for those who received a psychological intervention versus treatment as usual, antidepressant medication, or evaluation-only control (hazard ratio, 0.60; 95% confidence interval, 0.48–0.74). The number of previous depression episodes moderated the treatment effect, with psychological interventions demonstrating greater efficacy for patients with three or more previous episodes. Our results suggest that adding psychological interventions to current treatment to prevent depression relapse is recommended. For patients at lower risk of relapse, less-intensive approaches may be indicated.

Exosomes may be the carrier of acupuncture treatment for major depressive disorder.

The incidence of major depressive disorder (MDD) is increasing all over the world. There is a great need for complementary or alternative therapies with high safety, few side effects, and precise efficacy to care for MDD. In China, acupuncture has significant laboratory data and clinical trials to demonstrate its antidepressant efficacy. However, there is no clear answer as to how it works. Exosomes are membranous vesicles that rely on cellular multivesicular bodies (MVBs) fused to the cell membrane for release into the extracellular matrix. Almost all cell types are capable of producing and releasing exosomes. As a result, exosomes contain complex RNAs and proteins from their relatives (Cells that secretes exosomes). They can cross biological barriers and participate in biological activities, such as cell migration, angiogenesis, and immune regulation. These properties have made them a popular research topic. Some experts have suggested that exosomes may serve as delivery vehicles for acupuncture to work. This presents both an opportunity and a new challenge for improving the protocols of acupuncture as a treatment for MDD. To better define the relationship between MDD, exosomes, and acupuncture, we reviewed the literature from the last few years. Inclusion criteria included randomized controlled trials and basic trials evaluating acupuncture in the treatment or prevention of MDD, the role of exosomes in the development and progression of MDD, and the role of exosomes in acupuncture. We believe that acupuncture may affect the distribution of exosomes in vivo, and exosomes may be a new carrier for acupuncture treatment of MDD in the future.

Evaluation of brain structure and metabolism in currently depressed adults with a history of childhood trauma

Structural differences in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala were reported in adults who experienced childhood trauma; however, it is unknown whether metabolic differences accompany these structural differences. This multimodal imaging study examined structural and metabolic correlates of childhood trauma in adults with major depressive disorder (MDD). Participants with MDD completed the Childhood Trauma Questionnaire (CTQ, n = 83, n = 54 female (65.1%), age: 30.4 ± 14.1) and simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI). Structure (volume, n = 80, and cortical thickness, n = 81) was quantified from MRI using Freesurfer. Metabolism (metabolic rate of glucose uptake) was quantified from dynamic 18F-fluorodeoxyglucose (FDG)-PET images (n = 70) using Patlak graphical analysis. A linear mixed model was utilized to examine the association between structural/metabolic variables and continuous childhood trauma measures while controlling for confounding factors. Bonferroni correction was applied. Amygdala volumes were significantly inversely correlated with continuous CTQ scores. Specifically, volumes were lower by 7.44 mm3 (95% confidence interval [CI]: –12.19, –2.68) per point increase in CTQ. No significant relationship was found between thickness/metabolism and CTQ score. While longitudinal studies are required to establish causation, this study provides insight into potential consequences of, and therefore potential therapeutic targets for, childhood trauma in the prevention of MDD. This work aims to reduce heterogeneity in MDD studies by quantifying neurobiological correlates of trauma within MDD. It further provides biological targets for future interventions aimed at preventing MDD following trauma. To our knowledge, this is the first simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) study to assess both structure and metabolism associated with childhood trauma in adults with MDD.

Mendelian randomization analysis identified causal Association of Childhood Obesity with adult major depressive disorder

Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear. We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (nBMI =47 541, nobesity =24 160), the Genetic Investigation of Anthropometric Traits consortium (nadult_BMI =∼700 000) and the Psychiatric Genomics consortium (nMDD =500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results. Our study found that childhood obesity might increase the odds of developing MDD in adults (OR=1.03, 95% CI: 1.01-1.06, p=2.6 × 10-3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p=4.4 × 10-7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI. Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD.

