Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression

BACKGROUND: Antidepressant efficacy may be compromised by early discontinuation of treatment secondary to common, treatment-emergent side effects, including nausea, agitation, and somnolence. Paroxetine controlled-release (CR) was developed to improve general tolerability and, in particular, gastrointestinal tolerability. OBJECTIVE: To determine the antidepressant efficacy and tolerability of paroxetine CR in adult patients 18 to 65 years of age with DSM-IV major depressive disorder. METHOD: Paroxetine CR (25-62.5 mg/day; N = 212) and paroxetine immediate-release (IR; 20-50 mg/day; N = 217) were compared with placebo (N = 211) in the pooled dataset from 2 identical, double-blind, 12-week clinical trials. RESULTS: Both paroxetine CR and paroxetine IR exhibited efficacy in major depressive disorder as assessed by the reduction in 17-item Hamilton Rating Scale for Depression total score compared with placebo. Moreover, depressed mood and psychic anxiety symptoms improved as early as treatment week 1 in the paroxetine CR group compared with the placebo group. After 6 weeks of treatment, response and remission rates were 41.5% and 20.5% for placebo, 52.8% and 29.6% for paroxetine IR, and 58.9% and 34.4% for paroxetine CR, respectively. After 12 weeks of treatment, response and remission rates were 61.2% and 44.0% for placebo, 72.9% and 52.5% for paroxetine IR, and 73.7% and 56.2% for paroxetine CR, respectively. Rates of nausea were significantly lower for paroxetine CR (14%) than for paroxetine IR (23%; p < or = .05) during week 1. Rates of dropout due to adverse events were comparable between paroxetine CR and placebo, while significantly (p = .0008) more patients treated with paroxetine IR withdrew from the study prematurely compared with those treated with placebo. CONCLUSION: Paroxetine CR is an effective and well-tolerated antidepressant exhibiting symptomatic improvement as early as week 1. Paroxetine CR is associated with low rates of early-onset nausea and dropout rates due to adverse events comparable to those of placebo. The clinical improvement seen with paroxetine CR, coupled with its favorable adverse event profile, suggests a benefit for therapeutic outcome with paroxetine CR.     

Efficacy of controlled-release paroxetine in the treatment of late-life depression

BACKGROUND: Depression is the second most common neuropsychiatric disorder in older Americans, with significant clinical and public health costs. Despite advances in treatment, late-life depression remains a clinical challenge. Although the selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacologic intervention for late-life depression, few placebo-controlled trials have assessed the efficacy of SSRIs for this condition. METHOD: In this 12-week, multicenter, placebo-controlled, flexible-dose, double-blind, randomized trial, 319 elderly patients (mean age = 70 years) were treated with controlled-release paroxetine (paroxetine CR) up to 50 mg/day (N = 104), immediate-release paroxetine (paroxetine IR) up to 40 mg/day (N = 106), or placebo (N = 109). Patients met DSM-IV criteria for major depressive disorder and had a total score of 18 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D). The primary efficacy measure was change from baseline to endpoint in HAM-D total score. RESULTS: The primary efficacy analysis showed an adjusted difference between change from baseline in HAM-D score for paroxetine CR and placebo of -2.6 (95% confidence interval [CI] = -4.47 to -0.73, p = .007) at the week 12 last-observation-carried-forward (LOCF) endpoint. The adjusted difference between paroxetine IR and placebo was -2.8 (95% CI = -4.65 to -0.99, p = .003) at week 12. Paroxetine CR and IR were more effective than placebo, with mean +/- SD endpoint HAM-D total scores of 10.0 +/- 7.41 and 10.0 +/- 7.10, respectively, for the active treatments compared with 12.6 +/- 7.34 for placebo. Response, defined as a score of 1 or 2 on the Clinical Global Impressions-global improvement scale, was achieved by 72% of paroxetine CR patients (LOCF; p < .002 vs. placebo), 65% of paroxetine IR patients (p = .06 vs. placebo), and 52% of placebo patients. Remission, defined as a HAM-D total score < or = 7, was achieved by 43% of paroxetine CR patients (LOCF; p = .009 vs. placebo), 44% of paroxetine IR patients (p = .01 vs. placebo), and 26% of placebo patients. In a post hoc analysis, mean HAM-D improvement for paroxetine CR and paroxetine IR was greater than for placebo in both chronically depressed patients (duration > 2 years) and those with short-term (< or = 2 years) depression. Dropout rates due to adverse events were 12.5% for paroxetine CR, 16.0% for paroxetine IR, and 8.3% for placebo. CONCLUSION: Paroxetine CR and paroxetine IR are effective and well tolerated treatments for major depressive disorder in elderly patients, including those with chronic depression.     

