The Development of Clonazepam as a Psychotropic: The Massachusetts General Hospital Experience

The pathophysiology of anxiety disorders is not clearly understood; therefore, clinical observation, case reports, and case reviews continue to enhance physicians’ understanding of disease and treatment mechanisms. At Massachusetts General Hospital (MGH), physicians and researchers are guided by the recognition that available approved treatments are a small subset of what is sensible to try in anxiety disorders and have thus chosen to remain open minded and prepared to challenge assumptions about therapeutic agents and to explore new uses, including early work with high-potency benzodiazepines. Clinical trials established alprazolam as efficacious for panic disorder, and the agent was widely prescribed for patients at MGH after its approval. Soon, however, clinical observation suggested a short duration of benefit for a given dose in some patients. In some cases, patients who missed a dose reported rebound worsening. In response to the apparent problematic pharmacokinetics of alprazolam, members of the MGH psychiatry department pursued investigation that ultimately established the antipanicefficacy of clonazepam as well as examined its effectiveness in the treatment of other disorders, such as bipolar disorder and social phobia. The process of exploring new uses of older agents remains a worthy effort while we await newer agents with innovative mechanisms of action.