Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p=0.07; 60 mg b.i.d.: p=0.02; combined regimens: p=0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p<0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p<0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.
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PMID:Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. 1278

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake being investigated for the treatment of depression and urinary incontinence. The disposition of duloxetine was studied in four healthy human subjects after a single 20.2-mg (100.6 microCi) oral dose of [14C]duloxetine in an enteric-coated tablet. The mean total recovery of radioactivity (+/- S.E.M.) after 312 h was 90.5% (+/-0.4%) with 72.0% (+/-1.1%) excreted in the urine. Duloxetine was extensively metabolized to numerous metabolites primarily excreted into the urine in the conjugated form. The major biotransformation pathways for duloxetine involved oxidation of the naphthyl ring at either the 4-, 5-, or 6-positions followed by further oxidation, methylation, and/or conjugation. The major metabolites found in plasma were glucuronide conjugates of the following: 4-hydroxy duloxetine (M6), 6-hydroxy-5-methoxy duloxetine (M10), 4, 6-dihydroxy duloxetine (M9), and a sulfate conjugate of 5-hydroxy-6-methoxy duloxetine (M7). The major metabolites found in plasma were also found in the urine, but the urine contained many additional metabolites. In addition to duloxetine, 4-hydroxy duloxetine (M14) and an unidentified polar metabolite were observed in feces. Following [14C]duloxetine administration, Cmax was reached at a median of 6 h for both duloxetine and total radioactivity. Duloxetine accounted for less than 3% of the circulating radioactivity based on mean area under the curve values. The elimination half-life of total radioactivity (120 h) was substantially longer than that of duloxetine (10.3 h).
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PMID:Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. 1292 Jan 70

Most patients with major depressive disorder (MDD) have symptoms of anxiety associated with their depression. Duloxetine, a potent and balanced dual serotonin and norepinephrine reuptake inhibitor, is effective in the treatmentof depression. We investigated its effects in treating the symptoms of anxiety in depressed patients. This investigation includes all the placebo-controlled studies of duloxetine in MDD but focuses on four trials in which duloxetine was superior to placebo on the primary outcome measure of the 17-item Hamilton Depression Rating Scale (HAMD(17)) total score. Studies 1 and 2 included duloxetine at 60 mg/d (the recommended starting and therapeutic dose) and placebo. Study 3 included duloxetine 120 mg/d (administered as 60 mg b.i.d.), fluoxetine 20 mg/d, and placebo. Study 4 included duloxetine 40 mg/d (administered as 20 mg b.i.d.), duloxetine 80 mg/d (administered as 40 mg b.i.d.), paroxetine 20 mg/d, and placebo. Anxiety was assessed in all studies using the HAMD anxiety/somatization subfactor and the anxiety-psychic item (HAMD Item 10). Studies 3 and 4 also included the Hamilton Anxiety Rating Scale (HAMA). Across the four studies, duloxetine at doses of >/=60 mg was compared with placebo on 10 outcomes and with either paroxetine or fluoxetine on 6 outcomes. In 8 comparisons, mean improvement for duloxetine was significantly greater than placebo at the last study visit and/or across all study visits. In 3 comparisons, the mean improvement for duloxetine was significantly greater than paroxetine or fluoxetine. In these studies, duloxetine provided rapid relief of anxiety symptoms associated with depression. Previous reports have summarized duloxetine's efficacy in treating the core emotional symptoms and painful physical symptoms associated with depression. Duloxetine's efficacy in treating a broad spectrum of symptoms associated with depression, including mood, anxiety, and painful physical symptoms, may be attributed to dual reuptake inhibition of both serotonin and norepinephrine. Efficacy in these three key symptom domains may in turn explain the high probabilities of remission (43-57%) observed in these studies.
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PMID:Duloxetine in treatment of anxiety symptoms associated with depression. 1296 71