Controlled-release paroxetine in the treatment of patients with social anxiety disorder

BACKGROUND: This double-blind, placebo-controlled, flexible-dose study was conducted to investigate the efficacy and tolerability of the controlled-release (CR) formulation of paroxetine in adults with social anxiety disorder. METHOD: Outpatients with a primary diagnosis of social anxiety disorder according to DSM-IV criteria entered a 1-week, single-blind, placebo run-in period. Eligible patients were randomly assigned to receive paroxetine CR (flexible dose of 12.5-37.5 mg/day) or placebo for 12 weeks of treatment. The primary efficacy measures were the change from baseline in Liebowitz Social Anxiety Scale (LSAS) score and the proportion of responders based on Clinical Global Impressions (CGI)-Global Improvement scale score. Data were gathered from September 2001 to July 2002. RESULTS: The intent-to-treat population consisted of 186 patients randomly assigned to paroxetine CR and 184 patients randomly assigned to placebo. Statistically significant differences in favor of paroxetine CR compared with placebo were observed in the change from baseline to week 12 last-observation-carried-forward (LOCF) dataset in LSAS total score (difference = -13.33, 95% confidence interval [CI] = -18.25 to -8.41, p <.001). In the CGI-Global Improvement responder analysis, 57.0% of patients treated with paroxetine CR achieved response (very much improved or much improved), compared with 30.4% of patients treated with placebo at week 12 LOCF (odds ratio = 3.12, 95% CI = 2.01 to 4.83, p <.001). Dropout rates due to adverse events were low and comparable in both treatment groups. CONCLUSION: Paroxetine CR effectively treated the symptoms associated with social anxiety disorder and was well tolerated, with few patients stopping treatment due to adverse events. This favorable tolerability profile may enable more patients to experience the benefits of effective therapy.     

Long-term evaluation of paroxetine,clomipramine and placebo in panic disorder

Paroxetine has been shown to be effective in panic disorder in three 10- to 12-week studies. This trial studied the longer term effects of paroxetine in patients with DSM-III-R defined panic disorder. Patients who satisfactorily completed a 12-week, double-blind, placebo-controlled study of paroxetine and clomipramine could choose to continue receiving their randomized treatment for a further 36 weeks. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. In total, 176 patients were included in the intention-to-treat population. The number of full panic attacks decreased in all three groups during the 12-week study, and improvements continued with long-term therapy. Paroxetine was statistically significantly more effective than placebo throughout the long-term study with respect to reduction from baseline of full panic attacks, and at the end of treatment with respect to the proportion of patients who eventually experienced no panic attacks. There were no significant differences between paroxetine and clomipramine. The proportion of patients who withdrew from the study due to adverse effects was greater in the clomipramine group (19%) than in either the paroxetine group (7%) or the placebo group (9%). Paroxetine was significantly more effective than placebo and as effective as (but better tolerated than) clomipramine in the long-term treatment of panic disorder. Not only was efficacy maintained, but continued improvement was also seen, indicating the importance of long-term treatment in patients with panic disorder.     

Sertraline versus paroxetine in the treatment of panic disorder: an acute, double-blind noninferiority comparison

