Saturday, January 22, 2011

Chronotherapeutics for Affective Disorders

Little update 3/2/11 - Just found this website with research updates on chronotherapuetics which may be of interest:
(end little update)

I'm going to spend some more time discussing some nitty gritty, genetics, and biochemistry related to mood disorders (especially), treatments for mood disorders, and circadian rhythm abnormalities.  Bet you can't wait!  In the mean time, however, I came upon some neat articles (1)(2) about the process of chronotherapeutics.  That is, using light therapy, dark therapy, sleep deprivation and sleep phase delay or advance to treat mood disorders, such as depression and bipolar disorder.  A little warning - these methods are powerful, quick, and affect the same neurotransmitter systems as psychiatric medications (more on that in a different post), and it is not a good idea to experiment with these all on your lonesome.  Let me give you a worst case scenario - you try to treat depression with light therapy or sleep deprivation.  Turns out you are bipolar.  You get manic, spend $30,000 on a new stereo system, sleep with your boss, and antagonize your friends and relatives, and end up in a hospital after singing opera naked on your rooftop (this is an invented but not entirely unreasonable scenario).  So... best to let some loved ones know if you attempt these methods, and if you already have a psychiatric diagnosis, don't attempt these methods without the blessing and observation of your therapist or doctor.  In addition, if the methods aren't done quite right, you can very quickly relapse (within 1-2 days). 

Most of you will be familiar with the concept of light therapy.  Sitting in front of special 10,000 lux light sources on late autumn and winter mornings has been proven to be an effective treatment for seasonal affective disorder, major depressive disorders, and even bipolar depression (if you are careful - injudicious use of light therapy can also bring on mania).  The FDA approved lights (such as the ones from this company - this is just the company I typically recommend to patients, I have no relationship to them and receive no monetary or other benefit from them)  all have a 30 day money back guarantee, also, which is nice, and some insurance companies will pay for them if you are lucky.  The usual method is to sit in front of the lights in the morning for 15-30 minutes, glancing at the light every 30 seconds to a minute or so.  You have to do it nearly every day, and it works best if you begin when the seasons change (late September here at 40 degrees north).  Light therapy can nearly instantaneously improve seasonal depression, and I've heard tales of trucks of light therapy boxes driving around to small towns in Alaska and reducing the winter suicide rate along the way. 

But let's get back to the basics of chronotherapeutics.  In general, interventions that lead to sleep phase advance (waking up early and going to sleep early) have an antidepressant effect, and sleep phase delay (going to sleep later and waking up later) will have a depressant (or anti-manic) effect.  Also, reinforcing the natural circadian rhythm will tend to help mental illness - at hospitals in Canada (3) and Italy (4), they noticed that patients in sunny or easterly facing rooms were discharged on average 2&1/2 to 3&1/2 days earlier than patients in rooms without much sunlight. (Even more interestingly, the differences were minimal in the winter, but extended to up to 7 days in the autumn).  Not surprisingly, all of this has been discovered before by our intrepid ancestors.  Classical texts and descriptions of psychiatric wards from 1794 showed that depressed patients were advised to spend time out of doors, and agitated patients were closed up in darkened rooms (5).

One old-fashioned and newly-fashionable method of treating all sorts of depression is sleep deprivation (SD).  There is complete sleep-deprivation, which is self-explanatory, and partial sleep-deprivation,which generally involves waking people up for the second half of the night.  The only known contraindication to sleep deprivation is epilepsy (I've spent some time on the long-term seizure monitoring units in neurology, and we've been known to elicit seizures for diagnosis via EEG by sleep deprivation (basically, sending the medical students and residents - who were up anyway -  to keep the patient awake at all hours) and use of a judicious amount of red wine).  SD's efficacy has been reported in major depression, bipolar disorder, depression in schizophrenia and in Parkinson's disease, and post-partum depression.  Patients who respond best to sleep deprivation are the same patients who respond best to antidepressant medications - those with a diurnal pattern of mood (typically more depressed in the morning and feeling pretty good by afternoon), low IL-6 levels, and an abnormal dexamethasone suppression test.  Light therapy has similarly proved therapeutic (nearly instantly) with depression associated with ADHD, Parkinson's, Alzheimer's, pregnancy, post-natal, and regular depressive disorders.

