Duloxetine-induced liver injury in patients with major depressive disorder

Duloxetine is a balanced serotonin-norepinephrine reuptake inhibitor. Duloxetine-induced liver injury in patients with preexisting liver disease or chronic alcohol use is known. However, we have found that duloxetine can also induce liver injury in cases without those risk factors. We recommend that clinicians should monitor liver function carefully following duloxetine treatment.     

A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder

The efficacy, tolerability, and safety of LY2216684, a highly selective norepinephrine reuptake inhibitor, were studied in adult patients with major depressive disorder (MDD). This randomized, double-blind study compared flexible-dose LY2216684 6-18 mg once daily (N = 250) with placebo (N = 245) for 10 weeks acute therapy followed by 1 year LY2216684 treatment (results not reported here). Primary inclusion criteria consisted of GRID 17-item Hamilton Rating Scale for Depression total score ≥18 and Clinical Global Impressions-Severity score ≥4. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Response was defined as a ≥50% reduction in MADRS score and remission as MADRS total score ≤10. Global functioning was assessed using the Sheehan Disability Scale (SDS). LY2216684-treated patients showed significant improvement from baseline on the MADRS total score compared with placebo-treated patients (−13.3 vs. −9.8, p < .001), and they had a significantly higher probability of achieving response (49.5%) and remission (29.7%) compared with placebo-treated patients (29.3% and 18.8%, respectively). For the SDS global functional impairment score, LY2216684 treatment resulted in significantly greater improvement compared with placebo treatment (p < .001). More LY2216684-treated than placebo-treated patients discontinued from the study because of an adverse event or death (9.6% vs. 1.6%, p ≤ .001). LY2216684 was associated with significant increases (p < .01) from baseline in systolic (3 mm Hg) and diastolic (4 mm Hg) blood pressure and pulse (10 bpm) compared with placebo. LY2216684 6-18 mg demonstrated significant efficacy and was tolerated in the treatment of MDD.     

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD₁₇), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD₁₇ total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.     

A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder

BACKGROUND: Clinical trials assessing antidepressant therapies typically include separate assessments of efficacy (benefit) and adverse events (risk). Global benefit-risk (GBR) assessment allows the simultaneous evaluation of both efficacy and adverse events. The objective was to compare the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine using GBR assessment. METHODS: Data were combined from two similarly designed, multicenter, randomized, double-blind, parallel group studies in which patients with major depressive disorder were randomized to either duloxetine 60 mg/day or venlafaxine extended release (XR) 150 mg/day (75 mg/day for the first 2 weeks) for a 6-week fixed dosing period followed by an additional 6 weeks of treatment in which the dose could be increased up to 120 mg/day for duloxetine and 225 mg/day for venlafaxine. Patients completing the study (or receiving study drug for 2 weeks or more) were eligible to enter a taper period where the dose of study drug was gradually reduced over 1-2 weeks prior to drug discontinuation. The primary outcome measure (defined a priori) was the GBR comparison of duloxetine 60 mg/day and venlafaxine XR 150 mg/day after 6 weeks of treatment. In the GBR analysis, benefit was defined as remission at endpoint [17-item Hamilton Depression Rating Scale (HAMD17) 7]. Risk was defined by four categories: patients having either no adverse events (AEs), AEs with no severity rating greater than moderate, AEs with at least one severity rating of severe, or having discontinued with a reason of self-reported adverse event (regardless of any AE severity). Additional efficacy measures included HAMD17 total score and subscales, HAMA, CGI-S, and PGI-I. Safety and tolerability were assessed via analysis of reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. RESULTS: There were no significant differences between duloxetine 60 mg/day and venlafaxine 150 mg/day as measured by GBR assessment at the end of 6 weeks (-1.418 vs. -1.079, P = 0.217) or 12 weeks (-0.349 vs. -0.121, P = 0.440), nor were there significant differences between treatment groups on the majority of efficacy measures. Significantly more venlafaxine-treated patients (74.5%) completed 12 weeks of treatment compared with duloxetine-treated patients (64.8%, P =.006). Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. From a safety perspective, significantly more venlafaxine-treated patients (n = 4) than duloxetine-treated patients (n=0, P =.047) experienced sustained elevations of systolic blood pressure during the fixed dosing period. Otherwise, there were few significant differences in safety measures found between treatment groups during 6 and 12 weeks of therapy. CONCLUSIONS: Duloxetine 60 mg/day and venlafaxine XR 150 mg/day have similar benefit-risk profiles on the basis of a comparison utilizing GBR assessment. The implications of the more subtle differences between these drugs, as well as for interpreting the GBR assessment, are discussed.     