OBJECTIVE: Several classes of medications have demonstrated efficacy in panic disorder, but direct comparison of 2 proven treatments is still uncommon. The purpose of this study was to compare sertraline and paroxetine in the acute treatment of panic disorder. METHOD: Adult outpatients with panic disorder with or without agoraphobia (DSM-IV and ICD-10 criteria) were randomly assigned in double-blind fashion to 12 weeks of treatment with flexible doses of sertraline (titrated up to 50-150 mg/day; N = 112) or paroxetine (titrated up to 40-60 mg/day; N = 113). Patients were then tapered off medication over 3 weeks. The primary analysis was a noninferiority analysis of Panic and Agoraphobia Scale (PAS) scores. Secondary measures included panic attack frequency and the Clinical Global Impressions-Improvement scale (CGI-I) (with responders defined as those with a CGI-I score < or = 2). Data were collected from January 2000 to June 2001. RESULTS: Sertraline and paroxetine were associated with equivalent levels of improvement on the PAS total score, as well as on all secondary outcome measures. Eighty-two percent of patients taking sertraline versus 78% of those taking paroxetine were CGI-I responders at endpoint. Numerically more patients on paroxetine treatment compared with sertraline treatment discontinued due to adverse events (18% vs. 12%; NS), and a significantly higher proportion of paroxetine patients showed > or = 7% weight gain (7% vs. < 1%; p <.05). During the taper period, the proportion of panic-free patients increased by 4% with sertraline but decreased by 11% with paroxetine (p <.05). CONCLUSION: Sertraline and paroxetine had equivalent efficacy in panic disorder, but sertraline was significantly better tolerated and was associated with significantly less clinical worsening during taper than paroxetine.     

Paroxetine controlled-release formulation in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled study in Japan and Korea

Aim: The main purpose of this study was to evaluate the efficacy of paroxetine controlled‐release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective‐serotonin‐reuptake‐inhibitors‐induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate‐release (IR) formulation. Methods: We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end‐point was the adjusted mean change from baseline in the 17‐item Hamilton Rating Scale for Depression total score at Week 8. Results: A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17‐item Hamilton Rating Scale for Depression was ?12.8 in the CR group, ?12.5 in the IR group, and ?10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR (P < 0.001) and IR (P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). Conclusion: Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period.     

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.     

Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder

CONTEXT: Paroxetine controlled release (CR) is approved for the treatment of major depressive disorder (MDD) in the dosage range of 25 to 62.5 mg daily. However, lower daily doses (12.5 mg and 25 mg) of this formulation have not been investigated in the treatment of MDD. If the 12.5-mg and 25-mg doses are found to be efficacious, these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD. OBJECTIVE: To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States. PARTICIPANTS: 447 adult (> or = 18 years of age) outpatients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression (HAM-D) score of at least 20 comprised the intent-to-treat study population (mean age = 38.8 years; 58.4% female; 75.6% white). INTERVENTION: Eligible patients completing a 1-week single-blind placebo run-in period were randomly assigned to receive once-a-day study medication (paroxetine CR 12.5 mg [N = 156], paroxetine CR 25 mg [N = 154], or placebo [N = 149]) in an 8-week, double-blind, parallel cell comparison. MAIN OUTCOME MEASURES: The primary efficacy measure was the change from baseline to study endpoint (week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions (CGI) Severity of Illness scale (CGI-S). The proportion of patients considered at study endpoint to be in response (CGI-Improvement score of 1 or 2) or in remission (HAM-D < or = 7) in the 3 treatment groups was also compared. Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety observations were made by assessing the proportion of patients who had adverse experiences, including laboratory and electrocardiographic abnormalities, during the treatment period. RESULTS: The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects (change in HAM-D score) from baseline to study endpoint (LOCF: p = .038, 95% CI = -3.38 to -0.09 and p = .005, 95% CI = -4.06 to -0.74, respectively). Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D (p = .011, 95% CI = -0.57 to -0.07) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group. However, LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg (p = .018, 95% CI = -0.61 to -0.06) and 25-mg (p < .001, 95% CI = -0.78 to -0.22) treatment groups. Significantly more patients in the 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response (CGI-Improvement score of 1 or 2, p = .035, OR = 1.68, 95% CI = 1.04 to 2.73) as well as for remission (HAM-D score 相似文献   

Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial

OBJECTIVE: To assess the efficacy and safety of paroxetine for the treatment of pediatric obsessive-compulsive disorder. METHOD: Children (7-11 years of age) and adolescents (12-17 years of age) meeting DSM-IV criteria for obsessive-compulsive disorder were randomized to paroxetine (10-50 mg/day) or placebo for 10 weeks. The primary efficacy measure was change from baseline in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score at week 10 last observation carried forward end point. Safety was assessed primarily through adverse event monitoring. RESULTS: A total of 207 patients were randomized to treatment. Of these, 203 were included in the intention-to-treat population. Adjusted mean changes from baseline at week 10 observation carried forward end point in CY-BOCS total score for patients receiving paroxetine and placebo were -8.78 (SE=0.82) and -5.34 points (SE=0.77), respectively. The adjusted mean difference, -3.45 in favor of paroxetine, was statistically significant (95% confidence interval=-5.60 to -1.29, p=.002). Adverse events were generally mild to moderate in intensity. A total of 10.2% (10/98) of patients in the paroxetine group and 2.9% (3 of 105) in the placebo group discontinued treatment because of adverse events. CONCLUSIONS: Paroxetine is an effective and generally well-tolerated treatment for obsessive-compulsive disorder in children and adolescents.     

