Comparison of Site-Based Versus Central Ratings in a Study of Generalized Anxiety Disorder.

Lack of standardization across sites and raters, poor interrater reliability, and possible scoring bias affecting the primary outcome measure contribute to a high failure rate in anxiety trials. Remote centralized raters who are blinded to protocol inclusion and exclusion criteria as well as visit number may standardize assessments across raters and eliminate scoring bias, decreasing placebo response and thereby increasing signal detection. The purpose of the primary study was to test the safety and efficacy of an anxiolytic in a double-blind, placebo-controlled (no active comparator), multicenter trial. However, there was an additional prospective objective to explore site ratings compared with remote centralized ratings in the cohort of subjects on placebo. Site raters assessed subjects 6 times over an 8-week period. The primary outcome measure was the week 8 site-rated Hamilton Anxiety Scale (HAM-A). Remote centralized raters by telephone independently rated these subjects on the HAM-A at baseline and week 6. Of the 122 subjects selected by site raters and therefore randomized, remote centralized raters would have admitted 59 (48%) and excluded 63 (52%), based on their HAM-A ratings. The mean change from baseline in HAM-A total score in the placebo group admitted to the study by site raters was 9.3, significantly higher than the 5.9 point mean change on placebo as measured by the remote centralized raters.The data are consistent with the potential for qualification bias at baseline when rated by sites. The results make a strong case for using strategies to ensure that baseline scoring is truly independent of the pressure to enroll.

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.

Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.

INTRODUCTION: Sexual dysfunction (SD) is frequently associated with major depressive disorder (MDD) in the untreated state and may be worsened by antidepressant treatment. AIM: We evaluated SD in duloxetine-treated patients during an MDD recurrence prevention study. METHOD: Patients (N = 514) received open-label duloxetine 60-120 mg/day for up to 34 weeks. Responders (N = 288) were randomly assigned to duloxetine or placebo during a further 52-week double-blind maintenance phase. MAIN OUTCOME MEASURES: The Arizona Sexual Experience Scale (ASEX) was used to assess sexual functioning. RESULTS: At study entry, 73.4% of patients met ASEX criteria for SD. After open-label duloxetine treatment, the probability of continued SD was 77.9% for nonresponders and 53.2% for responders. In patients without SD at study entry, the probability of emergent SD was 49.6% (nonresponders) and 33.2% (responders). In the double-blind maintenance phase, there was no significant difference (P = 0.105) in the probability of emergent SD between placebo-treated (49.2%) and duloxetine-treated (27.9%) patients without SD at baseline, with no significant treatment-by-gender interaction. In patients with a recurrence of MDD, the probability of emergent SD was similar between placebo- (71.3%) and duloxetine-treated (82.7%) patients. However, in patients with no recurrence of MDD, the probability of emergent SD in placebo patients (40.0%) was numerically higher than in duloxetine patients (12.9%). Spontaneous reports of adverse events related to sexual function were infrequent and no patients discontinued due to these events. CONCLUSIONS: In patients with MDD, the probability of continued or emergent SD after up to 34 weeks of open-label duloxetine treatment was associated with the response status of the patients. In patients who responded to duloxetine treatment, after up to a further 52 weeks of double-blind treatment either with duloxetine or placebo, the probability of continued or emergent SD appeared to be more related to MDD itself than the treatments that the patients received.

Evaluating the maintenance of effect of duloxetine in patients with diabetic peripheral neuropathic pain.

