Treatments in depression

Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.     

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.     

Depression and end-of-life care for patients with cancer

Patients with cancer and depression experience more physical symptoms, have poorer quality of life, and are more likely to have suicidal thoughts or a desire for hastened death than are cancer patients who are not depressed. Despite the ubiquity of depressive symptoms in cancer patients at the end of life, critical questions remain unanswered with respect to etiopathogenesis, diagnosis, and treatment of depression in these vulnerable patients. The pharmacotherapy of depression in patients with advanced cancer should be guided by a palliative care approach focused on symptom reduction, irrespective of whether the patient meets diagnostic criteria for major depression. Earlier and more intensive supportive care for patients with cancer reduces symptom burden and may prolong life for patients with advanced disease. Symptom-oriented clinical trials are needed to improve end-of-life cancer care.     

Inflammation in depression: is adiposity a cause?

Mounting evidence indicates that inflammation may play a significant role in the development of depression. Patients with depression exhibit increased inflammatory markers, and administration of cytokines and other inflammatory stimuli can induce depressive symptoms. Mechanisms by which cytokines access the brain and influence neurotransmitter systems relevant to depression have also been described, as have preliminary findings indicating that antagonizing inflammatory pathways may improve depressive symptoms. One primary source of inflammation in depression appears to be adiposity. Adipose tissue is a rich source of inflammatory factors including adipokines, chemokines, and cytokines, and a bidirectional relationship between adiposity and depression has been revealed. Adiposity is associated with the development of depression, and depression is associated with adiposity, reflecting a potentional vicious cycle between these two conditions which appears to center around inflammation. Treatments targeting this vicious cycle may be especially relevant for the treatment and prevention of depression as well as its multiple comorbid disorders such as cardiovascular disease, diabetes, and cancer, all of which have also been associated with both depression and inflammation.     

Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan

Diagnosis and treatment of comorbid neuropsychiatric illness is often a secondary focus of treatment in individuals with autism spectrum disorder (ASD), given that substantial impairment may be caused by core symptoms of ASD itself. However, psychiatric comorbidities, including depressive disorders, are common and frequently result in additional functional impairment, treatment costs, and burden on caregivers. Clinicians may struggle to appropriately diagnose depression in ASD due to communication deficits, atypical presentation of depression in ASD, and lack of standardized diagnostic tools. Specific risk and resilience factors for depression in ASD across the lifespan, including level of functioning, age, family history, and coping style, have been suggested, but require further study. Treatment with medications or psychotherapy may be beneficial, though more research is required to establish guidelines for management of symptoms. This review will describe typical presentations of depression in individuals with ASD, review current information on the prevalence, assessment, and treatment of comorbid depression in individuals with ASD, and identify important research gaps.     

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.     

Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications

The majority of individuals with depression experience sleep disturbances. Depression is also over-represented among populations with a variety of sleep disorders. Although sleep disturbances are typical features of depression, such symptoms sometimes appear prior to an episode of depression. The bidirectional associations between sleep disturbance (especially insomnia) and depression increase the difficulty of differentiating cause-and-effect relationships between them. Longitudinal studies have consistently identified insomnia as a risk factor for the development of a new-onset or recurrent depression, and this association has been identified in young, middle-aged, and older adults. Studies have also observed that the combination of insomnia and depression influences the trajectory of depression, increasing episode severity and duration as well as relapse rates. Fortunately, recent studies have demonstrated that both pharmacological and nonpharmacological interventions for insomnia may favorably reduce and possibly prevent depression. Together, these findings suggest that sleep-related symptoms that are present before, during, andlor after a depressive episode are potentially modifiable factors that may play an important role in achieving and maintaining depression remission.     