Paroxetine in the treatment of obsessive-compulsive disorder: randomized, double-blind, placebo-controlled study in Japanese patients

The efficacy of paroxetine in the treatment of obsessive-compulsive disorder in Western populations is well established. The present study compares the efficacy and safety of paroxetine with placebo in the treatment of obsessive-compulsive disorder in Japanese patients. Patients aged 16 years or older who met Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for obsessive-compulsive disorder and had a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of >/=16 were randomized to receive 12 weeks' therapy in a double-blind manner. Paroxetine 20-50 mg/day or placebo was administered following a 1 week, placebo run-in phase. One hundred and ninety-one patients were randomized to either paroxetine or placebo, 188 patients were assessed as the full analysis set (FAS) and 144 patients completed the 12 week study. After adjustment for the Y-BOCS total score at baseline, reductions in obsessive-compulsive total score at week 6 and at the end of therapy were significantly greater in the paroxetine group than the placebo group. Most of the adverse events that occurred during the study were of mild to moderate intensity. Paroxetine is effective and well tolerated in Japanese adult patients with obsessive-compulsive disorder.     

A comparison of paroxetine,clomipramine and placebo in the treatment of panic disorder

The aim of this 12-week, double-blind, parallel group, placebo-controlled study was to compare paroxetine with clomipramine in 367 patients with DSM-III-R defined panic disorder. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. Paroxetine produced significant improvements compared with placebo in various measurements of panic attack frequency, and was as effective as clomipramine. However, paroxetine appeared to have a more rapid onset of action than clomipramine in reducing the number of panic attacks to zero. There was an equivalent improvement with both paroxetine and clomipramine in the supportive efficacy variables which assessed associated aspects of therapeutic improvement. Significantly more adverse effects were reported in the clomipramine group compared with the paroxetine group, while there was no difference between the paroxetine and placebo groups.     

Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder

BACKGROUND: Paroxetine has demonstrated efficacy in depression and anxiety disorders, including generalized anxiety disorder (GAD). This 32-week study evaluated the maintained efficacy and safety of paroxetine in GAD by assessing the potential for relapse after discontinuation of medication. METHOD: Adults (N = 652) with DSM-IV GAD and a Clinical Global Impressions-Severity of Illness (CGI-S) score > or = 4 received paroxetine (20-50 mg/day) for 8 weeks. Patients whose CGI-S score had decreased by at least 2 points to < or = 3 at week 8 were randomly assigned to double-blind treatment with paroxetine (N = 278) or placebo (N = 288) for a further 24 weeks. The primary efficacy parameter was the proportion of patients relapsing (an increase in CGI-S score of at least 2 points to a score < or = 4 or withdrawal resulting from lack of efficacy) during double-blind treatment. RESULTS: Significantly fewer paroxetine than placebo patients relapsed during the 24-week double-blind phase (10.9% vs. 39.9%; p <.001). Placebo patients were almost 5 times more likely to relapse than paroxetine patients (estimated hazard ratio = 0.213 [95% CI = 0.1 to 0.3]; p <.001). Statistical significance in favor of paroxetine was demonstrated for all secondary efficacy parameters, including functional status. Twice as many paroxetine patients as placebo patients (73%) achieved remission. Paroxetine was well tolerated, with no unexpected adverse events reported. CONCLUSION: Paroxetine was found to be effective and well tolerated for both the short- and long-term treatment of DSM-IV GAD. Continued treatment with paroxetine significantly reduced the potential for relapse of GAD symptoms.     

