Pregabalin in generalized anxiety disorder: a placebo-controlled trial.

OBJECTIVE: Current drug therapies for generalized anxiety disorder have limitations. In a controlled trial, the novel agent pregabalin was studied for the treatment of patients with generalized anxiety disorder. METHOD: In this double-blind study, patients with DSM-IV generalized anxiety disorder were randomly assigned to receive pregabalin (150 mg/day or 600 mg/day), lorazepam (6 mg/day), or placebo. A 1-week placebo lead-in was followed by 4 weeks of treatment and then a 1-week dose taper. The primary efficacy measure was the Hamilton Anxiety Rating Scale score at endpoint. RESULTS: A total of 276 patients were randomly assigned to a treatment group and received at least one dose of their assigned medication. Fewer patients given lorazepam (59%, N=40 of 68) completed the trial than did those given placebo (73%, N=50 of 69), 600 mg/day of pregabalin (71%, N=50 of 70), or 150 mg/day or pregabalin (90%, N=62 of 69). The mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the patients given 150 mg/day of pregabalin (-9.2), 600 mg/day of pregabalin (-10.3), and lorazepam (-12.0) were significantly greater than the decrease in those given placebo (-6.8). As early as the week 1 observation, pregabalin significantly reduced the total Hamilton anxiety scale score compared with placebo. The most frequent adverse events reported for pregabalin and lorazepam were somnolence and dizziness. There were no serious adverse events reported by patients given pregabalin, and no withdrawal syndrome was associated with pregabalin treatment. CONCLUSIONS: These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines.

Citalopram treatment of fluoxetine-intolerant depressed patients.

BACKGROUND: We assessed the tolerability of and response to citalopram in depressed patients who had discontinued fluoxetine treatment due to adverse events. METHOD: Fifty-five outpatients with DSM-IV major depressive disorder and a confirmed history of intolerance to fluoxetine (mean final dose = 24.6 mg/day) were switched to citalopram (20 mg/day) after a 2- to 4-week single-blind placebo washout period. During a 6-week, open-label treatment protocol, citalopram could be titrated up to 40 mg/day. Safety and tolerability, including reemergence of symptoms that previously had been associated with fluoxetine, were assessed by recording all spontaneously reported or observed adverse events. Efficacy was evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) scale, and several other measures. Response was defined as a CGI-Improvement score at endpoint of 1 or 2 (i.e., very much or much improved). RESULTS: Ninety-five percent of patients (N = 52) completed the citalopram trial. The only adverse events reported by more than 5 patients (>or= 10%) were pharyngitis (15%) and constipation (11%), and none of the 3 early terminations were attributed to adverse events. The rate of recurrence of the fluoxetine-associated adverse events was low, with headache (3 [27%] of 11 cases), nausea (2 [22%] of 9 cases), and decreased libido (5 [18%] of 28 cases) being the most common. Significant improvement from baseline HAM-D (p <.001) was observed by the first week of citalopram therapy and continued until study end. The intent-to-treat CGI response rate was 65% (36 of 55 patients) at study endpoint; 69% (36 of 52 patients) of the completers responded. CONCLUSION: These data suggest that fluoxetine-intolerant patients can be treated effectively with citalopram.

Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study.

BACKGROUND: Generalized social anxiety disorder is an early onset, highly chronic, frequently disabling disorder with a lifetime prevalence of approximately 13%. The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults. METHOD: After a 1-week single-blind placebo lead-in period, patients with DSM-IV generalized social phobia were randomly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline (50-200 mg/day) or placebo. Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale (LSAS) total score and the responder rate for the Clinical Global Impressions-Improvement scale (CGI-I), defined as a CGI-I score

Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression?

BACKGROUND: Clonazepam cotherapy of fluoxetine was previously demonstrated to accelerate efficacy over the first 3 weeks of treatment. A new 18-week double-blind study attempted to replicate these findings to determine whether superiority would extend to 3 months and assess risks of extension. METHOD: Fifty outpatient volunteers aged 18-65 from Seattle and Portland with moderate-marked depression received fluoxetine (20 mg) doubled at 6 weeks if needed; half took clonazepam (0.5 mg) and half took an identical placebo, 1 or 2 tablets adjusted during the first 2 weeks, until a 3-week taper at 3 months. RESULTS: No serious adverse events and no special problems with sedation or discontinuation were noted. Cotherapy was superior to fluoxetine monotherapy at Day 7 for HAM-D (t=2.03, df=48, P<0.05) and CGI-I (32 vs. 4% responders, P<0.03, Fisher Exact Test) but not otherwise. Cotherapy was effective in reducing insomnia but not anxiety or core symptoms (low mood, suicidality, reduced interest). The only significant benefit of extending treatment was a more rapid response to increased fluoxetine at 6 weeks manifested in a mean HAM-D of 9.0 and CGI-I responder rate of 76% after 8 weeks compared to 16 weeks for monotherapy. LIMITATIONS: Small sample size (N=50) limited power and rendered conclusions tentative. CONCLUSIONS: Extended clonazepam cotherapy of fluoxetine appeared safe and effective for depressed outpatients: it was superior to fluoxetine alone early in treatment and again following fluoxetine dose increase. Cotherapy might be considered at the start of fluoxetine treatment, especially for those with insomnia, and when a dose increase of fluoxetine is anticipated.

Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study.

Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.

Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study.

OBJECTIVE: To evaluate the efficacy and tolerability of extended-release gepirone (gepirone-ER), a 5-HT(1A) agonist, versus placebo in the treatment of adult outpatients with major depressive disorder (MDD). METHOD: A double-blind, randomized, placebo-controlled, parallel-group, 8-week study was conducted from October 2003 to August 2004 in outpatients 18 to 64 years old with moderate-to-severe MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), and a baseline Hamilton Rating Scale for Depression (HAM-D(17)) total score > or = 20. Patients were titrated from 20 to 80 mg/day of gepirone-ER or placebo (most patients received gepirone-ER 60 or 80 mg/day by week 3). The primary outcome measure was baseline-to-endpoint mean change in HAM-D(17) total score. Secondary outcome measures included the 28-item version of the HAM-D, HAM-D depressed mood (item 1), Bech Six-Item Scale, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions scale. RESULTS: Significantly greater reductions in HAM-D(17) total scores occurred in gepirone-ER-treated patients compared with placebo-treated patients by week 4 (p = .004) and continued through weeks 6 (p = .006) and 8 (p = .032). Secondary outcomes also improved significantly at multiple timepoints, including at endpoint. The most frequently reported adverse events in the gepirone-ER versus placebo groups were dizziness (45% vs. 10%), nausea (36% vs. 13%), and headache (24% vs. 16%). Dizziness occurred most frequently during initial dosing and up-titration. CONCLUSIONS: Gepirone-ER significantly reduced depression symptoms and illness severity in MDD outpatients through the end of the study and was generally well tolerated, confirming previous findings.

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.

CONTEXT: Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. OBJECTIVE: To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING: Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. PARTICIPANTS: Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. INTERVENTIONS: Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES: Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS: On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. CONCLUSION: This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.