The reduction of vitamin D in females with major depressive disorder is associated with worse cognition mediated by abnormal brain functional connectivity

Low vitamin D is linked to major depressive disorder (MDD) through affecting the brain. Gender difference is apparent in MDD and vitamin D level. We aimed to examine the association between gender, vitamin D, clinical presentations, and brain functional connectivity in a large cohort of MDD patients and comparison subjects. Resting-state functional MRI data from 122 patients and 119 controls were collected to perform a combined analysis of functional connectivity density (FCD) and seed-based functional connectivity (FC). Peripheral venous blood samples were obtained to measure serum concentration of vitamin D (SCVD). Clinical presentations (symptoms profiles and cognition) were also assessed. We found an interaction of group and gender on SCVD in which MDD patients demonstrated lower SCVD than controls in females rather than males. Concurrently, lower SCVD was associated with worse cognitive performance (prospective memory and sustained attention). Compared with controls, female MDD patients showed reduced FCD and FC of the left middle frontal gyrus, which were related to lower SCVD. Importantly, these FCD and FC changes mediated the relationship between lower SCVD and cognitive dysfunction. Our findings suggest that functional connectivity abnormalities may serve as neural substrates underlying the associations between low vitamin D and cognitive impairments in female MDD patients, providing unique insight into treatment and prevention of MDD and its related cognitive dysfunction from the perspective of regulating circulating vitamin D.

Allostasis, Action, and Affect in Depression: Insights from the Theory of Constructed Emotion.

The theory of constructed emotion is a systems neuroscience approach to understanding the nature of emotion. It is also a general theoretical framework to guide hypothesis generation for how actions and experiences are constructed as the brain continually anticipates metabolic needs and attempts to meet those needs before they arise (termed allostasis). In this review, we introduce this framework and hypothesize that allostatic dysregulation is a trans-disorder vulnerability for mental and physical illness. We then review published findings consistent with the hypothesis that several symptoms in major depressive disorder (MDD), such as fatigue, distress, context insensitivity, reward insensitivity, and motor retardation, are associated with persistent problems in energy regulation. Our approach transforms the current understanding of MDD as resulting from enhanced emotional reactivity combined with reduced cognitive control and, in doing so, offers novel hypotheses regarding the development, progression, treatment, and prevention of MDD.

The association between midlife living arrangement and psychiatrist-diagnosed depression in later life: who among your family members reduces the risk of depression?

This study investigates the longitudinal association between living arrangements and psychiatrists’ diagnosis of depression in the general population. In 1990, 1254 Japanese men and women aged 40–59 years were enroled and completed questionnaires on the living arrangement in the Japan Public Health Center-based Prospective Study (JPHC Study) and participated in a mental health screening (2014–2015). The study diagnosed a major depressive disorder (MDD) assessed by well-trained certified psychiatrists through medical examinations. During the follow-up, a total of 105 participants (36 men and 69 women) aged 64–84 years were diagnosed with MDD by psychiatrists. Living with a child (ren) was associated with a reduced risk of MDD for men but not for women; the respective multivariable ORs (95% CIs) were 0.42 (0.19–0.96) and 0.59 (0.32–1.09). These associations remained unchanged after adjusting for living with spouse and parent(s). In conclusion, living with a child (ren) was associated with a reduced risk of MDD in men, suggesting the role of a child (ren) in the prevention of MDD.

Clinical laboratory tests and five-year incidence of major depressive disorder: a prospective cohort study of 433,890 participants from the UK Biobank

Prevention of major depressive disorder (MDD) is a public health priority. Identifying biomarkers of underlying biological processes that contribute to MDD onset may help address this public health need. This prospective cohort study encompassed 383,131 white British participants from the UK Biobank with no prior history of MDD, with replication in 50,759 participants of other ancestries. Leveraging linked inpatient and primary care records, we computed adjusted odds ratios for 5-year MDD incidence among individuals with values below or above the 95% confidence interval (<2.5th or >97.5th percentile) on each of 57 laboratory measures. Sensitivity analyses were performed across multiple percentile thresholds and in comparison to established reference ranges. We found that indicators of liver dysfunction were associated with increased 5-year MDD incidence (even after correction for alcohol use and body mass index): elevated alanine aminotransferase (AOR = 1.35, 95% confidence interval [1.16, 1.58]), aspartate aminotransferase (AOR = 1.39 [1.19, 1.62]), and gamma glutamyltransferase (AOR = 1.52 [1.31, 1.76]) as well as low albumin (AOR = 1.28 [1.09, 1.50]). Similar observations were made with respect to endocrine dysregulation, specifically low insulin-like growth factor 1 (AOR = 1.34 [1.16, 1.55]), low testosterone among males (AOR = 1.60 [1.27, 2.00]), and elevated glycated hemoglobin (HbA1C; AOR = 1.23 [1.05, 1.43]). Markers of renal impairment (i.e. elevated cystatin C, phosphate, and urea) and indicators of anemia and macrocytosis (i.e. red blood cell enlargement) were also associated with MDD incidence. While some immune markers, like elevated white blood cell and neutrophil count, were associated with MDD (AOR = 1.23 [1.07, 1.42]), others, like elevated C-reactive protein, were not (AOR = 1.04 [0.89, 1.22]). The 30 significant associations validated as a group in the multi-ancestry replication cohort (Wilcoxon p = 0.0005), with a median AOR of 1.235. Importantly, all 30 significant associations with extreme laboratory test results were directionally consistent with an increased MDD risk. In sum, markers of liver and kidney dysfunction, growth hormone and testosterone deficiency, innate immunity, anemia, macrocytosis, and insulin resistance were associated with MDD incidence in a large community-based cohort. Our results support a contributory role of diverse biological processes to MDD onset.