Paroxetine: current status in psychiatry

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant and anxiolytic properties. It is commercially available in both an immediate-release (paroxetine) and a controlled-release formulation (paroxetine CR). The latter product was developed to improve gastrointestinal tolerability. Paroxetine is the most potent inhibitor of the reuptake of serotonin among the available SSRIs. It has approved indications for the treatment of major depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia in adults. Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults. While the overall efficacy of paroxetine appears to be comparable with other SSRIs in the treatment of major depression, it is approved for use in a wider variety of anxiety disorders than any other antidepressant. Long-term data suggest that paroxetine is effective in preventing relapse or recurrence of depression for up to 1 year. Limited data show that paroxetine maintains a therapeutic response over 1 year in obsessive-compulsive disorder and up to 6 months in panic disorder. The side-effect profile of paroxetine is largely similar to that of the other SSRIs, although paroxetine tends to be more sedating and constipating in some patients, perhaps due to its anticholinergic activity. The potential for discontinuation syndrome and weight gain appears to be slightly higher with paroxetine than with other SSRIs. This review focuses on the immediate release and controlled-release formulations of paroxetine. It summarizes the efficacy and tolerability data for both formulations, with a particular emphasis on paroxetine CR which was introduced in 2002. It also discusses emerging evidence in other clinical areas and recent data that have led to modifications in the safety profile of paroxetine.     

Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine

BACKGROUND: Limited information is available regarding optimal dosing or long-term pharmacotherapy with serotonin reuptake inhibitors in obsessive-compulsive disorder. This study evaluated the acute safety and efficacy and long-term efficacy, safety, and impact on relapse prevention of paroxetine in obsessive-compulsive disorder. METHOD: We enrolled 348 outpatients with DSM-III-R obsessive-compulsive disorder in phase 1, a 12-week randomized, double-blind, parallel study of fixed doses of paroxetine (20 mg/day, 40 mg/day, or 60 mg/day) and placebo. In phase 2, 263 phase 1 completers were enrolled in 6 months of flexibly dosed open-label paroxetine treatment. In phase 3, 105 responders to open-label paroxetine were randomized to 6-month double-blind, fixed-dose, parallel paroxetine/placebo treatment to evaluate long-term efficacy, safety, and impact on relapse prevention. The study was conducted from July 1991 to February 1994. RESULTS: Patients in phase 1 acute treatment receiving 40 mg/day or 60 mg/day of paroxetine improved significantly (p < .05) more than those receiving placebo; the mean reduction in Yale-Brown Obsessive-Compulsive Scale score was 25% on 40 mg/day of paroxetine and 29% on 60 mg/day compared with 13% on placebo. During phase 3, long-term treatment, a greater proportion of placebo- (59%) than paroxetine-treated (38%) patients relapsed. Paroxetine was well tolerated at all doses, with no significant increase in frequency of adverse events during long-term compared with short-term therapy. Greater adverse events in the placebo than in the paroxetine group in phase 3 probably represent a discontinuation effect. CONCLUSION: Paroxetine doses of 40 mg/day and 60 mg/day (but not 20 mg/day) are effective in treating acute obsessive-compulsive disorder. Long-term treatment with paroxetine is effective and safe, decreases the rate of relapse, and lengthens the time to relapse.     

Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder

BACKGROUND: This 12-week, placebo-controlled study was carried out to compare the relative efficacy of paroxetine, clomipramine, and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia. METHOD: After a 3-week single-blind, placebo run-in period, 131 patients were randomly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression scale, the Patient Global Evaluation, the Hamilton Rating Scale for Anxiety, the Marks-Sheehan Phobia Scale, the Montgomery-Asberg Depression Rating Scale, and the Sheehan Disability Scale. RESULTS: Comparisons with placebo revealed significant superiority of paroxetine (20-60 mg/day) and clomipramine (50-150 mg/day) on nearly all outcome measures. On most measures, paroxetine also showed higher efficacy than cognitive therapy. With few exceptions, cognitive therapy did not differ significantly from placebo. The number of subjects becoming panic-free (66%) was higher and the onset of action was faster in the paroxetine-treated group. Treatment with cognitive therapy yielded the highest drop-out rate (26%). CONCLUSION: In this short-term study assessing treatment of panic disorder and agoraphobia, paroxetine and clomipramine were consistently superior to pill placebo, whereas cognitive therapy was superior on only a few measures.     

