Neuroactive steroids and affective disorders

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.     

Getting better, getting well: understanding and managing partial and non-response to pharmacological treatment of non-psychotic major depression in old age

In general, the pharmacological treatment of non-psychotic major depressive disorder in old age is only partially successful, with only approximately 50% of older depressed adults improving with initial antidepressant monotherapy. Many factors may predict a more difficult-to-treat depression, including coexisting anxiety, low self-esteem, poor sleep and a high coexisting medical burden. Being aware of these and other predictors of a difficult-to-treat depression gives the clinician more reasonable expectations about a patient's likely treatment course. If an initial antidepressant trial fails, the clinician has two pharmacological options: switch or augment/combine antidepressant therapies. About 50% of patients who do not improve after initial antidepressant therapy will respond to either strategy. Switching has several advantages including fewer adverse effects, improved treatment adherence and reduced expense. However, as a general guideline, if patients are partial responders at 6 weeks, they will likely be full responders by 12 weeks. Thus, changing medication is not indicated in this context. However, if patients are partial responders at 12 weeks, switching to a new agent is advised. If the clinician treats vigorously and if the patient and clinician persevere, up to 90% of older depressed patients will respond to pharmacological treatment. Furthermore, electroconvulsive therapy is a safe and effective non-pharmacological strategy for non-psychotic major depression that fails to respond to pharmacotherapy. Getting well and staying well is the goal; thus, clinicians should treat to remission, not merely to response. Subsequently, maintenance treatment with the same regimen that has been successful in relieving the depression strongly improves the patient's chances of remaining depression free.     

Cognitive therapy in relapse prevention in depression

This paper reviews recent advances in application of cognitive therapy (CBT) to a therapeutic problem in depression. Modern follow-up studies indicate that, in spite of the efficacy of pharmacotherapy, relapse and recurrence rates in some depressed patients remain high. This does not appear mainly due to failure to receive medication, but to reflect intractability of the disorder. In acute treatment, psychological treatments, although beneficial, are less cost-effective than antidepressants, due to high costs of therapists. Benefit which lasts longer, particularly if combined with medication, may therefore be particularly valuable. There have now been seven randomized controlled trials of cognitive therapy designed specifically to test relapse and recurrence prevention. All have shown significant benefit, which lasts beyond the cessation of therapy. The effect appears to be more on preventing symptom return than on lessening current symptoms, to summate well with continuation and maintenance antidepressant, and not to be due simply to enhanced medication adherence. Incorporation into routine clinical practice is now appropriate and recommendations are proposed.     

Psychotic major depression: a benefit-risk assessment of treatment options.

Numerous studies in the past three decades have characterised 'psychotic major depression', a subtype of major depression which is accompanied by delusions or other psychotic features. Evidence from phenomenological and neurobiological investigations indicates that this is a unique disorder with clinical and biological characteristics that are distinct from those of nonpsychotic depression and from other psychotic disorders. Treatment studies have provided evidence of small placebo effects and good responses to electroconvulsive therapy or combination treatment with an antidepressant plus an antipsychotic agent. However, until recently, there were only a few small, prospective, double-blind, controlled trials investigating the efficacy of antidepressant-antipsychotic combination pharmacotherapy, yet this constitutes the currently accepted and most universally applied 'standard of care' for psychotic depression. Treatment guidelines have been based largely on uncontrolled investigations of electroconvulsive therapy and studies using tricyclic antidepressants and first-generation antipsychotic drugs, which are not frequently chosen as first-line agents today because of concerns regarding tolerability and risks. However, recent open-label studies and large controlled trials of newer antidepressants and antipsychotics have yielded very divergent results thus far, so that the best treatment approach remains elusive. This review discusses the phenomenology and treatment of psychotic depression with a focus on the benefits and risks of various treatment approaches. Problems with this literature are highlighted, and strategies for future research are suggested.     

