Abstract

This study systematically collated clinical evidence on refractory generalized anxiety disorder (GAD). Refractory GAD patients are those who have failed to respond adequately to at least one earlier treatment for GAD. MEDLINE, EMBASE, The Cochrane Library and conference proceedings were searched to identify trials. Four placebo-controlled trials (pregabalin, olanzapine, quetiapine, risperidone) and four single-arm studies (aripiprazole, risperidone, quetiapine, ziprasidone) evaluated the add-ons to initial treatment(s) or switch of treatment(s) because of inadequate efficacy. The most robust trial was the pregabalin study, with a study duration of 8 weeks and a largest sample size that consists of 356 patients. A significant reduction in the Hamilton Anxiety Scale (HAM-A) score was found for pregabalin and risperidone augmentation compared with placebo. Olanzapine augmentation resulted in a significantly higher proportion of responders (using HAM-A scores) compared with placebo. Quetiapine augmentation did not result in significantly greater mean reductions in the HAM-Ascores compared with placebo. There is a need for effective and safe augmentation treatments for patient's refractory to initial treatments for GAD. This study has located one large robust trial assessing the add-on to pregabalin. All other trials were small and unpowered studies with less than 50 patients. Further high-quality trials of augmentation treatment on refractory GAD are required.