Duloxetine in the treatment of major depressive disorder

Since depression impacts all body systems, antidepressant treatments should relieve both the emotional and physical symptoms of depression. Duloxetine demonstrated antidepressant efficacy at a dose of 60 mg qd in two placebo-controlled, randomized, double-blind studies and significantly improved remission rates compared with placebo. Duloxetine-treated patients had significant reduction in severity of the symptoms of depression as assessed by the HAM-D₁₇, anxious symptoms as measured by the HAM-A and quality of life measures compared to placebo. Duloxetine also improved somatic symptoms, particularly painful symptoms which may have contributed to significantly improved remission rates compared to placebo. Approximately 10% of the 1139 patients with major depressive disorder in placebo-controlled trials discontinued treatment due to an adverse event, compared to 4% of the 777 patients receiving placebo. In addition to nausea (1.4% incidence), which was the most common reason for discontinuation, dizziness, somnolence, and fatigue were the most common AEs reported as reasons for discontinuation and all were considered drug-related. Duloxetine treatment lacks effects on ECG, increases heart rate, and has little effect on blood pressure or weight.     

Diagnosis and treatment of major depressive disorder

Major depressive disorder is a common illness, particularly in patients with medical and neurologic conditions. This article summarizes current data on the epidemiology, diagnosis, and treatment of major depression, with special emphasis on the diagnosis and treatment of depression in medical and neurologic patients. We reviewed the role of pharmacotherapies, psychotherapies, somatic treatments, and alternative remedies and we included practical advice for clinician regarding the timing and sequence of these treatments, the role of standardized depression scales, and the criteria for referrals to specialty consultants.     

Glucocorticoid and mineralocorticoid receptor expression in the human hippocampus in major depressive disorder

Approximately 50% of mood disorder patients exhibit hypercortisolism. Cortisol normally exerts its functions in the CNS via binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Both MR and GR are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR or GR within this region may contribute to the dysregulation in major depressive disorder (MDD). Studies have also shown functional heterogeneity across the hippocampus, with posterior hippocampus preferentially involved in cognitive processes and anterior hippocampus involved in stress, emotion and affect. We therefore hypothesize that GR and MR expression in hippocampus of control and MDD patients may vary not only with disease, but also with regional specificity along the anterior/posterior axis. Student's t-test analysis showed decreased expression of MR in the MDD group compared to controls in the anterior, but not the posterior hippocampus, with no significant changes in GR. Linear regression analysis showed a marked difference in MR:GR correlation between suicide and non-suicide patients in the posterior hippocampus. Our findings are consistent with previous reports of hippocampal corticosteroid receptor dysregulation in mood disorders, but extend those findings by analysis across the anterior/posterior axis of the hippocampus. A decrease in MR in the anterior but not posterior hippocampus of MDD patients emphasizes the important functional role of the anterior hippocampus in neuroendocrine regulation in humans.     

Challenges and algorithm-guided treatment in major depressive disorder

Major depressive disorder is complicated and difficult to treat, primarily because of its chronic and recurrent nature and the poor efficacy of most pharmacologic treatment options. Until more effective treatments become available, clinicians must focus on optimizing patient outcomes through patient care. Implementing measurement-based care and using treatment algorithms can reduce symptoms of depression and help patients achieve and maintain remission.     