Towards the pharmacotherapy of eating disorders

The purpose of this review is to discuss pharmacological options for the treatment of patients with eating disorders. Sequentially described are pharmacotherapy studies of anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). The quantity of drug trials performed with AN patients has been very limited. While the majority of studies have failed to show medication efficacy for the acute treatment of AN, there is data which suggests that fluoxetine hydrochloride may play a role in preventing relapse during maintenance therapy. Atypical antipsychotics, most often olanzapine, have shown promise in a number of uncontrolled studies. BN has been most extensively studied, with the majority of pharmacological trials focusing on antidepressants. Fluoxetine, at a dose of 60 mg/day, is FDA-approved for the treatment of BN. Psychotherapy, particularly cognitive behavioural therapy (CBT) is of well-established utility in BN and data suggests that the combination of an antidepressant plus CBT is superior to either treatment alone. Recently, there has been interest in the 5-HT3 antagonist, ondansetron, and the anticonvulsant, topiramate. BED investigators have focused largely on antidepressants, which may reduce symptoms of depression and augment psychotherapy. While sibutramine and topiramate have both been associated with weight loss in controlled trials, the former appears to be fairly well-tolerated and the latter appears to be responsible for the emergence of significant cognitive and peripheral nervous system side effects in some patients. Further pharmacological research with eating disorder patients is needed, particularly in the areas of AN and BED. Also, pharmacological augmentation strategies for those not responding to primary therapies should be explored.     

Examining antidepressant drug response by smoking status: why is it important and how often is it done?

Despite an increasingly recognized relationship between depression and smoking, little is known about the degree to which treatment studies for depression consider the impact of smoking on outcomes. The aim of this study is to examine the extent to which smoking is considered in current antidepressant treatment research. We conducted a MEDLINE search of recent randomized clinical trials of pharmacotherapy for depression published between 1 January and 31 December 2007, and a search of current pharmacological intervention studies for depression using www.ClinicalTrials.gov. Only 5% of the 107 pharmacological trials for depression published in 2007 reported the smoking status of their samples. Two studies (1.9%) controlled for smoking in the analyses and no studies analyzed outcomes by smoking status. Excluding the eight studies of combined treatment for depression and nicotine dependence, no other study on www.ClinicalTrials.gov (total n?=?920) reported an intention to analyze outcomes by smoking status. Emerging data link smoking and depression, however, little attention has been directed toward the effects of smoking on antidepressant treatment outcomes. Conducting research to understand how nicotine and smoking affect responsiveness to antidepressants would advance our understanding of the neurobiology of depression and the development of new and targeted treatments.     

Treatment of recurrent depression: a sequential psychotherapeutic and psychopharmacological approach

The chronic and recurrent nature of major depressive disorder is receiving increasing attention. Approximately eight of ten people experiencing a major depressive episode will have at least one more episode during their lifetime, i.e. recurrent major depressive disorder. In the 1990s, prolonged or lifelong pharmacotherapy emerged as the main therapeutic tool for preventing relapses of depression. This therapeutic approach is based on the effectiveness of antidepressant drugs compared with placebo in decreasing relapse risk and on the improved tolerability profile of the newer antidepressants compared with their older counterparts. However, outcome after discontinuation of antidepressant therapy does not seem to be affected by the duration of administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. The use of intermittent pharmacotherapy with follow-up visits is an alternative therapeutic option. This leaves patients with periods free of drugs and adverse effects and takes into account that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (that a drug treatment may be associated with a diminished chance of response in subsequent treatments in those patients whose symptoms successfully responded to it but who discontinued it) and of discontinuation syndromes are substantial disadvantages of this therapeutic approach. In recent years, several controlled trials have suggested that sequential use of pharmacotherapy in the treatment of the acute depressive episode and psychotherapy in its residual phase may improve long-term outcome. Patients, however, need to be motivated for psychotherapy, and skilled therapists have to be available. Despite an impressive amount of research into the treatment of depression, there is still a paucity of studies addressing the specific problems that prevention of recurrent depression entails. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.     