The Depression Sensitivity Index: Initial Development and Tests of Convergent and Construct Validity

Background: Depression and suicide are prominent and increasing U.S. public health issues, which suggests novel assessment and treatment approaches are needed. Reiss’ Expectancy Model of Fear, Anxiety, and Panic states that fear is based on two classes of variables, expectations and sensitivities, which has led to much research on anxiety sensitivity as a significant risk factor for later anxiety psychopathology. Major depressive disorder also includes biased expectations and sensitivities; however, a depression sensitivity rooted in Expectancy Theory has never been formalized. Uncovering depression-related sensitivities may lead to earlier risk detection and prevention before mood disorders develop. Method: The goal of the paper was to create a Depression Sensitivity Index using exploratory factor analysis and item response theory and then conduct tests of convergent and construct validity using structural equation modeling using three independent samples. Results: indicated two lower order factors: 1) physical and cognitive concerns (DSPCC) and 2) social concerns (DSSC). Factors showed incremental associations with depression (DSPCC), social anxiety (both) and suicidal thoughts and behaviors (DSPCC), above and beyond anxiety sensitivity cognitive concerns. Both factors together predicted depressive disorder diagnoses Limitations: Mostly self-report data, large percentage of non-Hispanic White participants in Study 1. Conclusions: The results offer initial evidence that expectancy theory applies beyond “fear, anxiety, and panic” and that with further development depression sensitivity could be an important intervention target for prevention of major depressive disorder and suicidal thoughts and behaviors.

Effect of Multinutrient Supplementation and Food-Related Behavioral Activation Therapy on Prevention of Major Depressive Disorder Among Overweight or Obese Adults With Subsyndromal Depressive Symptoms

Effects of nutritional interventions on the prevention of major depressive disorder (MDD) in overweight adults are unknown. To examine the effect of 2 nutritional strategies (multinutrient supplementation, food-related behavioral activation therapy) and their combination for prevention of a new MDD episode in overweight adults with subsyndromal depressive symptoms. This multicenter 2 × 2 factorial randomized clinical trial included overweight adults (body mass index, 25-40) with elevated depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] scores ≥5) and no MDD episode in the past 6 months from 4 European countries. A total of 1025 adults were randomized (July 30, 2015-October 12, 2016) and followed up for 1 year (October 13, 2017). Daily multinutrient supplements (1412-mg omega-3 fatty acids, 30-μg selenium, 400-μg folic acid, and 20-μg vitamin D3 plus 100-mg calcium) vs placebo and 21 individual or group therapy sessions vs none (blinded to researchers) for 1 year. Participants were allocated to placebo without therapy (n = 257), placebo with therapy (n = 256), supplements without therapy (n = 256), and supplements with therapy (n = 256). Cumulative 1-year onset of MDD via the Mini International Neuropsychiatric Interview at 3, 6, and 12 months. Logistic regression using effect-coded variables (-1 indicating control, 1 indicating intervention) evaluated intervention effects both individually and in combination (interaction) on MDD onset. Among 1025 participants (mean age, 46.5 years; 772 women [75%]; mean BMI, 31.4), 779 (76%) completed the trial. During the 12-month follow-up, 105 (10%) developed MDD: 25 (9.7%) patients in the placebo without therapy, 26 (10.2%) in the placebo with therapy, 32 (12.5%) in the supplement without therapy, and 22 (8.6%) in the supplement with therapy group. None of the treatment strategies affected MDD onset. The odds ratio (OR) for supplements was 1.06 (95% CI, 0.87-1.29); for therapy, 0.93 (95% CI, 0.76-1.13); and for their combination, 0.93 (95% CI, 0.76-1.14; P for interaction, .48). One person in the supplementation with therapy group, died. Twenty-four patients in each of the placebo groups and 24 patients in the supplementation with therapy group were hospitalized, and 26 patients in the supplementation-only group were hospitalized. Among overweight or obese adults with subsyndromal depressive symptoms, multinutrient supplementation compared with placebo and food-related behavioral activation therapy compared with no therapy did not reduce episodes of major depressive disorder during 1 year. These findings do not support the use of these interventions for prevention of major depressive disorder. ClinicalTrials.gov Identifier: NCT02529423.

