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 anxiety disorder (GAD). However, some properties of imipramine may diminish or 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 purpose of this study was to determine whether the authors' previous findings were replicable and to gather information on the plasma levels of imipramine, desipramine (the major metabolite of imipramine), and anticholinergic levels. Fourteen patients with GAD were administered imipramine for 6 weeks. Their scores from self-administered and investigator-administered rating scales 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 in symptoms of anxiety in those who showed the smallest decreases in cardiac vagal tone and in those who showed the smallest increases in desipramine and anticholinergic plasma levels. Moreover, strong relationships were observed between desipramine and anticholinergic levels. These results demonstrate that imipramine not only has therapeutic effects, but it may also have properties that result in physiologic states that counteract its therapeutic effects. Future research should investigate the direct anticholinergic effects of desipramine and determine whether there is a parallel between the anticholinergic effects and the clinical outcome of other pharmacologic treatments, including antidepressants with predominantly norepinephrine or serotonin reuptake inhibitory properties.