Depression and sleep: pathophysiology and treatment

This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing the physiology and topography of normal sleep, the disturbances revealed in studies of sleep in depression using polysomnographic recordings and neuroimaging assessments are discussed. Next, treatment implications of the disturbances are reviewed at both clinical and neurobiologic levels. Most antidepressant medications suppress rapid eye movement (REM) sleep, although this effect is neither necessary nor sufficient for clinical efficacy. Effects on patients' difficulties initiating and maintaining sleep are more specific to particular types of antidepressants. Ideally, an effective antidepressant will result in normalization of disturbed sleep in concert with resolution of the depressive syndrome, although few interventions actually restore decreased slow-wave sleep. Antidepressants that block central histamine 1 and serotonin 2 tend to have stronger effects on sleep maintenance, but are also prone to elicit complaints of daytime sedation. Adjunctive treatment with sedative hypnotic medications--primarily potent, shorter-acting benzodiazepine and gamma-aminobutyric acid (GABA A)-selective compounds such as zolpidem--are often used to treat associated insomnia more rapidly. Cognitive behavioral therapy and other nonpharmacologic strategies are also helpful.     

Bipolar depression: trial-based insights to guide patient care

For the majority of patients with bipolar disorder, major depressive episodes represent the most debilitating and difficult-to-treat illness dimension. Patients spend significantly more time depressed than manic or hypomanic, and attempt suicide more frequently during this illness phase, yet the availability of treatments remains limited. The discovery of more effective therapeutics for managing depressive episodes is arguably the greatest unmet need in bipolar disorder. This article provides an evidence-based summary of pharmacological treatments for the acute and longitudinal management of bipolar depression. Clinical trial results are reviewed for a diverse array of compounds, inclusive of traditional mood stabilizers (eg, lithium and divalproex), atypical antipsychotics, unimodal antidepressants, and modafinil. Where applicable, differences in efficacy across compounds are examined through discussion of number needed to treat and effect size determinations. A pragmatic clinical approach is presented for management of the depressed phase of bipolar disorder.     

Sadness as an integral part of depression

Sadness is considered by numerous authors to be a core symptom of depression. Currently, many arguments exist for its particular importance in depressed patients. Sadness makes up part of the various definitions of the depressive syndrome, even if its presence is not required for diagnosis. Furthermore, it is closely linked to the other depressive symptoms, and has prognostic value, in particular for remission. The recognition and measurement of sadness seem important for therapeutic evaluation, in clinical studies, and in depressed patients at an individual level. This paper presents a selective review of some of the various aspects of sadness as an integral part of depression, and an examination of its links with a disease which is a major health concern.     

Neuroplasticity in mood disorders

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.     

Towards achieving remission in the treatment of depression

The burden of depressive illness constitutes a major public health issue. Despite real progress and better tolerance of new antidepressant medications, a significant number of depressed patients still suffer from rather severe residual depressive symptoms.This relative lack of efficacy clearly interferes with their psychosocial functioning and their quality of life. In addition, it is now well-recognized that the failure to reach full clinical remission after antidepressant treatment involves a high risk of relapse or recurrence in patients suffering from major depression. This paper reviews the concept of remission across different definitions, and the potential risk factors associated with the failure to reach clinical remission. The identification of specific residual symptoms in nonremitted patients is also of great importance, in order to assess the predictive value of those symptoms in relation to relapse and recurrence. Some methodological issues are also discussed, as well as various therapeutic strategies aimed at relieving residual depressive symptoms. Clinical remission remains a qold standard and a primary objective of modem antidepressant therapy.     

