Jill S. Gonzales

Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND Because the symptoms of premenstrual dysphoric disorder (PMDD) are limited to the luteal phase of the menstrual cycle, the potential benefit of luteal-phase dosing has been hypothesized. OBJECTIVE This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy and tolerability of enteric-coated fluoxetine 90 mg given once or twice during the luteal phase for the treatment of PMDD. METHODS Study drug was given 14 and 7 days before expected menses during the luteal phase of 3 menstrual cycles. After a screening period and single-blind placebo lead-in period, eligible women were randomized to I of 3 treatment groups: enteric-coated fluoxetine 90 mg on both days (LPWDx2); placebo 14 days before menses and enteric-coated fluoxetine 90 mg 7 days before menses (LPWDx1); or placebo on both days (PLC). The primary efficacy measure was change from baseline in mean luteal-phase scores on the Daily Record of Severity of Problems (DRSP). Secondary efficacy measures included scores on the Rating Scale for Premenstrual Tension Syndrome, Clinician-Rated (PMTS-C); the Clinical Global Impression (CGI)-Severity scale; and the Patient Global Impression (PGI)-Improvement scale. Quality of life was assessed using the Sheehan Disability Scale. RESULTS Two hundred fifty-seven women were randomized to treatment. At the end of the study, the LPWDx2 group had statistically significant improvements in DRSP total, DRSP mood subtotal, DRSP social functioning subtotal, PMTS-C, CGI-Severity, PGI-Improvement, and Sheehan Disability Scale work and family life scores compared with LPWDx1 and PLC (each measure, P < 0.05). There was also a statistically significant improvement in the score on the social life section of the Sheehan Disability Scale with LPWDx2 compared with PLC (P = 0.037). Across all treatment groups, 5 patients discontinued due to nonserious adverse events. Rates of discontinuation for any reason did not differ between the 3 treatment groups. CONCLUSION The findings of this study support the efficacy and tolerability of enteric-coated fluoxetine 90 mg given twice during the luteal phase of the menstrual cycle for the treatment of PMDD.

Long-term treatment of obsessive-compulsive disorder after an acute response: a comparison of fluoxetine versus placebo.

Few controlled studies have evaluated the long-term continuation of pharmacotherapy for relapse prevention in patients with obsessive-compulsive disorder (OCD). This study assessed efficacy and safety of fluoxetine versus placebo in preventing relapse of OCD during a 52-week period in responders to short-term administration of fluoxetine. Patients who met DSM-IV criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale score ≥19 were treated with single-blind fluoxetine 20, 40, or 60 mg/day (based on physician assessment of response and tolerability). After 20 weeks, responders were randomly assigned to receive continued treatment with fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Of 130 patients who entered the study, 71 (55%) were randomly assigned to receive fluoxetine (N = 36) or placebo (N = 35). Patients who received fluoxetine had numerically lower relapse rates compared with those who received placebo, although the difference was not significant (Kaplan-Meier 1-year relapse rates: fluoxetine, 20.6%; placebo, 31.9%; one-tailed p value = 0.137). In additional analyses evaluating patients on the basis of fluoxetine dose at randomization, patients who continued treatment with fluoxetine 60 mg/day (N = 52) had significantly lower rates of relapse than those who were switched to placebo (Kaplan-Meier 1-year relapse rates: fluoxetine, 17.5%; placebo, 38.0%; one-tailed p value = 0.041). Those who responded to the acute treatment phase with 40 (N = 18) or 20 (N = 1) mg/day had low overall rates of relapse, and the difference between continued fluoxetine and placebo treatment for these patients was not significant. For responders to the 60 mg/day dosage, those patients who continued treatment with fluoxetine were provided greater protection against relapse than those patients switched to placebo.

Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia.

This study assessed whether fluoxetine, sertraline, and paroxetine differ in efficacy and tolerability in depressed patients and the impact of baseline insomnia on outcomes. Patients (N = 284) with DSM-IV major depressive disorder were randomly assigned in a double-blind fashion to fluoxetine, paroxetine, or sertraline for 10 to 16 weeks of treatment. Using the Hamilton Rating Scale for Depression (HAM-D) sleep disturbance factor score, patients were categorized into low (<4) or high (≥4) baseline insomnia subgroups. Changes in depression and insomnia were assessed. Safety assessments included treatment-emergent adverse events (AEs), reasons for discontinuation, and AEs leading to discontinuation. In addition, AEs were evaluated within insomnia subgroups to determine emergence of activation or sedation. Depression improvement, assessed with the HAM-D-17 total score, was similar among treatments in all patients (p = 0.365) and the high (p = 0.853) and low insomnia (p = 0.415) subgroups. Insomnia improvement, assessed with the HAM-D sleep disturbance factor score, was similar among treatments in all patients (p = 0.868) and in the high (p = 0.852) and low insomnia (p = 0.982) subgroups. Analyses revealed no significant differences between treatments in the percentages of patients with substantial worsening, any worsening, worsening at endpoint, or improvement at endpoint in the HAM-D sleep disturbance factor in either insomnia subgroup. Treatments were well tolerated in most patients. No significant differences between treatments in the incidence of AEs suggestive of activation or sedation were seen in the insomnia subgroups. These data show no significant differences in acute treatment efficacy and tolerability across fluoxetine, sertraline, and paroxetine in major depressive disorder patients. Improvement in overall depression and in associated insomnia was achieved by most patients regardless of baseline insomnia.

