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.     

Sleep and anxiety disorders

Sleep disturbances-particularly insomnia - are highly prevalent in anxiety disorders and complaints such as insomnia or nightmares have even been incorporated in some anxiety disorder definitions, such as generalized anxiety disorder and posttraumatic stress disorder. In the first part of this review, the relationship between sleep and anxiety is discussed in terms of adaptive response to stress. Recent studies suggested that the corticotropin-releasing hormone system and the locus ceruleus-autonomic nervous system may play major roles in the arousal response to stress. It has been suggested that these systems may be particularly vulnerable to prolonged or repeated stress, further leading to a dysfunctional arousal state and pathological anxiety states, Polysomnographic studies documented limited alteration of sleep in anxiety disorders. There is some indication for alteration in sleep maintenance in generalized anxiety disorder and for both sleep initiation and maintenance in panic disorder; no clear picture emerges for obsessive-compulsive disorder or posttraumatic stress disorder. Finally, an unequivocal sleep architecture profile that could specifically relate to a particular anxiety disorder could not be evidenced; in contrast, conflicting results are often found for the same disorder. Discrepancies between studies could have been related to illness severity, diagnostic comorbidity, and duration of illness. A brief treatment approach for each anxiety disorder is also suggested with a special focus on sleep.     

Pharmacologic treatment of schizophrenia

Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.     

Dopamine in the history of the schizophrenic brain: recent contributions of brain-imaging studies

Recent developments in positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have enabled functional measurements of dopamine (DA) transmission at dopamine D(2) receptors in the living human brain. Studies using these techniques have demonstrated that, in schizophrenia, increased DA stimulation of striatal D(2) receptors is associated with the first episode of illness and subsequent episodes of illness exacerbation. While this dysregulation of DA function is not associated with the severity of positive symptoms per se, increased synaptic DA activity is predictive of good therapeutic response to antipsychotic treatment. Abnormalities of DA function were not detected during periods of illness remission. These findings are integrated into a clinical model proposing that, in schizophrenia, neurodevelopmental abnormalities of cortico-subcortical connectivity result in a vulnerability of the mesolimbic DA system to the development of a process of endogenous sensitization, and that the resulting sustained hyperstimulation of D(2) receptors induces neuroplastic changes within corticostriatal-thalamocortical loops, perturbing information processing and underlying the psychotic experience.     

Pharmacologic treatments for opioid dependence: detoxification and maintenance options

While opioid dependence has more treatment agents available than other abused drugs, none are curative. They can, however, markedly diminish withdrawal symptoms and craving, and block opioid effects due to lapses. The most effective withdrawal method is substituting and tapering methadone or buprenorphine. alpha-2 Adrenergic agents can ameliorate untreated symptoms or substitute for agonists if not available. Shortening withdrawal by precipitating it with narcotic antagonists has been studied, but the methods are plagued by safety issues or persisting symptoms. Neither the withdrawal agents nor the methods are associated with better long-term outcome, which appears mostly related to post-detoxification treatment. Excluding those with short-term habits, the best outcome occurs with long-term maintenance on methadone or buprenorphine accompanied by appropriate psychosocial interventions. Those with strong external motivation may do well on the antagonist naltrexone. Currently, optimum duration of maintenance on either is unclear. Better agents are needed to impact the brain changes related to addiction.     

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.     

Heading off depressive illness evolution and progression to treatment resistance

Viewing recurrent depression as a potentially progressive illness may help transform treatment toward earlier, more consistent intervention and prevention. Evidence indicates that recurrent stressors, episodes of depression, and bouts of substance abuse can each show sensitization (increased reactivity upon repetition) and cross-sensitization to the others, and drive illness progression and treatment resistance. These long-lasting increases in pathological responsivity appear to be mediated by epigenetic mechanisms involving alterations in chemical marks placed on DNA and histories. These types of sensitization effects are amenable to clinical attempts at amelioration and prevention, and provide treatment targets and strategies to minimize the likelihood of illness progression to treatment resistance.     

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.     

The impact of subjective well-being under neuroleptic treatment on compliance and remission

The patients' perspective of antipsychotic treatment was largely neglected for a long period. It has only been during the last 10 years, with the development of atypical antipsychotics, that scientific interest in this issue has markedly increased. Numerous studies have shown that the majority of schizophrenic patients are able to fill out a self-rating scale in a meaningful way, and several self-report scales with sufficient internal consistency and good construct validity have been developed. The effects of antipsychotic treatment on psychopathology and on subjective well-being (SW) are not strongly related; the perspectives of the patient and his/her psychiatrist markedly differ. Recent research indicates that SW/quality of life, much more improved by atypical than by typical antipsychotics, has a strong impact on compliance, as well as on the chance of achieving remission. The data strongly suggest that a systematic evaluation of the patient's perspective of antipsychotic treatment is meaningful and necessary to increase compliance, functional outcome, and long-term prognosis.     