Duloxetine in the long-term treatment of major depressive disorder

BACKGROUND: Depression is a chronic recurring disorder and guidelines recommend long-term therapy. This clinical trial evaluated the long-term (1 year) safety and efficacy of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, in patients with DSM-IV major depressive disorder. METHOD: This was an open-label, 52-week, multinational clinical trial in outpatients (age > or = 18 years) who received duloxetine at 80 mg/day (administered 40 mg twice daily) to 120 mg/day (administered 60 mg twice daily) for up to 1 year. RESULTS: A total of 1279 patients had postbaseline data. Of these, 520 were exposed to duloxetine for at least 360 days, yielding approximately 808 patient-years of total exposure. Mean changes in Clinical Global Impressions-Severity of Illness scale (CGI-S) score, 17-item Hamilton Rating Scale for Depression total score and subfactor scores, Beck Depression Inventory-II score, and Sheehan Disability Scale score and mean Patient Global Impression-Improvement scale (PGI-I) scores all showed highly significant (p <.001) improvements at all assessment times. The estimated probabilities of improvement in CGI-S and PGI-I scores at week 1 were 40.4% and 59.2%, respectively, and at week 2 were 70.0% and 78.3%. The estimated probabilities of remission at weeks 6, 28, and 52 were 50.8%, 75.6%, and 81.8%, respectively. Adverse events led to discontinuation in 218 patients (17.0%). The most frequent specific events leading to discontinuation were nausea (1.5%), somnolence (1.4%), vomiting (0.9%), hypomania (0.8%), pregnancy (0.8%), dizziness (0.6%), insomnia (0.6%), and hypertension (0.5%). Treatment-emergent adverse events that were reported by > 10% of patients included nausea, insomnia, headache, somnolence, dry mouth, dizziness, constipation, sweating increase, anxiety, diarrhea, and fatigue. Most events occurred early in the study. Of those events that first occurred or worsened after discontinuation, only dizziness (8.3%) occurred in more than 5% of patients. Mean changes from baseline to last observation for standing and supine pulse were less than 2 b.p.m. Mean changes in blood pressure (< 1.0 mm Hg), corrected QT interval (< 1 msec), and body weight (2.4 kg [5.3 lb]) were not clinically significant. Laboratory analyses varied across visits, and mean changes after 52 weeks were generally close to zero. The incidence of laboratory values above or below normal limits at any time during treatment was low. CONCLUSION: Duloxetine was effective, safe, and well tolerated in the long-term treatment of major depression at a dose of 80 to 120 mg/day in this study.     

Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment

BACKGROUND: The effects of extended selective serotonin reuptake inhibitor (SSRI) treatment on weight are not well characterized. Also unknown is whether different agents have differential effects. To examine these questions, we assessed weight changes in patients randomly assigned to long-term treatment with fluoxetine, sertraline, or paroxetine. METHOD: Patients (N = 284) with major depressive disorder (DSM-IV) were randomly assigned to double-blind treatment with fluoxetine (N = 92), sertraline, (N = 96), or paroxetine (N = 96) for a total of 26 to 32 weeks. The mean percent change in weight was compared for each group, as was the number of patients who had > or = 7% weight increase from baseline. RESULTS: Patients (fluoxetine, N = 44; sertraline, N = 48; paroxetine, N = 47) who completed the trial were included in these analyses. Paroxetine-treated patients experienced a significant weight increase, fluoxetine-treated patients had a modest but nonsignificant weight decrease, and patients treated with sertraline had a modest but nonsignificant weight increase. The number of patients whose weight increased > 7% from baseline was significantly greater for paroxetine-treated compared with either fluoxetine-treated or sertraline-treated patients. CONCLUSION: Risk of weight gain during extended SSRI treatment differs depending on which SSRI is used.     

Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder

Ahdidan J, Hviid LB, Chakravarty MM, Ravnkilde B, Rosenberg R, Rodell A, Stødkilde‐Jørgensen H, Videbech P. Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder. Objective: To determine whether long‐term course of treated major depression has an effect on the structure of the brain and the hippocampal volume. Method: An 11‐year follow‐up procedure was used with data collection at baseline and again at follow‐up. Tensor‐based morphometry (TBM) and automatic hippocampal volume measure was performed on different datasets. The baseline dataset consisted of T1‐weighted magnetic resonance images (MRIs) of 24 in‐patients suffering from major depression and 33 healthy controls. The second dataset consisted of T1‐weighted MRIs of 31 remitted depressive patients and 36 healthy controls. The longitudinal dataset consisted of 19 patients and 19 matched healthy controls present at both the first and the second dataset. Brain segmentation and hippocampal segmentation were fully automated and were based on a spatial normalization to the International Consortium of Brain Mapping (ICBM) non‐linear model. Results: Depressed patients were found to have smaller temporal lobes bilaterally, medulla and right hippocampus at baseline. However, these changes were not found at follow‐up 11 years later. Moreover, these changes did not significantly correlate with the illness outcome. Conclusion: Brain structure changes seem to be state dependent in major depression, only occurring in acute episode of major depression and normalizing after remission.     

Augmentation treatment in major depressive disorder: focus on aripiprazole

Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.     