Efficacy and moderators of psychological interventions in treating subclinical symptoms of depression and preventing major depressive disorder onsets: protocol for an individual patient data meta-analysis of randomised controlled trials

IntroductionThe long-term effectiveness of psychological interventions for the treatment of subthreshold depression and the prevention of depression is unclear and effects vary among subgroups of patients, indicating that not all...

The potential of transcranial photobiomodulation therapy for treatment of major depressive disorder.

Major depressive disorder is a common debilitating mood disorder that affects quality of life. Prefrontal cortex abnormalities, an imbalance in neurotransmitters, neuroinflammation, and mitochondrial dysfunction are the major factors in the etiology of major depressive disorder. Despite the efficacy of pharmacotherapy in the treatment of major depressive disorder, 30%-40% of patients do not respond to antidepressants. Given this, exploring the alternative therapies for treatment or prevention of major depressive disorder has aroused interest among scientists. Transcranial photobiomodulation therapy is the use of low-power lasers and light-emitting diodes in the far-red to near-infrared optical region for stimulation of neuronal activities. This non-invasive modality improves the metabolic capacity of neurons due to more oxygen consumption and ATP production. Beneficial effects of transcranial photobiomodulation therapy in the wide range of neurological and psychological disorders have been already shown. In this review, we focus on some issue relating to the application of photobiomodulation therapy for major depressive disorder. There is some evidence that transcranial photobiomodulation therapy using near-infrared light on 10-Hz pulsed mode appears to be a hopeful technique for treatment of major depressive disorder. However, further studies are necessary to find the safety of this method and to determine its effective treatment protocol.

The long-term outcome of subthreshold depression in later life.

Subthreshold depression (SUBD) in later life is common and important as prodromal state and prominent risk factor in the development of major depressive disorder (MDD). Indicated prevention can reduce the incidence of MDD among people with SUBD substantially, but needs to be targeted to those that are truly at risk of developing MDD. N = 341 eligible participants with SUBD were included from the first (1992/1993), second (1995/1996) and third (1998/1999) cycle from the Longitudinal Aging Study Amsterdam (LASA) by using a two-stage screening design. LASA is an ongoing prospective cohort study in The Netherlands among the older population (55-85 years). At baseline (1992/1993) N = 3107 participants were interviewed and follow-up cycles were conducted every 3 years until 2008/2009, resulting in maximal 17 years of observational period. The proportion of people that developed MDD, remained SUBD, or recovered from SUBD was measured and Cox proportional regression analyses were performed to investigate 29 putative predictors of MDD and recovery from SUBD. N = 153 (44.9%) recovered from SUBD, N = 138 (40.5%) remained chronically SUBD, and N = 50 (14.7%) developed MDD (incidence rate 15.1/1000 person-years). Women, high neuroticism, more chronic diseases, high body mass index, smoking and less social support predicted conversion to MDD. Men, low neuroticism and absence of pain predicted recovery from SUBD. Although older people with SUBD are clearly at risk of developing MDD, the majority did not, even after a long and thorough follow-up. Given the risk factors that were uncovered, targeting and prevention of MDD in those at very high risk is feasible.

Coaching in Healthy Dietary Practices in At-Risk Older Adults: A Case of Indicated Depression Prevention

Prevention of major depressive disorder is important because current treatments are only partially adequate in reducing symptom burden and promoting health-related quality of life. Lifestyle interventions may be a desirable prevention strategy for reasons of patient preference, particularly among older patients from minority groups. Using evidence from a randomized depression prevention trial for older adults, the authors found that coaching in healthy dietary practices was potentially effective in protecting at-risk older adults from developing incident episodes of major depression. The authors describe the dietary coaching program (highlighted in a case example) as well as the feasibility and potential efficacy of the program within the context of evidence-based interventions for preventing episodes of major depression and mitigating symptoms of depression. Older adults receiving dietary coaching experienced a low incidence of major depressive episodes and exhibited a 40%-50% decrease in depressive symptoms, as well as enhanced well-being, during the initial 6-week intervention; these gains were sustained over 2 years. The authors also describe why lifestyle interventions like coaching in healthy dietary practices may hold promise as effective, practical, nonstigmatizing interventions for preventing episodes of major depressive disorder in older adults with subsyndromal depressive symptoms.

