Depression development: From lifestyle changes to motivational deficits.

Until now, depression research has taken a surprisingly narrow approach to modelling the disease, mainly focusing on some form of psychomotor retardation within a mechanistic framework of depression etiology. However, depression has many symptoms and each is associated with a vast number of substrates. Thus, to deepen our insights, this SI ("Depression Symptoms") reviewed the behavioral and neurobiological sequelae of individual symptoms, specifically, psychomotor retardation, sadness, low motivation, fatigue, sleep/circadian disruption, weight/appetite changes, and cognitive affective biases. This manuscript aims to integrate the most central information provided by the individual reviews. As a result, a dynamic model of depression development is proposed, which views depression as a cumulative process, where different symptoms develop at different stages, referred to as early, intermediate, and advanced, that require treatment with different pharmaceutical agents, that is, selective serotonin reuptake inhibitors early on and dopamine-based antidepressants at the advanced stage. Furthermore, the model views hypothalamic disruption as the source of early symptoms and site of early intervention. Longitudinal animal models that are capable of modelling the different stages of depression, including transitions between the stages, may be helpful to uncover novel biomarkers and treatment approaches.

Trial of SAGE-217 in Patients with Major Depressive Disorder.

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).

Brain activity in patients with deficiency versus excess patterns of major depression: A task fMRI study.

OBJECTIVE: Patients with major depressive disorder (MDD) may experience a series of emotional and mental problems accompanied by characteristic clinical symptoms. Depressive patients often have emotional recognition disorders, but the reasons remain unclear. Though a great many functional abnormalities have been observed in the brains of depressed patients, such abnormalities are not often related to clinical symptoms. Currently in Traditional Chinese Medicine (TCM), syndrome differentiation for the MDD mainly consists of excess pattern (EP), and deficiency pattern (DP). EP and DP emphasize balance-regulation thought processes, and are widely used in diagnosis of diseases including depression, anxiety, insomnia, and other emotional disorders. We hope that syndrome differentiation in TCM can combine clinical symptoms and brain function more effectively. The present study investigated altered patterns and different association of brain activation in MDD patients with EP and DP during a facial emotion discrimination task with fMRI. METHODS: A total of 45 patients (20 with EP and 25 with DP) and 18 normal controls participated in this study. Whole-brain functional scans were collected for each subject. Different patterns of brain activation and association during the facial emotion discrimination task were analyzed statistically. RESULTS: Comparing all the MDD patients with the normal controls, there were no significant differences for sad vs. neutral condition or for happy vs. neutral condition (corrected p > 0.05). One-way ANCOVA showed significant differences in the left inferior frontal gyrus, the left insula, and the left caudate for sad vs. neutral condition across the DP, EP and NC groups (corrected p < 0.05). The whole brain activation comparison for sad vs. neutral condition between the EP MDD subtype and the DP MDD subtype further verified these differences in the left insula and left inferior frontal gyrus, discovering that these regions showed increased activation in EP MDD subtype compared with the DP MDD subtype (corrected p < 0.05). There were no significant differences in brain activation between each MDD subtype and the normal controls. CONCLUSION: Disparities in sad face processing exist between MDD patients with different TCM syndrome types, suggesting that TCM syndrome differentiation may provide a biological basis for negativity bias in depression, and may determine both symptom formation and social dysfunction.

The power of belief and expectancy in understanding and management of depression.

This article examines how beliefs can influence the definition, classification, understanding, and treatment of depression. It is organized in five parts: The first part critically reviews the definition of depression; the second part explores the medicalization of depression; the third part examines the role of the pharmaceutical industry in the promotion and marketing of antidepressant medications; the fourth part surveys the psychological therapies for depression and examines the role of expectancy in outcome; and the last part looks at the mechanisms involved in the placebo effect. A list of evidence-based strategies, including hypnosis, are discussed in the context of cognitive hypnotherapy for depression to illustrate how expectancy effect can be maximized in psychotherapy.

Depression and anxiety.

Depression and anxiety are the most common psychiatric conditions in late life. Despite their prevalence, we know relatively little about their unique manifestation in older adults. And, Although the most common intervention for late-life depression and anxiety continues to be medication, research on psychosocial interventions for late-life depression and anxiety has burgeoned in the past several years. Unfortunately, this growing body of intervention research has yet to be widely translated into improved systems of care for late-life depression. This article is one step toward synthesizing the knowledge in this growing area of research. The review of literature presents the conclusions of several meta-analyses that have reviewed psychosocial interventions for late-life depression and anxiety. In addition, intervention studies concerning the effectiveness of cognitive behavioral therapy, interpersonal therapy, reminiscence therapy, and alternative therapies with depressed and/or anxious older adults are reviewed. A brief description of various approaches to psychosocial intervention with anxious and/or depressed older adults is also presented.

A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders.

