[click image for the full version]
Some time back, I began to hear a new term – "New Vigil." I thought it was a street drug – slang – because the people where I live were traveling some 50 miles away during the recession to work in the numerous chicken processing plants there [shift work]. So I thought "New Vigil" was a nickname for some new version pep pill they were taking to stay up all night plucking chickens.
by Ketter TA, Yang R, and Frye MA.Journal of Affective Disorders. 2015 181:87-91.
BACKGROUND: In a previous study, adjunctive armodafinil 150mg/day significantly improved depressive symptoms associated with bipolar I disorder.METHODS: Multicenter, double-blind study of patients with a major depressive episode despite bipolar I disorder maintenance therapy randomized to adjunctive placebo or adjunctive armodafinil 150 or 200mg/day for 8 weeks; for logistical reasons, assignment to armodafinil 200mg/day was discontinued early. Primary efficacy was measured by change from baseline to week 8 in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score.RESULTS: Patients were randomized to adjunctive placebo (n=230), adjunctive armodafinil 150mg/day (n=232), or adjunctive armodafinil 200mg/day (n=30; analyzed for safety only). Least-square mean change in IDS-C30 total score was numerically superior for adjunctive armodafinil 150mg/day vs adjunctive placebo, but was not statistically significant (p=0.13). Armodafinil was well-tolerated. Adverse events (AEs) observed in >5% with adjunctive armodafinil 150mg/day and more frequently than with adjunctive placebo were headache (16% [38/231] vs 13% [30/229]) and nausea (7% [17/231] vs 2% [5/229]). The most common AEs with adjunctive armodafinil 200mg/day were diarrhea and dry mouth (17% [5/30] each vs 6% [13/229] and 1% [3/229], respectively, with adjunctive placebo).LIMITATIONS: Early study discontinuation for logistical reasons by the sponsor limited adjunctive armodafinil 200-mg/day assessment.CONCLUSIONS: FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance. Safety data indicate treatment with adjunctive armodafinil was well-tolerated.
Discover Magazine BlogsBy NeuroskepticJune 28, 2015A misleading piece of statistical rhetoric has appeared in a paper about an experimental antidepressant treatment. The study is published in the Journal of Affective Disorders. JAD is a respectable mid-ranked psychiatry journal – yet on this occasion they seem to have dropped the ball badly. The study examined whether the drug armodafinil [Nuvigil] improved mood in people with bipolar disorder who were in a depressive episode. In a double-blind trial, 462 patients were randomized to treatment with either armodafinil 150 mg/day, or placebo, in addition to their regular medication, for 8 weeks.
The results showed no statistically significant difference between the two groups in change on the depression rating scale, the IDS-C30. [p = 0.24 LOCF, p = 0.13 at week 8]. So this means that there was no evidence that armodafinil helped treat depression. Oh dear. It’s a textbook example of a negative, or null, result. Despite this, however, the paper’s abstract concludes on a remarkably upbeat note…
FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance.The second sentence is quite misleading. The mean reduction in symptoms was indeed slightly higher in the armodafinil group than in the placebo group, but in the absence of statistical significance, the difference of means is meaningless [no pun intended]. Even assuming that the drug has no effect, there would be a 50% chance of the drug group having the greater improvement – and a 50% chance of the placebo being greater. One of the values has to be greater, after all. There will always be some mean difference. Which is why we need statistical significance testing.
So we simply can’t say that the drug “reduced depressive symptoms to a greater extent”, not even if we qualify this with the caveat that the effect was not statistically significant. The caveat is so big that it negates the entire statement. Other statements about how the drug group showed “numerically greater” improvement appear in the main text…
There’s some other weirdness – like "Received 30 March 2015, Accepted 2 April 2015." When did they even do peer review? And there’s something else worthy of note. There are four studies of in Bipolar Depression, and three of them share something peculiar:
| Clinical Trials of Nuvigil® | ||
| subjects | sites | mean subjects/site |
|
|
||
| 499 | 92 | 5.4 |
| 257 | 55 | 4.6 |
| 399 | 130 | 3.0 |
| 897 | 33 | 27.2 |
The CROs spread their studies over multiple sites to make recruitment easier and and speed up the trial. But I’ve never seen anything that approximated this number of sites. There’s a statistical method to partition variance to separate out the effect of the sites from the effect of the drug, and testing the drug x site interaction checks for particular sites skewing the results [though I couldn’t see that they availed themselves of that test]. But even if they had, this pushes the practice of using multiple sites well beyond any credibility.