Impact of medical comorbid disease on antidepressant treatment of major depressive disorder

A major factor in evaluating and treating depression is the presence of comorbid medical problems. In this paper, the authors will first evaluate studies showing that medical illness is a risk factor for depression. The authors will review a series of randomized, controlled studies of antidepressant treatment in subjects with major depressive disorder (MDD) and comorbid medical illnesses (myocardial infarction, stroke, diabetes, cancer, and rheumatoid arthritis). Most of these studies report an advantage for an active antidepressant over placebo in improvement of depressive symptoms. The authors also will review a series of studies in which the outcome of antidepressant treatment is compared between subjects with MDD with and without comorbid medical illness. In these studies, subjects with medical illness tend to have lower improvement of depressive symptoms and higher rates of depressive relapse with antidepressant treatment compared with MDD subjects with no medical comorbidity. In addition, the authors will review hypotheses on the mechanism of the interaction between medical illness and clinical response in MDD. The paper will conclude that medical comorbidity is a predictor of treatment resistance in MDD.     

Pretreatment frontal EEG and changes in suicidal ideation during SSRI treatment in major depressive disorder

Objective: We investigated frontal quantitative EEG (QEEG) as predictor of changes in suicidal ideation (SI) during SSRI treatment in major depressive disorder (MDD). Method: Eighty‐two subjects meeting DSM‐IV criteria for MDD entered an 8‐week, prospective, open‐label treatment with flexible dose SSRIs and completed at least 4 weeks of treatment. We assessed MDD severity with the 17‐item Hamilton Depression Rating Scale (HAM‐D‐17); change in SI was measured with HAM‐D item no. 3. We recorded four‐channel EEGs (F7‐Fpz, F8‐Fpz, A1‐Fpz, A2‐Fpz) before treatment. Results: During the first 4 weeks of treatment 9 (11%) subjects experienced worsening SI. Left‐right asymmetry of combined theta + alpha power correlated significantly with change in SI from baseline, even when adjusting for changes in depression severity (HAM‐D‐17) and for the SSRI utilized. Conclusion: Frontal QEEG parameters before treatment may predict worsening SI during SSRI treatment in MDD.     

Duloxetine in the acute and continuation treatment of major depressive disorder

Duloxetine is a serotonin-noradrenaline reuptake inhibitor with indications for use in the short term, continuation and maintenance treatment of major depression. Although clinicians currently have access to a range of medications for the treatment of depression, a significant number of patients fail to respond or remit from their illness despite adequate trials of treatment with multiple agents. A developing concept is that antidepressant strategies that combine multiple mechanisms of action may have advantages over agents with single mechanisms (i.e., selective serotonin reuptake inhibitors). As a dual-acting agent, duloxetine offers the promise of advantages in terms of efficacy over selective serotonin reuptake inhibitors while retaining a favorable safety and tolerability profile in comparison to older agents. Likewise, duloxetine is of interest in the treatment of certain conditions commonly seen in conjunction with major depression, particularly anxiety and pain, both of which may respond more favorably to agents that act on both serotonin and noradrenaline neurotransmitter systems.     

Escitalopram in the long-term treatment of major depressive disorder.

BACKGROUND: Escitalopram has been proven safe and efficacious in the treatment of major depressive disorder (MDD) in short-term studies. The long-term clinical tolerability and response to treatment are presented from a 12-month open-label study with a total exposure time to escitalopram of 486 patient years. METHODS: Patients (n = 590) with MDD entered the study after completing one of two 8-week, double-blind, placebo-controlled, lead-in studies in primary care. Escitalopram was administered at doses of 10 or 20 mg/day (dose based on physician's clinical judgement) with an average exposure to escitalopram of 315 days. The primary efficacy parameter was the Montgomery Asberg Depression Rating Scale (MADRS) total score. RESULTS: The overall withdrawal rate was 26%; and the withdrawal rate due to adverse events was 9%. The most common adverse events were headache, back pain, upper respiratory tract infection, rhinitis and nausea, with an incidence ranging from 11% to 17%. No new types of adverse events were seen after the acute period of 8 weeks, and the incidence declined with time. At baseline (entry into the 12-month study), patients had a mean MADRS total score of 14.2, which decreased to 10.5 after 8 weeks and 7.2 after 52 weeks (LOCF). The percentage of patients in remission (MADRS total score 相似文献   

Transdermal selegiline for the treatment of major depressive disorder

Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the “cheese reaction”) when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM^®) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6–12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral MAO inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants.     

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = ?0.164 to ?0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = ?0.173 to ?0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.     