Future prospects in depression research

Major depression is a common, disabling, and often difficult-to-treat illness. Decades of research into the neurobiology and treatment of depression have greatly advanced our ability to manage this disorder. However, a number of challenges remain. A substantial number of depressed patients do not achieve full remission despite optimized treatment. For patients who do achieve resolution of symptoms, depression remains a highly recurrent illness, and repeated episodes are common. Finally, little is known about how depression might be prevented, especially in individuals at increased risk. In the face of these challenges, a number of exciting research efforts are currently under way and promise to greatly expand our knowledge of the etiology, pathophysiology, and treatment of depression. This review highlights these future prospects for depression research with a specific focus on lines of investigation likely to generate novel, more effective treatment options.     

Schizophrenia in late life: emerging issues

Schizophrenia in late life is emerging as a major public health concern worldwide. We discuss several areas of research and clinical care that are particularly pertinent to older persons with schizophrenia, including the public health challenge and the cost of care. We then discuss clinical issues relevant to late-life schizophrenia (course of illness and cognition), medical care and comorbidity in older psychiatric patients (general and illness-related), and treatment concerns related to the use of atypical antipsychotics in older persons with psychosis (efficacy and side effects). Clinical care for this ever-increasing segment of our population requires special consideration of the unique characteristics of older persons with schizophrenia.     

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.     

Translational neuroimaging research in pediatric obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a significant public health problem. Selective serotonin reuptake inhibitors (SSRIs) are the only FDA-approved medications for OCD. However, SSRIs are of limited efficacy in clinical practice. Given the persistence of symptoms and levels of treatment response, it is clear that the serotonin paradigm of OCD does not fully account for the neurobiology of the disorder, and that further translational research is needed. In this review, the glutamate hypothesis of pediatric OCD is explored, the neuroimaging evidence reviewed, and the translational impact highlighted. The traditional strategy of going from pharmacology to pathophysiology has failed to show real progress in our understanding of the neurobiology of psychiatric illness and, while still in the early stages, this work demonstrates the clear benefit of approaching psychiatric illness from the opposite direction.     

Body dysmorphic disorder

Body dysmorphic disorder (BDD) is a relatively common disorder that consists of a distressing or impairing preoccupation with imagined or slight defects in appearance. BDD is commonly considered to be an obsessivecompulsive spectrum disorder, based on similarities it has with obsessive-compulsive disorder. It is important to recognize and appropriately treat BDD, as this disorder is associated with marked impairment in psychosocial functioning, notably poor quality of life, and high suicidality rates. In this review, we provide an overview of research findings on BDD, including its epidemiology, clinical features, course of illness, comorbidity, psychosocial functioning, and suicidality We also briefly review recent research on neural substrates and cognitive processing. Finally, we discuss treatment approaches that appear efficacious for BDD, with a focus on serotonin-reuptake inhibitors and cognitive-behavioral therapy.     

Incomplete remission in depression: role of psychiatric and somatic comorbidity

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.     

Environmental risk factors for psychosis

Genetic factors are clearly important in the etiology of schizophrenia, but the environment in which an individual's genes find expression is also crucial to the development of the illness. In this review of environmental risk factors for schizophrenia, we consider risks operating prenatally and perinatally, during childhood, and then later in life prior to illness onset Some of these risk factors have been well documented, for example, early hazards causing fetal growth retardation or hypoxia, and hazards nearer the onset of illness like drug abuse and migration. Others are much less certain. The importance of interaction between genetic and environmental risk is, however, undoubtedly important and there is emerging evidence for this from a range of sources. As the etiology of schizophrenia is unraveled, the picture becomes more complex, but also more obviously relevant to the plight of the individual patient.     

Optimizing the treatment of mood disorders in the perinatal period

The perinatal period is a time of high risk for women with unipolar and bipolar mood disorders. We discuss treatment considerations for perinatal mood disorders, including unipolar and bipolar depression as well as postpartum psychosis. We further explore the unique issues faced by women and their families across the full trajectory of the perinatal period from preconception planning through pregnancy and following childbirth. Treatment of perinatal mood disorders requires a collaborative care approach between obstetrics practitioners and mental health providers, to ensure that a thoughtful risk : benefit analysis is conducted. It is vital to consider the risks of the underlying illness versus risks of medication exposure during pregnancy or lactation. When considering medication treatment, attention must be paid to prior medication trials that were most efficacious and best tolerated. Lastly, it is important to assess the impact of individual psychosocial stressors and lifestyle factors on treatment response.     

Clinical predictors of therapeutic response to antipsychotics in schizophrenia

The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.