具有抗炎作用的药物在抑郁症治疗中的研究进展

抑郁症是常见的精神疾病之一,其发病机制尚未完全明确,机体炎症水平升高是目前公认的抑郁症发病机制之一。大量研究表明,非甾体类抗炎药、ω-3脂肪酸、他汀类药物、吡格列酮、米诺环素、N-乙酰半胱氨酸、皮质类固醇等药物可能通过抗炎作用发挥抗抑郁疗效。本文就上述药物在抗抑郁治疗中的应用进行综述,探讨具有抗炎作用的药物对抑郁症治疗的效果及其可能的作用机制,为未来抗炎干预在抑郁症治疗中的应用提供参考。     

Topological network mechanisms of clinical response to antidepressant treatment in drug-naive major depressive disorder

AimThere is rapidly increasing evidence that remission of MDD is associated with substantial changes in functional brain connectivity. These New data have provided a holistic view on the mechanism of antidepressants on multiple levels that goes beyond their conventional effects on neurotransmitters.MethodThe study was approved by the Local Ethics Committee of Istanbul Medipol University (10840098-604.01.01-E.65129) and followed the Helsinki Declaration principles. In our study, we have evaluated the effect of six weeks of treatment with antidepressants (escitalopram and duloxetine), and tested the underlying brain functional connectivity through a Graph analysis approach in a well-defined first-episode, drug-naive, and non-comorbid population with MDD.ResultsBeyond indicating that there was a significant correlation between the antidepressant response and topological characteristics of the brain, our results suggested that global rather than regional network alterations may be implicated in the antidepressant effect.ConclusionDespite the small-sample size and non-controlled study design, our study provides important and relevant clinical data regarding the underlying mechanisms of the antidepressants on topological dynamics in the human brain.     

Cholestatic jaundice induced by duloxetine in a patient with major depressive disorder

Duloxetine is a balanced and potent serotonin and noradrenaline reuptake inhibitor (SNRI) and has adverse effects that are commonly associated with such drugs, including nausea, dry mouth, constipation, insomnia, and dizziness. Recently, duloxetine-induced liver injury has also been observed in patients with preexisting liver disease or chronic alcohol use. We investigated the effects of duloxetine in a healthy young adult with major depressive disorder (MDD) but no risk factors, and found that his total bilirubin level increased to 3.3 mg/dL and he developed jaundice after 5 months of duloxetine treatment. Discontinuation of duloxetine treatment saw his total bilirubin level decrease to 1.8 mg/dL. Thus, the administration of duloxetine might induce liver injury in a patient with MDD. However, the limitations of this single case report must be acknowledged. Although the cause of hepatic dysfunction in this case remains to be elucidated, clinicians should monitor liver function carefully after duloxetine treatment. Further investigations with a larger sample are needed.     

Predictors of depressive symptoms at hospital discharge in patients with major depressive disorder

Abstract

Objective. Often patients with major depressive disorder (MDD) leave the hospital with continued significant symptomatology. This study sought to evaluate demographic, clinical, and psychosocial predictors of the presence of clinically significant depressive symptoms, defined as a Modified Hamilton Rating Scale for Depression score of ≥ 14, immediately following hospitalization for MDD. Methods. The study enrolled 135 patients with MDD as part of a larger clinical trial investigating the efficacy of post-hospitalization pharmacologic and psychosocial treatments for depressed inpatients. Structured clinical interview and self-report data were available from 126 patients at hospital admission and discharge. Results. Despite the significant decreases in depressive symptoms over the course of hospitalization, 91 (72%) displayed clinically significant depressive symptoms at discharge. Multivariate logistic regression analysis revealed that female sex, earlier age of onset, and poorer social adjustment were unique predictors of symptom outcome. Conclusions. Results suggest that a large proportion of patients leave the hospital with continued significant symptomatology, and the presence of such symptoms following hospitalization for MDD is likely to be explained by a combination of factors.     

