Vascular Depression? Not so Fast.
More than a decade ago, researchers introduced the concept of “vascular depression,” a specific type of depression associated with cerebrovascular disease and loss of blood to the brain in older adults. The hypothesis was that conditions associated with the narrowing of blood vessels, such as stroke, “predispose, precipitate, or perpetuate” depression in the elderly (Alexopoulos GS et al, Arch Gen Psychiatry 1997;54(10):915–922). A recent study, however, challenges the entire theory of vascular depression.
As part of a large population-based study of chronic diseases in the Netherlands, 3,564 men and women (with a mean age of 72) were recruited for a prospective observational study. All participants had at least one measure of atherosclerosis at baseline (the most common being carotid plaques, aortic calcification, peripheral arterial disease, and intima-media thickness). Patients with pre-existing psychiatric disorders were excluded from the study.
These patients were observed for approximately eight years, and medical data were collected continuously through medical and pharmacy records. At the study’s endpoint, 682 of the original 3,564 patients had some degree of depression; 2,882 did not. Researchers found no causal relationship between atherosclerosis and increased risk of depression—even after controlling for variables such as age, sex, blood pressure, and cholesterol (Newson RS et al, Arch Gen Psychiatry 2010;67(11):1144–1151).
TCPR’s Take: This carefully designed prospective study puts a serious damper on the hypothesis that vascular disease directly leads to depression. By studying patients with atherosclerosis, an important precursor to cerebrovascular disease, researchers were able to capture data from this population early on in the course of their diseases. In addition, looking at these patients before depression developed, as opposed to making an association between cerebrovascular disease and depression after both have been diagnosed, allowed for a clearer evaluation of causality. The study authors did not dispute that there is a relationship between vascular disease and depression, only that it appears unlikely that atherosclerosis directly causes depression.
Adjunctive Nuvigil Possibly Effective for Bipolar Depression
The treatment of bipolar depression remains challenging. Only two medications are FDA approved for the condition—quetiapine (Seroquel) and olanzapine (Zyprexa)/fluoxetine (Prozac) combination—both of which cause weight gain and sedation, among other side effects.
One prior placebo-controlled trial of 85 patients found that modafinil (Provigil) outperformed placebo in improving depressive symptoms among bipolar patients with treatment-resistant depression (Frye MA et al, Am J Psychiatry 2007;164:1242–1249).
A recently published eight-week randomized trial used a larger sample of 247 patients to evaluate adjunctive armodafinil (Nuvigil)—the longer lasting isomer of modafinil. Patients with bipolar depression were randomly assigned to either a 150 mg dose of Nuvigil or to placebo. These patients were nonresponsive to treatment with lithium, valproic acid (Depakote), or Zyprexa and were in a depressive (not mixed) state. They remained on their current medication and Nuvigil or placebo was added as an adjunctive treatment.
On the primary outcome measure (Inventory of Depressive Symptomatology), Nuvigil was statistically superior to placebo—but only by a small effect size. There was no advantage for Nuvigil on several other depression, anxiety, global impressions, remission, treatment response, and quality of life measures.
The side effect profile of Nuvigil appeared relatively benign, with slightly higher rates of insomnia (10% vs 8%) and restlessness (6% vs <1%) compared to placebo. The Young Mania Rating Scale (YMRS) was used at each visit to assess for manic or hypomanic symptoms—if a participant’s score exceeded 15, he or she was immediately withdrawn from the study. The discontinuation rate in both groups was 30%. Switching to mania, hypomania, or mixed episodes was rare in both groups (three patients on Nuvigil and seven on placebo) (Calabrese JR et al, J Clin Psychiatry 2010;71:1363–1370).
TCPR’s Take: Interestingly, no specific measure of energy or concentration was used in the study; given Nuvigil’s profile, one might have expected to see benefits in these areas. While this trial’s results suggest that adding Nuvigil to a mood stabilizer offers little benefit for bipolar depression, at least two further trials are underway. Stay tuned.