The patient perspective in research on major depression

Although thousands of studies have examined the genetics, epidemiology, etiology, biology, treatment and prevention of major depressive disorder, we still lack very basic knowledge about what patients with depressive disorders need. Despite the thousands of studies that have been conducted on major depression and the hundreds of randomized trials that have examined the effects of treatments, many patients still do not know how to cope with the daily problems caused by depressive disorders. In this Commentary the need for more research on the perspectives of patients is described. This research should guide treatment studies as well as basic research much more than it currently does. This perpective is especially important to understand and solve the undertreatment of depression, one of the major problems in this area. Up to 50% of depressed patients do not seek treatment, resulting in huge avoidable disease burden and economic costs. In order to solve this problem we need a better understanding of the problems patients encounter in daily life, and what factors contribute to the reasons for seeking treatment or not. Research from the patients' perspective is also necessary to meet the currently unmet information needs of patients, including information about the nature and causes of depression, stigma, medication, treatment and coping with the daily problems of having depression.

PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology. Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophic factors, and circadian rhythms. Because all theories of depression apply to only some types of depressed patients but not others, and because depressive pathophysiology may vary considerably across the course of illness, the current extant knowledge argues against a unified hypothesis of depression. As a consequence, antidepressant treatments, including psychological and biological approaches, should be tailored for individual patients and disease states. Individual depression hypotheses based on neurobiological knowledge are discussed in terms of their interest to both clinicians in daily practice and clinical researchers developing novel therapies.

Translating progress in depression research to the clinic: one step at a time on a very long road

In his article, G. Hasler reviews the strengths and limitations of major theories regarding the neurobiology of depression. A fundamental premise on which the paper is based, which certainly appears warranted by the extant data, is that a unified model is unlikely to explain the variable results across studies of depression or the variable responses to treatments characterized by disparate receptor pharmacologies among patients with mood disorders. Instead, Hasler argues, each prevailing theory of depression likely applies only to mood disordered subtypes. Consequently, antidepressant treatments, including psychological and biological approaches, will continue to require tailoring to individual patients. Hasler provides examples of how several major models of depression’s pathophysiology have guided researchers to develop novel therapeutics for individuals suffering from major depressive disorder. Thus, research involving hypothalamic-pituitary-adrenal axis function, monoaminergic neurotransmitter function, and glutamatergic transmission recently led to reports that corticotropin releasing hormone antagonists, dopamine receptor agonists, and NMDA receptor antagonists/glutamate release inhibitors, respectively, exert antidepressant effects 1,2. In addition, neuroimaging findings implicating the neural circuits involving projections between the subgenual anterior cingulate cortex, amygdala, ventral striatum and medial thalamus have guided the development of deep brain stimulation therapies for treatment of refractory depression 3,4,5,6. As Hasler indicates, the results of genetic association studies suggest that most cases of major depressive disorder are associated with some combination of numerous variants that individually exert small effects, which interact together with environmental influences to confer vulnerability to affective disease. Thus, each pedigree in which depression is overrepresented may be unique with respect to the combination of single nucleotide polymorphisms and/or copy number variants that interact to increase vulnerability to depression. This observation highlights the importance of research aimed at identifying the neural circuits or systems where dysfunction arising via diverse etiologies can give rise to affective disease. Hasler concludes from these results that “the clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of major depressive disorder”. Nevertheless, the paper later reviews evidence that loss-of-function mutations in genes causing major functional effects may account for some cases of major depressive disorder, such as variation in the gene coding for the brain-specific enzyme tryptophan hydroxylase-2 that impairs serotonin synthesis 7. Such findings raise the possibility that genetic variants of large effect on risk for the disorder will be discovered that hold implications for pharmacotherapy which collectively will justify genetic testing in the management of depression. Another theme within the paper which conveys optimism that psychiatric morbidity can be reduced is Hasler’s conclusion that the large proportion of major depressive disorder cases for whom pathogenesis involves gene-environment interactions implies that “huge potential [exists] in the prevention of major depressive disorder by means of psychosocial interventions”. Within this context, Hasler reviews evidence that psychosocial approaches ultimately will prove most effective in preventing and treating major depressive disorder if they are gender-sensitive. This theme was highlighted by evidence that neuroendocrine responses to stress are sex-specific and that life events that increase vulnerability to depression differ between men and women. An integration of the data reviewed in Hasler’s manuscript illustrates how several seemingly unrelated pathological constructs may link together through interactions across brain systems to underlie the neurobiological bases of depression. Thus, accumulating evidence that increased pro-inflammatory cytokine expression plays a role in the pathophysiology of mood disorders also suggests mechanistic links to the abnormalities in stress-responsive neuroendocrine and monoaminergic neurotransmitter systems found in these disorders 8. This pathological construct also may confer susceptibility to the neuroplasticity effects evidenced by reductions in gray matter volume in neuroimaging studies and in glial cells and neuropil in neuropathological studies of mood disorders 4,9,10. The interactions across these systems are likely to illuminate the mechanisms underlying the medical comorbidities associated with depression, and elucidate targets for novel therapeutic interventions.

