Showing papers in "Dialogues in Clinical Neuroscience in 2008"

Sleep disorders as core symptoms of depression

Abstract: 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.

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

Abstract: 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.

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

Abstract: 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.

Neurobiological mechanisms of anhedonia

Abstract: Anhedonia refers to the reduced ability to experience pleasure, and has been studied in different neuropsychiatrie disorders. Anhedonia is nevertheless considered as a core feature of major depressive disorder, according to DSM-IV criteria for major depression and the definition of melancholic subtype, and regarding its capacity to predict antidepressant response. Behavioral, electrophysiological, hemodynamic, and interview-based measures and selfreports have been used to assess anhedonia, but the most interesting findings concern neuropharmacological and neuroanatomical studies. The analyses of anhedonic nonclinical subjects, nonanhedonic depressed patients, and depressed patients with various levels of anhedonia seem to favor the hypothesis that the severity of anhedonia is associated with a deficit of activity of the ventral striatum (including the nucleus accumbens) and an excess of activity of ventral region of the prefrontal cortex (including the ventromedial prefrontal cortex and the orbitofrontal cortex), with a pivotal, but not exclusive, role of dopamine.

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

Abstract: 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 a 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).

Malformations of cortical development and epilepsy.

Abstract: Malformations of cortical development (MCDs) are macroscopic or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical plate The human cortex develops its basic structure during the first two trimesters of pregnancy as a series of overlapping steps, beginning with proliferation and differentiation of neurons, which then migrate before finally organizing themselves in the developing cortex Abnormalities at any of these stages, be they environmental or genetic in origin, may cause disruption of neuronal circuitry and predispose to a variety of clinical consequences, the most common of which is epileptic seizures, A large number of MCDs have now been described, each with characteristic pathological, clinical, and imaging features The causes of many of these MCDs have been determined through the study of affected individuals, with many MCDs now established as being secondary to mutations in cortical development genes This review will highlight the best-known of the human cortical malformations associated with epilepsy The pathological, clinical, imaging, and etioiogic features of each MCD will be summarized, with representative magnetic resonance imaging (MRI) images shown for each MCD, The malformations tuberous sclerosis, focal cortical dysplasia, hemimegalencephaiy, classical iissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, polymicrogyria, and schizencephaly will be presented

Partial remission, residual symptoms, and relapse in depression.

Abstract: Partial remission from depression, with residual symptoms, is an important problem in depression. This paper reviews the frequency and features of this outcome, and its association with relapse. Residual symptoms occur in many depressed patients after acute treatment. They span the typical symptoms of depression, except those characteristic of severe disorders. Other persistent abnormalities include social dysfunction, dysfunctional attitudes, hypothalamic-pituitary-adrenal axis overactivity, shortened REM sleep latency, and mood lowering after tryptophan depletion. Associations of some of these with residual symptoms are not clear. There is growing evidence for similar residual symptoms in bipolar disorder, particularly bipolar depression. The most important consequence of residual symptoms is a much-increased risk of relapse, particularly in the first year. Residual symptoms are a strong indication for vigorous and longer than usual continuation of antidepressant treatment, in order to prevent relapse. There is good evidence for the use of cognitive therapy as an adjunct.

Cellular and molecular mechanisms in the long-term action of antidepressants

Abstract: The hypotheses on the pathophysiology of depression /mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the “hypothesis of neuroplasticity. ” In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.

Diurnal variation of depressive symptoms

Abstract: 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).

Electroconvulsive therapy and its different indications.

Abstract: 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.

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

Abstract: 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

Basic concepts of depression.