Adverse Events and Treatment Discontinuations in Clinical Trials of Fluoxetine in Major Depressive Disorder: An Updated Meta-Analysis

BACKGROUND A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agents more favorable adverse-event profile compared with tricyclic antidepressants (TCAs). OBJECTIVES The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted. METHODS Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups. RESULTS The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients. CONCLUSIONS Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.

Treatment Approaches to Major Depressive Disorder Relapse

Objective: Although continuing antidepressant treatment after patients have responded to medication has been shown to greatly reduce the risk of relapse, this risk is not eliminated. A number of theories have been proposed to account for this apparent loss of efficacy. A common initial approach to managing relapse is to increase the dose of antidepressant. We prospectively evaluated the likelihood of response to increasing the fluoxetine doses in patients relapsing during a long-term efficacy study of two fluoxetine dosing regimens. Method: Patients meeting the DSM-IV criteria for major depressive disorder with modified HAMD17 scores ≧18 and CGI-severity scores ≧4 were treated for 13 weeks with open-label 20 mg/day fluoxetine in a multicenter US study. Responders (n = 501) were randomized to 20 mg fluoxetine daily, placebo, or 90 mg enteric-coated fluoxetine weekly for 25 weeks of double-blind continuation treatment. If the patients relapsed during the continuation phase, they were offered a 25-week optional rescue treatment phase during which the study medication dose was increased as follows: (1) patients on placebo had treatment with fluoxetine 20 mg/day reinitiated, (2) patients on fluoxetine 20 mg/day had their dose increased to 40 mg/day, and (3) patients on a 90-mg weekly dose had their dose increased to 90 mg twice a week. The results of the rescue phase for the latter two groups who relapsed while on continuation treatment with fluoxetine are reported. Response was defined as a 50% reduction in the modified HAMD17 score since time of relapse and a CGI-severity score ≤2. Additional efficacy analyses included HAMD and CGI-severity changes from baseline to endpoint. Safety measures included assessment of treatment-emergent adverse events, vital signs, and laboratory measures. Results: Overall, patients relapsing during the continuation treatment responded to an increased dose (57% of the 40-mg-daily group and 72% of the enteric-coated 90-mg-twice-weekly group). Mean modified HAMD17 scores decreased from a mean of approximately 20 to below 8 and were maintained for up to 6 months in the responders. Thirty-five percent of patients either did not respond or initially responded but again relapsed after augmentation of medication. Conclusions: The patients relapsing after initially responding to fluoxetine can benefit from an increase in fluoxetine dose. These results also generally support increasing dose as a first-line treatment strategy for a patient who has relapsed while taking a previously effective dose of an antidepressant. Increasing enteric-coated fluoxetine 90 mg once weekly to twice weekly appeared to be as well-tolerated and effective in restoring response as increasing a daily fluoxetine dose from 20 to 40 mg.

Does Pain Mediate the Pain Interference with Sleep Problem in Chronic Pain? Findings from Studies for Management of Diabetic Peripheral Neuropathic Pain with Duloxetine

Although sleep problems are common in patients with chronic pain, it is unclear whether pain mediates (causes) impaired sleep. The relationship between pain and sleep has been difficult to investigate because of the potential confounds of depression and somnolence. This report used clinical trials data for duloxetine in the management of diabetic peripheral neuropathic pain (DPNP) to investigate the direction of this association. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP without mood disorder (n=1,139). DPNP patients reporting somnolence and those who were receiving sedating concomitant medications were removed from the analyses (n=93). Efficacy measures included weekly mean scores for average daily pain severity, night pain severity, and pain interference with sleep. Duloxetine at 60 and 120 mg per day separated from placebo for average pain and night pain improvement as early as one week after treatment began, whereas sleep interference improvement separated from placebo at the three visits it was assessed (Weeks 4, 8, and 12). Change in sleep interference was moderately to strongly correlated (P<0.001) with changes in average pain (r=0.46) and nighttime pain severity (r=0.53). These results confirm the association between the improvement in daily pain and nighttime pain, and improvement in sleep interference for a large population without depression or somnolence. Although this association cannot establish causality, these results provide some evidence for the possibility that pain may mediate the sleep problem associated with DPNP and perhaps chronic pain in general.