As with every other method (such as therapy and antidepressants) (except shock therapy, which is up to 90% effective), light therapy and sleep deprivation is at least modestly helpful in 60-70% of cases.  However, and interestingly, people with bipolar depression seem more likely to respond to sleep deprivation or light therapy than to standard antidepressant medications, suggesting to me (and truth be told I've read other papers with other evidence for this theory) that genetic issues with the circadian rhythm system is the primary problem leading to the vulnerability to bipolar disorder.Due to the tricky nature of bipolar depression and the risk of switching to mania with antidepressant drugs, some of the most robust data has been shown for chronotherapeutics (sleep deprivation, phase advance, or light therapy) for this condition, and mood stabilizers (which work upon the circadian rhythm proteins) can enhance and continue the initial benefits brought about via chronotherapeutics.  The medicine remains useful, as once chronotherapeutics are discontinued (one can't be sleep-deprived forever, for example), the depression can return within a hours of a normal night's sleep.  In fact, only 5-10% of the studied bipolar depressed patients remain with a normal mood through  chronotherapeutics alone.  Repeating the intervention doesn't always help, as people tend to become tolerant to the treatment.

One way of ameliorating the tolerance to chronotherapeutic techniques is to combine them.  For example, there is a severely depressed patient with known bipolar disorder in the hospital.  Start with a few days of sleep deprivation, then begin phase advance treatment (going to bed early, waking up early) and morning light therapy to retain the benefits over time.  Perhaps add in some mood stabilizers to enhance the effect (again, I will go into more specifics as to how mood stabilizers and antidepressants affect, directly, the circadian rhythm system in another post - but to give you a preliminary taste, both serum and PET, SPECT, and fmri data has shown that antidepressants and sleep deprivation/phase delay/light therapy affect the same neurotransmitter system in similar areas of the brain), and we have a recipe for nearly immediate reversal of severe bipolar depression with maintenance of normal mood for the foreseeable future.

An interesting part of the discussion of chronotherapeutics is that the techniques (other than the physical lights of light therapy) cannot be patented.  Therefore there is less (short-term) economic motivation for future study (as is the case with most evolutionary medicine ideas).  However, in countries with socialized medicine, far-sighted bureaucrats might see the writing on the wall - cheap interventions (such as sticking all the depressed patients in easterly-facing rooms in the autumn) decreasing hospital times saves real taxpayer money very quickly.  Days in the hospital equals thousands of dollars.  It is that simple.

So if you are depressed, seek light and wakefulness (an old timey depression remedy was to wake up at 3am once a month for those known to be vulnerable to the condition), and if you are manic, seek darkness and low stimuli.  Under close supervision, of course.


  1. This has been an interesting series, Emily. Thank you for writing it.

    You said in your previous post:

    "All told, sleep problems and fatigue arise from a complicated array of too much or too little in a number of neurochemical systems. There are natural chemicals promoting wakefulness, and chemicals promoting sedation as part of the circadian rhythm, and issues with any of these can lead to complaints of poor sleep, insomnia, or fatigue."

    I have several sleep disorders (OSA, PLM - discovered during sleep studies at Stanford Sleep Clinic) and have dreaded going to bed and getting up throughout my life. I've read many books on sleep and have tried light therapy. I am currently taking three meds to calm my legs and get to sleep. My circadian rhythm has never been great and travel completely messes with it. Magnesium and melatonin have no noticeable effect, though I take magnesium daily.

    I certainly seem to have a mood disorder, and have often wondered if it is tied to the sleep issues. Not something like you describe above (bipolar), but more of a nagging sense of anxiety and lack of ability to focus and be as productive as I would like to be.

    All this to ask how one goes about finding qualified supervision?

  2. People are notoriously shortsighted. Agreed. Honest question though: why would bureaucrats be less shortsighted than than providers in the private sector?

    Most of the historical evidence in my view suggests that bureaucrats are just as motivated by short-run self-interest considerations as anyone else. They have to be persuaded too. How much easier is it to persuade a person to save someone else's money than to save their own money (private insurer).

    I really believe this boils down to a lack of controlled trials. Private insurers would jump at the chance to pay for something that both works and is cheaper!