重复经颅磁刺激或无抽搐电休克治疗联合抗抑郁药物对重度抑郁障碍的疗效和安全性

背景 重度抑郁障碍是致残性最强的精神疾病之一,目前对该病的治疗多采用药物联合物理治疗和心理治疗,关于物理治疗之间的对照研究较少,药物联合物理治疗的对照研究更少。目的 探讨重复经颅磁刺激（rTMS）和无抽搐电休克治疗（MECT）分别联合抗抑郁药物对重度抑郁障碍的疗效和安全性,以期为重度抑郁障碍患者提供更优的治疗方案。方法 连续选取2019年1月1日—2023年4月30日在山东省戴庄医院住院治疗的、符合《国际疾病分类（第10版）》（ICD-10）诊断标准的重度抑郁障碍患者（n=335）。入院后,患者根据病情接受MECT联合药物治疗（n=141）或rTMS联合药物治疗（n=194）。于基线期及治疗第1、2、3、4周末,采用汉密尔顿抑郁量表24项版（HAMD-24）评定抑郁症状,阅读患者病程记录,了解不良反应发生情况。结果 两组HAMD-24评分的时间效应有统计学意义（F=3.081,P=0.042）,组间效应无统计学意义（F=1.023,P=0.313）,时间与组间的交互效应无统计学意义（F=1.642,P=0.191）。治疗后各时点,两组显效率及痊愈率比较,差异均无统计学意义（P均>0.05）。在整个治疗过程中,MECT联合药物组中,有58人（41.13%）出现近记忆力受损,74人（52.48%）出现头痛或颈部肌肉痛;rTMS联合药物组中,27人（13.92%）出现头痛或头皮不适。结论 rTMS联合抗抑郁药物与MECT联合抗抑郁药物治疗重度抑郁障碍的效果相当,rTMS联合抗抑郁药物的安全性更高。     

阿戈美拉汀治疗重度抑郁症的临床疗效

目的 探讨新型抗抑郁药物阿戈美拉汀在治疗重度抑郁患者方面的临床疗效和安全性.方法 选取我院2013年2月～2014年2月收住院的重度抑郁症患者58例随机分为两组,研究组应用阿戈美拉汀25～50mg/d,平均剂量（46.36±4.48）mg/d,对照组选用艾司西酞普兰10～20mg/d,平均剂量（16.83±2.94）mg/d,均治疗8周.治疗前及治疗后第2,4,8周分别采用汉密尔顿抑郁量表（HAMD-17）对两组进行评估,在治疗过程中应用治疗不良反应量表（TESS）进行测量.结果 治疗2周后研究组HAMD减分为（8.36±4.07）分,对照组为（6.19±3.68）分,两组减分情况比较差异有统计学意义（q=3.38,P＜0.05）.治疗8周后阿戈美拉汀组HAMD减分为（18.15±4.29）分,艾司西酞普兰组HAMD减分为（16.26±3.83）分,两组减分情况比较差异有统计学意义（q=4.12,P＜ 0.05）.药物安全性方面,研究组主要不良反应依次是头痛（5例）、便秘（4例）和肝功能异常（3例）;对照组主要不良反应依次是头痛（9例）、恶心呕吐（6例）和血压升高（5例）.TESS总分比较,研究组（3.42±1.24）分低于对照组（4.08±1.69）分,差异有统计学意义（t=7.45,P＜0.01）.结论 阿戈美拉汀在治疗重度抑郁症方面,较艾司西酞普兰起效快,疗效明显,不良反应少.     