Paroxetine Controlled Release for Premenstrual Dysphoric Disorder: Remission Analysis Following a Randomized, Double-Blind, Placebo-Controlled Trial

Objective: To compare the efficacy and safety of paroxetine controlled release (CR) (12.5 mg/day or 25 mg/day) versus placebo in premenstrual dysphoric disorder (PMDD).Method: A double-blind, randomized, placebo-controlled trial was conducted over 3 menstrual cycles in women aged 18-45 years with confirmed DSM-IV PMDD in 47 outpatient centers across the United States and Canada from November 1999 to January 2002. The primary efficacy measure was the visual analog scale (VAS)-Mood, which is the mean of 4 core symptoms: irritability, tension, depressed mood, and affective lability.Results: A statistically significant difference was observed in favor of paroxetine CR 25 mg versus placebo on the VAS-Mood (adjusted mean difference = -12.58 mm, 95% CI = -18.40 to -6.76; p < .001) and for paroxetine CR 12.5 mg versus placebo (adjusted mean difference = -7.51 mm, 95% CI = -13.40 to -1.62; p = .013). Paroxetine CR was generally well tolerated.Conclusion: Paroxetine CR doses of 12.5 mg/day and 25 mg/day are effective in treating PMDD and are well tolerated.     

Duloxetine in the treatment of major depressive disorder: a placebo- and paroxetine-controlled trial.

OBJECTIVE: Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and safety in the treatment of major depressive disorder (MDD). METHODS: In this randomized, double-blind trial, patients age > or =18 meeting DSM-IV criteria for MDD were randomized to placebo (N=99), duloxetine 80 mg/day (N=93), duloxetine 120 mg/day (N=103), or paroxetine 20 mg/day (N=97). The primary outcome measure was mean change from baseline in the 17-item Hamilton rating scale for depression (HAMD(17)) total score after 8 weeks of treatment; a number of secondary efficacy measures also were assessed. Safety and tolerability were assessed via collection and analysis of treatment-emergent adverse events (TEAEs), vital signs, and weight. The Arizona sexual experiences scale was used to assess sexual functioning. Patients who had a > or =30% reduction from baseline in the HAMD(17) total score at the end of the acute phase entered a 6-month continuation phase where they remained on the same treatment as they had taken during the acute phase; efficacy and safety/tolerability outcomes were assessed during continuation treatment. RESULTS: More than 87% of patients completed the acute phase in each treatment group. Duloxetine-treated patients (both doses) showed significantly greater improvement (P<0.05) in the HAMD(17) total score at week 8 compared with placebo. Paroxetine was not significantly different from placebo (P=0.089) on mean change on the HAMD(17). Duloxetine 120 mg/day also showed significant improvement on most secondary efficacy measures (six of nine) compared with placebo while duloxetine 80 mg/day (three of nine) and paroxetine (three of nine) were significantly superior to placebo on fewer secondary measures. HAMD(17) mean change data from this study and an identical sister study were pooled as defined a priori for the purposes of performing a non-inferiority test versus paroxetine. Both duloxetine doses met statistical criteria for non-inferiority to paroxetine. TEAE reporting rates were low in all treatment groups and no deaths occurred in the acute or continuation phases. CONCLUSIONS: The efficacy of duloxetine at doses of 80 and 120 mg/day in the treatment of MDD was demonstrated. Tolerability, as measured by TEAEs, and safety were similar to paroxetine 20 mg/day and consistent with previous published data on duloxetine in the treatment of MDD.     

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.     

A randomized, double-blind, fixed-dose comparison of paroxetine and placebo in the treatment of generalized social anxiety disorder

BACKGROUND: This multicenter, double-blind, placebo-controlled study was carried out to determine the effectiveness and safety of various daily dosages of paroxetine for the treatment of generalized social anxiety disorder. METHOD: A 1-week, single-blind, placebo run-in was followed by 12 weeks of double-blind treatment. 384 eligible patients meeting DSM-IV criteria for social anxiety disorder were randomly assigned to receive paroxetine, 20 (N = 97), 40 (N = 95), or 60 mg (N = 97), or placebo (N = 95) once daily in a 1:1:1:1 ratio. Primary efficacy variables included mean change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and proportion of patients exhibiting a therapeutic response (defined as a Clinical Global Impressions-Global Improvement scale [CGI-1] score of 1 or 2). RESULTS: In the last-observation-carried-forward analyses, patients treated with paroxetine, 20 mg/day, had significantly greater improvement on mean LSAS total scores compared with those receiving placebo (p < .001), while the incidence of responders, based on the CGI-I rating, was significantly greater with paroxetine, 40 mg/day, than with placebo (p = .012). Patients treated with paroxetine, 20 and 60 mg, also had significantly better responses on the social item of the Sheehan Disability Scale than did patients treated with placebo (p < .019). The completer analyses showed a significant difference between the placebo group and the 20-mg and 40-mg paroxetine groups on LSAS total score and rate of response (p < or = .006). There were no serious adverse experiences attributed to paroxetine treatment. CONCLUSION: Paroxetine, 20 mg/day, is an effective and safe treatment for patients with generalized social anxiety disorder and significantly improves social anxiety, avoidance of social interactions, social disability, and overall clinical condition. Further data analyses are needed to determine whether more specific guidelines for paroxetine dosage escalation in social anxiety disorder can be drawn.     

