It is unclear why delusional depressives respond poorly to usual doses of tricyclic antidepressants alone. Seventeen elderly, delusional depressives were treated with high doses of imipramine or desmethylimipramine while monitoring plasma levels in an open study. Four of seven patients who received an adequate trial responded, but over half of the total sample had to be dropped due to intolerable side effects or worsening clinical condition. Antidepressants in high doses may be effective for part of the delusional depression sample, but this potentially effective pharmacologic therapy is not feasible in a large percentage of elderly or agitated patients.