The 'resting-state hypothesis' of major depressive disorder-a translational subcortical-cortical framework for a system disorder

Major depressive disorder (MDD) has traditionally been characterized by various psychological symptoms, involvement of diverse functional systems (e.g., somatic, affect, cognition, reward, etc.), and with progress in neuroscience, an increasing number of brain regions. This has led to the general assumption that MDD is a stress–responsive brain ‘system disorder’ where either one or several alterations infiltrate a large number of functional systems in the brain that control the organism's somatic, affective, and cognitive life. However, while the effects or consequences of the abnormal changes in the functional systems of, for instance affect, cognition or reward have been investigated extensively, the underlying core mechanism(s) underlying MDD remain unknown. Hypotheses are proliferating rapidly, though. Based on recent findings, we will entertain an abnormality in the resting-state activity in MDD to be a core feature. Based on both animal and human data, we hypothesize that abnormal resting-state activity levels may impact stimulus-induced neural activity in medially situated core systems for self-representation as well as external stimulus (especially stress, specifically separation distress) interactions. Moreover, due to nested hierarchy between subcortical and cortical regions, we assume ‘highjacking’ of higher cortical affective and cognitive functions by lower subcortical primary-process emotional systems. This may account for the predominance of negative affect in somatic and cognitive functional system operations with the consecutive generation of the diverse symptoms in MDD. We will here focus on the neuroanatomical and biochemical basis of resting-state abnormalities in MDD including their linkage to the diverse psychopathological symptoms in depression. However, our ‘resting-state hypothesis’ may go well beyond that by being sufficiently precise to be linked to genetic, social, immunological, and endocrine dimensions and hypotheses as well as to clinical dimensions like endophenotypes and various diagnostic-prognostic biomarkers. Taken together, our ‘resting-state hypothesis’ may be considered a first tentative framework for MDD that integrates translational data, the various dimensions, and subcortical–cortical systems while at the same time providing the link to the clinical level of symptoms, endophenotypes and biomarkers.     

Serum brain-derived neurotrophic factor level in dysthymia: a comparative study with major depressive disorder

In this present work, it is aimed to demonstrate BDNF serum concentrations in patients with dysthymia and to compare them with BDNF serum concentrations in patients with major depressive disorder and healthy subjects. The study was carried out in Celal Bayar University Hospital, Manisa, Turkey. Seventeen patients with dysthymia, 24 patients with major depressive disorder and 26 subjects without any psychiatric diagnosis and any psychiatric treatment were included in the study. The severity of depression was assessed with 17-item HAM-D. All subjects were asked to give their written consent. Blood samples were collected at baseline. Serum BDNF was kept at -70 degrees C before testing, and assayed with an ELISA Kit (Promega; Madison, WI, USA), after dilution with the Block and Sample solution provided with the kit. The data were subjected to the analysis of variance. The BDNF serum concentrations of the dysthymia group (mean=28.9+/-9.2 ng/ml) were significantly higher than that of the major depressive disorder group (21.2+/-11.3 ng/ml) (p=0.002), and it was not different from the level of the control group (31.4+/-8.8 ng/ml). BDNF serum concentrations and HAM-D score did not have any significant correlation in the dysthymia and major depression groups (r=-0.276, p=0.086). The low level of BDNF in patients with dysthymic disorder seems to point out that BDNF changes in mood disorders are state-dependent and vary according to the severity of depressive episodes.     

抑郁症的睡眠质量及其相关影响因素

目的了解保定市抑郁症睡眠质量特点及其相关影响因素。方法采用多阶段分层整群抽样方法随机抽取≥18周岁的人群，共10073名，用扩展的一般健康问卷（GHQ-12）将调查对象分为高、中、低危险组，以美国精神障碍诊断与统计手册-第四版（DSM—Ⅳ）轴Ⅰ障碍定式临床检查病人版（SCID—L／P）对调查对象进行抑郁症的诊断。以匹兹堡睡眠质量指数（PSQI）评定睡眠质量。结果8773人完成了TPSQI调查，抑郁症现患125例，睡眠障碍（PSQI总分〉7）的发生比率为68．8％；PSQI总分与有无支持群体、社会环境、教育、职业、住房、经济、卫生保健、法律与犯罪等社会心理与环境问题无相关。结论睡眠障碍是抑郁症的常见症状，受社会心理与环境问题的影响较小。     