Abstract: This paper reviews concepts of depression, including history and classification. The original broad concept of melancholia included all forms of quiet insanity. The term depression began to appear in the nineteenth century, as did the modern concept of affective disorders, with the core disturbance now viewed as one of mood. The 1980s saw the introduction of defined criteria into official diagnostic schemes. The modern separation into unipolar and bipolar disorder was introduced following empirical research by Angst and Perris in the 1960s. The partially overlapping distinctions between psychotic and neurotic depression, and between endogenous and reactive depression, started to generate debate in the 1920s, with considerable multivariate research in the 1960s. The symptom element in endogenous depression currently survives in melancholia or somatic syndrome. Life stress is common in various depressive pictures. Dysthymia, a valuable diagnosis, represents a form of what was regarded earlier as neurotic depression. Other subtypes are also discussed.

Mood disorder and epilepsy: a neurobiologic perspective of their relationship.

Abstract: Mood disorders are the most frequent psychiatric comorbidity in epilepsy, and in particular in temporal lobe epilepsy For a long time, depressive disorders were considered to be the expression of a reactive process to the obstacles of a life with epilepsy Data obtained in the last two decades, however, have demonstrated biochemical, neuropathological, and neurophysiologic changes mediating the development of mood disorders, which in fact can be tested in animal models Furthermore, there is also evidence that mood disorders and epilepsy have a complex relationship which is bidirectional; that is, not only are patients with epilepsy at greater risk of developing depression, but patients with depression have a higher risk of developing epilepsy Such a relationship can only be explained by the existence of common pathogenic mechanisms that are operant in both conditions These include changes in neurotransmitters, such as serotonin, norepinephrine, glutamate, and y-aminobutyric acid Such a bidirectional relationship also appears to have important clinical consequences Indeed, patients with a history of mood disorders are twice as likely to develop pharmacoresistant epilepsy as those without such a history These data are reviewed in this article

Toward achieving optimal response: understanding and managing antidepressant side effects.

Abstract: The safety and tolerability of antidepressants have improved considerably over the past two decades. Nevertheless, antidepressant side effects are still common and problematic. The majority of patients treated with contemporaty agents experience one or more bothersome side effects. These side effects often create barriers to achieving depressive remission, as well as to preventing relapse and recurrence. Clinicians tend to underestimate the prevalence of side effects, and as many as one quarter of patients discontinue their antidepressants because of difficult-to-tolerate side effects; others may continue on antidepressant therapy but experience diminished quality of life related to troublesome side effects. This article reviews the prevalence of side effects, the impact of side effects on treatment adherence, and methodological issues including the challenge of distinguishing side effects from residual depressive symptoms, discontinuation effects, and general medical problems. In addition, we address the most common side effects such as sexual dysfunction, gastrointestinal problems, sleep disturbance, apathy and fatigue, and offer strategies for management that may help patients achieve optimal response to pharmacotherapy

The relationship between creativity and mood disorders.

Abstract: 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.

Incomplete response in late-life depression: getting to remission

Abstract: Incomplete response in the treatment of late-life depression is a large public health challenge: at least 50% of older people fail to respond adequately to first-line antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment-resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of empirical data on how best to manage TRLLD. A pilot study by our group on aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole, and that remission was sustained in all participants during 6 months of continuation treatment. In addition to controlled assessment, evidence is needed to support personalized treatment by testing the moderating role of clinical (e.g., comorbid anxiety, medical burden, and executive impairment) and genetic (eg, selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while also controlling for variability in drug exposure. Such studies may advance us toward the goal of personalized treatment in late-life depression.

Epilepsy surgery: eligibility criteria and presurgical evaluation.

