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New Medicines for GAD: Duloxetine and Quetiapine
Probably all serotonergic antidepressants would be effective to treat pathological worry and other symptoms of generalized anxiety disorder (GAD). However, only a few companies have gone through the expensive process of conducting studies to demonstrate efficacy of their agents. At this time, the selective serotonin reuptake inhibitors (SSRIs) paroxetine (Paxil and others) and escitalopram (Lexapro) carry the US Food and Drug Administration's imprimatur for GAD. The first agent to receive a GAD indication was the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine (Effexor and others). Now a second SNRI, duloxetine (Cymbalta) is being examined for this condition.
Davidson and others studied almost 900 adult GAD patients.1 Initially, patients were treated open-label with duloxetine, up to 120 mg daily, for 6 months. Those who had at least a 50% symptom reduction were then assigned at random in double-blind fashion either to continue duloxetine or switch to placebo for another 6 months.
By the end of open-label treatment, almost 80% of patients were deemed responders, and nearly half achieved the more stringent criteria of "remission." During the double-blind continuation phase, only 13.7% of duloxetine-treated patients suffered a relapse versus 41.8% of those switched to placebo(P ≤ .001). Of patients who did relapse, those taking duloxetine had a longer time to relapse than those switched to placebo(P ≥ .001). During the open-label phase, 13.6% of duloxetine-treated patients discontinued due to adverse effects. During the double-blind continuation phase, this number fell to 1.9%.
Another presentation reviewed data from two 10-week, multicenter, randomized, double-blind trials that compared duloxetine, 60 to 120 mg/day, and extended-release (XR) venlafaxine (Effexor XR), 75 to 225 mg/day, with placebo in approximately 1000 patients with GAD.2 Patients treated with either SNRI improved significantly more (P ≤ .001) than placebo-treated control subjects. Response rates(≥ 50% relief in anxiety symptoms) were 56% and 58% for the two antidepressants, respectively, and 40% for placebo. Discontinuation due to adverse effects was higher for duloxetine (13.4%) than for venlafaxine XR (11.4%) and only 5.4% with placebo. (Differences between each drug and placebo were significant for side effect dropouts.) Nausea was the most common treatment-emergent adverse effect with both drugs, occurring in 26.9% of those treated with duloxetine and 20.1% among those taking venlafaxine XR. There were no statistically significant differences in vital signs between active treatments and placebo.
Second-generation antipsychotics are being used as adjuncts and occasionally as monotherapy for patients with depression. GAD and depression frequently coexist and share many of the same clinical features. Quetiapine (Seroquel) has shown promise as an adjunct to antidepressants for GAD, which led Chouinard and associates to conduct a double-blind trial of extended-release (XR) quetiapine (Seroquel XR) by itself in GAD.3
In this 8-week, double-blind trial, investigators randomly assigned 873 patients to receive either quetiapine XR, 50 mg daily; quetiapine XR, 150 mg daily; paroxetine (Paxil and others), 20 mg daily; or placebo.
Both doses of quetiapine, as well as paroxetine, produced significantly greater reductions in anxiety scores compared with placebo. Similarly, the response rates at week 8 were significantly higher with all three active agents than with placebo. More subjects in the quetiapine groups withdrew due to adverse effects (11.8% and 15.6% for the 50-mg and150-mg treatments, respectively) than with paroxetine (7.9%) or placebo (4.1%). The most common cause for dropouts in both quetiapine groups was somnolence.
It is interesting to contemplate the use of antipsychotics for patients with GAD. For most patients, antidepressants should be tried first. They are usually better tolerated and, in today's market, less expensive. Whether there will be a role for antipsychotics alone or as adjuncts in more difficult GAD cases remains to be determined by future research. As we stated at the outset, probably all serotonergic antidepressants will help alleviate the anxiety and associated symptoms of GAD. Although practitioners frequently prescribe benzodiazepines for these patients, in clinical trials, antidepressants show greater efficacy. In addition, GAD typically coexists with depression. At this time, duloxetine appears to be comparably effective to other antidepressants for the treatment of GAD. For difficult cases, off-label use of an antipsychotic might be considered.
1Davidson JRT, Wittchen HU, Llorca PM, Erickson J, Detke MJ, Ball SG, Russell JM: Duloxetine 60 to 120 mg once daily for the prevention of relapse in adults with generalized anxiety disorder: A double-blind placebo-controlled trial. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.
2Detke MJ, Nutt D, Allgulander C, Erickson J, Spann M, Walker D, Ball SG, Russell JM: A noninferiority comparison of duloxetine and venlafaxine XR for the treatment of adult patients with generalized anxiety disorder. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.
3Chouinard G, Bandelow B, Ahokas A, Eggens I, Liu S, Brecher M: Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder: A phase III, double-blind, placebo-controlled study. Poster presented at the 46th annual meeting of the American College of Neuropsychopharmacology, Boca Raton, FL, December 9-13, 2007.