Emerging drugs for eating disorder treatment

Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) comprise the currently recognised eating disorders. Although distinct diagnostic entities, they share certain forms of comorbid psychopathology, particularly anxiety and mood disorders. BN and BED have been studied most intensively as targets for pharmacotherapy. The list of drugs tested in eating disorders is substantial; however, the number of therapeutic classes of medications tested in these conditions is relatively modest. Antidepressant medications, including tricyclic antidepressants, selective serotonin re-uptake inhibitors, as well as some of the novel antidepressants, have shown evidence of some therapeutic value in both BN and BED. Their efficacy in AN, however, has been disappointing. The pharmacological options for AN are very limited. The number of controlled trials that have been conducted is small, and the research that has been successfully completed has generally failed to demonstrate medication efficacy. Patients with BN typically show reduced binge eating and purging frequency in medication trials, but rarely attain abstinence. In BED, patients often measure the value of their medication therapy by its ability to stimulate weight loss, which is another area on which future pharmacotherapy may improve. Novel pharmacological interventions are needed for each of these conditions. Peptide hormones are increasingly being evaluated for eating disorder treatment, including ghrelin agonists, neuropeptide Y1 and -5 antagonists, orexin receptor antagonists, corticotropin-releasing factor receptor 2 antagonists, histamine 3 antagonists, melanocortin 4 receptor antagonists, beta3-adrenoceptor agonists, 5-hydroxytryptamine-2A antagonists and growth hormone agonists. Although these compounds are in early phases of clinical testing for eating disorder treatments, data from these studies will be instructive in the quest for effective pharmacotherapy for these conditions. An overview of the current pharmacotherapy options for eating disorders is presented with a discussion of the emerging potential treatments.     

Therapeutic Options for Treating Major Depression,and the Role of Venlafaxine

Major depression is a debilitating disorder that is often undertreated. Psychotherapy, electroconvulsive therapy, and pharmacotherapy are options for management. Tricyclic antidepressants and selective serotonin reuptake inhibitors are the cornerstones of drug therapy. Venlafaxine, a phenylethylamine antidepressant that primarily inhibits reuptake of norepinephrine and serotonin, is an alternative to those agents. It has been studied in short-term and continuation studies and appears to have efficacy similar to that of imipramine, trazodone, and fluoxetine. Moreover, venlafaxine is effective in approximately one-third of patients with treatment-resistant depression. Venlafaxine is metabolized by the P-450 enzyme system to an active metabolite O-desmethyl-venlafaxine, which is excreted renally. Nausea, somnolence, and dizziness are dose-related adverse effects that often occur with initiation of therapy. Increases in blood pressure, particularly with high dosages, also may occur. Drug-drug interactions appear to be minimal.     

Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action

The naturally occurring 3α-reduced neurosteroids allopregnanolone and its isomer pregnanolone are among the most potent positive allosteric modulators of γ-aminobutyric acid type A receptors. They play a critical role in the maintenance of physiological GABAergic tone and display a broad spectrum of neuropsychopharmacological properties. We have reviewed existing evidence implicating the relevance of endogenous 3α-reduced neuroactive steroids to depression and to the mechanism of action of antidepressants. A wide range of preclinical and clinical evidence suggesting the antidepressant potential of 3α-reduced neuroactive steroids and a possible involvement of a deficiency and a disequilibrium of neuroactive steroid levels in pathomechanisms underlying the etiology of major depressive disorder have emerged in recent years. Antidepressants elevate 3α-reduced neurosteroid levels in rodent brain, and clinically effective antidepressant pharmacotherapy is associated with normalization of plasma and cerebrospinal fluid (CSF) concentrations of endogenous neuroactive steroids in depressed patients, unveiling a possible contribution of neuroactive steroids to the mechanism of action of antidepressants. In contrast, recent studies using nonpharmacological antidepressant therapy suggest that changes in plasma neuroactive steroid levels may not be a general mandatory component of clinically effective antidepressant treatment per se, but may reflect distinct properties of pharmacotherapy only. While preclinical studies offer convincing evidence in support of an antidepressant-like effect of 3α-reduced neuroactive steroids in rodent models of depression, current clinical investigations are inconclusive of an involvement of neuroactive steroid deficiency in the pathophysiology of depression. Moreover, clinical evidence is merely suggestive of a role of neuroactive steroids in the mechanism of action of clinically effective antidepressant therapy. Additional clinical studies evaluating the impact of successful pharmacological and nonpharmacological antidepressant therapies on changes in neuroactive steroid levels in both plasma and CSF samples of the same patients are necessary in order to more accurately address the relevance of 3α-reduced neuroactive steroids to major depressive disorder. Finally, proof-of-concept studies with drugs that are known to selectively elevate brain neurosteroid levels may offer a direct assessment of an involvement of neurosteroids in the treatment of depressive symptomatology.     

