Whew. Between making up for my holiday vacation and the snow days (we might get yet another storm, up to 18 inches, tomorrow, and there is still 2&1/2 feet on the ground!!), work has been incredibly busy. At the same time, my children have decided to run sleep deprivation experiments on me. The problem with being sleep-deprived is that when you try to read rather clunky textbooks on the basic and clinical science of sleep and mental illness, you tend to nod off rather quickly. (the reference for this post is the aforementioned clunky textbook)
That's a rather verbose introduction to the fact that I need a perky song or two to blog by today. Let's start with Ra Ra Riot's Boy. (right click in new tab if you want to keep reading).
So - appetite, sleep, and mood. We psychiatrist types ask about such things all the time, because we know they are inexorably related. In fact, problematic appetite, sleep and energy levels have a clinical nickname - "neurovegetative symptoms." Well, that's not much of a nickname. We call it "neuroveg" for short. We also call ending a relationship with a patient "termination." And emotions "affects." We aren't particularly fun people, really. (Kidding! Sort of.)
So let's talk neurotransmitters. Wakefulness in general is supported by several excitatory neurotransmitter pathways, among them acetylcholine and norepinephrine. These brain chemicals send wakey wakey signals to the forebrain, and when this happens, our brain EEG signals go from large sleepy floppy slow wave sleep to the brisk jagged beta waves of being awake. If we lack acetylcholine and norepinephrine signals to the forebrain, we get all drowsy and fall into non-REM sleep (all our restorative sleep). If you are into the whole neurochemistry/electricity thing, the excitatory neurotransmitters lead to rapid firing and depolarization of the wakeful brain neurons. The lack of that signal leads to a relative hyperpolarization and long, slow lazy signal of the sleeping brain.
To get into even more nitty gritty, remember that the basic energy currency of the cells is ATP. That's short for adenosine triphosphate. In order to lend power to chemical reactions, the ATP gives up its three phosphates one by one until it becomes plain old adenosine again. And in the brain, the more adenosine, the more difficult it becomes to send signal to the wakey wakey neurons. That makes sense - you've spent your energy reserves and have a bunch of waste adenosine around? Chill out, cool down, and rest, so the nighttime healing and restoration of reserves can commence.
(Time for another song? I really like this one by The Black Keys. It's overplayed but, some songs are never really overplayed.)
To recap - the neurotransmitter monoamines, norepinephrine and acetylcholine, promote wakefulness. Non-REM sleep (stage 1-4) is the opposite of wakefulness, and lack of monoamine input leads to progressively more slow wave sleep. BUT, remember that during polysomography, it is difficult to tell the difference between someone waking up and someone in REM sleep. The EEG waves of REM sleep are impossible to tell from being awake - only the rapid eye movements and the paralyzing of our major large muscle groups can let the sleep researcher know that the subject is in REM sleep and hasn't woken up.
Turns out REM sleep neurons turn on when there is almost NO input from the monoamines, while sleepy-inducing neurotransmitters like GABA (GABA receptors are activated by GABA (duh), benzos like valium, alcohol, and sleep medicines like lunesta or ambien.) seem to activate both non-REM and REM sleep.
So - in major depressive disorder, we seem to have a lack of monoamines in the right places at the right time in the brain. GABA is more or less okay. Therefore, you get a classic sleep hypnogram for major depression - lots of REM sleep that starts way too early in the night, lots of wakefulness, and almost no restorative slow wave sleep. All clinically effective medicinal treatments for major depressive disorder will improve your hypnogram by increasing the amount of time it takes you to get to REM sleep 10 DAYS EARLIER than you notice any improvement in mood.
(If your depressive disorder has a lot of anxiety symptoms too, your GABA is probably lacking, so then the sleep gets really messed up.)
