Core symptoms of major depressive disorder: relevance to diagnosis and treatment

The construct of major depressive disorder makes no etiological assumptions about populations with diverse symptom clusters. "Depressed mood" and "loss of interest or pleasure in nearly all activities" are core features of major depressive episode, though a strong case can be made to pay increasing attention to symptoms of fatigue, sleep disturbance, anxiety, and neurocognitive and sexual dysfunction in the diagnosis and evaluation of treatment outcome. Mood, guilt, work, and interest, as well as psychic anxiety, are consistently identified across validated subscales of the Hamilton Depression Rating Scale as prevalent and sensitive to change with existing treatments. A major limitation of these antidepressant therapies is their narrow spectrum of action. While the core "mood and interest" symptoms have been the main focus of attention, the associated symptoms listed above are often unaffected or exacerbated by current treatments. Careful clinical evaluation should address all of these dimensions, recognizing that improvement may occur sooner in some symptoms (eg, mood) compared with others (eg, sleep disturbance).     

Incorporation of molecular data and redefinition of phenotype: new approaches to genetic epidemiology of bipolar manic depressive illness and schizophrenia

Considerable advances have been made in identifying specific genetic components of bipolar manic depressive illness (BP) and schizophrenia (SZ), despite their complex inheritance. Meta-analysis of all published whole-genome linkage scans reveals overall support for illness genes in several chromosomal regions. In two of these regions, on the lonq arm of chromosome 13 and on the long arm of chromosome 22, the combined studies of BP and SZ are consistent with a common susceptibility locus for the two disorders. This lends some plausibility to the hypothesis of some shared genetic predispositions for BP and SZ. Other linkages are supported by multiple studies of specific chromosomal regions, most notably two regions on chromosome 6 in SZ. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BP and SZ. Endophenotypes of SZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to the short arm of chromosome 6, and abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to illness, and other genes have been associated with susceptibility to side effects of pharmacological treatment. These genetic findings may eventually be part of an integrated genetic, environmental, and interactive-factor epidemiology of the major mental illnesses.     

Neuroimaging-based biomarkers for treatment selection in major depressive disorder

The use of neuroimaging approaches to identify likely treatment outcomes in patients with major depressive disorder is developing rapidly. Emerging work suggests that resting state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy or medication and may function as a treatment-selection biomarker. In contrast, high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes to both medication and psychotherapy, suggesting that nonstandard treatments may be pursued earlier in the treatment course. Although these findings will require replication before clinical adoption, they provide preliminary support for the concept that brain states can be measured and applied to the selection of a specific treatment most likely to be beneficial for an individual patient.     

New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum

Maternal perinatal mental health has enormous consequences for the well-being of the mother, her baby, and the family. Although it is well documented that perinatal depression is both common and morbid, with a prevalence of 10% to 15% in the general population, there remain many critically important unanswered questions about the pathogenesis of perinatal depression and most effective treatment regimens. Current lines of evidence from both human and animal models implicate hormonal dysregulation, abnormalities in hypothalamic-pituitary-adrenal axis activity, and the contributions of genetics and epigenetics as playing key roles in the development of perinatal reproductive mood disorders. Investigations into both human and animal models of perinatal depression offer much promise for the future identification of the underlying pathophysiology and subsequent early identification and/or prevention and appropriate treatment for women at risk for postpartum depression. Lastly, although it is generally accepted that pregnancy is not protective with regard to new onset or relapse of depression, the way to best treat maternal depression during pregnancy and lactation remains hotly debated. Future research in this area will more clearly elucidate the underlying pathogenesis, the potential long-term impact of perinatal depression on the developing fetus, and how best to counsel pregnant women about the risks of untreated major depressive disorder versus the risks of psychopharmacologic treatment during pregnancy and lactation.     

Epidemiology and treatment of depression in patients with chronic medical illness

There is a bidirectional relationship between depression and chronic medical disorders. The adverse health risk behaviors and psychobiological changes associated with depression increase the risk for chronic medical disorders, and biological changes and complications associated with chronic medical disorders may precipitate depressive episodes. Comorbid depression is associated with increased medical symptom burden, functional impairment, medical costs, poor adherence to self-care regimens, and increased risk of morbidity and mortality in patients with chronic medical disorders. Depression may worsen the course of medical disorders because of its effect on proinflammatory factors, hypothalamic-pituitary axis, autonomic nervous system, and metabolic factors, in addition to being associated with a higher risk of obesity, sedentary lifestyle, smoking, and poor adherence to medical regimens. Both evidence-based psychotherapies and antidepressant medication are efficacious treatments for depression. Collaborative depression care has been shown to be an effective way to deliver these treatments to large primary care populations with depression and chronic medical illness.     

