David J. Goldstein

Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine.

Context: Major depressive disorder causes significant morbidity and mortality. Current therapies fail to fully treat both emotional and physical symptoms of major depressive disorder. Objective: To evaluate duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on improvement of emotional and painful physical symptoms. Design: Randomized, double-blind, evaluation of duloxetine at 40 mg/d (20 mg twice daily) and 80 mg/d (40 mg twice daily) versus placebo and paroxetine 20 mg/d in depressed outpatients. Main Outcome Measures: The primary efficacy measure was the 17-item Hamilton Depression Rating Scale. Visual Analog Scales for pain, Clinical Global Impression of Severity, Patients Global Impression of Improvement, and Quality of Life in Depression Scale were also used. Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Results: Duloxetine 80 mg/d was superior to placebo on mean 17-item Hamilton Depression Rating Scale total change by 3.62 points (95% CI 1.38, 5.86; P = 0.002). Duloxetine at 40 mg/d was also significantly superior to placebo by 2.43 points (95% CI 0.19, 4.66; P = 0.034), while paroxetine was not (1.51 points; 95% CI −0.55, 3.56; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; 95% CI 0.14, 4.65; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). The only adverse event reported significantly more frequently for duloxetine 80 mg/d than for paroxetine was insomnia (19.8% for duloxetine 80 mg/d, 8.0% for paroxetine; P = 0.031). Hypertension incidence was not affected by any treatment. Conclusion: Duloxetine therapy was efficacious for emotional and physical symptoms of depression, with a selective serotonin reuptake inhibitor-like profile of side effects.

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 (HAMD(17)), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patients 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 HAMD(17) 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.

Olanzapine-exposed Pregnancies and Lactation: Early Experience

Psychosis frequently occurs in women of childbearing potential who may have unplanned pregnancies. Understanding the risk of prenatal antipsychotic exposure can be of benefit in selecting therapies. The authors evaluated the in utero and lactation exposure effects of olanzapine, a novel antipsychotic that is used in treating schizophrenia, bipolar disorder, and other conditions and that may have expanded use in the childbearing population. All prospectively and retrospectively ascertained pregnancy reports were collected as a registry in the Lilly Worldwide Pharmacovigilance Safety Database. Outcomes were available from 23 prospectively ascertained olanzapine-exposed pregnancies. Spontaneous abortion occurred in 13%, stillbirth in 5%, major malformation in 0%, and prematurity in 5%, all within the range of normal historic control rates. There were 11 retrospectively ascertained cases of pregnancy. Two retrospectively ascertained cases of lactation exposure did not suggest infant risk. The early experience with olanzapine use in pregnancy and lactation is encouraging in that no obvious added risk to the fetus or infant was observed. Additional cases of pregnancy and lactation exposure need to be evaluated to determine whether these early findings are representative of the risks of olanzapine exposure to the fetus and infant. At this time, olanzapine should only be used during pregnancy and lactation when the potential benefit justifies the potential risk to the fetus or infant.

Effectiveness of fluoxetine therapy in bulimia nervosa regardless of comorbid depression

OBJECTIVE To evaluate fluoxetine efficacy in the treatment of bulimia nervosa patients with or without comorbid depression. METHOD Two parallel, multicenter, double-blind, randomized, placebo-controlled fluoxetine clinical trials were retrospectively analyzed to determine the effect of comorbid depression on bulimia treatment response. Patients were stratified by their 21-item Hamilton Rating Scale for Depression (HAMD21) scores at baseline and by the presence or absence of historical or current depression. Change from baseline to endpoint in the number of binge eating and vomiting episodes was used to assess efficacy. RESULTS Fluoxetine 60 mg treatment statistically significantly reduced (p < .05) the median number of binge eating and vomiting episodes. These improvements were independent of baseline HAMD21 score and of historical or current comorbid depression diagnosis. DISCUSSION Fluoxetine 60 mg was effective in treating bulimia nervosa, regardless of the presence or absence of comorbid depression. Fluoxetines efficacy in treating bulimia nervosa is not simply a secondary effect of its antidepressant properties.

Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy.

Lanepitant is effective in the formalin analgesic model suggesting efficacy in painful neuropathy. This study was designed to evaluate the dose-response effect of lanepitant in patients with daily moderate to severe, bilateral, distal neuropathic pain. After a 1-to 3-week lead-in period, patients were randomly allocated to double-blind, parallel treatment with lanepitant 50 mg daily (n = 27), 100 mg daily (n = 27), 200 mg twice daily (n = 13), or placebo (n = 26) over 8 weeks. Patients reported average daytime pain and average nighttime pain intensity. Plasma concentrations and amount of adjunctive analgesic medication were obtained at all visits after baseline. Patient global evaluation and clinician global impression were obtained at weeks 3 and 8. Safety was assessed by adverse events, vital signs, laboratory analytes, and electrocardiogram. No dosage of lanepitant differed significantly from placebo. Efficacy did not increase with lanepitant dosage, and higher plasma concentrations were no more effective than lower plasma concentrations. The adverse event diarrhea was more frequent for lanepitant-treated patients. Although well tolerated, lanepitant was ineffective in relieving pain of diabetic neuropathy.

