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

Imperial College School of Medicine, London, UK.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 05/2006; 67(5):771-82.
Source: PubMed


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.
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.
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%.
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.

13 Reads
    • "In addition, it should be noted that, for most of the patients, the treatment with pregabalin was combined with two other drugs: an antidepressant and a benzodiazepine . Similar to the overall results, the effects of pregabalin on psychic and somatic anxiety were also similar to those found in the 6–8-week randomized trials (Allgulander et al., 2003; Pohl et al., 2005; Montgomery et al., 2006) that also reported slightly larger effects on psychic anxiety than on somatic anxiety. The changes in the CGI-severity scores support the beneficial effect observed on the HAM-A; in fact, almost identical effect sizes were observed on the CGI-severity score and the HAM-A total score. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222 mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms.
    International clinical psychopharmacology 06/2015; 30(5). DOI:10.1097/YIC.0000000000000087 · 2.46 Impact Factor
  • Source
    • "Considering the neurobiology of GAD, pharmacological guidelines recommend treatment with selective serotonin reuptake inhibitors, selective serotonin– norepinephrine reuptake inhibitors, or pregablin (Montgomery et al., 2006; Hoffman and Mathew, 2008; Baldwin et al., 2012; Bandelow et al., 2012). Approved selective serotonin reuptake inhibitors for GAD include escitalopram (Davidson et al., 2004; Allgulander et al., 2006; Lenze et al., 2009) and paroxetine (Pollack et al., 2001; Rickels et al., 2003; Stocchi et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This was a flexible-dosed study to evaluate the efficacy and safety of duloxetine 30-120 mg once daily in the treatment of generalized anxiety disorder (GAD) in older adult patients. Patients with GAD, who were at least 65 years of age, were randomly assigned to double-blind treatment with either duloxetine (N = 151) or placebo (N = 140). The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) total score, and the primary endpoint was at week 10. Global functioning was assessed by the Sheehan Disability Scale (SDS). Safety and tolerability was assessed by the occurrence of treatment-emergent adverse events, serious adverse events, laboratory analyses, and vital signs. Analyses were conducted on an intent-to-treat basis. The overall baseline mean HAM-A total score was 24, and SDS global score was 14. Completion rates were 75% for placebo and 76% for duloxetine. At week 10, duloxetine was superior to placebo on mean changes from baseline in HAM-A total scores (-15.9 vs. -11.7, p < 0.001) and in SDS global scores (-8.6 vs. -5.4, p < 0.001). Treatment-emergent adverse events occurred in ≥5% of duloxetine-treated patients and twice the rate than with placebo including constipation (9% vs. 4%, p = 0.06), dry mouth (7% vs. 1%, p = 0.02), and somnolence (6% vs. 2%, p = 0.14). Duloxetine treatment was efficacious in the improvement of anxiety and functioning in older adult patients with GAD, and the safety profile was consistent with previous GAD studies. © 2014 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 09/2014; 29(9). DOI:10.1002/gps.4088 · 2.87 Impact Factor
  • Source
    • "Furthermore , by using the corresponding mutation and generating ␣ 2 ␦-2 (R279A) point mutant mice, which remain sensitive to the anticonflict properties of pregabalin in the same test, we have shown that the ␣ 2 ␦-1 subunit of voltage-gated calcium channels seems to be solely responsible for the anxiolytic activity of pregabalin. Gabapentin and pregabalin show a wide range of activities in various preclinical models (de-Paris et al., 2000; Field et al., 2001; Lotarski and Kinsora, 2004; Vartanian et al., 2006; Taylor et al., 2007; Zohar et al., 2008) and demonstrate clinical efficacy in several indications (Rickels et al., 2005; Montgomery et al., 2006; Taylor et al., 2007; Arnold et al., 2010; Dworkin et al., 2010). They show selective and potent binding to ␣ 2 ␦-1 and ␣ 2 ␦-2, but not to ␣ 2 ␦-3 or ␣ 2 ␦-4 voltagegated calcium channel subunits (Thorpe and Offord, 2010), and the particular importance of the ␣ 2 ␦-1 subunit in mediating the therapeutic effects of these ␣ 2 ␦ ligands is gaining support. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The α(2)δ auxiliary subunits (α(2)δ-1 and α(2)δ-2) of voltage-sensitive calcium channels are thought to be the site of action of pregabalin (Lyrica), a drug that has been shown to be anxiolytic in clinical trials for generalized anxiety disorder. Pregabalin and the chemically related drug gabapentin have similar binding and pharmacology profiles, demonstrating high-affinity, in vitro binding to both α(2)δ-1 and α(2)δ-2 subunits. Two independent point mutant mouse strains were generated in which either the α(2)δ-1 subunit (arginine-to-alanine mutation at amino acid 217; R217A) or the α(2)δ-2 subunit (arginine-to-alanine mutation at amino acid 279; R279A) were rendered insensitive to gabapentin or pregabalin binding. These strains were used to characterize the activity of pregabalin in the Vogel conflict test, a measure of anxiolytic-like activity. Pregabalin showed robust anticonflict activity in wild-type littermates from each strain at a dose of 10 mg/kg but was inactive in the α(2)δ-1 (R217A) mutants up to a dose of 320 mg/kg. In contrast, pregabalin was active in the α(2)δ-2 (R279A) point mutants at 10 and 32 mg/kg. The positive control phenobarbital was active in mice carrying either mutation. These data suggest that the anxiolytic-like effects of pregabalin are mediated by binding of the drug to the α(2)δ-1 subunit.
    Journal of Pharmacology and Experimental Therapeutics 05/2011; 338(2):615-21. DOI:10.1124/jpet.111.180976 · 3.97 Impact Factor
Show more