Now, let's bring in appetite. The Nurses' Health Study and some other studies show that chronic short duration of sleep and chronic long duration of sleep are associated with type II diabetes. Laboratory subjects who are studied in sleep restriction and sleep deprivation have impaired glucose tolerance and increased appetite. In the majority of serious psychiatric disorders, disruption of the circadian rhythm and sleep occurs, and major psychiatric disorders are also associated with an increase in appetite and risk of diabetes. Some of this increase is medication-driven, but there also appears to be an increase in risk of diabetes and weight gain independent of medications.
The center of appetite and mental problems appears to be the hormone orexin. As we learned earlier, orexin is a hormone that makes you hungry. Serotonin seems to suppress orexin. Folks with schizophrenia and atypical depression seem to be pretty low on serotonin, and they will be hungrier and have more central obesity than folks without those disorders.
Putting it all together, disturbances in the sleep-wake cycle reported in psychosis and in atypical depression seem to disrupt the feedback mechanisms of energy and metabolism in a way that decreases glucose tolerance and reduces sleep efficiency and effectiveness. All the usual neurotransmitter suspects are implicated.
Another song? Sure, why not. How about The Cave by Mumford and Sons.
Or if you want a nice modern classical romantic song, try this little piece from the newest Pride and Prejudice movie. Good date movie - not too many tears.
Tuesday, January 25, 2011
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: http://www.chronotherapeutics.org/Index.html
(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.
(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.
Friday, January 21, 2011
Sleep Architecture
At the risk of recreating a wikipedia article, we need to lay some groundwork here and discuss the structure of normal sleep. Of course it is never as simple as that - normal sleep architecture changes throughout the life cycle. However, the basics are similar for everyone except perhaps preemies.
Sleep is defined using EEG readings (where you have a bunch of leads taped to your head, and the electrical output of the brain is measured on a polysomnography - which also includes muscle measurements and eye movement measurements to be completely accurate.) In general, all stages of non-REM sleep are characterized by a slowing and deepening of the waveforms as we get deeper and deeper into sleep. When we are awake but zoning out, or meditating, we have a type of waveform detected on the EEG called an "alpha wave." When the alpha waves start to become theta waves, we've progressed to stage 1 sleep. In general, someone who has been awakened from stage 1 sleep will not think he or she was actually sleeping. (Think Dad nodding in his chair on Sunday afternoon, and when you bug him, he blinks and goes back to watching the game as if nothing happened).
A few minutes into stage I, if all goes well, you go to stage 2, and then after another few minutes into stage 3 and 4. These last two stages are characterized by "delta waves" and are commonly referred to as "slow wave sleep" and represent the deep, refreshing sleep. After about an hour or a little more (total for 1-4), normal adults will transition to REM sleep, where eyes move rapidly and large muscle groups are paralyzed. This stage is when a lot of dreaming occurs (though dreaming also happens during slow wave sleep). REM sleep waves are somewhere in between stage I and wakefulness - in fact, the sleep scientists rely on the muscle readings and eye movement readings to distinguish between someone who has woken up, and someone who is in REM sleep.
Once the REM cycle is finished, one drops down through stage 1-4 again. The cycle repeats itself every 90 minutes or so (for newborns, every 45 minutes) throughout the night, though the last couple of cycles one spends more time in REM sleep and less time in slow wave sleep.
A couple of important things - the first cycle or two are the ones where we spend the most time in the deep, refreshing slow wave sleep, so it is vital that these cycles are of good quality. In classic Major Depressive Disorder, for example, patients will often never reach full slow wave sleep throughout the night, thus the common complaint of insomnia, feeling constant fatigue, irritability, or being too easily awakened. These same patients typically aren't hungry and lose weight. In "atypical" depression, seasonal affective disorder, or bipolar disorder, some patients will actually spend too much time in slow wave sleep. They also feel lethargic, and will be hungry and tend to gain weight.
Alcohol consumed close to bedtime will tend to decrease sleep latency (that is, the amount of time from being awake to being asleep when we go down for the night), increases the length of time to get to REM sleep, and increases slow wave sleep for the first half of the night. However, the second half of the night, there will be more wakefulness, more REM sleep, and less slow wave sleep. Alcohol is the most common go-to substance that chronic insomniacs use to get some shut-eye, and overall it decreases the quality and efficiency of sleep.
