Psychosocial determinants of recovery in depression

There is a growing body of literature on residual symptoms after apparently successful treatment The strong prognostic value of subthreshold symptomatology upon remission and the relationship between residual and prodromal symptomatology (the rollback phenomenon) have been outlined. Most residual symptoms also occur in the prodromal phase of depression and may progress to become prodromes of relapse. These findings entail important implications. It is necessary to closely monitor the patient throughout the different phases of illness and to assess the quality and extent of residual symptoms. A more stringent definition of recovery, which is not limited to symptomatic assessment, but includes psychological well-being, seems to be necessary. Wen therapeutic strategies for improving the level of remission, such as treatment of residual symptoms that progress to become prodromes of relapse and/or increasing psychological well-being, appear to yield more lasting benefits. The sequential model may provide room for innovative treatment approaches, including the use of drugs for specifically addressing residual symptoms. As occurs in other medical disorders (such as diabetes and hypertension), the active role of the patient in achieving recovery (self-therapy homework) should be pursued.     

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.     

Various forms of depression

The current subtyping of depression is based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder. Types of depression which have recently been the focus of most research will be reviewed: bipolar II depression, mixed depression, agitated depression, atypical depression, melancholic depression, recurrent brief depression, minor depressive disorder, seasonal depression, and dysthymic disorder. Most research has focused on bipolar II depression, mixed depression (defined by depression and superimposed manic/hypomanic symptoms), and atypical depression. Mixed depression, by its combination of opposite polarity symptoms, has been found to be common by systematic probing for co-occurring manic/hypomanic symptoms. Mixed depression is a treatment challenge for clinicians, because antidepressants alone (ie, not protected by mood-stabilizing agents) may worsen its manic/hypomanic symptoms, such as irritability and psychomotor agitation, which the Food and Drug Administration (FDA) has listed as possible precursors to suicidality.     

Psychosocial interventions and medication adherence in bipolar disorder

Recent research has indicated that psychosocial interventions can have a valuable role in reducing the substantial psychosocial disability associated with bipolar disorder. Randomized controlled trials of these interventions indicate that improvements are seen in symptoms, psychosocial functioning, and treatment adherence. These interventions, systematically presented in the form of standardized treatment manuals, vary in format, duration, and theoretical basis. All are meant to augment pharmacotherapy, which represents the standard of treatment in the field. Modalities that have gathered the most empirical support include cognitive-behavioral therapy, family-focused therapy, interpersonal and social rhythms therapy, and psychoeducation. The enhancement of adherence to pharmacotherapy is a common therapeutic target, due to the association of nonadherence with higher relapse rates, hospitalization, and health care costs among people with bipolar disorder. Given the complexity of nonadherence behavior, multicomponent interventions are often required. In this review, we provide an overview of the rationale, evidence base, and major psychotherapeutic approaches in bipolar disorder, focusing on the assessment and enhancement of medication adherence.     

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.     

Sleep disorders as core symptoms of depression

Links between sleep and depression are strong. About three quarters of depressed patients have insomnia symptoms, and hypersomnia is present in about 40% of young depressed adults and 10% of older patients, with a preponderance in females. The symptoms cause huge distress, have a major impact on quality of life, and are a strong risk factor for suicide. As well as the subjective experience of sleep symptoms, there are well-documented changes in objective sleep architecture in depression. Mechanisms of sleep regulation and how they might be disturbed in depression are discussed. The sleep symptoms are often unresolved by treatment, and confer a greater risk of relapse and recurrence. Epidemiological studies have pointed out that insomnia in nondepressed subjects is a risk factor for later development of depression. There is therefore a need for more successful management of sleep disturbance in depression, in order to improve quality of life in these patients and reduce an important factor in depressive relapse and recurrence.     

Assessment and treatment of mood disorders in the context of substance abuse

Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.     

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).     

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.     

Challenges in the diagnosis and treatment of pediatric bipolar depression

There has been great public and academic interest in the diagnosis and treatment of bipolar disorders (BD) in children and adolescents over the past decade, originally in the US, but now extending internationally. Much of the interest in pediatric BD has focused on the unique manifestation of mania in younger populations. Depression is often overlooked, both as a topic, and as a clinical reality, in these children. While it is becoming clear that adults with BD spend the majority of their symptomatic time in depressive rather than manic episodes, less is known about the pediatric experience of bipolar depression. However, children and adolescents with BD clearly do experience significant depressive symptoms as well as depressive episodes, and therefore early recognition and treatment is necessary. This review addresses what is known about the prevalence, presentation, and treatment of depressive symptoms and episodes in youth with BD, and includes a discussion about the recognition and treatment of bipolar depressive episodes that occur before the first manic episode.     

