FORT MYERS, FLA—Findings from the first treatment study for poststroke generalized anxiety disorder (GAD) reveal that nortriptyline substantially reduces symptoms and improves patient functioning, researchers reported at the annual meeting of the American Neuropsychiatric Association (ANPA). Moreover, the anxiety symptoms responded more quickly than did comorbid depressive symptoms, supporting the view that the two disorders are distinct entities in stroke patients.

Although poststroke depression has been the focus of numerous studies and several treatment trials, poststroke anxiety continues to receive little attention, even though 20% to 25% of acute stroke patients meet criteria for GAD. The impact of this anxiety is compounded by the fact that two thirds of these patients are also depressed, a combination that, compared to depression alone, results in substantially more impairment of social functioning and activities of daily living. Moreover, poststroke GAD is not a transient phenomenon, noted Robert G. Robinson, MD, Professor of Psychiatry at the University of Iowa College of Medicine and a coauthor of the new study. “If you look two years after stroke, there are still 20% to 25% of patients who meet criteria for chronic GAD.”

Fortunately, the new findings, reported by Dr. Robinson and Mahito Kimura, MD, of Nippon Medical School in Tokyo, indicate that, with pharmacologic treatment, poststroke GAD need not persist. The researchers examined data from 106 stroke patients who participated in two earlier randomized trials designed to assess the efficacy of nortriptyline for poststroke depression. Because 27 of these patients had also met DSM-IV criteria for GAD (excluding the requirement for a six-month duration of symptoms), the researchers were able to evaluate, in a post-hoc analysis, nortriptyline’s effects on poststroke anxiety. All but five of the GAD patients had motor deficits; about half had sensory deficits.

NOT AN ARTIFACT OF DEPRESSION RESPONSE

In the two trials, patients received either placebo or escalating doses of nortriptyline, up to a maximum of 100 mg/d, for six to nine weeks. Despite the relatively small number of patients, nortriptyline treatment resulted in statistically significant improvements on a variety of measures. For example, mean scores on the Hamilton Rating Scale for Anxiety (Ham-A) declined by about 10 points, from roughly 16 to 6, in patients receiving nortriptyline; the corresponding decrease for placebo recipients was only about 4 points. Similarly, scores on the Hamilton Rating Scale for Depression dropped far more with nortriptyline (10.2 points) than with placebo (2.8 points); patients receiving medication also showed greater improvement than the placebo group in social functioning, as measured by the Johns Hopkins Functioning Inventory.

Interpretation of these findings, however, is complicated by the fact that patients had both GAD and depression. “The major question,” Dr. Robinson said, “is that since there is overlap in symptoms [between the two diagnoses], are we really just treating the depressive disorder?” Although a definitive answer requires looking at patients with pure GAD, Dr. Robinson noted that in the current study “anxiety symptoms responded significantly more promptly than the depressive symptoms did.” This, he said, “suggests that they really are two separate disorders that are often comorbid” and that the decreased Ham-A scores are not merely an artifact of antidepressant effects. Indeed, the symptoms specific to GAD (eg, irritability) improved more quickly than did symptoms specific to depression.

BEYOND TRICYCLICS

At this point, it is unclear whether other antidepressant or anxiolytic medications have similar benefits for patients with poststroke GAD. The concern that medications effective for the general GAD population may not work as well for stroke patients is not merely hypothetical: A study published by Dr. Robinson’s group in the March 2000 American Journal of Psychiatry showed that poststroke depression responded well to nortriptyline but that fluoxetine was no more effective than placebo. The presence of GAD was not assessed in that study, but the investigators did measure anxiety levels; these data revealed a 2.9-point decrease in Ham-A scores for depressed patients receiving nortriptyline and a 3.2-point increase with fluoxetine, though the differences between groups were not statistically significant.

POSTSTROKE DEPRESSION: A REBOUND EFFECT?

In related news, a study in which Dr. Robinson and Kenji Narushima, MD, also from the University of Iowa College of Medicine, attempted to prevent depression in stroke patients yielded both encouraging and disturbing results. Although a prophylactic course of nortriptyline or fluoxetine seemed to prevent depression in the aftermath of a stroke, patients who received these medications were more likely than placebo recipients to develop depression in the months after treatment was discontinued, the researchers reported at the ANPA meeting.

The study participants, who did not meet criteria for depression at baseline, completed three months of treatment with nortriptyline, fluoxetine, or placebo. Initially, the prophylactic efforts appeared highly successful: By the end of treatment, a third of the placebo group but only 8% of antidepressant recipients were depressed. But many of the latter patients did develop depressive symptoms after treatment ended; six months after discontinuation, four of the 12 fluoxetine recipients and four of the 10 nortriptyline recipients were depressed, whereas none of the 12 patients in the placebo group were.

The cause of this rebound effect is unclear. But the investigators suspect that the antidepressants up- or down-regulated neurotransmitter receptors and that these alterations, in concert with the changes in neurotransmitter production that occur following stroke, resulted in mood dysfunction. “What we’ve done,” Dr. Robinson said, “is fend off the depression by giving them nortriptyline or fluoxetine for the first three months. When we stop giving it to them, they have not only this underlying reduction in neurotransmitter production but an altered receptor sensitivity that leads to an increase in depression above what you would normally see.”

Although unexpected, the finding is not as counterintuitive as one might think, Dr. Robinson added. “Given the fact that the antidepressants prevented depression from developing during the first three months, it makes sense that there might be a rebound phenomenon if you stop treatment too soon.” To further investigate this effect, the Iowa researchers will be extending the length of antidepressant treatment in future patients to see if this reduces the likelihood of posttreatment rebound.

—Peter Doskoch

Suggested Reading
1. Castillo CS, Schultz SK, Robinson RG. Clinical correlates of early-onset and late-onset poststroke generalized anxiety. Am J Psychiatry. 1995;152:1174-1179.
2. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry. 2000;157:351-359.

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