As I commented over on Neuroskeptic’s blog, it’s even fishier what the authors reported in a 2013 conference presentation about the same study, where they claimed: “At week 8 endpoint, armodafinil 150-mg compared to placebo yielded a significantly greater decrease in mean IDS-C30 total score (–21.7 vs. –17.9; P=0.0097) and a significantly higher IDS-C30 responder (?50% decrease from baseline) rate (46.2% vs. 34.2%; P=0.0147, number needed to treat = 9).”
Those of us in the trenches do not read the studies and could not understand them if we did. We are perfectly cognizant that it is the job of drug representatives to push their products and take what they say cum grano salis. We are always glad to have a new agent that is potentially useful – and if we are reasonably comfortable with the reported side effects, are eager to try it out, usually with patients refractory or not fully responsive to other treatments. Our pharmacologic epistemology is primitive and unscientific and can be described as “Seeing is believing.”
When Provigil(modafinil, precursor of armodafinil) was first released the local rep made no off label claims but was generous with samples. I tried them with a few depressives in partial remission on antidepressants and was surprised to observe immediate and lasting positive effects in almost every case. No side effects of any kind emerged. My unscientific impression was that the medication was strikingly effective in improving mood, energy, alertness and interest in at least 80% of those treated. Perhaps it is too bad that I and my patients never read the studies and recognized their inadequacies. Had we done so, we would never have thought that Provigil was the excellent drug it was for partially responsive depressive disorders.
I still regard Provigil(modafinil) and Nuvigil(armodafinil) as extremely effective and safe medications for augmentation in the treatment of depressive disorders. There is absolutely no doubt in my mind that these drugs work. I have repeatedly witnessed their frequently dramatic effect in countless patients. That this is a placebo effect is effectively refuted for me by the simple observation that I have used numerous other augmenting agents which provided little or no positive response.
My bone to pick with the manufacturer is not the off-label effectiveness of these medications for depression, which was never so much as hinted at by the drug reps, but the absurd, almost insane pricing structure that eventually made it impossible to prescribe them once insurers caught on and began to demand highly specific documentation of a sleep disorder before they would pay for them. Provigil(modafinil) actually reached $30 a pill at one time and Nuvigil*armodafinil) was about the same. This ridiculous and rapacious pricing destroyed the usefulness of both drugs. I no longer attempt to prescribe them even though they are wonderfully effective and remarkably safe and side effect free agents that can be extremely useful in the management of difficult cases of depression. It seems to me I read recently that the manufacturer was slapped with a huge penalty for payola to potential generic competitors not to bring their products on the market so that the brand prices could remain absurdly and now criminally high.
There seems to be a latent political agenda in much of the criticism of so-called Big Pharma, an implied assertion that for-profit drug makers are doing something wrong simply by promoting their products, and an expectation that such product promotion could and should always be above the reproach of purists. These insinuations are commonly associated with another to the effect that practicing clinicians such as myself are so gullible and easily influenced by drug company salespersons that we will continue to prescribe medications that provide no benefit to our patients merely because we have been falsely led to believe that they are helpful by the representations of company operatives.
There was an ad in one of the throw away journals praising our shift workers (American flag displayed). Here it is:
http://nuvigil.com/hcp/SWD/Overview.aspx
To Dr. Garrett- I am glad this drug has worked well for your patients but it might be nice to have some data on adverse effects. I have not observed modafinil to be so benign but even of more concern I have observed it added to heavily sedating drug cocktails before any attempt at reducing doses has been tried.
As we look at drugs and effectiveness we find some insurance plans are catching on:
http://blogs.wsj.com/pharmalot/2015/07/02/novo-nordisk-halts-sale-of-its-insulin-in-germany-over-pricing-dispute/?mod=WSJBlog
This is the German market and refers to a diabetes drug. One of the many important quotes:
“Several drug makers have refrained from selling some medicines in Germany ever since the agency began comparing the benefits of new drugs with existing medicines,…”
The comments are interesting in that they refute the claim of millions injured when there are only 40,000 patients using this drug in Germany.
We can only hope this type of scrutiny comes to the US and all classes of drugs.