Abstract: Epilepsy surgery has benefited from major advances during the last 20 years, thanks to the development of neuroimaging and long-term video-electroencephalographic (EEG) monitoring. However, it remains the case that only a small minority of potential epilepsy surgery candidates will have access to a comprehensive presurgical evaluation. Furthermore, this subset of patients are operated on after an average of 20 to 25 years of epilepsy duration. Among the various reasons that prevent many patients from benefiting from a timely presurgical evaluation, we need to emphasize the role of inaccurate information regarding eligibility criteria and lack of standardized practice. This review aims at providing an in-depth discussion of the current views regarding the definition of surgical candidates, and the role of the numerous investigations used in the presurgical evaluation of patients with drug-resistant epilepsy. The eligibility criteria required to enter a presurgical evaluation in 2008 should be relatively liberal, provided that the patient suffers from disabling seizures unrelated to an idiopathic generalized epileptic syndrome, despite appropriate antiepileptic drug treatment. However, the decision as to whether or not to perform a presurgical evaluation must be individualized, and take into account the likelihood of meeting the patient's expectations in terms of outcome. These expectations need to be balanced with the apparent severity of the epileptic condition, the chance of achieving a successful surgical treatment, and the risk of a postoperative neurological, cognitive, or psychiatric deterioration. The roles and specific features of the main types of presurgical investigations are reviewed.

Treatment strategies to improve and sustain remission in major depressive disorder

Abstract: 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.

Genetics and epilepsy.

Abstract: The term “epilepsy” describes a heterogeneous group of disorders, most of them caused by interactions between several or even many genes and environmental factors. Much rarer are the genetic epilepsies that are due to single-gene mutations or defined structural chromosomal aberrations, such as microdeletions. The discovery of several of the genes underlying these rare genetic epilepsies has already considerably contributed to our understanding of the basic mechanisms epileptogenesis. The progress made in the last 15 years in the genetics of epilepsy is providing new possibilities for diagnosis and therapy. Here, different genetic epilepsies are reviewed as examples, to demonstrate the various pathways that can lead from genes to seizures.

Acute and long-term treatment of mania.

Abstract: The treatment of mania starts with a correct diagnosis and elementary measures to prevent risks for the patient, relatives, and others. Sometimes, compulsory admission and treatment may be required for a few days. Patients with psychotic or mixed mania may be more difficult to treat. At the present time, there is solid evidence supporting the use of lithium, the anticonvulsants valproate and carbamazepine, and the antipsychotics chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in acute mania, and some evidence supporting the use of clozapine or electroconvulsive therapy in treatment-refractory cases. However, in clinical practice, combination therapy is the rule rather than the exception. The treatment of acute mania deserves a long-term view, and the evidence base for some treatments may be stronger than for others. When taking decisions about treatment, tolerability should also be a major concern, as differences in safety and tolerability may exceed differences in efficacy for most compounds. Psychoeducation of patients and caregivers is a powerful tool that should be used in combination with medication for optimal long-term outcome. Functional recovery should be the ultimate goal.

Cognitive neuroscience and brain imaging in bipolar disorder.

Abstract: Bipolar disorder is characterized by a combination of state-related changes in psychological function that are restricted to illness episodes, coupled with trait-related changes that persist through periods of remission, irrespective of symptom status. This article reviews studies that have investigated the brain systems involved in these state-and trait-related changes, using two techniques: (i) indirect measures of neurocognitive function, and (ii) direct neuroimaging measures of brain function during performance of a cognitive task. Studies of neurocognitive function in bipolar disorder indicate deficits in three core domains: attention, executive function, and emotional processing. Functional imaging studies implicate pathophysiology in distributed neural circuitry that includes the prefrontal and anterior cingulate cortices, as well as subcortical limbic structures including the amygdala and the ventral striatum. Whilst there have been clear advances in our understanding of brain changes in bipolar disorder, there are limited data in bipolar depression, and there is limited understanding of the influence of clinical variables including medication status, illness severity, and specific symptom dimensions.

Psychosocial interventions and medication adherence in bipolar disorder.

Abstract: 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.

The effectiveness of anticonvulsants in psychiatric disorders

Abstract: Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.

Incomplete remission in depression: role of psychiatric and somatic comorbidity.