Curcumin in antidepressant treatments: An overview of potential mechanisms,pre‐clinical/clinical trials and ongoing challenges

Depression is one of the most common but serious psychiatric disorders affecting millions of people globally, which has become increasingly prevalent during the past few decades. To alleviate this challenging health and social burden, various therapeutic strategies have been developed to achieve efficient treatments for depression. In particular, plenty of chemical ingredients of natural origin have been investigated as new direct antidepressants or served as adjuvants to improve the current treatment outcomes of existing antidepressant drugs. Among them, curcumin, a natural compound derived from the herb Curcuma longa, exhibits a wide range of pharmacological properties and has been considered a potent antidepressant drug with diverse mechanisms including monoaminergic imbalances (associated with serotonin, dopamine, noradrenaline and glutamate), effect on neurotransmitters, neuroprogression, the hypothalamic‐pituitary‐adrenal (HPA) axis disturbances, dysregulated inflammation and immune pathways, oxidative and nitrosative stress, and mitochondrial disturbances. In this review, multiple potential mechanisms of curcumin for treating depression demonstrated in either animal or human studies are summarized. To better understand the significant role of curcumin, specific emphasis will be placed on the aetiopathogenesis of depression. Finally, current pre‐clinical/clinical trials and ongoing challenges of curcumin used for antidepressant treatments will be discussed and their future outlooks will be briefly presented.     

Emerging drugs for eating disorder treatment

Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) comprise the currently recognised eating disorders. Although distinct diagnostic entities, they share certain forms of comorbid psychopathology, particularly anxiety and mood disorders. BN and BED have been studied most intensively as targets for pharmacotherapy. The list of drugs tested in eating disorders is substantial; however, the number of therapeutic classes of medications tested in these conditions is relatively modest. Antidepressant medications, including tricyclic antidepressants, selective serotonin re-uptake inhibitors, as well as some of the novel antidepressants, have shown evidence of some therapeutic value in both BN and BED. Their efficacy in AN, however, has been disappointing. The pharmacological options for AN are very limited. The number of controlled trials that have been conducted is small, and the research that has been successfully completed has generally failed to demonstrate medication efficacy. Patients with BN typically show reduced binge eating and purging frequency in medication trials, but rarely attain abstinence. In BED, patients often measure the value of their medication therapy by its ability to stimulate weight loss, which is another area on which future pharmacotherapy may improve. Novel pharmacological interventions are needed for each of these conditions. Peptide hormones are increasingly being evaluated for eating disorder treatment, including ghrelin agonists, neuropeptide Y1 and -5 antagonists, orexin receptor antagonists, corticotropin-releasing factor receptor 2 antagonists, histamine 3 antagonists, melanocortin 4 receptor antagonists, β₃-adrenoceptor agonists, 5-hydroxytryptamine-2A antagonists and growth hormone agonists. Although these compounds are in early phases of clinical testing for eating disorder treatments, data from these studies will be instructive in the quest for effective pharmacotherapy for these conditions. An overview of the current pharmacotherapy options for eating disorders is presented with a discussion of the emerging potential treatments.     

Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similar way as antidepressant pharmacotherapy. Progesterone, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta- tetrahydroprogesterone (3alpha,5beta-THP), 3beta,5alpha-tetrahydroprogesterone (3beta, 5alpha-THP) and dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients suffering from a major depressive episode before and after 10 sessions of left prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was a significant reduction of depressive symptoms after rTMS. However, plasma concentrations of neuroactive steroids were not affected by rTMS and not related to clinical response. Clinical improvement after extended daily treatment with rTMS is not accompanied by changes in neuroactive steroid levels. Changes in neuroactive steroid levels after antidepressant pharmacotherapy more likely reflect specific pharmacological effects of antidepressant drugs and are not necessary for the amelioration of depressive symptoms.     

Expert opinion on current therapies for nonalcoholic fatty liver disease

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of most common liver diseases in industrialized countries owing to the increasing prevalence of obesity and being overweight. Until now, loss of weight and physical activity have represented the cornerstone of treatment, but they are very difficult to achieve and to maintain. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish an effective pharmacological therapy for this disorder. AREAS COVERED: An overview of current therapeutic interventions to treat NAFLD is given. This review provides evidence of the efficacy of natural and pharmacological agents used so far in the treatment of both adult and pediatric NAFLD, on the basis of clinical trials published in the last 10 years. EXPERT OPINION: In the last 10 years, many pharmacological agents on the basis of the pathogenetic mechanism of NAFLD have been attempted, but so far guidelines for the management of NAFLD are lacking. We believe that the advance in the understanding of pathogenesis and factors involved in the progression of the disease may disclose the way to defining new, solid, therapeutic strategies. A multidisciplinary approach considering the risk factors and comorbidities of fatty liver will represent in the future a successful therapeutic strategy for NAFLD.     