Predictors,moderators, and mediators (correlates) of treatment outcome in major depressive disorder

Major Depressive Disorder (MDD) is a prevalent illness that is frequently associated with significant disability, morbidity and mortality. Despite the development and availability of numerous treatment options for MDD, studies have shown that antidepressant monotherapy yields only modest rates of response and remission. Clearly, there is an urgent need to develop more effective treatment strategies for patients with MDD, One possible approach towards the development of novel pharmacotherapeuiic strategies for MDD involves identifying subpopulations of depressed patients who are more likely to experience the benefits of a given (existing) treatment versus placebo, or versus a second treatment. Attempts have been made to identify such “subpopulations, ” specifically by testing whether a given biological or clinical marker also serves as a moderator, mediator (correlate), or predictor of clinical improvement following the treatment of MDD with standard, first-line antidepressants. In the following article, we will attempt to summarize the literature focusing on several major areas (“leads”) where preliminary evidence exists regarding clinical and biologic moderators, mediators, and predictors of symptom improvement in MDD, Such clinical leads will include the presence of hopelessness, anxious symptoms, or medical comorbidity. Biologic leads will include gene polymorphisms, brain metabolism, quantitative electroencephalography, loudness dependence of auditory evoked potentials, and functional brain asymmetry     

Epigenetic alterations in depression and antidepressant treatment

Epigenetic modifications control chromatin structure and function, and thus mediate changes in gene expression, ultimately influencing protein levels. Recent research indicates that environmental events can induce epigenetic changes and, by this, contribute to long-term changes in neural circuits and endocrine systems associated with altered risk for stress-related psychiatric disorders such as major depression. In this review, we describe recent approaches investigating epigenetic modifications associated with altered risk for major depression or response to antidepressant drugs, both on the candidate gene levels as well as the genome-wide level. In this review we focus on DNA methylation, as this is the most investigated epigenetic change in depression research.     

Treatment strategies to improve and sustain remission in major depressive disorder

Major depressive disorder (MDD) is an often chronic, recurrent illness affecting large numbers of the general population. In recent years, the goal of treatment for MDD has moved from mere symptomatic response to that of full remission (ie, minimal/no residual symptoms). The recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial stewed that even with systematic measurement-based treatment, approximately one third of patients reach full remission after one treatment trial, with only two thirds reaching remission after four treatment trials. Treatment-resistant depression (TRD) is therefore a common problem in the treatment of MDD, with 60% to 70% of all patients meeting the criteria for TRD, Given the huge burden of major depressive illness, the low rate of full recovery remains suboptimal. The following article reports on some current treatment strategies available to improve rates of, and to sustain, remission in MDD.     

Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression

The discovery that stress and depression, as well as other psychiatric illnesses, are characterized by structural alterations, and that these changes result from atrophy and loss of neurons and glia in specific limbic regions and circuits, has contributed to a fundamental change in our understanding of these illnesses. These structural changes are accompanied by dysregulation of neuroprotective and neurotrophic signaling mechanisms that are required for the maturation, growth, and survival of neurons and glia. Conversely, behavioral and therapeutic interventions can reverse these structural alterations by stimulating neuroprotective and neurotrophic pathways and by blocking the damaging, excitotoxic, and inflammatory effects of stress. Lifetime exposure to cellular and environmental stressors and interactions with genetic factors contribute to individual susceptibility or resilience. This exciting area of research holds promise and potential for further elucidating the pathophysiology of psychiatric illness and for development of novel therapeutic interventions.     

Characteristics,correlates, and outcomes of childhood and adolescent depressive disorders

Depressive illness beginning early in life can have serious developmental and functional consequences. Therefore, understanding the disorder during this developmental stage is critical for determining its etiology and course, as well as for deveiopinq effective intervention straieqies. This paper summarizes current knoviedqe reqardinq the etiology, phenomenoiogy, correlates, natural course, and consequences of unipolar depression in children and adolescents. Using adult depression as a framevork, the unique aspects of childhood and adolescence are considered in order to better understand depression within a developmental context. The data suggest that the clinical presentation, correlates, and natural course of depression are remarkably similar across the lifespan. There are, however, important developmental differences. Specifically, the familial and psychological context in which depression develops in youngsters is associated with variability in the frequency and nature of depressive symptoms and comorbid conditions among children and adolescents. Maturational differences have also been identified in the neurobiological correlates of depression. These developmental differences may be associated with the observed variability in clinical response to treatment and longitudinal course. Characterization of the developmental differences will be helpful in developing more specific and effective interventions for youngsters, thereby allowing them to reach their full potential as adults.     

