Pharmacotherapy for stress urinary incontinence : present and future options.

Stress urinary incontinence (SUI) is the accidental leakage of urine associated with physical activities such as running, jumping or lifting, or with sneezing and coughing. Worldwide, SUI is a highly prevalent condition, both in young and elderly women, and is a condition fraught with social isolation, loss of self-esteem and significant financial burden. Most women with SUI assume that it is an inevitable part of aging and "suffer in silence", relying on absorbent pads or lifestyle changes to cope with their condition.Unfortunately, for those who do seek medical treatment, the absence of effective and well tolerated pharmacological treatments for SUI limits the clinician's choices to behavioural modification, biofeedback and surgery. Many of the nonsurgical approaches have low success rates, particularly in the elderly and more severely afflicted. Although most continence surgeries have been reported to produce very high cure rates, many women are willing to live with their condition rather than undergo such invasive options. In an attempt to help these patients, some physicians prescribe off-label agents, including tricyclic antidepressants such as imipramine, alpha- and beta-adrenoceptor agonists, and estrogen replacement therapy. The use of these therapies has been limited by unpredictable results and adverse reactions. In addition, acetylcholine receptor antagonists are often prescribed for SUI, despite the fact that these medications have never been shown to be effective in this condition. This lack of a reliable pharmaceutical agent led to the development of duloxetine, a balanced dual reuptake inhibitor of serotonin and norepinephrine that is also being studied for the treatment of major depressive disorder. Based on in vivo data in animals, duloxetine is believed to increase the strength of urethral sphincter contractions and, thereby, prevent accidental urine leakage by increasing urethral closure forces. In clinical trials in women with SUI, duloxetine has demonstrated efficacy in reducing incontinence episodes and increasing the quality of life with no serious adverse effects. Nausea was the most common adverse event; however, in most patients it was reported early in treatment, mild-to-moderate in severity and transient. A medication such as duloxetine, if approved, would go a long way towards expanding the available treatment options for patients with SUI.

Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder.

BACKGROUND: Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse. AIMS: To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse. METHOD: This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse. RESULTS: Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups. CONCLUSIONS: Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.

Safety and efficacy of fluoxetine in patients who receive oral contraceptive therapy.

OBJECTIVE: Because many women who receive pharmacologic therapy with antidepressants are also prescribed oral contraceptives, it is important to assess the risk of clinically significant drug interactions. We reviewed the United States fluoxetine clinical trial database, specifically analyzing women ages 18 to 45 years, for differences in safety, antidepressant efficacy, and unplanned pregnancies that were associated with oral contraceptive use. STUDY DESIGN: Data from 17 double-blind, placebo-controlled clinical trials in 1698 women were analyzed retrospectively. A subgroup of women with oral contraceptive use was compared with a subgroup of women with no oral contraceptive use. Differences in treatment-emergent adverse events, unplanned pregnancies, and 17-item Hamilton Depression Scale (HAMD-17) scores were analyzed. RESULTS: The only treatment-emergent adverse events that showed a statistically significantly different odds ratio for oral contraceptive use versus no oral contraceptive use were headache, asthenia, and pain. There was not a statistically significant interaction in the incidence of unintended pregnancies (P =.111) or in the changes from baseline in HAMDD-17 scores. CONCLUSION: There is no clinical evidence that concomitant use of oral contraceptives and fluoxetine affects the safety or efficacy of either agent.

Fluoxetine versus placebo in posttraumatic stress disorder.

BACKGROUND: This study was designed to address the efficacy and tolerability of fluoxetine in patients with posttraumatic stress disorder (PTSD) as diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders and the Clinician-Administered PTSD Scale (CAPS). The patient population included both civilians and combat veterans. METHOD: This was a double-blind, randomized, placebo-controlled study conducted in Europe, Israel, and South Africa, primarily in war-torn countries. Patients were predominantly male (81%) and white (91%), with 48% exposed to a combat-related traumatic episode. Patients were randomly assigned to 12 weeks of acute treatment with fluoxetine, 20 to 80 mg/day (N = 226), or placebo (N = 75). The primary efficacy measurement was the mean change from baseline in the Treatment Outcome PTSD rating scale (TOP-8) total score, which was analyzed using a repeated-measures analysis of variance. Secondary assessments included the CAPS, the Davidson Trauma Scale, the Clinical Global Impressions-Severity of Illness scale (CGI-S), the CGI-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Anxiety (HAM-A), and the Hopkins 90-Item Symptom Checklist-Revised. RESULTS: Fluoxetine was associated with a greater improvement from baseline in total TOP-8 score than was placebo. This difference was statistically significant by week 6 of treatment (p < .001) through the end of the acute phase of the study (week 12; p = .006). Compared with placebo, fluoxetine was also associated with significantly greater improvement in CAPS total score as well as intrusive and hyperarousal subscores and in CGI-S, CGI-I, HAM-A, and MADRS scores (p < .05). The presence of dissociative symptoms at baseline appeared to be a predictor of high placebo response. The mean fluoxetine dose at endpoint was 57 mg. There were no clinically significant safety differences. CONCLUSION: Fluoxetine is effective and well tolerated in the treatment of PTSD. Most PTSD patients will respond satisfactorily at doses in the upper normal range for the usual antidepressant doses of fluoxetine.

A placebo-controlled study of fluoxetine in continued treatment of bulimia nervosa after successful acute fluoxetine treatment.

OBJECTIVE: The efficacy of fluoxetine in the acute management of bulimia nervosa is well established; however, few controlled studies have examined whether continuation of pharmacotherapy provides protection from relapse. This study compared the efficacy and safety of treatment with fluoxetine versus placebo in preventing relapse of bulimia nervosa during a 52-week period after successful acute fluoxetine therapy. METHOD: Patients who met DSM-IV criteria for bulimia nervosa, purging type, were assigned to single-blind treatment with 60 mg/day of fluoxetine. After 8 weeks of treatment, patients were considered responders if they experienced a decrease > or =50% from baseline in the frequency of vomiting episodes during 1 of the 2 preceding weeks. Responders were randomly assigned to receive 60 mg/day of fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Patients met relapse criteria if they experienced a return to the baseline vomiting frequency that persisted for 2 consecutive weeks. RESULTS: Of the 232 patients who entered the acute phase, 150 patients (65%) met response criteria and were randomly assigned to receive fluoxetine (N=76) or placebo (N=74). Fluoxetine-treated patients exhibited a longer time to relapse than placebo-treated patients. Quantitative analysis of other efficacy measures, including frequency of vomiting episodes, frequency of binge eating episodes, Clinical Global Impression severity and improvement scores, the patient's global impression score, and Yale-Brown-Cornell Eating Disorder Scale score, indicated that the efficacy of fluoxetine treatment was statistically superior, compared to placebo. There were no clinically relevant differences in safety between groups. Attrition in this study was high, especially in the first 3 months after random assignment to treatment groups. CONCLUSIONS: Continued treatment with fluoxetine in patients with bulimia nervosa who responded to acute treatment with fluoxetine improved outcome and decreased the likelihood of relapse.