Time course of response to antidepressants in late-life major depression: therapeutic implications

In the treatment of depression, there is considerable interest in the time course of response and, in particular, the speed with which individuals recover from depressive episodes. Examination of the time course and speed of response is critical for assessing the usefulness of specific treatments. However, while this issue has received attention in mid-life adult populations, it has received little consideration in the context of late-life major depression. The synthesis of empirical reports indicates that, while older adults with depression seem to respond with the same speed as mid-life adults, several factors have consistently been associated with reduced speed of response to antidepressant treatment, including greater severity of depressive symptoms and co-occurring anxiety symptoms. Limited evidence suggests that sleep impairment and genetic factors (e.g. presence of the s allele of the serotonin transporter gene promoter region) may also be associated with reduced speed of response. Some factors have consistently been found to be unrelated to speed of response (demographic characteristics, nonpsychiatric physical illnesses) whereas other factors have only mixed evidence supporting any effect (psychosocial and other clinical factors). While there is little work available to date, some evidence suggests that time course and speed of response affect longer-term outcomes of depression pharmacotherapy; thus, older adults with more rapid versus slower patterns of response may differ in the types of maintenance treatment needed to avert additional depressive episodes. None of potential strategies for accelerating speed of response have been clearly shown to be effective in late-life depression. Future treatment studies for late-life depression should routinely consider not only overall efficacy of a given pharmacotherapy (i.e. total rate of response), but time course and speed of response. To this end, new investigations must be designed to overcome the methodological limitations of prior studies that have examined time course and they should include a range of potential covariates and outcomes of between-patient differences in speed of response. Better understanding of factors related to such differences may suggest new intervention strategies to accelerate response.     

Depression and anxiety in individuals with amyotrophic lateral sclerosis: epidemiology and management

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no curative treatment. Considering the devastating nature of the disease, a high prevalence of depression and anxiety in affected patients would be expected. A review of the literature shows prevalence rates for depression in ALS patients ranging from 0% to 44%, but studies using the structured interview according to DSM-IV criteria find highly consistent rates of 9-11%. Prevalence rates for anxiety in ALS range from 0% to 30%. Depression and anxiety appear to be not always properly addressed aspects of ALS, as there are only a few references in the literature about psychological and pharmacological interventions. Additionally, pharmacological antidepressant therapy is often not continuously monitored and its effectiveness remains unevaluated. A review of the literature and our own experiences show that there is a lack of psychological care and, to our knowledge, there is no specific psychological intervention method for ALS patients. Concerning pharmacological treatment of depression in patients with ALS, there is broad consensus among clinical experts that SSRIs and TCAs are helpful, but there have been no controlled clinical studies of these medications in ALS patients. TCAs can be prescribed if anticholinergic effects are desired simultaneously for treating pseudohypersalivation or insomnia. Anxiety is usually treated with anxiolytics, but again there have been no systematic studies of these drugs in patients with ALS. For psychological intervention we suggest a cognitive behavioural approach, which has to be integrated into an intervention programme that includes teaching of appropriate coping strategies and reappraisal skills and encourages engagement in activities that are still practicable and pleasant. We propose that the treatment of depression and anxiety should involve both cognitive behavioural therapy and pharmacological intervention. Pharmacological treatment should be strictly monitored for effectiveness. To date, no clinical trials are available that would allow us to recommend pharmacotherapy over psychotherapy or vice versa; however, evidence from other patient groups, such as elderly patients diagnosed with major depressive disorder, suggests that a combination of both therapies has the potential to also improve depression and anxiety in patients with ALS.     

Drug treatment of depression in HIV-positive patients : safety considerations.