Steve Lucas
I too have found Nuvigil effective and it works great for jet lag (in combo with bookended sleeper). What is odd is that we don’t exactly understand why. Histamine agonist maybe? Orexin/hypocretin system?
Provigil has had impacts, but, when companies are grossly focused on profiting, then it is time to turn one’s back on the product and use the usual and customary forces to alter pathological supply and demand agendas against the seller. It is that simple. Also, where the hell was the FDA on this grossly obvious profit agenda years ago with Provigil?
Also, Nuvigil has had issues with side effects because it is more potent than Provigil, so once again, this wannabe product does more harm than good just in the name of staying Brand.
Oh well, once again the business of medicine seems to be winning, eh?…
Does anyone else feel like a mechanic for the human machines that keep businesses running? There are a few businesses in my area that make unreasonable demands on their employees with regard to shift work, efficiency, bathroom breaks, rest breaks, etc. I see many workers for these businesses for anxiety disorders, depression, and substance use disorders. Many of them have come to be for modafinil/armodafinil so that they can meet their employers’ work demands. It makes me wonder how many social problems we are treating with medications.
It’s the racemic R enantiomer of Provigil, so at least in theory it should have less side effects. Same deal as Lexapro-Celexa. In reality I don’t see much difference. I agree that I don’t get it as a bipolar treatment but as a wakefulness and jet lag agent it certainly works.
As far as medicines as a business efficiency tool, the number one drug would be caffeine. These drugs certainly are a better alternative to amphetamines. As of 2012, modafinil is the only drug approved by the Air Force for fatigue management. Dextroamphetamine which they used to use is no longer approved
James,
An aside:
When I was in college and medical school, we all used amphetamines as ‘study aids.’ It wasn’t drug abuse in those days, it was ‘being a good student.’ At one point in Med School, I got in trouble for cutting a pathology lab and had to go talk to the Dean. Rather than come clean that it was just too boring for words and tell him that we had a microscope and a box with all the slides at the fraternity house and it was much preferable to do my work there, I claimed that it was after lunch and I was just too sleepy. The Dean was a mensch who told me some years later that the classmate who had “turned me in” was always doing things like that, but I was a class officer and he couldn’t let it slide. But my point is this. The Dean, with no prompting from me, wrote me a prescription for enough diet pills to get me a mandatory prison sentence in a modern world.
I don’t doubt that Nuvigil® is a better choice for staying awake than amphetamines or Caffeine. And I know there are people who have thrown a little speed into an antidepressant cocktail since it was there to throw. I’m balking at two things. I don’t think it’s an Adjunct in Bipolar Depression. It just makes some people feel ‘peppier.’ Second, this study is negative, negative, negative – being presented otherwise.
Alienist,
100% agreement with your point.
Stimulants with a risk of Bipolar Disorder as a rule out, quite the risk factor in offering meds of this sort. Peppier becomes euphoric and then the comparison of the abyss of depression is certainly a wide gap to the mountain of mania, hmm?
And yes, to Alienist’s point, we are asked to medicate life. More and more everyone who works in health care seems to sell that message, true? I just wonder, are we headed to a Logan’s Run future, or, Mad Max?
Depends on where ISIS and Illegal Immigration progress, or more hopefully regress to, one hopes.
A lot of the pharma bipolar depression research is garbage IMHO.
Alienist, what you mentioned is happening to kids big time regarding being in the wrong school for them and as a result, they enter the world of psych meds at a very early age. I am not going to sound judgmental and say that the adults mentioned as part of your scenarios can switch jobs because many times, they are in a tough situation. But at least, they do have the option whereas kids are at the mercy of their parents and don’t have any choice in the manner.
What a bizarre world we live in, where the “antidepressant” effects of Provigil, Nuvigil, and the amphetamine analogs (all addictive prescription drugs) are considered salutary while those of cocaine and methamphetamine are not.
And now lisdexamfetamine for menopausal executive functioning problems:
http://www.healthnewsreview.org/2015/06/vyvanse-a-life-cycle-drug-or-disease-mongering/
LOL… that’s the sort of thing I call pharmaceutical bottom fishing.
A lucrative bottom fishing. The expansion of the use of stimulants without regard to long term consequences is so worrisome. It is also a kind of “Back to the Future” phenomenon.