BACKGROUND: To evaluate the maintenance of effect of duloxetine 60 mg QD over 26 weeks in patients with diabetic peripheral neuropathic pain (DPNP). METHODS: Adult patients with DPNP and Brief Pain Inventory (BPI) 24-h average pain >or=4 were treated in this open-label study with duloxetine 60 mg QD for 8 weeks. Responders (>or=30% pain reduction) continued on duloxetine 60 mg QD (maintenance arm) for 26 weeks while non-responders had duloxetine increased to 120 mg QD (rescue arm). The primary outcome measure was the mean change from baseline (Week 8) to endpoint (Week 34) in BPI average pain in the maintenance arm. A number of secondary efficacy measures, as well as safety and tolerability, were assessed. RESULTS: Two hundred and sixteen patients entered the study and their baseline BPI average pain was 5.9. Thirty-two patients (15%) discontinued during the acute phase. One hundred and fifteen (53%) patients were found to be responders to 60 mg dose and they entered the maintenance arm. During the maintenance period they reported a mean change of BPI average pain of 0.35, with 0.79 as the upper bound of the one-sided 97.5% CI, which was less than the pre-specified non-inferiority margin of 1.5 (p < 0.001). Non-responders, upon dose increase to 120 mg QD, reported a statistically significant pain reduction. Total of 119 patients completed either arm of the study. Twenty patients experienced 27 serious adverse events including one death. CONCLUSION: In this open-label study, the effect of duloxetine 60 mg QD in patients with DPNP was maintained over 6-month period.

Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine.

Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome. Substantial preclinical evidence shows that duloxetine, an approved drug for the treatment of MDD, generalized anxiety disorder, and the management of diabetic peripheral neuropathic pain, inhibits reuptake of both 5-HT and NE. This paper reviews clinical and neurochemical evidence of duloxetine's effects on 5-HT and NE reuptake inhibition. The clinical evidence supporting duloxetine's effects on NE reuptake inhibition includes indirect measures such as altered excretion of NE metabolites, cardiovascular effects, and treatment-emergent adverse event profiles similar to those for other drugs believed to act through the inhibition of NE reuptake. In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition.

Use of effect size to determine optimal dose of duloxetine in major depressive disorder.

OBJECTIVE: At effective doses, patients with major depressive disorder (MDD) treated with duloxetine have been found to experience significant symptom improvement as measured by HAMD(17) total score. In addition, duloxetine-treated patients have significantly higher remission and response rates compared with placebo. The objective of this analysis is to determine the optimal dose of duloxetine in MDD. MATERIALS AND METHODS: Effect size for duloxetine 40mg, 60mg, 80mg, and 120mg per day were estimated using all 6 acute phase III clinical trials in patients with MDD. The tolerability of duloxetine 40mg, 60mg, 80mg, and 120mg were evaluated using pooled data from the 6 studies. The primary efficacy measure in all trials was the HAMD(17) total score, from which were determined the effect size for HAMD(17) change scores, response rates (50% reduction from baseline to endpoint), and remission rates (HAMD(17) total score < or =7). RESULTS: A total of 1619 randomized patients were included in these studies, of which 632 were treated with placebo; 177 with duloxetine 40mg/day; 251 with 60mg/day; 363 with 80mg/day; and 196 with 120mg/day. An evaluation of increments in effect size between doses consistently showed that the most notable gain in effect size for efficacy was the 40-60mg/day dosage range. All dosages from 60 to 120mg were effective. The tolerability assessment indicated duloxetine at 40-120mg/day is well tolerated. Furthermore, the initial doses of 40-80mg/day were found to have comparable tolerability. CONCLUSIONS: The effect size analyses demonstrate that duloxetine 40mg has minimum efficacy, and that duloxetine 60-120mg/day is effective in the treatment of patients with MDD. An initial dose less than 60mg/day might provide better tolerability for some patients diagnosed with MDD.

Differential antidepressant symptom efficacy: placebo-controlled comparisons of duloxetine and SSRIs (fluoxetine, paroxetine, escitalopram).

OBJECTIVE: To test the hypothesis that in patients with major depressive disorder (MDD), the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors (SSRIs) and that patterns of response will differ based on symptom severity at baseline. METHOD: Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD: 7 randomized, double-blind, fixed-dose, 8-week studies of duloxetine (n = 1,133) versus SSRI (n = 689) versus placebo (n = 641). Duloxetine doses were 40, 60, 80 and 120 mg/day. SSRI doses were 10 mg/day (escitalopram) and 20 mg/day (fluoxetine and paroxetine). RESULTS: Compared to SSRI-treated patients, duloxetine-treated patients had a significantly greater (p < or = 0.05) reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score and HAMD17 items of work and activities, psychomotor retardation, genital symptoms and hypochondriasis. Differences favoring the SSRIs approached significance for middle insomnia (p = 0.057) and late insomnia (p = 0.06), with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine. Similarly, the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms (p = 0.056), with an effect size twice that observed for the SSRIs. The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity (HAMD17 total score < or = 19), where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant (p = 0.031). CONCLUSION: Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity, and different HAMD17 items responded differently to duloxetine compared with SSRIs. Understanding these differences may be useful in tailoring antidepressant therapy for individual patients.

Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression.

Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.

Duloxetine in the treatment of major depressive disorder: an open-label study.

BACKGROUND: Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined. METHODS: Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score >or=18 and a Clinical Global Impression of Severity (CGI-S) score >or=4 at baseline. Efficacy measures included the HAMD17 total score, HAMD17 subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale. RESULTS: The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by >or=10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD17, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment. CONCLUSION: In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.

Efficacy of duloxetine for the treatment of generalized anxiety disorder: implications for primary care physicians.

OBJECTIVE: This study examined the efficacy and tolerability of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of patients with generalized anxiety disorder (GAD). METHOD: Patients were ≥ 18 years old and recruited from 5 European countries, the United States, and South Africa. The study had a 9-week, multicenter, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. A total of 513 patients (mean age = 43.8 years; 67.8% female) with a DSM-IV-defined GAD diagnosis received treatment with duloxetine 60 mg/day (N = 168), duloxetine 120 mg/day (N = 170), or placebo (N = 175). The primary efficacy measure was the Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included the Sheehan Disability Scale, HAM-A psychic and somatic anxiety factor scores, and HAM-A response, remission, and sustained improvement rates. The study was conducted from July 2004 to September 2005. RESULTS: Both groups of duloxetine-treated patients demonstrated significantly greater improvements in anxiety symptom severity compared with placebo-treated patients as measured by HAM-A total score and HAM-A psychic and somatic anxiety factor scores (p values ranged from ≤ .01 to ≤ .001). Duloxetine-treated patients had greater functional improvements in Sheehan Disability Scale global and specific domain scores (p ≤ .001) than placebo-treated patients. Both duloxetine doses also resulted in significantly greater HAM-A response, remission, and sustained improvement rates compared with placebo (p values ranged from ≤ .01 to ≤ .001). The rate of study discontinuation due to adverse events was 11.3% for duloxetine 60 mg and 15.3% for duloxetine 120 mg versus 2.3% for placebo (p ≤ .001). CONCLUSION: The results of this study demonstrate that duloxetine 60 mg/day and 120 mg/day were efficacious and well tolerated and thus may provide primary care physicians with a useful pharmacologic intervention for GAD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00122824.

Is PTSD caused by traumatic stress?

Sequential subjects (N=103) presenting for pharmacologic treatment of major depression were examined prior to treatment for history of traumatic experiences. Subjects were also examined for symptoms of posttraumatic stress disorder (PTSD). Two blinded raters subsequently judged whether subjects' experiences met DSM-IV criteria for trauma (criterion A of PTSD). Among 54 subjects scored by both raters as having experienced trauma, 42 (78%) met all other DSM-IV criteria for PTSD. Among 36 subjects scored by both raters as not having experienced trauma, 28 displayed all other DSM-IV criteria for PTSD--also a rate of 78%. This equivalence suggests that in a treatment-seeking population, caution should be exercised in attributing the PTSD syndrome to trauma.

Management of depression relapse: re-initiation of duloxetine treatment or dose increase.

