Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine

OBJECTIVE: Pregabalin has demonstrated robust, rapid efficacy in reducing symptoms of generalized anxiety disorder (GAD) in 4 placebo-controlled clinical trials. The current study compared the efficacy and safety of pregabalin and venlafaxine in patients diagnosed with moderate to severe GAD. METHOD: The study was conducted from December 21, 1999, to July 31, 2001. Outpatients (N = 421) in primary care or psychiatry settings meeting DSM-IV criteria for GAD were randomly assigned to 6 weeks of double-blind treatment with pregabalin 400 or 600 mg/day, venlafaxine 75 mg/day, or placebo. The primary analysis was change in Hamilton Rating Scale for Anxiety (HAM-A) total score from baseline to last-observation-carried-forward (LOCF) endpoint. Secondary analyses included the change in HAM-A psychic (emotional) and somatic (physical) factor scores, significant improvement at week 1, and week 1 improvement sustained at every visit through endpoint. RESULTS: Pregabalin at both dosages (400 mg/day, p = .008; 600 mg/day, p = .03) and venlafaxine (p = .03) produced significantly-greater improvement in HAM-A total score at LOCF endpoint than did placebo. Only the pregabalin 400-mg/day treatment group experienced significant improvement in all a priori primary and secondary efficacy measures. Pregabalin in both dosage treatment groups (400 mg/day, p < .01; 600 mg/day, p < .001) significantly improved HAM-A total score at week 1, with significant improvement through LOCF endpoint. Statistically significant improvement began at week 2 for venlafaxine. Discontinuation rates due to associated adverse events were greatest in the venlafaxine treatment group: venlafaxine, 20.4%; pregabalin 400 mg/day, 6.2%; pregabalin 600 mg/day, 13.6%; placebo, 9.9%. CONCLUSION: Pregabalin was safe, well tolerated, and rapidly efficacious across the physical-somatic as well as the emotional symptoms of GAD in the majority of patients studied in primary care and psychiatric settings.     

Pregabalin in the treatment of post‐traumatic peripheral neuropathic pain: a randomized double‐blind trial

Background: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post‐traumatic peripheral neuropathic pain (including post‐surgical). Methods: Patients with a pain score ≥4 (0–10 scale) were randomized and treated with either flexible‐dose pregabalin 150–600 mg/day (n = 127) or placebo (n = 127) in an 8‐week double‐blind treatment period preceded by a 2‐week placebo run‐in. Results: Pregabalin was associated with a significantly greater improvement in the mean end‐point pain score vs. placebo; mean treatment difference was ?0.62 (95% CI ?1.09 to ?0.15) (P = 0.01). The average pregabalin dose at end‐point was ～326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain‐related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all‐patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end‐point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. Conclusion: Flexible‐dose pregabalin 150–600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post‐traumatic peripheral neuropathic pain.     

Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials

BACKGROUND: Pregabalin has been evaluated in randomised clinical trials in patients with generalised anxiety disorder (GAD) in a fixed-dose design and with the Hamilton Anxiety Scale (HAM-A) as outcome measure. Four of the available six placebo-controlled trials were found acceptable for a pooled analysis of dose-response relationship. METHOD: Both the full HAM-A (14) and the six-item subscale covering the core items of GAD (HAM-A (6)) were analysed. The unbiased effect size statistic was used to evaluate the advantage of pregabalin over placebo. An effect size of 0.40 or higher was used to indicate a clinically significant effect. RESULTS: Four placebo-controlled trials running over four weeks and covering the dose range from 150 mg to 600 mg pregabalin were sufficiently homogeneous to be pooled for the analysis. Both HAM-A (6) and HAM-A (14) showed that for the dose of 150 mg pregabalin daily the effect size was clearly below 0.40. For the dose range of 200-450 mg daily, the effect sizes exceeded 0.40, with a plateau-like curve. The maximum dose of 600 mg daily did not increase effect size. On the HAM-A (14) as well as the item of sleep, effect size was generally higher, but followed the same pattern as the HAM-A (6). DISCUSSION: The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily.     

Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study

OBJECTIVE: Quetiapine monotherapy shows efficacy in bipolar depression. The analyses in this multicenter, double-blind, randomized, fixed-dose, placebo-controlled study evaluated effects of quetiapine monotherapy on anxiety symptoms in bipolar depression. METHOD: Of 542 outpatients randomly assigned to treatment, 539 with bipolar I (N = 358) or bipolar II (N = 181) disorder experiencing a major depressive episode (DSM-IV) received 8 weeks of quetiapine monotherapy (600 or 300 mg/day) or placebo between September 2002 and October 2003. Anxiety assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and relevant items from the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Rating Scale for Depression (HAM-D). Analyses evaluated the pooled dose groups versus placebo. RESULTS: At week 8, quetiapine 600 and 300 mg/day each demonstrated significant improvements in HAM-A total score versus placebo (-10.8 and -9.9 vs. -6.7, p < .001). Quetiapine (pooled doses) significantly improved HAM-A total score from week 1. In bipolar I depression, quetiapine showed significant improvement in HAM-A total score versus placebo (-10.4 vs. -5.1, p < .001). In bipolar I depression, quetiapine also showed significant improvements versus placebo on the HAM-A anxious mood and tension items, HAM-A psychic and somatic subscales, MADRS inner tension item, and HAM-D psychic anxiety item (all p < .001), but not the HAM-D somatic anxiety item. In bipolar II depression, quetiapine reduced the HAM-A total score more than placebo, but the difference was not statistically significant (-9.8 vs. -9.0, p = .473). In bipolar II depression, quetiapine showed significant improvement versus placebo on the HAM-A anxious mood, MADRS inner tension, and HAM-D psychic anxiety items (all p < .01). CONCLUSION: Quetiapine monotherapy shows efficacy in treating anxiety symptoms in bipolar I depression; however, the anxiolytic effects in bipolar II disorder require further investigation.     

Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial.

BACKGROUND: The objective of this randomized, double-blind, placebo-controlled study was to investigate the efficacy and safety of paroxetine in outpatients with generalized anxiety disorder (GAD). METHOD: Male and female outpatients 18 years and older who met DSM-IV criteria for GAD and had baseline scores of at least 20 on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with paroxetine (20-50 mg/day) or placebo for 8 weeks. The primary efficacy variable was the mean change from baseline in the total score of the HAM-A. Additional key efficacy variables were the change from baseline in the scores of the HAM-A items anxious mood and tension, the anxiety subscale of the Hospital Anxiety and Depression Scale, and the Sheehan Disability Scale (SDS). The proportions of patients fulfilling response and remission criteria at week 8 were also determined. RESULTS: The intent-to-treat population included 324 patients. At week 8, compared with the placebo group (N = 163), the paroxetine group (N = 161) had a significantly greater reduction of GAD symptoms on all of the above-mentioned efficacy variables. On the HAM-A anxious mood item, which encompasses the cardinal symptoms of GAD, significantly greater efficacy was observed from week 1 and on the SDS significantly greater improvement was documented in the domain "social life" as early as week 4 for paroxetine compared with placebo. In both the last-observation-carried-forward and completer data sets, significantly greater proportions of paroxetine-treated patients achieved response or remission by week 8. Treatment with paroxetine was well tolerated, and the number and type of adverse events recorded in the paroxetine group correspond to the known safety profile of this medication. CONCLUSION: Paroxetine in doses of 20 to 50 mg once daily is effective in the treatment of patients with GAD. Improvement of core symptoms of GAD occurs early and is associated with significant reduction in disability after only 8 weeks of treatment.     

Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study

PURPOSE: To evaluate pregabalin as add-on therapy for patients with partial seizures administered as fixed dose or as flexible dose adjusted to optimal seizure reduction and tolerability. METHODS: Patients receiving antiepileptic drugs (98.8% between 1 and 3 AEDs; 1.2% on more than 3 AEDs) and experiencing > or =4 partial seizures during the 6-week baseline period and no 4-week seizure-free interval were randomized (1:2:2) to placebo (n = 73), pregabalin fixed dose (600 mg/day BID; n = 137), or pregabalin flexible dose (n = 131; 150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each, BID) for 12 weeks. Dosage could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved. Primary efficacy parameter was reduction in seizure frequency from baseline. RESULTS: Both pregabalin regimens significantly reduced seizure frequency compared with placebo, by 35.4%, for flexible dose (p = 0.0091) and 49.3% for fixed dose (p = 0.0001) versus 10.6% for placebo, and the fixed-dose group was superior to the flexible-dose group (p = 0.0337). Most adverse events were mild or moderate. Discontinuation rates due to adverse events were 6.8% (placebo), 12.2% (pregabalin flexible dose), and 32.8% (pregabalin fixed dose). Patients receiving pregabalin fixed dose discontinued due to adverse event earlier than other groups. CONCLUSIONS: Pregabalin administered twice daily, either as fixed (600 mg/day), or as flexible (150-600 mg/day) dose, was highly effective and generally well-tolerated as add-on therapy for partial seizures with or without secondary generalization. Lower incidence of adverse events and discontinuations were achieved in patients receiving pregabalin when dosing was individualized to optimize efficacy and tolerability.     

