Therapeutic effects of imipramine are counteracted by its metabolite, desipramine, in patients with generalized anxiety disorder

Imipramine has been shown to reduce anxiety in patients with generalized an xiety disorder (GAD). However, some properties of imipramine may diminish o r counteract its anxiolytic effects. The authors previously found that the greater the reduction in cardiac vagal control after 6 weeks of imipramine treatment, the smaller the improvement in anxiety-related symptoms. The pur pose of this study was to determine whether the authors' previous findings were replicable and to gather information on the plasma levels of imipramin e, desipramine (the major metabolite of imipramine), and anticholinergic le vels. Fourteen patients with GAD were administered imipramine for 6 weeks. Their scores from self-administered and investigator-administered rating sc ales were obtained before and after the treatment, and the changes in these scores were contrasted with the changes in cardiac vagal tone, along with the absolute plasma levels of imipramine, desipramine, and anticholinergic activity at the end of week 6. The authors observed a greater improvement i n symptoms of anxiety in those who showed the smallest decreases in cardiac vagal tone and in those who showed the smallest increases in desipramine a nd anticholinergic plasma levels. Moreover, strong relationships were obser ved between desipramine and anticholinergic levels. These results demonstra te that imipramine not only has therapeutic effects, but it may also have p roperties that result in physiologic states that counteract its therapeutic effects. Future research should investigate the direct anticholinergic eff ects of desipramine and determine whether there is a parallel between the a nticholinergic effects and the clinical outcome of other pharmacologic trea tments, including antidepressants with predominantly norepinephrine or sero tonin reuptake inhibitory properties.