Psychiatric side effects associated with the ten most commonly dispensed prescription drugs: a review

Journal of Family Practice, August, 1991 by John R. Hubbard, James L. Levenson, Graham A. Patrick

POTENTIAL PSYCHIATRIC SIDE EFFECTS

**** Depressed libido

*** Delirium

*** Depression

* Dementia

* Hallucinations and psychosis

* Mania and hyperactivity

* Lethargy

Discussion. Although the adverse cardiac effects of digoxin are well known, it is less commonly recognized that digoxin has numerous neuropsychiatric side effects.[12,13] For example, a retrospective study at the Mayo Clinic reported approximately a 2% to 3% incidence of adverse psychiatric side effects occurring between 1958 and 1962, which included delirium, depression, and personality changes.[13] About a 7% to 8% incidence of psychiatric side effects was found between 1940 and 1944.[13] It should be taken into account, however, that these early reports, limited by their unsophisticated retrospective design, allowed potential bias.

The elderly appear to be more susceptible to adverse (including psychiatric) effects of digoxin than other population groups. [14-17] They experience both increased endorgan sensitivity to digoxin and altered pharmacokinetics organ sensitivity to digoxin and altered pharmacokinetics with increasing age.[14] Digoxin half-life in patients over 80 years of age is about 70 hours, compared with 30 to 40 hours in younger patients.[14] Delirium and psychosis have been noted in numerous case reports and range from mild disorientation to violent agitation with hallucinations.[13-19] Psychosis can occur in patients receiving long-term digoxin therapy when dosage is increased and disappears with dose reduction,20 indicating that the psychiatric side effects of digoxin are dose-dependent. Rechallenge with higher digoxin dosage was not attempted in these cases.

While hyperactive states have occasionally been reported, [12,21,22] lethargy and depression are likely side effects of digoxin.[12,13,15,17,21,23] Digoxin-induced depressive states have been misdiagnosed as primary depression.[20] Rose[24] postulated that this effect of digoxin may be related to alteration in hypothalamic Na, K-ATPase activity.

Most cases of adverse psychiatric effects of digoxin appear to have occurred at toxic levels of the drug; however, many toxic effects occur in the therapeutic range. Two cases have recently been reported in which patients with normal therapeutic levels of digoxin (0. 5 to 2.0 ng/mL) had impaired cognitive function (tested by a cognitive capacity screening test), depression, and anorexia.[17] Within 3 days of discontinuation of the drug, these symptoms returned to normal.

In a long-term controlled study, potential sexual side effects of digoxin were investigated using questionnaires and patient interviews.[25] Results showed a significant decrease in sexual desire and frequency in the digoxin-treated group of patients. The mechanism of this change did not appear to be due to alterations in androstenedione or dehydroepiandrosterone, as their plasma levels were unchanged by digoxin.[25]

Although most of the evidence for psychiatric effects of digoxin consists of retrospective and case studies, the number of reports is rather striking, including many other older reports of the effects of digitalis on behavior that have not been mentioned here. Taken together with a long history of investigation, it appears that physicians should take special note of the potentially serious psychiatric side effects of digoxin.