Pregabalin for generalized anxiety disorder.

The Problem

You have a patient with generalized anxiety disorder who previously has been treated with selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and buspirone with inadequate relief. In an attempt to avoid a benzodiazepine, you consider pregabalin (Lyrica).

The Question

Is pregabalin effective in treating GAD?

The Analysis

We performed a Medline search combining "pregabalin" and "anxiety."

The Evidence

Pregabalin is an [allpha.sub.2]-delta voltage-gated calcium channel blocker that reduces the release of excitatory neurotransmitters. It has Food and Drug Administration approval for diabetic peripheral neuropathic pain, postherpetic neuralgia, adjunctive treatment in partial-onset seizures, and fibromyalgia.

In one double-blind, placebo-controlled study, investigators compared the efficacy of pregabalin with that of lorazepam (Am. J. Psychiatry 2003;160:533-40). In this study, 276 patients with GAD were randomly assigned to receive either pregabalin 150 mg/day or 600 mg/day, lorazepam 6 mg/day, or placebo.

The study consisted of a 1-week, single-blind placebo lead-in to allow washout of prior treatments and to establish a baseline, followed by 4 weeks of study medications and a 1-week taper. Participants were evaluated with the Hamilton Rating Scale for Anxiety (HAM-A), which quantifies anxiety with scores from 0 to 56 (most severe). Patients in the placebo group experienced a decrease of 6.8 points in HAM-A score, compared with drops of 9.2 points in the pregabalin 150-mg/day group, 10.3 points in the pregabalin 600-mg/day group, and 12.0 points in the lorazepam group.

In a similar study of 271 patients with GAD, participants received the same medications at the same dosages and over the same timeline, and were assessed in the same manner (J. Clin. Psychopharmacol. 2003;23:240-9). HAM-A scores decreased by 13.2 and 9.3 points in the pregabalin 200-mg/day and placebo groups, respectively.

Investigators who conducted a 6-week, double-blind, placebo-controlled study evaluated the efficacy of pregabalin using twice-daily vs. thrice-daily dosing in patients with GAD (J. Clin. Psychopharmacol. 2005;25:151-8). Participants were randomized to receive either pregabalin 100 mg b.i.d. (n = 78), 200 mg b.i.d. (n = 89), or 150 mg t.i.d. (n = 88), or placebo (n = 86). The primary measure of efficacy was the HAM-A score. Reductions in HAM-A scores were 12.4 (100 mg b.i.d.), 12.9 (200 mg b.i.d.), and 12.4 (150 mg t.i.d). The placebo group experienced a HAM-A reduction of 9.3.

In another double-blind, placebo-controlled study, researchers compared the efficacy of pregabalin with that of alprazolam in patients with GAD (Arch. Gen. Psychiatry 2005;62:1022-30). Outpatients with a HAM-A score of 20 or greater were randomized to 4 weeks of treatment with pregabalin 300 mg/day (n = 91), pregabalin 450 mg/day (n = 90), pregabalin 600 mg/day (n = 89), alprazolam 1.5 mg/day (n = 93), or placebo (n = 91). Reductions in HAM-A scores were 12.2, 11.0, 11.8, 10.9, and 8.4. Improvements were noted in psychic and somatic symptoms of GAD.

The efficacy of pregabalin was compared with that of venlafaxine in a double-blind, placebo-controlled study (J. Clin. Psychiatry 2006;67:771-82). Outpatients with a HAM-A score of 20 or higher were randomized to pregabalin 400 mg/day (n = 97), pregabalin 600 mg/day (n = 110), venlafaxine 75 mg/day (n = 113), or placebo (n = 101). Patients experienced reductions in HAM-A scores of 14.7, 14.1, 14.1, and 11.6. Again, improvements were noted in psychic and somatic symptoms of GAD. The proportion of patients experiencing a reduction of 50% or more in HAM-A score was 61% for the pregabalin 400-mg/day group, and 62% for the venlafaxine group. Statistical significance was not reached in the pregabalin 600-mg/day group (58%) when compared with placebo (45%).

Investigators have also looked at the long-term efficacy of pregabalin in GAD (Int. Clin. Psychopharmacol. 2008;23:18-28). In this study, 624 outpatients with GAD of at least a year in duration and HAM-A score of 20 or greater were treated with open-label pregabalin 450 mg/day for 8 weeks. If a clinical response was observed, patients were randomized in a double-blind fashion to either pregabalin 450 mg/day (n = 168) or placebo (n = 170) for 24 weeks. Time to relapse was determined by a return to a HAM-A score of 20 or greater, an assessment of the patient as "much worse," or a clinical judgment that intervention was necessary. At the study end point, 65% of the placebo group and 42% of the pregabalin group had relapsed.

The Conclusion

Well-designed, large, multicenter studies have shown that pregabalin is effective in treating and preventing GAD, but these conclusions ought to be tempered by the observation that all were funded, at least in part, by Pfizer Inc., maker of Lyrica. Also, we have no way of knowing if negative results have been withheld from publication, and we are not certain that the results have been independently reproduced, as one investigator's name appears in five of the six studies cited above, and another appears in all six studies.

DR. LEAD-HANSSON is a forensic psychiatrist who practices in San Diego. DR. GUTTMACHER is chief of psychiatry at the Rochester (N.Y.) Psychiatric Center. They have no financial interest in any product or service discussed in this column. They can be reached at cpnews@elsevier.com.

BY JAN LEARD-HANSSON, M.D.

BY LAURENCE GUTTMACHER, M.D.