Adjunctive atomoxetine for residual fatigue in major depressive disorder

OBJECTIVE: To assess the effectiveness and safety of atomoxetine as an adjunctive medication for residual fatigue in a naturalistic treatment setting. METHODS: A retrospective chart review was conducted to identify major depressive disorder (MDD) patients who had experienced significant symptom improvement (either partial response or remission) following treatment with conventional antidepressants but who were continuing to complain of fatigue. Fourteen such patients (42.2+/-13.4 years of age, five women, baseline HDRS 6.2+/-2.4) with a 17-item Hamilton Depression Rating Scale (HDRS17)<11 who received adjunctive atomoxetine for fatigue were included in the report. Antidepressants augmented were the selective serotonin reuptake inhibitors (SSRIs) (n=11; 78.6%), mirtazapine (n=2, 14.3%), and amitriptyline (n=1, 7.1%). RESULTS: Twelve (85.7%) patients (nine remitters, three partial responders) received at least 4 weeks of atomoxetine treatment. The remaining two (partial responders) discontinued atomoxetine within 1-3 days due to increased anxiety. The brief fatigue inventory (BFI) and Clinical Global Impressions Scale (CGI) were administered when atomoxetine was first prescribed, and following 4-10 weeks of treatment (mean of 5.4+/-1.8 weeks). There was a significant decrease in BFI scores (41.9+/-14.9 versus 24.3+/-13.4, p=0.0015), and HDRS-17 scores (6.2+/-2.4 versus 3.5+/-2.8, p=0.0466), but not CGI-S scores (1.3+/-1.4-1.0+/-0.0, p=0.08) following treatment with atomoxetine. 5/12 (41.6%) patients had a 50% or greater decrease in BFI scores. All 12 patients were remitters at follow-up. The mean atomoxetine dose was 42.8+/-10.6 mg. Side effects included insomnia (n=6), increased anxiety (n=3), nausea (n=1) and dry mouth (n=1). CONCLUSIONS: Although preliminary, these results suggest a possible augmentation role for atomoxetine when used in conjunction with conventional antidepressants for residual fatigue in MDD. Prospective as well as controlled studies are necessary to further explore the role of atomoxetine augmentation in MDD.     

Metabolic syndrome in subjects with bipolar disorder and major depressive disorder in a current depressive episode: Population-based study: Metabolic syndrome in current depressive episode

ObjectiveTo assess the differences in the prevalence of the metabolic syndrome (MetS) and their components in young adults with bipolar disorder (BD) and major depressive disorder (MDD) in a current depressive episode.MethodsThis was a cross-sectional study with young adults aged 24–30 years old. Depressive episode (bipolar or unipolar) was assessed using the Mini International Neuropsychiatric Interview – Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III).ResultsThe sample included 972 subjects with a mean age of 25.81 (±2.17) years. Both BD and MDD patients showed higher prevalence of MetS compared to the population sample (BD = 46.9%, MDD = 35.1%, population = 22.1%, p < 0.001). Higher levels of glucose, total cholesterol and LDL cholesterol, Body Mass Index, low levels of HDL cholesterol, and a higher prevalence of abdominal obesity were observed in both BD and MDD individuals with current depressive episode compared to the general population. Moreover, there was a significant difference on BMI values in the case of BD and MDD subjects (p = 0.016).ConclusionMetabolic components were significantly associated with the presence of depressive symptoms, independently of the diagnosis.     

Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder

Major depressive disorder (MDD) is highly prevalent and is a significant cause of mortality and morbidity worldwide. Currently, conventional pharmacological treatments for MDD produce temporary remission in < 50% of patients; therefore, there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms. Accumulated evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. In this review, we summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating the inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD, and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.     