Vascular depression: a new view of late-onset depression

We have suggested that cerebrovascular disease may predispose, precipitate, or perpetuate some late-life depressive syndromes. The mechanisms of "vascular depression" include disruption of cortico-striato-pallido-thalamo-cortical (CSPTC) pathways or their modulating systems. This view is supported by the presentation of vascular depression, which consists of depressive symptoms, cognitive abnormalities, as well as neuroimaging findings that may result from CSPTC impairment. Moreover, clinical and electrophysiological evidence of CSPTC impairment, an abnormality frequently found in patients with vascular depression, appears to be associated with poor response to antidepressant treatment and early relapse and recurrence. The vascular depression hypothesis provides the conceptual background for studies that may have clinical and theoretical impact. Agents influencing dopamine, acetylcholine, and opioid neurotransmitters may be studied in vascular depression, since these are essential neurotransmitters of the frontostriatal circuitry. Drugs used for prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurological recovery from ischemic lesions. Finally, identification of specific relationships between specific symptoms, cognitive deficits, and disability may lead to interventions that target the patients' deficits as well as their interactions with psychosocial factors known to contribute to depression. Research can clarify the pathways to vascular depression by focusing on the site of lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.     

Pathways linking late-life depression to persistent cognitive impairment and dementia

There is a strong association between late-life depression, cognitive impairment, cerebrovascular disease, and poor cognitive outcomes, including progressive dementia, especially Alzheimer's disease. While neuroimaging evidence suggests that cerebrovascular disease plays a prominent role, it seems that depression alone may also confer substantial risk for developing Alzheimer's disease. The relationships between the prominent cerebrovascular changes, other structural abnormalities, specific forms of cognitive dysfunction, and increased risk for developing Alzheimer's disease among those with late-life depression have been difficult to reconcile. The varied findings suggest that there are likely multiple pathways to poor cognitive outcomes. We present a framework outlining multiple, non-mutually exclusive etiologic links between depression, cognitive impairment, and progressive decline, including dementia. Importantly, the model is both testable and falsifiable. Going forward, using models such as this to inform research should accelerate knowledge acquisition on the depression/dementia relationship that may be useful for dementia prevention, monitoring the impact of depression treatment on clinical status and course of illness.     

Depression in late life: psychiatric-medical comorbidity

The links between late-life depression and the medical comorbidities that are often associated with it can be divided into two paths. The path from medical illness to depression reflects general mechanisms related to stress, disability, and loss, as well as more specific physiological mechanisms, including those related to subclinical cerebrovascular disease, adverse drug effects, and endocrine/metabolic effects. Similarly the path from depression to medical illness includes general mechanisms related to self-neglect, decreased adherence to medical treatments, maladaptive health-related behaviors, and, possibly, more specific physiological mechanisms including those related to altered endocrine and autonomic functions, in the clinical context, these two paths can interact to constitute a vicious cycle. With further research, it should be possible to translate current understanding in these areas into advances in both basic knowledge and treatments that could initiate virtuous cycles with beneficial effects for both menial and physical health.     

Depressogenic effects of medications: a review

The literature is filled with reports that link medications with the onset or progression of depression. Because depression is so common in patients with medical illness, assessing whether a medication has in fact caused depression, or whether the relationship is coincidental, can be challenging. In this article, we review the literature on the association between medications and depression. For most agents, there are case reports or small studies linking the medication with the onset of depression, but more rigorous prospective studies are either lacking or found no association between the agent and depression. However, several medications, (eg, barbiturates, vigabatrin, topiramate, flunarizine, corticosteroids, mefloquine, efavirenz, and interferon-alpha) do appear to cause depression in some patients and should be used with caution in patients at risk for depression.     

Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression

The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders.     

Cellular consequences of stress and depression

Stress is known to activate distinct neuronal circuits in the brain and induce multiple changes on the cellular level, including alterations in neuronal structures. On the basis of clinical observations that stress often precipitates a depressive disease, chronic psychosocial stress serves as an experimental model to evaluate the cellular and molecular alterations associated with the consequences of major depression. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neurotransmitters, such as serotonin or noradrenaline, suggesting that imbalances viihin the monoaminergic systems contribute to the disorder (monoaminergic hypothesis of depression). Here, we reviev the results that comprise our understanding of stressful experience on cellular processes, with particular focus on the monoaminergic systems and structural changes within brain target areas of monoaminergic neurons.