Safe and effective treatment of major depression, one of the most common comorbid conditions in individuals infected with HIV, significantly lowers morbidity and mortality from HIV disease. However, optimal treatment of both conditions is complicated by interactions between the disease processes as well as the pharmacological agents used to treat them. In patients with HIV it may be difficult to distinguish major depression from other physiological and emotional states that present with similar symptoms. Accurate diagnosis of major depression is thus complex and essential to preventing inappropriate exposure of patients to potentially harmful psychotropic medications. This review outlines important initial steps in making this diagnosis. All patients with HIV should be screened for depression by their medical providers and referred to a psychiatrist for full evaluation when necessary. The mainstay of treatment for major depression in patients with HIV disease is pharmacotherapy. Depressed patients with HIV respond to the same wide variety of antidepressant-class medications as depressed patients without HIV, including tricyclic antidepressants, paroxetine, fluoxetine and trazodone. Notably, new studies have also shown that some psychiatric medications can inhibit HIV replication. No particular antidepressant medication is superior for the treatment of depressed HIV-infected patients; however, the most important component of treatment of major depression in HIV-disease is patient adherence, which is highly influenced by antidepressant adverse effects. This review outlines adverse effects of antidepressant-class medications that are of particular concern in HIV-infected patients and describes pharmacological strategies for overcoming these potential barriers to medication adherence. This review also describes situations in which some adverse effects of antidepressant-class medications may be safely exploited to benefit depressed patients with HIV disease. Potential interactions between antidepressant-class medications and HIV medications, as well as pharmacological treatment strategies for treating the psychiatric adverse effects of HIV medications, are also discussed.     

Ketamine for treatment-resistant unipolar depression: current evidence

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5?mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.     

Brain Functional Effects of Psychopharmacological Treatment in Major Depression: A Focus on Neural Circuitry of Affective Processing

In the last two decades, neuroimaging research has reached a much deeper understanding of the neurobiological underpinnings of major depression (MD) and has converged on functional alterations in limbic and prefrontal neural networks, which are mainly linked to altered emotional processing observed in MD patients. To date, a considerable number of studies have sought to investigate how these neural networks change with pharmacological antidepressant treatment. In the current review, we therefore discuss results from a) pharmacological functional magnetic resonance imaging (fMRI) studies investigating the effects of selective serotonin or noradrenalin reuptake inhibitors on neural activation patterns in relation to emotional processing in healthy individuals, b) treatment studies in patients with unipolar depression assessing changes in neural activation patterns before and after antidepressant pharmacotherapy, and c) predictive neural biomarkers of clinical response in depression. Comparing results from pharmacological fMRI studies in healthy individuals and treatment studies in depressed patients nicely showed parallel findings, mainly for a reduction of limbic activation in response to negative stimuli. A thorough investigation of the empirical findings highlights the importance of the specific paradigm employed in every study which may account for some of the discrepant findings reported in treatment studies in depressed patients.     

Efficacy and tolerance profile of agomelatine and practical use in depressed patients

Agomelatine is a new agent with a unique pharmacological profile, as the first melatonergic antidepressant. Its antidepressant efficacy has been demonstrated in the treatment of major depressive disorder (MDD) at a dose of 25 mg/day. Expectations from antidepressant therapies now go beyond efficacy alone, to include advantages in tolerability and safety. Due to its pharmacological profile, agomelatine does not induce the side-effects typical of other therapies, such as selective serotonin reuptake inhibitors (i.e. gastrointestinal disorders, weight gain, serotonergic syndrome and insomnia). Moreover, a placebo-controlled trial in MDD comparing the effects of agomelatine and venlafaxine on sexual dysfunction (another significant side-effect with current antidepressant medications) indicated the very favourable profile of agomelatine; in the same study, there was similar antidepressant efficacy in the same two groups. A double-blind, placebo-controlled trial investigating the effect of abrupt cessation of treatment demonstrated the absence of discontinuation symptoms with agomelatine, which was in contrast with the results observed with paroxetine. The ability of an antidepressant to relieve sleep complaints with no sedative effects is a key advantage because sleep complaints are a major presenting feature of depression. Again due to its unique pharmacological profile, agomelatine has been shown to positively influence disturbed circadian rhythms in depressed patients by significantly improving all phases of disturbed sleep and the overall quality of sleep, with a favourable impact on daytime alertness. In conclusion, experience with agomelatine across a range of clinical studies suggests that this compound offers a novel approach to the treatment of depression combining efficacy, even in severe depression, with an extremely favourable side-effect profile and sleep regulation. These properties give agomelatine a definite clinical advantage in the treatment of depression.