Continuation of antidepressant therapy after patients have responded to medication has been shown to greatly reduce but not eliminate relapse. We evaluated response to reinstating or increasing drug doses in patients who relapsed during a long-term, randomized, double-blind, continuation phase study of duloxetine treatment for major depressive disorder (MDD). Patients with HAMD17 scores of >18 and CGI-Severity scores of >4 received duloxetine 60 mg QD for 12 weeks, responders then received 26 weeks of duloxetine 60 mg QD or placebo. The relapsing patients who started 12 weeks of rescue treatment received duloxetine 60 mg QD (if relapsing on placebo) or duloxetine 60 mg BID (if relapsing on duloxetine). In the continuation phase, 87 patients received duloxetine 60 mg QD (n=58) or 60 mg BID (n=29) as treatment for relapse. The percentage of patients who responded to treatment after relapse was 62% of those whose dose was increased from 60 mg QD to 60 mg BID, and 74% for those who switched from placebo to duloxetine 60 mg daily. By the end of the study, 32 patients taking duloxetine 60 mg QD were in remission (57%), compared with 11 patients taking duloxetine 60 mg BID (38%). There was significant improvement in HAMD17 and CGI-Severity scores for both groups at endpoint vs. start of treatment for relapse. Significant improvements were seen for all visual analog scale parameters in the 60 mg QD group, but only Interference with Daily Activities and Back Pain parameters showed significant improvement for patients receiving 60 mg BID. Significant within-group improvement from baseline was seen for both groups in Symptom Questionnaire-Somatic Subscale total and pain subscales. Treatment-emergent adverse events were mild/moderate in severity; no clinically significant changes were noted in laboratory results or vital signs. Reinstatement of duloxetine 60 mg QD was effective for patients who relapsed after discontinuing drug. Patients relapsing on duloxetine 60 mg QD benefited from an increase to 60 mg BID. These duloxetine doses were well tolerated and effective, and appear appropriate for MDD patients requiring treatment of relapse.

The safety and tolerability of duloxetine compared with paroxetine and placebo: a pooled analysis of 4 clinical trials.

BACKGROUND: To compare the safety and tolerability of duloxetine with paroxetine and placebo in patients with major depressive disorder (MDD). METHOD: Data from four 8-week randomized, double-blind, placebo- and paroxetine-controlled studies of duloxetine for MDD (DSM-IV criteria) were pooled to compare the safety and tolerability of duloxetine 40 to 120 mg/day with paroxetine 20 mg q.d. Two of the 4 trials included a 26-week extension. RESULTS: The pooled database included 1466 patients (duloxetine, N = 736; paroxetine, N = 359; placebo, N = 371). No deaths occurred in the acute phase trials. Discontinuation rates for adverse events did not differ significantly for duloxetine, 8.0%, and paroxetine, 6.1%. Nausea was the most frequent treatment-emergent adverse event for duloxetine (duloxetine, 14.4%; paroxetine, 12.0%; placebo, 3.8%). Blood pressure and corrected QT (QTc) interval changes were modest and did not differ significantly for the 3 groups. Mean heart rate increased slightly in the duloxetine group, 1.0 beat/minute, and did differ significantly (p < .001) from that in the paroxetine group, but the change is of doubtful importance. Mean changes in laboratory analytes remained within the reference range. Emergent sexual dysfunction was significantly greater among duloxetine- and paroxetine-treated patients than placebo-treated patients (p = .007 vs. duloxetine and p < .001 vs. paroxetine); however, it was significantly lower in duloxetine-treated patients than in paroxetine-treated patients (46.4% vs. 61.4%; p = .015). During the extension phase, weight gain (≥ 7% of initial body weight) was greater in both active-treatment groups than in the placebo group (duloxetine, 10.8%; paroxetine, 13.8%; placebo, 3.1%), but the active-treatment groups did not differ. CONCLUSIONS: Duloxetine is safe and well tolerated in patients with MDD, with safety and tolerability comparable to that of paroxetine.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression.

Major depressive disorder (MDD) poses a significant health problem and is estimated to be the third most costly and disabling disorder in the United States. Pharmacotherapy of depression has been successful, but improvements in response rates, remission rates, side effects, compliance and faster onset of therapeutic action have become prime objectives in drug development. There is considerable support for the hypothesis that dysfunctional serotonergic or noradrenergic neurotransmission may be etiological in depressed patients. Duloxetine is a balanced and potent reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) being studied as an antidepressant medication. In this review, we highlight the preclinical pharmacology, pharmacokinetic profile, and effects of duloxetine in the pharmacotherapy of depression. Evidence for 5-HT and NE reuptake inhibition by duloxetine comes from in vitro and in vivo transporter binding and functional uptake studies. Taken together with efficacy data from in vivo microdialysis, electrophysiological and behavioral studies, it is evident that duloxetine is balanced as a dual serotonin norepinephrine uptake inhibitor in vivo. The clinical efficacy and safety of duloxetine in the treatment of MDD has been studied in 6 multicenter, randomized, double-blind, placebo-controlled trials. In these studies, duloxetine was found to be effective in the treatment of emotional/psychological and painful physical symptoms associated with depression. More importantly, duloxetine appears to have better response rates and remission from depressive symptoms, perhaps due to its ability to treat a wider range of symptoms.