The Kraepelinian classification of psychiatric disorders, in particular the dichotomy of dementia praecox and manic-depressive psychosis is under discussion since a long time. In recent years, not only new research in the fields of psychopathology and clinical outcome, but also findings of biological markers in the areas of neurophysiology, neuroendocrinology, psychoneuroimmunology, genetics, or psychopharmacology show a big overlap between both groups of disorders. This overlap of symptoms and markers of both disorders intensified the discussion and the proposals for new criteria for the classification of psychiatric disorders. By means of findings from the field of psychoneuroimmunology and inflammation it will be shown that different pathological mechanisms in depression and schizophrenia may lead to the same final common pathway of inflammation. These mechanisms include the immunological balance between type-1 and type-2 immune activation which influences the tryptophan-degradating enzyme indoleamine 2,3-dioxygenase (IDO) in the CNS in opposite ways, leading to an altered availability of tryptophan and serotonin, and a disturbance of the kynurenine metabolism with an imbalance in favor of the production of the NMDA-receptor agonist quinolinic acid in depression and of the NMDA-receptor antagonist kynurenic acid in schizophrenia. In both disorders, however, an increased production of prostaglandin E2 and increased expression of cyclo-oxygenase-2 reflect a slight inflammatory process taking place probably in different regions of the CNS. Albeit this common inflammatory pathway--inflammation is a general pathway of the body as answer to a lot of different noxae and pathogens--the Kraepelinian dichotomy is important with respect to pathological mechanisms and therapeutic approaches, not only for further research in understanding the exact pathological mechanisms but also for the development of preventive strategies in high risk individuals and in patients. Opposite pathways regarding the immune activation, the neurotoxic versus neuroprotective kynurenine metabolites and the agonistic versus antagonistic effects on the NMDA receptor and the glutamatergic neurotransmission show despite a possible therapeutic advantage of anti-inflammatory therapy in both disorders that the Kraepelinian dichotomy still has a significant value from a biologic-psychiatric point of view.

Acupuncture for depression: a randomized controlled trial.

OBJECTIVE: To assess the efficacy of acupuncture as an intervention for major depressive disorder (MDD). METHOD: Acupuncture was examined in 151 patients with MDD (DSM-IV) who were randomly assigned to 1 of 3 groups in a double-blind randomized controlled trial. The specific intervention involved Traditional Chinese Medicine (TCM)-style acupuncture with manual stimulation for depression; the control conditions consisted of (1) a nonspecific intervention using a comparable number of legitimate acupuncture points not specifically targeted to depressive symptoms and (2) a waitlist condition, which involved waiting without intervention for 8 weeks. After 8 weeks, all patients received the depression-specific acupuncture. Each 8-week intervention regimen consisted of 12 acupuncture sessions delivered in an acupuncturist's office in the community. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression. The study was conducted from February 1998 to April 2002. RESULTS: Twenty patients terminated treatment before the completion of the 8-week intervention (13%) but not differentially by study group. Random regression models of the intent-to-treat sample revealed that although patients receiving acupuncture improved more than those awaiting intervention, no evidence of differential efficacy of the depression-specific over nonspecific intervention was found. Response rates in acupuncture-treated patients were relatively low after 8 weeks (22% and 39% for specific and nonspecific intervention groups, respectively), with the response rate after the entire 16-week trial reaching 50%. CONCLUSION: Although TCM manual acupuncture is a well-tolerated intervention, results fail to support its efficacy as a monotherapy for MDD. It can't be ruled out that factors unique to the implementation of acupuncture in this research study may have limited the efficacy of interventions compared to those provided in naturalistic settings. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00010517.

A pharmacoeconomic evaluation of escitalopram versus citalopram in the treatment of severe depression in the United Kingdom.

BACKGROUND: Severe depression can increase the risk of psychiatric hospitalization, as well as inpatient and outpatient care; it may also lead to long-term absenteeism from work. However, the cost-effectiveness of antidepressant therapy for severe depression has been little studied. OBJECTIVE: The aim of this work was to investigate the cost-effectiveness of escitalopram compared with citalopram in patients with severe depression (Montgomery-Asberg Depression Rating Scale [MADRS] total score > or = 30) in the United Kingdom. METHODS: A probabilistic decision tree with a 6-month time horizon was adapted to the UK setting. The model incorporated clinical data, resource use directly related with care of severe depression, and lost productivity costs due to absenteeism. Primary results were remission (MADRS < or = 12) and costs (in year-2003 British pounds [1.00 British pound = 0.62 US dollars in January 2003]) of treatment calculated from the perspectives of UK society and the National Health Service (NHS). Secondary outcome was first-line success of treatment (ie, remission [MADRS < or = 12] without switch of drug). Remission, discontinuation, and response rates were derived from a meta-analysis of 506 patients with severe depression and extrapolated to 6 months. Standard UK price lists and literature were used to identify costs of resources. Societal costs of lost productivity were calculated using the human capital approach. RESULTS: Treatment of patients with escitalopram instead of citalopram rendered a higher overall remission rate (relative difference, 10.3%) and first-line success rate (relative difference, 35.4%). The mean cost per successfully treated patient was 15.7% (146 British pounds) lower for escitalopram (786 British pounds [range, 702-876 British pounds]) compared with citalopram (932 British pounds [range, 843-1028 British pounds]) from the NHS perspective and 15.6% (238 British pounds) lower for escitalopram (1283 British pounds [range, 1157-1419 British pounds]) than for citalopram (1521 British pounds [range, 1383-1675 British pounds]) from the societal perspective. The mean cost per severely depressed patient treated (overall study group) was 32 British pounds lower for escitalopram (422 British pounds [range, 404-441 British pounds]) than citalopram (454 British pounds [range, 436-471 British pounds]) from an NHS perspective and 50 British pounds lower for escitalopram (690 British pounds [range, 665-714 British pounds]) than citalopram (740 British pounds [range, 715-767 British pounds]) from the societal perspective. Using multivariate sensitivity analyses, we found that, in 99.8% of the cases, escitalopram was dominant from both perspectives at all ranges of probabilities tested. A sensitivity analysis on the acquisition cost of citalopram verified that, from the societal perspective, escitalopram remained the dominant strategy, even at a cost of 0.00 British pounds for citalopram. CONCLUSIONS: These results suggest that escitalopram is a cost-saving alternative to citalopram for the treatment of severe depression in the United Kingdom from the perspectives of both the NHS and society. Therefore, a possible advantage may exist at the population level in the treatment of severe depression with escitalopram in the United Kingdom.