The FDA may not like it, but Provigil (modafinil) is hot, and getting hotter.

When it first gained FDA approval for narcolepsy in 1998, no one took much notice of Provigil. Sure, it helped narcoleptics stay awake, but when was the last time you diagnosed narcolepsy, which occurs at a rate of about 1 in 5000?

However, a funny thing happened to Provigil since 1998: most of it got prescribed off-label. Prescribers realized that here was a safe, relatively nonabusable medication that extinguished sleepiness in all of its forms, and so they started using it symptomatically, regardless of the underlying diagnosis. Currently, 90% of Provigil prescriptions are off-label.

With two new FDA-approved indications under its belt, Provigil may soon find its way into everyone’s medicine cabinet.

A casual Medline search reveals an explosion of Provigil trials over the last 2 years, with efficacy demonstrated (mostly in uncontrolled trials) for the following conditions: major depression (more on this below), ADHD, schizophrenia, seasonal affective disorder, sedation due to brain injury, opioid-induced sedation, and recovery after general anesthesia, to name a few.

This doesn't even include the two new FDA-approved indications as of 2004: excessive sleepiness associated with sleep apnea and "shift work sleep disorder." Cephalon had requested a broader approval for excessive sleepiness due to any sleep disorder, but the FDA refused. Why? Probably not because of lack of efficacy, since by now it is clear that Provigil will wake up any human being on the planet who is sleepy, regardless of the cause. More likely, the FDA is concerned that Provigil is too effective, and that it will become an over-prescribed "lifestyle" drug that will be used by the excessively driven as a sleep-substitute.

Nobody knows how Provigil works, although we know it doesn't work via dopamine release--which is how both Ritalin (methylphenidate) and Dexedrine (dextroamphetamine) keep you up. It's available in 100 mg and 200 mg tablets, both of which are scored and easily breakable. Starting patients too high can cause terrible initial jitteriness. Start most patients with a prescription for 200 mg tablets and have them take half a tablet initially. If they don't notice an improvement after 3 days, increase to a full tablet. With a 15-hour half-life, a morning dose will usually last into the afternoon, and the amount left in the body at bedtime generally doesn't cause insomnia. The most common side effects are jitteriness, nervousness, diarrhea, headache, and nausea. The most clinically significant drug-drug interaction is the induction of clearance of steroidal contraceptives, necessitating increased OCP dosing in some patients.

As psychiatrists, we are unlikely to be prescribing Provigil for its FDA-approved indications, since such bonafide sleep disorders are generally treated by primary care physicians or in sleep clinics. Psychiatrists use Provigil mainly for depression, ADHD, and medication-induced sedation. Here's some of the evidence on Provigil and depression.

There are four published studies on adjunctive Provigil for major depression. Three of these studies involved adding Provigil to pre-existing antidepressants in patients with partially-treated depression. Of these three, two were small uncontrolled trials and yielded predictably positive results (J Clin Psychopharmacol 2003; 23:1-3, and J Clin Psychopharmacol 2004; 24:87-90). The larger double-blind placebo-controlled study enrolled 136 patients who had been on antidepressants (ADs) for at least 6 weeks and exhibited only partial responses (J Clin Psychiatry 2003; 64:1057-1064). They were randomized to receive either adjunctive Provigil or placebo for 6 weeks. Those on Provigil took 100 mg QAM on days 1 through 3, then 200 mg QAM, after which the dose could be raised or lowered as necessary. All patients continued on their ADs (mostly SSRIs) throughout the study.

How did the two groups fare? Those on Provigil rapidly became less fatigued and sleepy--separating from placebo by week one or two, depending on the scale used. However, this difference disappeared by week 6. What about measures of depression? Unfortunately, there was no significant difference between adjunctive Provigil and placebo in HAM-D scores, at any time point. The bottom line appears to be that prescribing adjunctive Provigil to patients already on ADs may wake them up a bit, especially over the first 2 weeks, but it probably won't improve their overall depression.

What about starting patients on a combination of an AD and Provigil? Since Provigil has been shown to jumpstart wakefulness, perhaps its ideal use would be to speed up the initial response to an AD. One recent study has looked at this, though without the crucial ingredient of a control group (J Clin Psychiatry 2004;65:414-420). In order to be included in this study, patients had to have both major depression and significant fatigue. A total of 29 patients were enrolled in this Cephalon-funded study; at study entry, they were all started on either Prozac 20 mg QD or Paxil 20 mg QD, in addition to Provigil 100 mg QAM for 3 days, increasing to 200 mg QD on day 4. Depression in these patients improved robustly and quickly, with 42% responding by week 2, 65% by week 4, and 79% by week 6.

Of course, we can critique this study for its open-label design and lack of a control group. A comparison group given ADs plus placebo might have responded just as well. However, these response rates are pretty high when compared to other open label antidepressant trials published. So while this study doesn't prove anything, it does suggest that starting fatigued depressed patients on Provigil along with an AD is a potential psychopharmacologic pearl.

TCR VERDICT
Provigil: It’ll jump start just about anyone.