Although highly selective antidepressants such as the selective serotonin reuptake inhibitors represent an advance over older drugs with respect to tolerability, they are not more effective than previous agents. Antidepressants that enhance transmission in more than one monoamine system may have greater efficacy than highly selective drugs, while equaling or improving their adverse effect profiles. This article reviews the properties of duloxetine, a potent and balanced inhibitor of norepinephrine and serotonin reuptake. Controlled studies indicate a high degree of efficacy, tolerability, and safety for duloxetine in the treatment of major depressive disorder. In particular, rapid therapeutic onset and high remission rates have been noted. Duloxetine appears to have significant benefit in the treatment of the painful physical symptoms associated with depression. The continued presence of such symptoms may predict relapse. Accordingly, it is hoped that duloxetine therapy may reduce the likelihood of depressive relapse.
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PMID:Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorder. 1455 54

A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
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PMID:Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake. 1464 50

BACKGROUND: Duloxetine is a novel antidepressant that is anticipated to be clinically available soon. It exerts simultaneous noradrenergic and serotonergic neurotransmitter effects. Because of these influences, it is postulated to have a role in management of pain. DATA SOURCES: An Index Medicus search from 1997 to 2003 was conducted using the search terms duloxetine, Cymbalta, and pain. DATA ANALYSIS: Preclinical animal studies suggest that duloxetine may have a direct analgesic role. Premarketing studies have emphasized its utility in alleviating somatic, specifically pain, complaints among patients with major depression. CONCLUSION: Although promising, these results cannot be generalized to patients with pain disorders; the reasons for this are discussed herein. While duloxetine may be useful among somatizing depressed patients and possibly chronic pain patients with comorbid depression, its analgesic role has yet to be elucidated in future research.
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PMID:Antidepressant Use in Chronic Pain Management: Is There Evidence of a Role for Duloxetine? 1515 22

BACKGROUND: Depression is underdiagnosed in the primary care setting. Physical symptoms such as aches, pains, and gastrointestinal disturbance are frequently associated with major depressive disorder (MDD) and are often the presenting symptoms. Duloxetine, a dual-reuptake inhibitor of serotonin and norepinephrine, may have a positive effect on physical symptoms in addition to efficacy in treating emotional symptoms of depression. METHOD: Efficacy was evaluated in 6 double-blind, placebo- and/or active comparator-controlled trials of duloxetine for patients with MDD (DSM-IV criteria). Efficacy in depression was determined primarily using the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Secondary efficacy measures included subscales of the HAM-D-17 and assessment of physical symptoms. Safety evaluations included adverse events, vital signs, laboratory analyses, and electrocardiograms. Safety was evaluated by pooling the data from the MDD trials and a study of duloxetine in nondepressed patients. RESULTS: Duloxetine demonstrated significant differences from placebo on core mood symptoms, physical symptoms (e.g., back pain), and global functioning as early as week 1 of treatment. The estimated probabilities of remission in the studies that demonstrated efficacy ranged from 43% to 57%. The most frequently observed adverse events for duloxetine-treated patients included nausea, dizziness, insomnia, fatigue, and somnolence. Duloxetine did not prolong corrected QT intervals, and the rate of sustained elevations of blood pressure did not differ significantly from placebo. CONCLUSION: In these studies, duloxetine was safe and effective in the treatment of both emotional and physical symptoms of MDD. Based on dose assessments, 60 mg q.d. appears to be the optimum starting and therapeutic dose.
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PMID:Duloxetine: A New Treatment for the Emotional and Physical Symptoms of Depression. 1515 43