Efficacy and tolerability of escitalopram in anxiety disorders: a review

INTRODUCTION: Anxiety disorders are highly prevalent and disabling disorders, for which selective serotonin reuptake inhibitor (SSRI) antidepressants are an effective treatment. Escitalopram is the most selective SSRI available. Beyond its well-established efficacy in depression with or without anxiety, preclinical studies have demonstrated that escitalopram has a broad spectrum of anxiolytic activity. AIM OF THE REVIEW: This review focuses on the therapeutic use and the tolerability issues of escitalopram in the treatment of adult patients with panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, and obsessive-compulsive disorder (OCD), on the basis of numerous recent short-term and long-term controlled studies in these disorders. In a 10-week randomised, double-blind trial in patients with panic disorder, escitalopram (flexible doses 5-10 mg/d) was significantly more effective than placebo in reducing the panic attack frequency, with a faster onset of action than citalopram. Fifty percent of escitalopram recipients and 38% of placebo recipients experienced no panic attacks, with a similar incidence of the most common adverse events for both groups. LITERATURE FINDINGS IN PD: In an open-label study in elderly (>65 years) patients with panic disorder, improvement in panic attack frequency and secondary efficacy variables occurred more rapidly in escitalopram than citalopram recipients. LITERATURE FINDINGS IN GAD: In four double-blind, comparative, eight- to 12-week studies in patients with GAD, escitalopram was more effective than placebo and at least as effective as paroxetine in reducing the mean Hamilton Rating Scale for Anxiety total score. Escitalopram 10-20 mg/d demonstrated continued efficacy in a 24-week extension study of short double-blind trials and in a placebo-controlled, double-blind, 24/76-week relapse-prevention study. In this trial, escitalopram recipients showed a significantly longer time to relapse and reduced risk of relapse than placebo recipients, and the risk of relapse was 4.04 times higher in the placebo group than in the escitalopram group. Escitalopram was well tolerated and only 7% patients withdrew, due to adverse events in the escitalopram group, versus 8% in the placebo group. LITERATURE FINDINGS IN SOCIAL PHOBIA: In two randomised, double-blind, 12- and 24-week studies in patients with social anxiety disorder (social phobia), escitalopram 10-20 mg/d was generally more effective than placebo and at least as effective as paroxetine in reducing the mean Liebowitz Social Anxiety Scale total scores. In a 24-week double-blind, placebo-controlled relapse-prevention study, escitalopram recipients had a longer time to relapse and reduced risk of relapse compared with placebo recipients, and significantly fewer escitalopram than placebo recipients relapsed (22% versus 50%). In these studies, the treatment effects of escitalopram were independent of gender, symptom severity and chronicity, and comorbid depressive symptoms, and the drug was tolerated well. LITERATURE FINDINGS IN OCD: Finally, in patients with OCD, escitalopram 20mg/d for 12 weeks was more effective than placebo, and at least as effective as paroxetine 40 mg/day, with respect to a mean reduction from baseline in the Yale-Brown Obsessive Scale total score. In a 24-week, randomised, placebo-controlled relapse-prevention study, the proportion of patients who relapsed in the escitalopram group (23%) was 2.74 times lower than in the placebo group (52%). In both groups, the majority of adverse events reported were mild to moderate. CONCLUSION: On the whole, numerous clinical data indicate that escitalopram, 10-20 mg/d, is an effective and well-tolerated first-line treatment option for the management of panic disorder, GAD, social anxiety and OCD. Beyond short-term demonstrations of efficacy in these disorders, several controlled relapse-prevention studies showed the necessity and utility of maintaining the treatment six months or more after the remission has been obtained.