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.     

Donepezil in Parkinson's disease dementia: A randomized, double-blind efficacy and safety study

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. ? 2012 Movement Disorder Society.     

The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study

OBJECTIVE: To evaluate the efficacy and tolerability of tiagabine, a selective gamma-aminobutyric acid (GABA) reuptake inhibitor, in adults with generalized anxiety disorder (GAD). METHOD: This 8-week, randomized, double-blind, multicenter, placebo-controlled study enrolled patients with GAD (DSM-IV). Tiagabine was initiated at 4 mg/day and then flexibly dosed twice a day to a maximum dose of 16 mg/day. Study drug was tapered after week 8 in decrements of 2 mg every other day. Efficacy assessments included the Hamilton Rating Scale for Anxiety (HAM-A) and Sheehan Disability Scale. Adverse events, sexual functioning, and change in depressive symptoms were monitored. Data were collected from May 2003 to January 2004. RESULTS: A total of 266 patients (tiagabine, N = 134; placebo, N = 132) were included in safety analyses; 260 patients (tiagabine N = 130; placebo N = 130) were included in efficacy analyses. Tiagabine reduced symptoms of GAD according to the observed case and mixed models repeated-measures (MMRM) analyses but not the primary last-observation-carried-forward (LOCF) analysis. At final visit, the reduction from baseline in mean HAM-A total score was 11.8 for tiagabine, compared with 10.2 for placebo (LOCF analysis, p = .27). In a post hoc MMRM analysis, a significant difference in the mean reduction in HAM-A total score over the efficacy evaluation period was found, favoring tiagabine over placebo (p < .01). Tiagabine had an early onset of effect, as shown by significant reduction from baseline in mean HAM-A total score compared with placebo at week 1 (observed cases, p < .05). Tiagabine was generally well tolerated and not associated with changes in sexual functioning or depressive status. Symptoms of a discontinuation syndrome during taper were not observed. CONCLUSION: The primary LOCF analysis was negative; however, results from the observed case and MMRM analyses suggest that tiagabine may be a useful treatment option for adult patients diagnosed with GAD. These findings warrant further evaluation in randomized clinical studies.     

Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder.

BACKGROUND: The objective of this randomized, double-blind study was to compare the efficacy and safety of venlafaxine extended release (XR) and buspirone in outpatients with generalized anxiety disorder (GAD) but without concomitant major depressive disorder. METHOD: Male and female outpatients at least 18 years old who met the DSM-IV criteria for GAD and had scores of 18 or higher on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with either venlafaxine XR (75 or 150 mg/day), buspirone (30 mg/day in 3 divided doses), or placebo for 8 weeks. The primary efficacy variables were changes in anxiety as determined by final on-therapy HAM-A total and psychic anxiety scores and Clinical Global Impressions scale (CGI) scores. Other key efficacy variables were HAM-A anxious mood and tension scores and the anxiety subscale scores of the patient-rated Hospital Anxiety and Depression scale (HAD). RESULTS: The efficacy analysis included 365 patients and the safety analysis, 405. At week 8, adjusted mean HAM-A psychic anxiety, anxious mood, and tension scores were significantly lower for venlafaxine XR-treated patients than for placebo-treated patients. On the HAD anxiety subscale, venlafaxine XR, 75 or 150 mg/day, was significantly more efficacious than placebo at all time points except weeks 1 (both dosages) and 2 (150-mg/day dosage only) and significantly more efficacious than buspirone at all time points except week 1. On the CGI-Improvement scale, scores for venlafaxine XR (both dosages) and buspirone were numerically superior to those for placebo at all time points, and statistical significance was observed at weeks 3, 4, 6, and 8 for venlafaxine XR and at weeks 6 and 8 for buspirone. The adverse events were not essentially different between treatment groups. CONCLUSION: Venlafaxine XR is an effective, safe, and well-tolerated once-daily anxiolytic agent in patients with GAD without comorbid major depressive disorder. This agent was significantly superior to buspirone on the HAD anxiety subscale. Buspirone demonstrated statistical significance versus placebo on a measure of anxiolytic response.     

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.     

Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention

Pregabalin is the first anxiolytic pharmacologic alternative for the treatment of generalized anxiety disorder (GAD) to be introduced in more than 10 years. GAD is a significant psychiatric condition with lifetime prevalence rates ranging between 5.7 and 6.4%. It causes significant impairment in quality of life and functional abilities equivalent to those associated with major depression. Randomized, controlled trials confirm that pregabalin is superior to placebo and comparable with lorazepam, alprazolam and venlafaxine for the treatment of patients with moderate-to-severe GAD. The onset of anxiolytic activity for pregabalin is apparent within 1 week following initiation of treatment, which is more rapid than that obtained with paroxetine and venlafaxine. Additionally, pregabalin has demonstrated potential for the prevention of relapse of GAD. Recently, the efficacy, safety and tolerability of pregabalin were also shown in a placebo-controlled study with elderly patients. Safety and tolerability profiles are favorable, with transient dizziness and somnolence of mild-to-moderate severity being the most commonly reported adverse events. Pregabalin has minimal potential for drug-drug interactions and does not provoke a clinically significant withdrawal response. Furthermore, pregabalin has low potential for abuse and dependence, unlike other classes of medications used for the treatment of GAD. Clinicians may consider the use of pregabalin in lieu of benzodiazepines as an alternative therapy for their patients with GAD.     

Analysis of individual symptoms in generalized anxiety--a pooled, multistudy, double-blind evaluation of buspirone

Pooled data for 427 patients with generalized anxiety disorders were analyzed retrospectively from six double-blind trials evaluating buspirone, a nonbenzodiazepine anxiolytic, in the treatment of generalized anxiety disorder. After a 4- to 7-day washout period, patients were allocated at random to receive treatment over a 4-week period. Buspirone dose ranged from 10 to 60 mg. Patients were assessed on entry and at weekly intervals using the 14 symptom groups (items) of the Hamilton Anxiety Rating Scale (HAM-A). Buspirone improved all symptom groups significantly; onset of anxiolytic activity was observed at week 1 in 3 groups of psychic symptoms of anxiety. Within 2 weeks, 8 of the 14 symptom groups were improved significantly by buspirone versus placebo, and symptoms of anxiety improved further up to the 4-week end point. Psychic symptoms of anxiety improved earlier in general than the somatic symptoms of anxiety. At the end of treatment, analyses of the HAM-A scores indicated that all of the 14 symptom groups (individual items), the total HAM-A score, and the 2 composite Psychic and Somatic Anxiety Factors were significantly improved with buspirone as compared to placebo. The beneficial effects of buspirone were not compromised by any significant side effects.     

Analysis of outcome in retrieved dropout patients in a rivastigmine vs placebo, 26-week,Alzheimer disease trial

BACKGROUND: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. OBJECTIVE: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine.Design and METHODS: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). RESULTS: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n = 17) compared with the rivastigmine 6- to 12-mg/d group (n = 33) at week 26 (MMSE score, -8.2 vs -3.0; P =.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n = 38) compared with the rivastigmine 6- to 12-mg/d group (n = 88) at week 26 (MMSE score, -5.69 vs -2.5; P =.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P =.007, P =.009) and the pooled studies (P =.002, P =.017). CONCLUSIONS: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.     

生物反馈治疗广泛性焦虑障碍对照研究

目的：比较生物反馈放松疗法与阿普唑仑治疗广泛性焦虑障碍的临床疗效。方法：102例广泛性焦虑障碍患者随机分为研究组（n=51）和对照组（n=51）,研究组采用每日1次生物反馈放松治疗,每次治疗30min;对照组采用阿普唑仑0．8mg／次,每日2次口服治疗。两组患者于治疗前及治疗2周、4周分别进行汉密尔顿焦虑量表（HAMA）和焦虑自评量表（SAS）评定。结果：研究组临床有效率为76．5％,对照组临床有效率为80．4％,两组疗效差异无显著性（χ^2=0．43,P〉0．5）。结论：生物反馈放松疗法治疗广泛性焦虑障碍疗效肯定。     

Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. METHODS: A total of 347 patients were randomized to oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. RESULTS: No difference between any oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. CONCLUSIONS: Although the primary efficacy variable did not reach statistical significance, patients taking oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.     

Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder

BACKGROUND: A subset of patients with comorbid major depressive disorder and generalized anxiety disorder (GAD) was examined from a double-blind. placebo-controlled study comparing the efficacy and safety of venlafaxine extended release (XR) and fluoxetine. METHOD: From a total of 368 patients, 92 patients meeting DSM-IV criteria for major depressive disorder who also had comorbid GAD were identified. The comparison group comprised 276 evaluable noncomorbid patients. Patients received venlafaxine XR (75-225 mg/day), fluoxetine (20-60 mg/day), or placebo for 12 weeks. Efficacy evaluations included Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions (CGI) scale. RESULTS: By the final assessment at week 12, comorbid patients in the venlafaxine XR group, but not in the fluoxetine group, showed a significantly greater decrease than those in the placebo group in the primary efficacy variables of mean HAM-D and HAM-A total scores (p < .05, pairwise comparison). In comorbid patients, significant pairwise differences were noted between venlafaxine XR and placebo at week 12 for the secondary variables of HAM-D anxiety-somatization and retardation factors, HAM-D depressed mood item. HAM-A psychic anxiety factor, the Hospital Anxiety and Depression scale (HAD) anxiety subscale score, and the Covi Anxiety Scale score. Fluoxetine was significantly different from placebo only on the HAD depression subscale score. Response, defined as > or = 50% decrease in symptoms score, was achieved in 66% and 59% of the comorbid patients for HAM-D and HAM-A, respectively, in the venlafaxine XR group at week 12. This response was higher than that seen with fluoxetine (52% and 45%) or placebo (36% and 24%). Onset of efficacy appeared to be slower in comorbid than in noncomorbid patients. CONCLUSION: This is the first evidence from a controlled study of the effectiveness of pharmacotherapy in patients with comorbid major depressive disorder and GAD. The delayed improvement in comorbid patients compared with noncomorbid patients suggests that a longer treatment period may be necessary in comorbid patients.     

Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control

BACKGROUND: Gamma-aminobutyric acid (GABA) plays a central role in the pathophysiology of anxiety. Tiagabine, a selective GABA reuptake inhibitor, enhances normal GABA tone. This 10-week, randomized, open-label trial evaluated tiagabine in patients with generalized anxiety disorder (GAD), with paroxetine serving as a positive control. METHOD: Adult patients with DSM-IV GAD were randomly assigned to receive either tiagabine or paroxetine. Tiagabine was initiated at 4 mg/day (2 mg morning and evening) during week 1. Between weeks 2 and 6, the dose was individually titrated in 2-mg increments (maximum increase of 4 mg/week) for optimal response to a maximum dose of 16 mg/day (8 mg morning and evening). During weeks 7 through 10, patients received the dosage determined during the titration period. Paroxetine was initiated at 20 mg nightly for the first week and similarly titrated in 10-mg increments to a maximum dose of 60 mg/day. Assessments included the Hamilton Rating Scale for Anxiety (HAM-A), Hospital Anxiety and Depression Scale (HADS), Hamilton Rating Scale for Depression (HAM-D), Pittsburgh Sleep Quality Index (PSQI), and Sheehan Disability Scale (SDS). RESULTS: Forty patients were enrolled (tiagabine, N = 20; paroxetine, N = 20). Mean final doses were tiagabine 10 mg/day (range, 4-16 mg/day) or paroxetine 27 mg/day (range, 20-40 mg/day). Tiagabine and paroxetine significantly reduced anxiety (HAM-A and HADS total and anxiety subscales). Although patients were not diagnosed with a mood disorder, both tiagabine and paroxetine reduced comorbid depressive symptoms (HAM-D total and HADS total and depressive subscale). Tiagabine and paroxetine significantly improved sleep quality (PSQI) and functioning (SDS). Both tiagabine and paroxetine were well tolerated. CONCLUSION: The selective GABA reuptake inhibitor tiagabine and the positive control paroxetine significantly reduced anxiety and comorbid depressive symptoms, improved sleep quality and functioning, and were well tolerated in patients with GAD. Tiagabine may be a therapeutic option for the treatment of anxiety disorders.     

Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR

OBJECTIVE: To characterize the response to the serotonin and norepinephrine reuptake inhibitor, venlafaxine extended release (XR), during the long-term treatment of generalized anxiety disorder. METHODS: Data from two double-blind, placebo-controlled, 6-month trials of venlafaxine XR for the treatment of generalised anxiety disorder were pooled. Criteria for response (> or = 50% improvement from baseline HAM-A score) and remission (HAM-A score < or = 7) and their temporal profile were used to characterize patient improvement over 6 months of treatment with venlafaxine XR and placebo. RESULTS: Venlafaxine XR was associated with significantly (P<0.001) higher response and remission rates (66 and 43%, respectively) compared with placebo (39 and 19%), regardless of the level of baseline anxiety. In the venlafaxine XR group, 61% of the patients who had responded but not remitted by week 8 showed remission by the end of 6 months. In comparison, only 39% of placebo responders who did not qualify for remission at the end of the first 8 weeks of therapy remitted by the end of the 6 months (P=0.007). Relapse occurred in 6% of venlafaxine XR-treated patients and 15% of placebo-treated patients (P<0.01). CONCLUSION: This analysis provides further insight into the outcome of long-term treatment of generalised anxiety disorder with venlafaxine XR and shows for the first time that long-term treatment might be necessary to achieve and maintain remission of symptoms.     

Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study.

BACKGROUND: There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine. METHODS: Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation. RESULTS: Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A 相似文献