BACKGROUND: The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine at the recommended starting dose, have been demonstrated in the treatment of major depressive disorder (MDD) in men and women and in the treatment of stress urinary incontinence (SUI) in women. Since the mechanism of action of duloxetine in the treatment of SUI is believed to be related to enhanced urethral closure forces, it is important to clarify the risk of acute urinary retention. METHOD: The relationship between duloxetine and obstructive voiding symptoms was examined in 8 double-blind, 8- to 9-week, placebo-controlled studies and 1 open-label study in men and women treated for MDD with duloxetine 40 to 120 mg/day and in 4 double-blind, 12-week, placebo-controlled studies and 4 ongoing open-label studies in women treated for SUI with duloxetine 80 mg/day. RESULTS: In 378 men and 761 women with MDD treated in placebo-controlled trials, 0.4% (4/1139; 3 men and 1 woman) of those treated with active medication reported subjective urinary retention versus none (0/777) of those treated with placebo (p =.15). In 958 women with SUI treated with duloxetine in placebo-controlled trials, none reported subjective urinary retention. Overall, in the duloxetine placebo-controlled clinical studies in the treatment of MDD and SUI, obstructive voiding symptoms (reported either as subjective urinary retention or other obstructive voiding symptoms) occurred more often in patients receiving duloxetine (1.0%, 20/2097) than in patients receiving placebo (0.4%, 6/1732) (p <.05). Of the 4719 MDD and SUI patients treated with duloxetine in placebo-controlled and ongoing open-label studies, 2 men and 1 woman discontinued because of obstructive voiding symptoms. Although such an evaluation was not required by protocol, no cases of objective acute urinary retention with postvoid residual urine verified with a bladder scan or requiring catheterization were reported in patients treated with duloxetine. CONCLUSION: Duloxetine treatment in women and men with depression and in women with SUI was rarely associated with obstructive voiding symptoms, and no subjects had objective acute urinary retention requiring catheterization.
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PMID:Urinary Side Effects of Duloxetine in the Treatment of Depression and Stress Urinary Incontinence. 1525 99

Double-blind, placebo-controlled clinical trials have evaluated and demonstrated the efficacy of duloxetine as an antidepressant in patients with major depressive disorders. The drug has been noted to be well tolerated and effective in the control of depressive symptoms. In addition, duloxetine has been shown to be better than placebo and as effective as paroxetine as an antidepressant and also better than placebo for reducing pain in both experimental models and patients. Duloxetine is a safe and well-tolerated new treatment option for depression including anxiety and painful physical symptoms. Furthermore, duloxetine has proven robust efficacy in stress urinary incontinence.
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PMID:Duloxetine: a new serotonin/noradrenaline reuptake inhibitor for the treatment of depression. 1553 50

This analysis assessed the effects of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on indices of cardiovascular safety, including heart rate, blood pressure (BP), and electrocardiograms (ECGs), in a large group of clinical trial patients with depression. Data were available from 8 double-blind, randomized, placebo-controlled (n = 777), and active comparator-controlled depression trials. Duloxetine (n = 1139) doses ranged from 40 to 120 mg/d, and fluoxetine (n = 70) and paroxetine (n = 359) were administered at a dose of 20 mg/d. Patients were treated for 8 to 9 weeks. There was a significant increase for duloxetine compared with placebo for heart rate (1.6 vs. -0.6 beats per minute) and for systolic BP (1.0 vs. -1.2 mm Hg); the difference for diastolic BP (1.1 vs. 0.3) was not significant. There were no significant differences between duloxetine and placebo treatment groups in the incidence of sustained (at least 3 consecutive visits) elevations in systolic (duloxetine 1.0%, placebo 0.4%), diastolic (duloxetine 0.4%, placebo 0.4%), or either (duloxetine 1.3%, placebo 0.8%) BP. Moreover, the effect of duloxetine on mean changes in supine systolic and diastolic BP was not significantly different from that of fluoxetine or paroxetine. Drug-placebo differences in mean changes in electrocardiograms (eg, QTc, PR, and QRS intervals) were neither statistically nor clinically significant, with the exception that duloxetine 120 mg/d had significant decreases in PR and QRS intervals compared with placebo. These data demonstrate that duloxetine has modest effects on heart rate and BP and no clinically meaningful effect on electrocardiogram profiles in a relatively healthy cohort of clinical trial patients. The cardiovascular effects of duloxetine appear to be comparable with medications considered to be first-line options for depression.
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PMID:Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. 1573 44


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