Abstract: Depression is one of the most pressing public health issues, because of its high lifetime prevalence and because it is associated with substantial disability. In depressed patients, psychiatric and medical comorbidity is the rule rather than the exception. About 60% to 70% of depressed patients have at least one, while 30% to 40% have two or more, concurrent psychiatric disorders. Among these, anxiety disorders and substance use disorders are the most common axis I comorbidities. Furthermore, two thirds of depressed patients have at least one comorbid medical illness. Among depressed patients, those with a current comorbid psychiatric condition (in particular an anxiety or substance use disorder) or medical illness seem to have an impaired response and remission rate during treatment compared with those patients without comorbidity. However, in depressed patients who all have the same comorbid condition, the relative benefit of an antidepressant compared with placebo appears to be equal to those effects achieved in depressed patients without comorbidity. These findings raise important research and treatment issues regarding the generalizability from randomized controlled trials that tend to exclude patients with comorbidity.

Bipolar disorder--methodological problems and future perspectives.

Abstract: Since its "rebirth" in 1966, bipolar disorder (BPD) has rapidly come to occupy a central position in the research and treatment of mood disorders. Compared with major depressive disorder (MDD), BPD is a more serious condition, characterized by much more frequent recurrence, more complex comorbidity, and higher mortality. One major problem is the lack of valid definitions in adult and in child psychiatry; the current definitions are unsatisfactory, and heavily favor an overdiagnosis of MDD. Biological research is partially based on those definitions, which have a short half-life. An additional, dimensional, approach, quantifying hypomania, depression, and anxiety by self-assessment and symptom checklists is recommended. A further, related problem is the early recognition of the onset of BPD, especially in adolescence, and the identification of correlates in childhood. Early and timely diagnosis of BPD is necessary to enable prompt intervention and secondary prevention of the disorder. The paper describes the current status and future directions of developing clinical concepts of bipolarity.

Genetics of bipolar disorder

Abstract: Bipolar disorder, especially the most severe type (type I), has a strong genetic component. Family studies suggest that a small number of genes of modest effect are involved in this disorder. Family-based studies have identified a number of chromosomal regions linked to bipolar disorder, and progress is currently being made in identifying positional candidate genes within those regions, A number of candidate genes have also shown evidence of association with bipolar disorder, and genome-wide association studies are now under way, using dense genetic maps. Replication studies in larger or combined datasets are needed to definitively assign a role for specific genes in this disorder. This review covers our current knowledge of the genetics of bipolar disorder, and provides a commentary on current approaches used to identify the genes involved in this complex behavioral disorder.

Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities.

Abstract: It is well established that individuals with bipolar disorder are differentially affected by substance-related as well as medical disorders (ie, cardiometabolic disorders, respiratory disorders, neurological disorders, and infectious diseases). Emerging evidence indicates that some comorbid conditions (eg, diabetes mellitus) in bipolar individuals may be subserved by overlapping neurobiological networks. Disturbances in glucocorticoid/insulin signaling and immunoinflammatory effector systems are points of pathophysiological commonality between bipolar disorder and “stress-sensitive” medical disorders. Subphenotyping bipolar disorder as a function of comorbidity and temporality of onset may provide an opportunity for refining disease pathophysiological models and developing innovative disease-modifying therapies.

Epilepsies and neuronal plasticity: for better or for worse?

Abstract: Extensive experimental investigations have confirmed that "seizures beget seizures." Thus, in adults, limbic seizures lead to cell loss, followed by the formation of novel excitatory synapses that contribute to generating further seizures. The triggering signal is an enhancement of synaptic efficacy, followed by a molecular cascade that triggers axonal sprouting. New synapses are aberrant, since they are formed in regions in which they are not present in controls. They also involve receptors that are not present in controls, and this facilitates the generation of seizures. Therefore, an aberrant form of reactive neuronal plasticity provides a substrate for the long-lasting sequelae of seizures. Since these events take place in brain structures involved in integrative and mnemonic functions, they will have an important impact. Reactive plasticity is documented for other insults and disorders, and may be the basis for the long-term progression of neurodegenerative disorders.

Towards achieving remission in the treatment of depression.

Abstract: 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 symptomsThis 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

Sadness as an integral part of depression

Abstract: 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.