Behavioral activation treatment for major depressive disorder: A pilot investigation.

Abstract Behavioral activation (BA) has emerged as an effective intervention for major depressive disorder. Previous research has indicated that it is as effective as the full cognitive treatment package (CBT). Conceptualized to consume fewer participant sessions, BA may be more efficient and cost-effective than CBT. With depression among the most common diagnoses in practice settings, NIMH's recent vision statement calls for continued research devoted to cost- and time-effective targeted treatment alternatives, including behavioral activation as a more simply form of CBT (NIMH, 2005, p. 92). The present investigation piloted a 10-week individual intervention model of BA with medicated and unmedicated participants in a clinical research setting. This follows our earlier report (Porter, Spates, & Smitham, 2004) of an efficacious group-administered BA intervention. In comparison to the group intervention, end state functioning of participants in the present investigation revealed more robust symptom reductions to within the fully recovered range of functioning. Keywords: depression, activation, behavior therapy, cognitive therapy. ********** Major depressive disorder (MDD) is the most prevalent psychological disorder (Kimerling, Ouimette, Cronkite, & Moos, 1999) and is now the 4th leading cause of disability across the lifespan and the 2nd leading cause of disability among people aged 15-44 (World Health Organization, 2005). According to a National Comorbidity Survey Replication (NCS-R) the lifetime prevalence rate of MDD is 16% (Kessler et al., 2003). The prevalence of MDD is expected to rise such that by the year 2020, MDD will be second only to heart disease in terms of global burden of disease (World Health Organization, 2005). Although high, prevalence rates may be underestimated given that only about 70% of individuals with depression seek treatment (Angst, 1998). The effective treatment and prevention of MDD are of paramount importance and rank high among both mental health research and clinical objectives. A number of psychological interventions have been identified as holding at least partial efficacy towards this end. Among them are cognitive behavior therapy (CBT), cognitive therapy (CT), behavior therapy (BT), and interpersonal therapy (IT). Both and cognitive theories of depression are supported with substantial clinical and empirical evidence (Beck, Rush, Shaw, & Emery, 1979; Dobson, 1989; McLean, Ogston, & Grauer, 1973; Steinbrueck, Maxwell, & Howard, 1983), and distinct treatment modalities have emerged from each perspective. A conceptualization of depression first emerged in the 1970s, and suggested that depression is a result of a reduction in positively reinforcing behavior either via reduced availability of reinforcing alternatives, lack of skill to obtain reinforcing alternatives, or increased punishment (Lewinsohn, 1974). The treatment emanating from behavior theory is referred to as activation (BA). In BA, restoring an adequate schedule of reinforcement by having the patient increase activity levels is instrumental in decreasing depressive symptoms (Lewinsohn, Biglan, & Zeiss, 1976). BA has been reconceptualized since its original introduction. According to Martell and colleagues (Martell, Addis, & Jacobson, 2001), BA no longer aims to replenish a broad class of positive reinforcing activities but rather to replenish positive reinforcing activities that specifically move the patient toward personal goals while blocking avoidance patterns that prevent the patient from reaching those goals. The approach is both functional analytic and idiographic, in which contingencies that maintain behavior for each patient are identified via self-monitoring. Avoidance patterns are changed by integrating new behaviors into a daily routine, observing the outcome, and assessing whether the behavior serves to approach or avoid personal goals. …