From college days, many of us can recall a more or less pervasive
culture of “getting high and pulling all-nighters.” Whether we pursued
this lifestyle ourselves or merely watched our classmates go wild,
intoxication and sleep deprivation were often part of daily life on
campus. After graduating and entering the workforce, we probably chalked
up such behaviors to adolescent foolishness, if we gave them any
thought at all.
So it may come as a bit of a shock to realize that neuropsychiatric
researchers are now seriously investigating just about every part of
going wild, searching for effective treatments for depression and other psychiatric disorders. (Not entirely illogical. After all, why would stressed-out college kids mess up sleep-wake cycles and try every licit and illicit chemical if they didn’t get at least momentary relief?)
The most publicized line of such research is related to "psychotropic" recreational drugs. Studies on ketamine, an anesthetic medication known among drug users as "Special K," have led to searches for new rapidly-acting antidepressant
treatments. Ketamine has been shown to relieve severe depression in a
matter of hours, even minutes, probably by changing the activity of the
neurotransmitter glutamate. Similarly, LSD, Ecstasy, hallucinogenic
mushrooms, marijuana derivatives, and a host of other drugs are also being explored for their possible therapeutic effects in depression, post-traumatic stress disorder, and other conditions.
Studying all-nighters-- a 'Chronotropic' exploration
In contrast, much less attention has been paid to the other pole of
college exploration: the occasional (or more often) all-nighter in which
students, usually in pursuit of a passing grade, prop their eyes open
for a last-minute study binge. In the natural laboratory of campus life,
college students engage in what you could call "Chronotropic"
explorations. Just as they explore all manner of recreational
'psychotropics', they also seek psychological effects by testing the
bounds of the clock, that is, in search of chronotropia.
Hence, they disrupt their sleep-wake cycles with incredible ingenuity, perhaps lying
in bed all day, or staying awake all night, or both; sometimes to
study, other times to party, and other times for no discernable reason.
Some of these experiments can lead to bad outcomes--for instance, kids
who test whether they need to sleep at all; or those who abandon the 24
hour cycle entirely, sleeping willy-nilly whenever they feel the urge. And those who flip their sleep cycle
around entirely, being awake all night and sleeping all day, may get
into academic difficulties. For researchers, the prolonged wakefulness
of all-nighters is of particular interest. Numerous studies have shown
that sleep deprivation itself, or 'wake therapy' can be an effective
treatment for depression, even among suicidal psychiatric inpatients.
But in contrast to the many ongoing federally- and industry-funded
studies of ketamine and related drugs, little funding is available for
studies of wake therapy, at least in part because there is no product
for which to seek FDA approval and little room for profit. Most studies
to date are small, and none are placebo-controlled. Which is a shame.
After all, it has been known for decades that prolonged
wakefulness—that is, keeping a depressed person awake for more than 24
hours—often quickly relieves depression. This rapid relief of often
previously intractable symptoms is eerily similar to what occurs with
ketamine, where symptoms also may melt away almost instantly. Like
ketamine, studies have shown that prolonged wakefulness leads to major
neurotransmitter effects, including on glutamate (though prolonged
wakefulness also has powerful effects on the genes that control the brain’s biological clock, and perhaps mood as well.)
The problem with wake therapy—just like ketamine, incidentally—is
that the relief from depression may be transitory, lasting only a few
days. Then the symptoms may come back.
Thus, ketamine and wake therapy researchers face the same challenge:
how to preserve improvement, how to keep depression in remission for
weeks or months, and how to turn a powerful short-term biological effect
into an effective ongoing treatment.
For wake therapy researchers, the search to maintain wakefulness
improvement has gone two ways: some have tried medications, like lithium
(especially for bipolar depression, depressed episodes seen in people
with manic-depressive illness). Other researchers have tried adding one
or another "environmental manipulation.” The latter include: 1) bright
light therapy, 2) sleep phase advancement or 3) both together. Each of
these approaches on its own has been shown to help depression.
Initially, light therapy was tested in people with seasonal affective disorder,
whose episodes of depression are keyed to seasonal changes. In a 2016
study, Dr. Raymond Lam and colleagues showed that light therapy was also
effective in people with non-seasonal depression. In recent years,
figuring that more might be better, light therapy and sleep phase
advancement are often combined with prolonged wakefulness, in what is
called “triple therapy.” Several studies have been done with different
versions of this triple therapy, in which depressed patients are exposed
to bright morning lights and have various adjustments of their sleep
schedule, in combination with different schedules of sleep deprivation.
In search of a reliable treatment
And yet, doctors and therapists who treat patients with chronotherapy
are still far from having a reliable alternative to the standard
antidepressant regimens, either medication (especially the serotonin
reuptake inhibitors) or psychotherapy (particularly cognitive behavioral therapy and interpersonal psychotherapy).
Scientifically, the biggest problem is that the existing triple therapy
studies, combining sleep deprivation, bright lights, and sleep phase
changes, all lack a comparison condition, so it’s unclear whether to
what degree improvement comes from the treatment itself or from placebo
effects. Beyond this, we still don’t know the best way to combine these
various chronotherapy interventions. Dosing, timing, duration; the usual
questions arise. And we have no way of predicting who will respond to
one or another component of treatment, and for whom it is a waste of
time.
A new RCT
Which leads to an exciting study we have started at the Depression
Evaluation Service (DES) at Columbia University’s Department of
Psychiatry in New York. After much consideration, we’ve decided to
compare two forms of triple therapy in people with depression in a
randomized controlled study, the first to our knowledge. (See below for
links related to the study.)
The goal of our ongoing DES study, which is being crowd-funded,
is to test the effectiveness of chronotherapy further and to begin to
investigate its possible mechanisms, including testing whether changes
in the biological clock and the normalization of sleep are related to
improvement in depression. Depending on what we find, further studies
could investigate the biology of sleep changes, the effects on hormone levels, and brain structure and connectivity as measured by MRI imaging and neuropsychological tests.
Whatever we find should be of interest, which is the best kind of
study to pursue. We are about halfway through this study, and hope to be
done within about a year—so stay tuned
Psychologytoday
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