  3. Nick - there are many routes to becoming a sleep medicine specialist, and one of them is via psychiatry. I bet the Stanford clinic has an affiliated psychiatrist. Otherwise, maybe the best route is through a bright therapist who can read the papers and would be game. SD and phase shifting are really only turbo boosters. for other treatments, though. If one is chronically sleep-deprived I'm not sure they would work. Light therapy it sounds like you are doing already. In *some* cases Ive heard of morning and afternoon treatments but, again, you want to be pretty sure you aren't bipolar if you are going to do LT in the afternoon.

  4. Wade - having worked with a number of private insurers over the years I must say their brilliance and efficiency is not exactly forefront. Many of them carve out the mental health coverage to a second company (true story, once I was working in the ER and at 2am a woman 500 miles away was trying to deny the admission of a guy who had thrown gasoline over his car, lit it on fire, and tried to jump inside. The denial was on the basis that he no longer had the means to kill himself on him! We had to get insurance approval before anyone could set foot in the hallowed ground of the locked ward. Eventually we got it sorted through her supervisor who was none to pleased to be woken up).

    I think if insurance companies really cared about saving money, they would have figured out this whole high carb low fat whole grains scam years ago. No, insurance companies seem to care about adding checks quality assurance and justifying their existence. But I could be jaded. ;-). For some reason I cannot imagine a zillion different insurance companies getting it together enough to deman evidence base in a waynthat doesn't make everything even more ridiculous (as ismthe case now)

  5. Very interesting Emily. There seems to be a high correlation between having manic episodes and being a college professor. (This seems to apply to professions that require some creative intelligence; and as you surely know, some evolutionary theories exist to explain this phenomenon.)

    From what you are saying, those folks’ own bodies may be trying to help relieve the problem when they have insomnia attacks. If this were the case, maybe those folks should not try to take any sleep medication, and just understand that the lack of sleep may be itself a therapy. Am I correct?

  6. I would say ADHD and Bipolar can give one a creative and productive advantage in the right environment and if someone is high functioning. There is discussion that the "early awakening" that is classic for depression is the body's way of trying to self-correct the problem. In bipolar disorder you have the additional issue of going too far into mania if you miss sleep - so you really need to know what you are doing if you want to use chronotherapeutics (an ideal setting, though would be in the hospital with 24 hour supervision for serious cases, for example)

  7. Its like you know what I have learned by being an observant, scientific minded person who also happens to be a little crazy.

    I always assumed my case was so mild these things helped me but would not help people with severe clinically significant forms of illness. My mild manias and my depressions must be different than people who have proper manic depression. I can be afflicted with a heavy, achy body, dim vision as if I have blinders on, incredibly sad morbid hopeless thoughts that make me cry pathetically for expression, in vain, unable to get dressed other than to bring my corpse into work, during which I plunder about unable to remember what I am doing or what is going on, to slump at my desk and try not to cry in front of cowowrkers.

    I can go from that, use a light box, and a month later laughing hysterically, wanting to dance in the street, stay up all night and see the world as living breathing moving art, literally the trees look like a painting and it is magical.

    I assumed, perhaps something this mild and obvious as light therapy only works for me because my condition is also mild. If I stay up, my depression improves, or if I am manic, my mania flies. If my light exposure increases, I predictably become high and euphoric and energetic and elated.

    If the seasons turn and the light dwindles, I am apt to enter a depressive fog which progressively worsens. When tangible it leaves me as described above... pathetic and hopeless and in such irrational pain.

    Do these things really work for people with severe illnesses? If so, why do so many people choose to live a horrible life on seroquel and depakote, when these things (like ketosis, light therapy, sleep deprivation) work for them? It can't be that simple. If it is, that's criminal. I suspect in reality, these interventions must not be that effective for the severely ill... and in severe bipolar especially, neuroleptics are going to be necessary.

  8. Inthewoo - I agree that in most situations the severe cases will do better with medications. I've seen the right medications lead to remarkable improvement in a matter of days. Chronotherapuetics stop working after you stop the intervention. So light therapy is likely the most useful version. However, combining chronotherpaeutics with other interventions (in a hospitalization, for example), would seem to be a good way to get treatment headed the right direction.

  9. I would be curious to know how effective using a sleep schedule which more closely follows the circadian rhythm(i.e waking up with the light and going to sleep pre-midnight) would have on depression in the long term. Would this be a feasible long term treatment for depression? And how strictly would that have to be maintained. Could a patient make exceptions once or twice a week while maintaining a regular sleeping schedule for the rest of the week?
    I really enjoy reading your blog. It is most informative!