Numerous double-blind studies have assessed the efficacy of antidepressants in treating chronic depressive disorder, including dysthymic disorder, low-grade chronic depression. However, there are no double-blind, placebo-controlled studies of serotonin-norepinephrine reuptake inhibitors in chronic depressive disorder.
Outpatients with chronic depressive disorder, but without concurrent major depressive disorder (MDD), were randomly assigned to prospective double-blind duloxetine (beginning at 30 mg/d, increased to a maximum dose of 120 mg/d) versus placebo for 10 weeks. Inclusion criteria were current DSM-IV-TR diagnosis of dysthymic disorder or depression not otherwise specified, age 18-75 years, and a Hamilton Depression Rating Scale (HDRS) score ≥ 12. Exclusion criteria included current major depression. The study was conducted between August 2006 and December 2011. HDRS, Cornell Dysthymia Rating Scale (CDRS), Clinical Global Impressions (CGI), Beck Depression Inventory (BDI), Global Assessment of Functioning (GAF), Social Adjustment Scale (SAS), and other assessments were administered at each visit. We hypothesized that duloxetine would be superior to placebo in (1) 24-item HDRS total score, (2) the percentage of subjects classified as responders and remitters, and (3) secondary measures (CDRS, BDI, CGI). Response was defined as > 50% decrease in 24-item HDRS and CGI-Improvement scale score of 1 or 2 ("very much improved" or "much improved"). Remission was defined as HDRS-17 item score ≤ 4 and 0 on item 1 of the HDRS (depressed mood).
65 subjects were enrolled, of whom 57 began medication. They ranged in age from 19 to 70 years (mean ± SD = 41.63 ± 11.22) and included 24 women and 33 men. Baseline 24-item HDRS score (mean ± SD) for both groups was 20.75 ± 4.92. After 10 weeks, duloxetine-treated subjects had significantly lower 24-item HDRS scores than placebo-treated subjects (time-by-drug group effect on analysis of variance: F1,55 = 9.43, P = .003). Responder and remitter analyses significantly favored duloxetine treatment. The response rate was 65.5% for duloxetine versus 25.0% for placebo (χ(2)(1) = 9.43, P = .003); and the remitter rate was 55.2% for duloxetine versus 14.3% for placebo (χ(2)(1) = 10.46, P = .002). After 10 weeks, duloxetine-treated subjects did not differ significantly better from placebo-treated subjects on the SAS (time-by-drug group effect on analysis of variance: F(1,46) = 0.35, P = .555) or on the GAF (time-by-drug group effect on analysis of variance: F(1,51) = .01, P = .922).
Results on the 24-item HDRS, CGI, and CDRS suggest that duloxetine is efficacious in acute treatment of chronic nonmajor depressive disorder. Response and remission rates also differed significantly, favoring duloxetine treatment, but BDI, GAF, and social functioning (Social Adjustment Scale) did not. Duloxetine appears to be effective in acute treatment of nonmajor chronic depression.
ClinicalTrials.gov identifier: NCT00360724.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. OBJECTIVE To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity. DESIGN After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011. SETTING University research institute. PARTICIPANTS Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex. MAIN OUTCOME MEASURES We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity. RESULTS Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brain's DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity. CONCLUSIONS AND RELEVANCE The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.
[Show abstract][Hide abstract] ABSTRACT: Objective:
We evaluated the efficacy and side effects of the selective serotonin and norepinephrine reuptake inhibitor antidepressant duloxetine in older adults with dysthymic disorder.
Patients ≥ 60 years old with dysthymic disorder received flexible dose duloxetine 20-120 mg daily in an open-label 12-week trial. The main outcomes were change from baseline to 12 weeks in 24-item Hamilton Depression Rating Scale scores and Treatment Emergent Symptoms Scale scores. Response required ≥ 50% decline in Hamilton Depression Rating Scale scores with a Clinical Global Impression of much improved or better, and remission required final Hamilton Depression Rating Scale ≤ 6. Intent-to-treat analyses were conducted with the last observation carried forward.
In 30 patients, the mean age was 70.7 (standard deviation (SD) = 7.6) years and 56.7% were female. In intent-to-treat analyses, there were 16 responders (53.3%) and 10 remitters (33.3%). Of these, 19 patients completed the trial. The mean maximum dose was 76.3 mg (SD = 38.5) in the total sample and 101 mg (SD = 17.9) in completers. In the total sample, the mean final dose was 51 mg (SD = 27.2) and correlated significantly with decline in Hamilton Depression Rating Scale (p < .03); decline in Hamilton Depression Rating Scale correlated significantly with decline in Treatment Emergent Symptoms Scale (p < .001). Daily doses above 60 mg were associated with greater improvement and well tolerated. This result was partly confounded by early dropouts having received low doses. Demographic and medical comorbidities, including cardiac disease and hypertension, were not related to response. Somatic side effects were common prior to duloxetine treatment and improved rather than worsened with duloxetine. There were no serious adverse events.
Duloxetine at relatively high doses showed moderate efficacy in elderly patients with dysthymic disorder and was well tolerated in successful completers. Reduced somatic symptoms were associated with improvement in depressive symptoms. A systematic placebo-controlled trial of duloxetine in older patients with dysthymic disorder may be warranted.
[Show abstract][Hide abstract] ABSTRACT: Approximately 20–30% of patients with Major depressive disorder (MDD) develop a chronic course of their disease. Chronic depression is associated with increased health care utilisation, hospitalisation and a higher disease burden. We identified clinical correlates and differences in treatment response of chronic MDD (cMDD) patients compared with non-chronic episodic depression in a huge sample of depressive inpatients.Methods
Data were collected from 412 inpatients who had been diagnosed with a major depressive episode (MDE; according to ICD-10) and scored 15 or higher on the 21-item Hamilton Depression Rating Scale (HRSD-21). All subjects were participants in the German Algorithm Project, phase 3 (GAP3). Patients who were diagnosed with a MDE within the last two years or longer (herein referred to as CD) were compared with non-chronic depressive patients (herein referred to as non-CD). CD and non-CD patients were assessed for the following: psychosocial characteristics, symptom reduction from hospital admission to discharge, symptom severity at discharge, remission and response rates, and pharmacological treatment during inpatient treatment. The primary outcome measure was the HRSD-21.Results13.6% (n=56) of patients met the criteria for chronic depression. Compared with non-CD patients, patients with CD showed increased axis I comorbidities (74% vs. 52%, χ2 (1)=7.31, p=.02), a higher level of depressive symptoms at baseline and discharge, increased duration of inpatient treatment (64.8 vs. 53.3 days; t=2.86, p=.03) and lower response (HRSD: 60.0% vs. 72.0%; χ2 (1)=3.61, p<.04; BDI: 40.5% vs. 54.2%; χ2 (1)=3.56, p=.04) and remission rates (BDI 17.9.% vs. 29.7%; χ2 (1)=3.42, p=.05. However, both groups achieved a comparable symptom reduction during inpatient treatment. The prescribed pharmacological strategy had no significant influence on treatment outcome in patients with CD.Conclusion
Inpatients with CD show higher symptom severity, lower response and remission rates and a longer duration of inpatient treatment, although they achieve comparable symptom reduction during treatment. These findings support the need to recognise CD and its defining characteristics as a distinct subclass of depression.
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