Slow Wave Sleep, Diabetes and Depression

Chris Ballas, M.D.
Friday, January 25, 2008

The issue with poor sleep is actually poor slow wave sleep. This is the specific subtype of overall sleep that is reduced in depression, even when the individual sleeps too much. Several studies have investigated the question, but a very recent one best illustrates the possible relationship between sleep and insulin/glucose control. The study took "normal" non-diabetic subjects, and selectively reduced their slow wave sleep-- the deep sleep that is often found in naps-- but left the light sleep and the REM sleep (the dreaming sleep that runs usually about 90 minutes per cycle in most people) and studied the effects on insulin release and insulin sensitivity.

Insulin sensitivity is how strongly a given amount of insulin will affect (i.e. lower) blood sugar. High sensitivity means that a given amount can reduce the glucose a lot; low sensitivity means that even in the presence of a lot of insulin, glucose doesn't go down (much.)

Type II diabetes is characterized not by insufficient insulin, but by insulin resistance. By way of analogy, your body is so used to having a lot of glucose in it that it doesn't respond to insulin as well as it did. The study found that thein the past; this is why it becomes more common in overweight and/or older individuals. Selective decrease in SWS-- even when total sleep time was the same--caused marked decreases in insulin sensitivity.

But there's a little more to it. Importantly, people who started with low amounts of SWS had the worst outcome when (what little they had) SWS was decreased.

This is what becomes relevant to people with depression. Depression, in general, reduces SWS even when total sleep time is intact. Obviously, it reduces it even more if overall sleep is reduced as well-- but even patients with hypersomnia ("atypical depression") have decreased SWS. We already know from unrelated studies that patients with depression have higher rates of diabetes-- and this may be one of the causes.

Next up are the medications, which, as a class, have little effect on totalsleep (may reduce it), reduce REM sleep, but increase SWS. This is particularly important for two reasons: first, it may have the potential to mitigate the effect of clinical depression on SWS and diabetes; second, a significant number of people on antidepressants also take sleeping pills-- pills, which, like antidepressants, typically suppress REM sleep but increase SWS and total sleep.

This is clearly not to say that sleeping pills will prevent diabetes; but it does suggest that sleep normalization in the context of the treatment of depression has an effect on the long term morbidity of depression--e.g. Diabetes.

Teaching an Old Drug New Tricks

Chris Ballas, M.D.
Wednesday, April 02, 2008

There is some new data concerning an old drug. Mecamylamine is an old medication originally used to treat hypertension. It had numerous side effects, such as hypotension and sedation, and thus was not often used. It had a bit of a resurgence later on as an anti-smoking drug (it is a nicotine antagonist) but the overall efficacy was poor, and the side effects made it difficult to use. It was then suggested for use as an augmentation agent to traditional nicotine replacement drugs (gum, patch, etc.) It also has some off label and occasional use for autism, Tourette's, and OCD.

Recently, it has been tested for the treatment of depression. It was found to be better than placebo on the traditional rating scales for patients who had failed citalopram. While this is good, what made it particularly interesting is that the doses used were considerably less (by a factor of 10) than what had been used for hypertension—and at these low doses, mecamylamine only blocks central nervous system nicotinic receptors, not peripheral ones—resulting in much less sedation and hypotension.

It also had considerable efficacy in reducing irritability. Think what it may be like for a smoker to have a cigarette after a long plane ride.

All of this is well and good, but it brings up three questions:

First,why are we testing old medications? The answer probably has a lot to do with the current anti-Pharma climate. Antidepressants in general have already come under fire, both from researchers who have recently "discovered" they may not be very effective, as well as insurance companies, lawyers, and the media. Drug companies, even if they could, would be hard pressed to bring a novel compound for depression into an environment like this. It's easier to re-approve an existing drug. So you see repackaging of old drugs (consider Pristique), expanding the approval for medications already used in psychiatry (Abilify getting approval for adjunct use in MDD; Seroquel as monotherapy for bipolar depression), and looking through what already exists for new indications.

Second, if old drugs can be used for mood (in this case, specifically depression) then what does that say about depression itself? The norepinephrine hypothesis of depression was in vogue for some ten years, soon to be replaced by serotonin; but how do you explain how some people respond to Seroquel and others to Wellbutrin, when the two have nothing in common pharmacologically? More importantly, how do you explain it when the same person responds to both meds?

Third—and I've checked—there is no evidence so far that mecamylamine increases the suicide risk. (The same can be said of Seroquel and Abilify.) If mecamylamine does indeed get approval for depression, will it automatically inherit a black box warning for suicidality? The drug shares no chemical similarities to any existing antidepressant; but if we call it an antidepressant, does it inherit all the risks of one?

This isn't an idle question; warnings like this, attached to drugs which science has no reason to suspect—but which words indict—contribute to the environment I wrote about earlier, in which no one wants to try anything novel because it simply isn't worth it. And so we offer up the faint hope that old, barely tolerable blood pressure pills will save us.

Do Antidepressants Cause SUICIDE?

by Chris Ballas, M.D.

Monday, May 14, 2007

First, and most importantly, the answer is no. No single thing can cause a complex behavior such as suicide (or violence), and to say that a drug, or event, or illness made someone do something is simplistic and, well, wrong.

A more refined question would be whether antidepressants (or anything else) can contribute to the suicide process, move someone further along. Cocaine doesn't cause violence, but if you see a violent guy on cocaine, it's best to get out of the way.

The FDA, in 2002 and 2004, issued warnings about suicidal ideations in children who take antidepressants. Here are a couple of points for us to consider.

1. These were kids
2. The point of discussion is suicidal ideation, not suicide (death) per se.

The FDA reviewed nine, then later 24 pediatric studies and found that the risk of ideation "doubled" from two to four percent.

The authors of a recent review of 29 studies found a similar small increase in risk.

Importantly, however, no actual suicides occurred.

They also analyzed whether or not the antidepressants were actually helpful to people, and weighted that finding against the risk of suicide. Their results determined the risk/reward ratio to be about 11:1, meaning that patients have 11 times better chance of being helped than hurt by antidepressants.

I should point out that, in my opinion, while there is absolutely no compelling evidence that these drugs promote suicidality, there is also a lack of compelling evidence indicating that they reduce suicidality. Nor would I expect there to be. Again, these drugs may change how someone feels, but there are a million steps between a feeling and an action. Which has the greater impact on suicidality: medications or the availability of a gun?

Asking the question simply, "do antidepressants cause suicide?" misses the meat of the argument. Cause? In whom? When, and under what circumstances? The real question is whether someone who is depressed is more likely to commit suicide off of the medicines than on them.

So while we ponder that question, let me offer a sobering statistic.

Only 30% of the people who committed suicide had seen a psychiatrist in the past year. That means 70% hadn't.

Source: JAMA. 2007;297:1683-1696.

Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment, A Meta-analysis of Randomized Controlled Trials,Jeffrey A. Bridge et al,JAMA.2007;297:1683-1696.

Conclusions: Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.








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