Verbal learning by major depressive disorder patients during treatment with fluoxetine or amitriptyline

After 1 week of a single-blind placebo period, and prior to being randomly assigned to receive treatment with either fluoxetine or amitriptyline, patients meeting strict criteria for a diagnosis of major depressive disorder were given an auditory verbal learning test of working memory, and a blood sample was drawn. After 3 weeks of drug treatment with either amitriptyline or fluoxetine, the patients' symptoms were evaluated, the verbal learning test was repeated, and a second blood sample was taken. The clinical evaluation, the verbal learning test and the blood drawing were repeated a third time 3 weeks after the second assessment. The amount of anticholinergic activity in the blood samples was measured by a competitive radioligand binding assay and expressed in atropine equivalents. Analyses of variance indicated that there were no significant differences at the predrug Assessment 1 between patients subsequently assigned to the fluoxetine group compared with those assigned to the amitriptyline group. At Assessments 2 and 3, the fluoxetine and the amitriptyline groups showed equal clinical improvement but patients receiving amitriptyline did not perform as well on the verbal learning task. Serum anticholinergic activity at Assessments 2 and 3 was considerably higher in the amitriptyline group. This supports the hypothesis that blockade of muscarinic receptors impairs working memory formation. Equally effective antidepressant drugs with little or no anticholinergic action, such as fluoxetine, may be preferable in patients with pre-existing mild cognitive impairment or in patients where a slight reduction in cognitive performance is not acceptable.