Diurnal variation of depressive symptoms

Diurnal variation of depressive symptoms appears to be part of the core of depression. Yet, longitudinal investigation of an individual's pattern, regularity, relation to clinical state, and clinical improvement reveals little homogeneity. Morning lows, afternoon slump, evening worsening-all can occur during a single depressive episode. Mood variability, or the propensity to produce mood swings, appears to be the characteristic that most predicts capacity to respond to treatment. Laboratory studies have revealed that mood, like physiological variables such as core body temperature, is regulated by a circadian clock interacting with the sleep homeostat. Many depressed patients, particularly bipolar patients, show delayed sleep phase (late chronotype). Even small shifts in the timing and duration of sleep affect mood state (sleep deprivation and sleep phase advance have an antidepressant effect). The implications for treatment are to stabilize mood state by enhancing synchronization of the sleep-wake cycle with the biological clock (eg, with light therapy).     

Drug discovery and mental illness

Mental disorders are among the most disabling of all diseases. Effective well-documented medications have been available for many decades. Yet, limited understanding of the pathophysiology of mental disorders has impeded the development of novel treatments. Drug discovery must move toward a net* mechanism-based paradigm using the tools of contemporary genetic and molecular medicine. At the same time, this new paradigm must be matched by an equivalent effort to modernize established approaches to clinical trials methodology.     

Role of DNA methylation and the DNA methyltransferases in learning and memory

Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.     

Promising avenues of therapeutics for bipolar illness

Basic scientific advances in understanding the neuropsychobiology of bipolar disorder have given us a multitude of opportunities to explore and exploit new avenues of therapeutics. Pharmacotherapeutic approaches include: neuropeptides (agonists such as thyrotropin-releasing hormone and antagonists such as corticotropin-releasing hormone), neurotrophic factors (especially brain-derived neurotrophic factor), and glutamatergic mechanisms (such as riluzole, ketamine, and antagonists of the NR-2B subunit of the glutamate receptor). Physiological interventions that would offer alternatives to electroconvulsive therapy include: repeated transcranial magnetic stimulation, especially at more intense stimulation parameters; magnetic stimulation therapy (seizures induced more focally by magnetic rather than electrical stimulation with resulting reduced meaning loss); vagal nerve stimulation, and deep brain stimulation. However, these, as well as the panoply of existing treatments, require further intensive investigation to place each of them in the proper therapeutic sequence and combination for the individual patient, based on development of better clinical and biological predictors of response. Large clinical trial networks and development of systematic research in clinical practice settings, such as that featured by the National Cancer Institute for cancer chemotherapy, would greatly accelerate the progress in incorporating new, as well as existing, agents into the best treatment strategies. The bipolar disorders, which are increasingly recognized as complex, highly comorbid conditions with a high morbidity and mortality, of which the majority start in childhood and adolescence, are not likely to respond completely to any single new treatment agent, and new public health initiatives and research strategies are needed as much as any new single treatment advance.     

Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications

Major depressive disorder (MDD) is a major public health concern. Despite tremendous advances, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recent studies demonstrating the involvement of miRNAs in several aspects of neural plasticity, neurogenesis, and stress response, and more direct studies in human postmortem brain provide strong evidence that miRNAs can not only play a critical role in MDD pathogenesis, but can also open up new avenues for the development of therapeutic targets. Circulating miRNAs are now being considered as possible biomarkers in disease pathogenesis and in monitoring therapeutic responses because of the presence and/or release of miRNAs in blood cells as well as in other peripheral tissues. In this review, these aspects are discussed in a comprehensive and critical manner.     

Proteomics,metabolomics, and protein interactomics in the characterization of the molecular features of major depressive disorder

Omics technologies emerged as complementary strategies to genomics in the attempt to understand human illnesses. In general, proteomics technologies emerged earlier than those of metabolomics for major depressive disorder (MDD) research, but both are driven by the identification of proteins and/or metabolites that can delineate a comprehensive characterization of MDD''s molecular mechanisms, as well as lead to the identification of biomarker candidates of all types—prognosis, diagnosis, treatment, and patient stratification. Also, one can explore protein and metabolite interactomes in order to pinpoint additional molecules associated with the disease that had not been picked up initially. Here, results and methodological aspects of MDD research using proteomics, metabolomics, and protein interactomics are reviewed, focusing on human samples.