CHICAGO—Apathetic symptoms persisted in nearly half of a sample of outpatients whose mood disorder had remitted, supporting the view that apathy and depression are related but distinct phenomena, according to a preliminary study presented at the annual meeting of the American Psychiatric Association. Robert O. Morton, MD, and colleagues at the University of Oklahoma Health Sciences Center in Tulsa reported that apathetic symptoms—but not depressive symptoms—responded to cholinesterase inhibition in an open-label trial. This suggests that dysregulation of the cholinergic system may induce apathy in some depressed patients and that medications targeting this system may be useful in improving motivation.

Apathy is commonly associated with such neuropsychiatric disorders as Alzheimer's, Huntington's, and Parkinson's diseases, as well as with stroke and traumatic brain injury; in these settings, apathy is often considered a distinct syndrome. Its relationship to depression is less clear, however. Although apathy has long been viewed as a component of depressive illness, some recent evidence indicates that the two are independent. While the new findings do not resolve the nosologic debate, they do suggest that "the apathetic components of depression may be mediated through a different neurotransmitter system and different neural circuits than the dysphoric component," Dr. Morton stated in an interview.

The researchers examined the prevalence of apathy in 126 outpatients receiving treatment for mood disorder, primarily major depression (64%) or bipolar disorder (30%); the patients' mean age was 38. All subjects were assessed for depressive symptoms using the Zung Self-Rating Depression Scale, while apathy levels were measured with a slightly modified version of the Apathy Evaluation Scale devised by Robert Marin, MD, of the University of Pittsburgh Medical Center.

DEPRESSION GONE BUT APATHY LINGERS

Not surprisingly, apathy—defined as a score of at least 43 on the modified apathy scale—was quite common, affecting 79% of patients in the sample. Most of these subjects also had current depressive symptoms. However, 16 (48%) of the 33 patients whose depression was in remission nonetheless had significant apathy, and 36 other patients had what Dr. Morton and colleagues described as "a disproportionate amount of apathy relative to their depression."

Because the cholinesterase inhibitor donepezil appears to reduce apathy in patients with Alzheimer's disease, Dr. Morton—a third-year psychiatry resident at the University of Oklahoma who recently switched specialties after nearly two decades in internal medicine—initiated an open-label trial to examine the potential utility of the drug in depressed patients. Fifteen patients with apathy–depression score ratios of at least 0.879 received donepezil for 60 days, starting at 5 mg/d for the first 30 days and 10 mg/d thereafter; all continued to receive standard antidepressant therapy as well.

At the end of the trial, the mean apathy score for donepezil recipients had decreased from 59.3 to 44.9, a statistically and clinically significant reduction. Their depression scores declined slightly but did not reach statistical significance. For comparison, the researchers also examined changes in apathy levels in several subsamples of patients who did not receive donepezil, including one group with similar baseline apathy levels and another with similar apathy–depression ratios. "None of these groups showed any change in their apathy," Dr. Morton reported; one group actually had an increase in apathy scores.

Seven patients (47%) receiving donepezil wished to continue the medication after the trial, and as of mid-June five continued to use it, nine months after beginning therapy. Meanwhile, apathy levels reverted to baseline in five patients who discontinued the medication, without any change in dysphoric symptoms. Three patients stopped using the drug during the trial owing to minor adverse effects or substance abuse problems.

DO ANTIDEPRESSANTS INDUCE APATHY?

Evidence from animal studies suggests that serotonergic manipulations may affect acetylcholine levels, and some researchers have suggested that selective serotonin reuptake inhibitors (SSRIs) may induce apathy in humans. However, Dr. Morton and colleagues found no relationship between SSRI usage and apathy; some patients with high apathy levels were not even using SSRIs. Perhaps, Dr. Morton suggested, any pharmacologic manipulation of the circuits regulating mood can induce apathy. (Interestingly, in a separate study reported at the meeting, the Oklahoma team found that 17 patients with obsessive-compulsive disorder [OCD] experienced fewer obsessive or compulsive symptoms while receiving SSRI therapy but had increased apathy levels. "Maybe the reason SSRIs work in OCD is because they create an apathetic condition," decreasing patients' motivation to perform their compulsions, Dr. Morton speculated.)

Overall, the findings indicate that "apathy exists in a fairly high percentage of depressed patients," Dr. Morton said. "In many cases it occurs as a component of depression but [in others] it can be teased out." While donepezil appears to reduce apathy "remarkably," the findings need to be replicated in a controlled trial before cholinesterase inhibitors can be recommended, Dr. Morton said. In the meantime, clinicians treating depressed patients whose apathy does not respond to antidepressants "might want to consider a brief trial course of donepezil." The Oklahoma researchers hope to conduct a randomized controlled trial themselves.

—Peter Doskoch

Suggested Reading
1. Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci.1998;10:314-319.
2. Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry.1990;147:22-30.
3. Steckler T, Sahgal A. The role of serotonergic–cholinergic interactions in the mediation of cognitive behavior. Behav Brain Res.1995;67:165-199.

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