Comorbid posttraumatic stress disorder and major depressive disorder: The usefulness of a sequential treatment approach within a randomised design

Cognitive Processing Therapy (CPT) and Behavioural Activation Therapy (BA) were used to treat individuals with comorbid posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Fifty-two individuals (48 women, 4 men) were randomized to CPT alone (n = 18), CPT then BA for MDD (n = 17), or BA then CPT (n = 17). Presenting trauma was primarily interpersonal (87 %). Participants were assessed at pre-, posttreatment, and 6-month follow-up. PTSD and MDD symptoms were the main outcome of interest; trauma cognitions, rumination, and emotional numbing were secondary outcomes. All groups showed sizeable reductions in PTSD and depression (effect sizes at follow-up ranging between 1.02–2.54). A pattern of findings indicated CPT/BA showed better outcomes in terms of larger effect sizes and loss of diagnoses relative to CPT alone and BA/CPT. At follow-up greater numbers of the CPT/BA group were estimated to have achieved good end-state for remission of both PTSD and depression (49 %, CI₉₅ [.26, .73]) relative to CPT alone (18 %, CI₉₅ [.03, .38]) and BA/CPT (11 %, CI₉₅ [.01, .29]). Although tempered by the modest sample size, the findings suggest that individuals with comorbid PTSD and MDD may benefit from having PTSD targeted first before remaining MDD symptoms are addressed.     

Duloxetine for the treatment of major depressive disorder: safety and tolerability associated with dose escalation

Duloxetine has demonstrated efficacy for the treatment of major depressive disorder (MDD) at a dose of 60 mg/day (given once daily). Whereas the target dose for the majority of patients is 60 mg/day, higher duloxetine doses (up to 120 mg/day) have been studied using a twice-daily dosing schedule. To further investigate the pharmacological profile of duloxetine within a once-daily dosing regimen at doses above 60 mg, we examined the safety and tolerability of duloxetine during a dose escalation from 60 mg/day to 120 mg/day. This single-arm, non-placebo-controlled study incorporated a 7-week dose escalation phase, in which patients and investigators were blinded as to timing of dose increases, followed by an open-label extension phase of up to 2 years duration. Patients (age >or=18 years) meeting DSM-IV criteria for MDD (n=128) received placebo for 1 week, followed by duloxetine (60 mg/day) titrated after 1 week to 90 mg/day, and after a further week to 120 mg/day. The dose of 120 mg/day was then maintained for 4 weeks. The extension phase comprised an initial 6-week dose stabilization period, during which duloxetine was tapered to the lowest effective dose, followed by continuation therapy at the stabilized dose. We assessed safety using spontaneously reported treatment-emergent adverse events (TEAEs), changes in vital signs, electrocardiograms (ECGs), laboratory analytes, and visual analogue scales (VAS) for gastrointestinal (GI) disturbance. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and VAS assessments of pain severity and interference. The rate of discontinuation due to adverse events during the acute phase of the study was 15.6%. The most frequently reported TEAEs were nausea, headache, dry mouth, dizziness, and decreased appetite. The majority of TEAEs were associated with initial duloxetine dosing; further escalations in dose produced few additional adverse events. VAS measures of GI disturbance worsened significantly compared with baseline values after 1 week of duloxetine treatment. Subsequent assessments of GI disturbance, following dose escalation to 90 mg/day and 120 mg/day, showed either no significant difference or a significant improvement from baseline. Significant improvements (P<.001) were observed in all assessed depression efficacy measures, and in five of six VAS pain outcomes, during acute phase treatment. During 2 years of extension phase therapy, the rate of discontinuation due to adverse events was 11.9%, and the only TEAEs reported by >10% of patients were upper respiratory tract infection (13.1%), headache (10.7%), and insomnia (10.7%). Mean changes from baseline to the end of the extension phase in supine systolic and diastolic blood pressure were 3.8 and 0.5 mm Hg, respectively, and there were no reports of sustained hypertension. Mean increase in heart rate was 5.9 bpm, while patients exhibited a mean weight increase of 3.1 kg over 2 years of treatment. Results from this study suggest that rapid dose escalation of duloxetine (60 mg/day --> 90 mg/day --> 120 mg/day) is safe and tolerable. Despite weekly escalation, the majority of adverse events were mild and transient and occurred in the first week of duloxetine dosing (at 60 mg once daily). Long-term treatment at a stabilized duloxetine dose was associated with a relatively low incidence of TEAEs and treatment discontinuation due to adverse events. Time course profiles of body weight and heart rate showed modest increases during 2 years of treatment [ClinicalTrials.gov number, NC T000 42575].     

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.