Qualitative changes in symptomatology as an effect of treatment with escitalopram in generalized anxiety disorder and major depressive disorder

The purpose of this article is to examine the similarities and differences between patients with Major Depressive Disorder (MDD) versus Generalized Anxiety Disorder (GAD) versus MDD with anxiety symptoms. Data were analysed from all randomized double-blind clinical studies with escitalopram that measured symptoms using either Hamilton Anxiety Scale (HAMA) or Montgomery-Asberg Depression Rating Scale (MADRS). The contribution of each item of a scale to the total score was calculated before and after treatment, in remitters. Most single items of the HAMA contribute nearly equally in patients with GAD. In patients with MDD, four symptoms (i.e. anxious mood, tension, insomnia and concentration) contribute to most to the HAMA total score. In patients with GAD, three symptoms (tension, sleep and concentration) contribute two-thirds of the MADRS total score. In contrast, most MADRS items contribute equally to the total score in patients with MDD. After treatment to remission, the profile of residual symptoms MDD or GAD was similar to the symptom profile before treatment. Anxiety symptoms are very common in patients with MDD or GAD, and the symptomatic pattern is similar. In both disorders, the symptomatic pattern of residual symptoms is similar to the pattern of symptoms before treatment.     

Depression and major depressive disorder in patients with Parkinson's disease

The prevalence of depression in Parkinson's disease (PD) varies greatly. In this study, we investigated major depressive disorder (MDD) and depressive symptoms without MDD in patients with PD. The psychopathological characteristics of depressive symptoms were assessed by a psychiatric interview. A total of 105 Japanese patients with PD without dementia were included. The Japanese version of the Beck Depression Inventory‐II (BDI‐II) with a cutoff score of 13/14 was used to screen for depression. Using a structured interview, a comprehensive psychiatric evaluation of patients with BDI‐II scores >13 (high BDI patients) was completed using the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)‐IV‐TR. Forty patients (38%) had a BDI‐II >13, but 29 did not show any depressed mood. Five cases met the criteria for MDD (three current, two past) and one patient was diagnosed with minor depressive disorder. A slight depressed mood that was associated with worrying about PD was seen in 6 of 34 patients without any depressive disorder and fluctuated with aggravation of PD symptoms in two of these patients. For the diagnosis of MDD, the number of positive items from the DSM‐IV‐TR definition of MDD is most important and useful for differentiating MDD and non‐MDD. The low‐prevalence rate of MDD in our patient population suggests that PD may be a psychological stressor for MDD, but does not necessarily induce MDD. © 2009 Movement Disorder Society     

Maternal depressive symptoms in pediatric major depressive disorder: relationship to acute treatment outcome

Objective:In the present study, we assess maternal depressive symptoms at the beginning and end of treatment to investigate the possible reciprocal relationship of maternal illness with the child's depressive illness and treatment.Method:We present data on 146 children and their mothers who were participating in a pediatric acute treatment study of fluoxetine. Patients were assessed with the Children's Depression Rating Scale-Revised at baseline and at each treatment visit. Mothers completed the Quick Inventory of Depressive Symptomatology-Self Report at baseline and end of acute treatment.Results:Thirty percent of mothers had moderate to severe levels of depressive symptoms at the child's baseline assessment. Overall, mothers reported improvement in maternal depressive symptoms at the end of their child's acute treatment, although maternal depression was not specifically targeted for intervention. Furthermore, mother's depressive symptoms appear to be associated with the child's depression severity both at the beginning and end of treatment. Mothers with higher levels of depressive symptoms had children with higher levels of depression severity at baseline and over the course of treatment. However, maternal depressive symptoms at baseline had no association with the rate of improvement of child depression severity.Conclusions:This study indicates a positive relationship between the depression severity of mothers and their children. These findings highlight potential areas of intervention in the acute treatment of childhood depression.     

Affective state-dependent changes in the brain functional network in major depressive disorder

In major depressive disorder (MDD), as a network-level disease, the pathophysiology would be displayed to a wide extent over the brain. Moreover, the network-wide changes could be dependent on the context of affective processing. In this study, we sought affective state-dependent changes of the brain functional network by applying a graph-theoretical approach to functional magnetic resonance imaging data acquired in 13 patients with MDD and 12 healthy controls who were exposed to video clips inducing the negative, neutral or positive affective state. For each affective condition, a group-wise brain functional network was constructed based on partial correlation of mean activity across subjects between brain areas. Network parameters, global and local efficiencies, were measured from the brain functional network. Compared with controls’, patients’ brain functional network shifted to the regular network in the topological architecture, showing decreased global efficiency and increased local efficiency, during negative and neutral affective processing. Further, the shift to the regular network in patients was most evident during negative affective processing. MDD is proposed to provoke widespread changes across the whole brain in an affective state-dependent manner, specifically in the negative affective state.