Scopolamine as an Antidepressant?
Scopolamine is an anticholinergic most often used in patch form to prevent sea-sickness or post-surgical nausea. A recent double-blind, placebo-controlled trial looked at intravenous scopolamine’s effects as a treatment for unipolar depression. This was an attempt to replicate the results of an earlier trial by the same researchers.
Researchers randomly assigned 22 adults with major depressive disorder to one of two groups: the first received a series of three placebo (saline) infusions over two weeks, followed by three scopolamine infusions (dosed at 4 μg/kg) over the following two weeks—researchers called this the P/S group. The second group received the same treatments in reverse order—the socalled S/P group. Participants were evaluated for depression (using the MADRS scale) and anxiety (using the Hamilton Anxiety scale) before each infusion.
The P/S group (which received placebo first) showed no significant improvement in depression symptoms after the placebo portion of the trial, but had a 53% reduction in MADRS scores after the scopolamine portion. The S/P group (which received scopolamine first) showed 32% reduction in MADRS scores after the scopolamine portion of the trial, with no further improvement or worsening during placebo treatment.
In both groups, improvement in depression symptoms was apparent three to five days after initiating scopolamine (ie, after the first infusion of scopolamine). In fact, many participants reported improvement in symptoms by the morning after the first infusion.
Patients reported more side effects on scopolamine than placebo, most commonly typical anticholinergic symptoms such as dry mouth, drowsiness, and blurred vision (16 reported) (Drevets et al., Biol Psychiatry 2010;67:432-438). (To read the original research that was replicated in this trial, see Furey M et al., Arch Gen Psychiatry 2006:63:1121–1129.)
TCPR’s Take: These results are promising, especially the speed at which patients responded to scopolamine. However, IV infusion of medication is impractical for most psychiatrists. In addition, our confidence in the results is tempered by the difficulty of maintaining the blind in this trial because of the side effects of scopolamine. In a phone conversation, one of the authors, Maura Furey, PhD, told us that they are currently studying the scopolamine patch as an antidepressant, but that the results have thus far been unimpressive, possibly because the patch releases scopolamine too slowly to attain high enough serum levels. Nonetheless, she mentioned that anecdotally she has heard of depressed patients who started using the patch for seasickness, found that it improved their mood, and have continued using it as self-prescribed “antidepressant.”
Popular Bipolar Screening Measure Questioned
We have often heard that bipolar disorder is frequently underdiagnosed, leading to inappropriate treatments. This idea has been confirmed in several studies, but the plot has thickened—research also suggests that bipolar disorder is being overdiagnosed in some settings. Further complicating matters is the symptomatic overlap between bipolar disorder and borderline personality disorder, both of which involve strong mood shifts and impulsive behavior.
A recent study investigated 480 psychiatric outpatients who completed a popular bipolar screening measure, the Mood Diagnostic Questionnaire (MDQ). In addition to the MDQ, all patients received a thorough structured interview (Structured Clinical Interview for DSM-IV; SCID) to establish psychiatric diagnosis. About 20% of patients scored as bipolar on the MDQ. Surprisingly, however, of the patients termed “bipolar” on the MDQ, only 24% were diagnosed with bipolar disorder on the SCID, while 28% were diagnosed with borderline personality disorder. Other diagnoses for those who were falsely screened as bipolar on the MDQ included depression (29%), substance abuse/dependence (18%), social phobia (17%), GAD (17%), and ADHD (16%). (Some of these figures were not reported in the article and were provided in a personal communication by Dr. Zimmerman) (Zimmerman M et al., J Clin Psychiatry online ahead of print).
TCPR’s Take: The study was limited by its use of a sample that was predominantly white (88%), female (62%), and insured (100%), so replication is needed. The MDQ has been popularly suggested as a bipolar screening measure, both in the psychiatric literature and by the pharmaceutical industry. However, this study suggest that MDQ results should be taken with a grain of salt. A thorough diagnostic interview is needed to soundly establish the presence of bipolar disorder.
Generic Anticonvulsants as Effective as Brand Name
In June 2009, TCPR devoted an entire issue to generic medications. We concluded that 1. The few controlled studies published thus far indicate generic drugs are as safe and effective as brand name products; 2. There is not enough high quality research to make any solid conclusions; and 3. There may be some specific problems with generic Wellbutrin XL (bupropion XL), because it releases bupropion more quickly than the brand name product.
Now we have another data point, courtesy of our June 2009 interview subject, Aaron Kesselheim. Dr. Kesselheim and colleagues just published a meta-analysis of studies on the safety of generic anti-epileptic drugs (AEDs), including Dilantin (phenytoin), Tegretol (carbamazepine), and Depakene (valproic acid). While this study focused on the use of AEDs for epilepsy, it’s likely that the results apply equally to psychiatric uses, such as bipolar disorder and treatment of aggression.
The authors did a literature search and located 16 high quality studies to analyze, most being either randomized controlled trials or observational studies. The controlled trials varied in methodology. Some randomly assigned newly diagnosed epileptic patients to either brand name AEDs or generics, while others switched patients from existing brand name treatments to generics. The results were reassuring: None of the studies found any significant difference in seizure frequency between brands and generics.
The six observational studies painted a different picture. All were sponsored by pharmaceutical companies (fewer than half of the controlled trials were industry-sponsored). Patients were switched from brand to generic AEDs. Using insurance claims data, researchers reported that patients switched to generic AEDs tended to have higher “switchback” rates than patients who had been switched to generic drugs in other therapeutic classes. In one study, switched patients had increases in some measures of healthcare use, such as clinic visits, but other measures, such as hospitalization rates, showed no difference. Finally, the three studies with a case-control design reported that patients who had hospital visits for seizures were more likely than patients without seizures to have switched to generic AEDs in the prior six months (Kesselheim AS et al., Drugs 2010;70:605–621).
TCPR’s Take: The data in which patients were actually randomly assigned to brand vs. generic are more believable than the observational studies, which, by their nature, cannot control for many confounding variables. The fact that all the observational studies were funded by manufacturers of brand-name drugs also gives one pause, since the design of such studies is complex and is subject to design “tweaks” that would be hard to identify by even the most seasoned researcher. The authors of the meta-analysis concluded that there is little evidence of risk from switching from brand name to generic AEDs, but that intensive monitoring of high-risk patients using these drugs is always advised.