Duloxetine vs. placebo in patients with painful diabetic neuropathy.

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder.

OBJECTIVE: The onset or worsening of sexual dysfunction is a common treatment-emergent side effect of antidepressant medications. Post hoc analyses of pooled data from placebo-controlled studies were utilized to assess sexual functioning in patients receiving duloxetine or paroxetine. METHOD: Acute-phase data were obtained from four 8-week, double-blind, placebo- and paroxetine-controlled trials of similar design in which patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive placebo (N = 371), duloxetine (40-120 mg/day; N = 736), or paroxetine (20 mg/day; N = 359). Pooling of data from these studies was anticipated during study design. This represented all available data from duloxetine studies in which the Arizona Sexual Experience Scale (ASEX) was administered both at baseline and endpoint. Long-term data were available from extension phases in 2 of these trials in which acute treatment responders received placebo (N = 129), duloxetine (80-120 mg/day; N = 297), or paroxetine (20 mg/day; N = 140) for an additional 26 weeks. Data were collected between March 2000 and July 2002. RESULTS: The incidence of acute treatment-emergent sexual dysfunction was significantly lower among duloxetine-treated patients compared with those receiving paroxetine (p = .015), although both rates were significantly higher than placebo (p = .007 and p < .001 for duloxetine and paroxetine, respectively). Treatment group differences in the incidence of treatment-emergent dysfunction did not vary significantly by gender. In female patients, acute treatment-emergent sexual dysfunction was significantly lower in the duloxetine treatment group compared with the paroxetine treatment group (p = .032), with both rates being significantly higher than placebo (p = .049 and p < .001 for duloxetine and paroxetine, respectively). In the somewhat smaller group of male patients, acute treatment-emergent dysfunction did not differ significantly between duloxetine and placebo treatment groups, but the incidence was significantly higher in paroxetine-treated male patients compared with male placebo patients (p = .012). The long-term incidence of treatment-emergent dysfunction did not differ significantly between duloxetine-, paroxetine-, and placebo-treated patients. CONCLUSION: In this analysis of pooled data, patients receiving duloxetine (40-120 mg/day) or paroxetine (20 mg/day) had a significantly higher incidence of acute treatment-emergent sexual dysfunction when compared with placebo patients. However, the incidence of acute treatment-emergent dysfunction for duloxetine was significantly lower than that observed for paroxetine.

Onset of action for duloxetine 60 mg once daily: double-blind, placebo-controlled studies.

BACKGROUND: It is widely believed that most antidepressant medications exhibit a delay of 2-4 weeks before clinically relevant improvement can be observed among patients. During this latency period, patients continue to be symptomatic and functionally impaired. Thus, time to onset of effect is an important attribute of a new pharmacotherapy. We assessed the onset of effect for duloxetine, utilizing analytical methods previously recommended in the literature. METHOD: Efficacy data were pooled from two identical, but independent, randomized, double-blind, placebo-controlled, 9-week clinical trials of duloxetine (60 mg QD). Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)), HAMD(17) subscales (Maier, core, and anxiety), and the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales. In each individual study, duloxetine demonstrated statistically significant advantages over placebo on multiple outcomes. The present analysis utilized pooled data to more accurately and fully characterize the onset of effect for duloxetine. RESULTS: Median times to sustained improvements of 10% and 20% in the HAMD(17) total score among duloxetine-treated patients were 14 days and 21 days, respectively, compared with 34 days and 49 days, respectively, for placebo-treated patients (p < 0.001 for both results). The median time to sustained 30% improvement in HAMD(17) total score was 35 days for duloxetine-treated patients, while the median time for placebo-treated patients was not estimable since less than half of the patients met this criterion by the end of the trial. For duloxetine-treated patients, median times to sustained 10%, 20%, and 30% improvements on the Maier subscale of the HAMD(17) were the same as those for the HAMD(17) total score: 14, 21, and 35 days, respectively. However, in other analyses, changes in core emotional symptoms as measured by subscales of the HAMD(17) were somewhat faster than changes in overall symptomatology. The probabilities of achieving a sustained 30% improvement (Maier subscale) at Week 1 for duloxetine- and placebo-treated patients were 16.2% vs. 4.8%, respectively (p < 0.001). The corresponding probabilities of sustained improvement at Weeks 2 and 3 for duloxetine were 32.5% and 45.4%, respectively, compared to 12.8% and 21.4% for placebo ((p < 0.001 for both comparisons). CONCLUSION: The absence of an active comparator limits the conclusions which can be drawn regarding the rapidity of onset of clinically meaningful improvement. However, results from the present investigation may be useful to clinicians in consideration of treatment options for individual patients.