The pharmacological management of depression

Depressive disorders are common, recurrent, and chronic, and require treatment A review of the symptom picture and current drug targets demonstrates the need for accurate assessment of depression severity, including suicidality. The initial focus of treatment is rapid resolution of symptoms during an acute phase, followed by continuation. Maintenance treatment is indicated if the risk of recurrence is high. The range of available medications is considerable and the benefit/risk ratio is acceptable. Depression is diagnosable across the life span and treatable at every age (although recent disagreement has arisen with regard to young patients). Comorbidity, both psychiatric and medical, need to be assessed, as does the possible presence of two subtypes of depression (psychotic and bipolar) often requiring different interventions. It is expected that the next generation of antidepressants would be associated with more specific disease and outcome biomarkers.     

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.     

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.     

Cytokines, neurophysiology, neuropsychology, and psychiatric symptoms

Recent research has overcome the old paradigms of the brain as an immunologically privileged organ, and of the exclusive role of neurotransmitters and neuropeptides as signal transducers in the central nervous system. Growing evidence suggests that the signal proteins of the immune system - the cytokines - are also involved in modulation of behavior and induction of psychiatric symptoms. This article gives an overview on the nature of cytokines and the proposed mechanisms of immune-to-brain interaction. The role of cytokines in psychiatric symptoms, syndromes, and disorders like sickness behavior, major depression, and schizophrenia are discussed together with recent immunogenetic findings.     

Electroconvulsive therapy and its different indications

In spite of recent developments in the pharmacotherapy of depressive disorders, the delay until clinical improvement can be achieved, and the considerable rate of nonresponse and nonremission, are major problems which remain unresolved. Electroconvulsive therapy (ECT) is a nonpharmacologic biological treatment which has been proven to be a highly effective treatment option, predominantly for depression, but also for schizophrenia and other indications. Though there is a lack of controlled investigations on long-term treatments, ECT can also be used for relapse prevention during maintenance therapies. The safety and tolerability of electroconvulsive treatment have been enhanced by the use of modified stimulation techniques and by progress in modern anesthesia. Thus, today a safe treatment can also be offered to patients with higher somatic risks. ECT still represents an important option, especially in the therapy of treatment-resistant psychiatric disorders after medication treatment failures. Earlier consideration of ECT may reduce the rate of chronic and difficult-to-treat psychiatric disorders.     

Effects of different antidepressant treatments on the core of depression

Core symptoms of depression are a combination of psychological and somatic symptoms, often combined with psychomotor and cognitive disturbances. Diagnostic classification of depression including the concepts of melancholic, endogenous, or severe depression describe severely depressed patients suffering from most of the core symptoms, together with clinical characteristics of a cyclic unipolar or bipolar course, lower placebo response rates, higher response rates to electroconvulsive therapy, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of hypothalamic-pituitary-adrenal axis hyperactivity and specific electroencephalographic patterns have also been shown in this patient group. Summarizing the symptomatology of depression in these patients, a broad overlap between the abovementioned subgroups can be suggested. Because the positive diagnosis of those core symptoms of depression may include clinical consequences, it would be of use to integrate all the mentioned concepts in the upcoming new versions of the diagnostic systems DSM-V and ICD-11.     

The relationship between creativity and mood disorders

Research designed to examine the relationship between creativity and mental illnesses must confront multiple challenges. What is the optimal sample to study? How should creativity be defined? What is the most appropriate comparison group? Only a limited number of studies have examined highly creative individuals using personal interviews and a noncreative comparison group. The majority of these have examined writers. The preponderance of the evidence suggests that in these creative individuals the rate of mood disorder is high, and that both bipolar disorder and unipolar depression are quite common. Clinicians who treat creative individuals with mood disorders must also confronta variety of challenges, including the fear that treatment may diminish creativity, in the case of bipolar disorder, hovt/ever, it is likely that reducing severe manic episodes may actually enhance creativity in many individuals.     

Neuroendocrine predictors of the evolution of depression

Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.