Fluoxetine in medically stable, depressed geriatric patients : Effect on weight

This study assessed the effect of fluoxetine 20 mg/day on weight loss in older patients treated for major depression in a multicenter, double-blind placebo-controlled, 6-week clinical trial. Thirty U.S. outpatient clinics affiliated with psychiatric programs participated in the study that involved 671 medically stable outpatients at least 60 years old who had normal cognition and met DSM-III-R criteria for major depression. Weight was recorded at weekly visits. As a measure of adiposity, patients were categorized into two groups, high and low/normal body mass index (BMI) groups. Analyses were done for each group. The high BMI group, but not the low/normal BMI group, had a statistically greater proportion of fluoxetine-treated patients who lost at least 5% of their baseline weight. Overall mean weight change for the fluoxetine-treated patients was about 1% compared with essentially no change for placebo-treated patients. Only one patients, who was treated with fluoxetine and in the low/normal BMI group, discontinued from the study because of weight loss. Although 5% weight loss occurred in more fluoxetine-treated than placebo-treated patients, most of the patients who lost weight had higher adiposity at baseline. There was not a statistically significant difference in the proportion of fluoxetine-treated and placebo-treated patients in the low/normal group who had at least 5% weight loss. Medically relevant weight loss in older patients treated with fluoxetine was uncommon.

Treatment of persistent pain

firms Avon and Revlon announced that they had found ways to ensure the safety of their products without animal experimentation. This was a response to years of pressure from the animal liberation group. It will save thousands of animals every year from painful, often lethal, tests.2 Opposition to animal experimentation shows every sign of being with us for many years to come, since its philosophical foundation is clear and difficult to gainsay. Among scientists in the United States, where standards of regulation for animal experimentation lag far behind even those in Britain, there are signs of a reflex defensiveness which can lead only to polarisation and increasing hostility between experimenters and the animal liberation movement.3 Doctors and scientists in Britain should resist this tendency to overrespond. Instead they should look for ways in which they can make a radical break with a past in which animal experimentation has been accepted with far too little questioning. PETER SINGER Director, Centre for Human Bioethics, Monash University, Melbourne, Victoria 3168, Australia

The tyramine pressor test may have limited sensitivity, especially in the presence of dual serotonin/norepinephrine uptake inhibition.

The Tyramine Pressor Test May Have Limited Sensitivity, Especially in the Presence of Dual Serotonin/Norepinephrine Uptake Inhibition ★

Duloxetine in the treatment of depression: A double-blind placebo-controlled comparison with paroxetine

CONTEXT Major depressive disorder causes significant morbidity and mortality. Current therapies fail to fully treat both emotional and physical symptoms of major depressive disorder. OBJECTIVE To evaluate duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on improvement of emotional and painful physical symptoms. DESIGN Randomized, double-blind, evaluation of duloxetine at 40 mg/d (20 mg twice daily) and 80 mg/d (40 mg twice daily) versus placebo and paroxetine 20 mg/d in depressed outpatients. MAIN OUTCOME MEASURES The primary efficacy measure was the 17-item Hamilton Depression Rating Scale. Visual Analog Scales for pain, Clinical Global Impression of Severity, Patients Global Impression of Improvement, and Quality of Life in Depression Scale were also used. Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. RESULTS Duloxetine 80 mg/d was superior to placebo on mean 17-item Hamilton Depression Rating Scale total change by 3.62 points (95% CI 1.38, 5.86; P = 0.002). Duloxetine at 40 mg/d was also significantly superior to placebo by 2.43 points (95% CI 0.19, 4.66; P = 0.034), while paroxetine was not (1.51 points; 95% CI -0.55, 3.56; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; 95% CI 0.14, 4.65; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). The only adverse event reported significantly more frequently for duloxetine 80 mg/d than for paroxetine was insomnia (19.8% for duloxetine 80 mg/d, 8.0% for paroxetine; P = 0.031). Hypertension incidence was not affected by any treatment. CONCLUSION Duloxetine therapy was efficacious for emotional and physical symptoms of depression, with a selective serotonin reuptake inhibitor-like profile of side effects.

Biological Theories of Depression and Implications for Current and New Treatments

Unipolar major depressive disorder is a common condition that has both emotional (mood and anxiety) and physical aspects (1). The physical manifestations are common features of depression present in up to 80% of depressed patients (2). These physical symptoms occur in nearly all body systems and are often the presenting features in the nonpsychiatric setting. The most common physical symptoms are sleep disruption, fatigue, pain and discomfort, and appetite disturbance.