Is treatment-associated hypomania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression.

BACKGROUND: Selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) like duloxetine have the efficacy of tricyclic antidepressants (TCAs) with a more tolerable side-effect profile. Bipolar disorder is often undetected, with the most common misdiagnosis being unipolar depression. Studies have suggested that treatment of bipolar and unipolar depression with heterocyclic TCAs may increase the risk of switch rate to mania. Studies of antidepressants in unipolar major depression show a small risk of mania or hypomania, presumably because some bipolar depressives were mistakenly studied. This study investigated the rate of hypomania, mania, and hypomanic-like symptoms observed during treatment with duloxetine in patients with major depression. METHODS: This was a retrospective analysis of data from eight placebo-controlled, double-blind, randomized clinical trials of duloxetine in patients with non-bipolar major depression. LIMITATIONS: The studies were of limited duration. Manic or hypomanic symptoms were not elicited using standardized mania rating scale instruments. RESULTS: One case of mania occurred in the placebo group (0.1%), and two cases of hypomania were observed in the duloxetine-treated group (0.2%). Among hypomanic-like symptoms, only insomnia was significantly higher in the duloxetine group than in the placebo group (p<0.05). CONCLUSIONS: Duloxetine was associated with a low incidence of treatment-emergent hypomania, mania, or hypomanic-like symptoms in patients with major depressive disorder (MDD). The low incidence reported here may be due to greater diagnostic diligence on the part of the investigators. It is possible that the cases reported likely reflect inclusion of misdiagnosed bipolar II patients rather than true unipolar MDD cases. The effect of duloxetine in patients with bipolar depression is not known.

Antidepressant-like effects of cytidine in the forced swim test in rats.

BACKGROUND: Altered brain phospholipid metabolism may be involved in the pathophysiology of cocaine dependence and mood disorders. Evidence suggests that citicoline, a rate-limiting metabolite for phospholipid synthesis, reduces cocaine craving in human addicts. Because antidepressants can reduce cocaine craving, we explored in rats the possibility that citicoline has antidepressant effects. We also tested the primary metabolites of citicoline, cytidine and choline. METHODS: We examined if citicoline or metabolites alter immobility in the forced swim test. We used two scoring methods: latency to become immobile, a simple method that identifies antidepressants, and behavioral sampling, a complex method that differentiates antidepressants according to pharmacological mechanisms. RESULTS: Over a range of doses, citicoline did not affect behavior in the forced swim test. At molar equivalent doses, cytidine dramatically decreased immobility, whereas choline tended to increase immobility. The effects of cytidine resemble those of desipramine, a standard tricyclic antidepressant. None of the treatments affected locomotor activity, and cytidine did not establish conditioned place preferences. CONCLUSIONS: Citicoline does not have effects in the forced swim test, but its primary metabolites have opposing effects: cytidine has antidepressant-like actions, whereas choline has prodepressant-like actions. At antidepressant doses, cytidine lacks stimulant and rewarding properties. This is the first report of potential antidepressant effects of cytidine.