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 hope to get to more of the details in future posts!
Sleep is defined using EEG readings (where you have a bunch of leads taped to your head, and the electrical output of the brain is measured on a polysomnography - which also includes muscle measurements and eye movement measurements to be completely accurate.) In general, all stages of non-REM sleep are characterized by a slowing and deepening of the waveforms as we get deeper and deeper into sleep. When we are awake but zoning out, or meditating, we have a type of waveform detected on the EEG called an "alpha wave." When the alpha waves start to become theta waves, we've progressed to stage 1 sleep. In general, someone who has been awakened from stage 1 sleep will not think he or she was actually sleeping. (Think Dad nodding in his chair on Sunday afternoon, and when you bug him, he blinks and goes back to watching the game as if nothing happened).
 |
| EEG tracing of stage 1 sleep with mostly theta waves and some alpha |
A few minutes into stage I, if all goes well, you go to stage 2, and then after another few minutes into stage 3 and 4. These last two stages are characterized by "delta waves" and are commonly referred to as "slow wave sleep" and represent the deep, refreshing sleep. After about an hour or a little more (total for 1-4), normal adults will transition to REM sleep, where eyes move rapidly and large muscle groups are paralyzed. This stage is when a lot of dreaming occurs (though dreaming also happens during slow wave sleep). REM sleep waves are somewhere in between stage I and wakefulness - in fact, the sleep scientists rely on the muscle readings and eye movement readings to distinguish between someone who has woken up, and someone who is in REM sleep.
Once the REM cycle is finished, one drops down through stage 1-4 again. The cycle repeats itself every 90 minutes or so (for newborns, every 45 minutes) throughout the night, though the last couple of cycles one spends more time in REM sleep and less time in slow wave sleep.
 |
| Normal sleep architecture |
A couple of important things - the first cycle or two are the ones where we spend the most time in the deep, refreshing slow wave sleep, so it is vital that these cycles are of good quality. In classic Major Depressive Disorder, for example, patients will often never reach full slow wave sleep throughout the night, thus the common complaint of insomnia, feeling constant fatigue, irritability, or being too easily awakened. These same patients typically aren't hungry and lose weight. In "atypical" depression, seasonal affective disorder, or bipolar disorder, some patients will actually spend too much time in slow wave sleep. They also feel lethargic, and will be hungry and tend to gain weight.
Alcohol consumed close to bedtime will tend to decrease sleep latency (that is, the amount of time from being awake to being asleep when we go down for the night), increases the length of time to get to REM sleep, and increases slow wave sleep for the first half of the night. However, the second half of the night, there will be more wakefulness, more REM sleep, and less slow wave sleep. Alcohol is the most common go-to substance that chronic insomniacs use to get some shut-eye, and overall it decreases the quality and efficiency of sleep.
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 hope to get to more of the details in future posts!
Monday, January 17, 2011
Circadian Rhythm, Psychiatric Symptoms, and Pineal Gland Tumor
Today's Green Journal had an interesting letter to the editor. "Ivan," a 19 y/o, had a history of a pineal gland tumor (the pineal gland secretes melatonin) that had been resected in 2001. In order to decrease building pressure in his brain, he had a second surgery for a VP shunt to drain his cerebrospinal fluid into his abdominal region. After the second surgery, he had insomnia, a disturbed sleep-wake cycle, and fragmented sleep. In June 2004 he began to exhibit paranoia and other classic signs of bipolar disorder. By 2007 he was on several psychiatric medications, and he was not able to continue school due to severe fatigue and bipolar symptoms. A sleep study showed an irregular sleep/wake cycle, and 24 hour urine measure of a melatonin metabolite showed barely detectable levels.
The patient was started on melatonin (a controlled release formulation), his sleep cycle stabilized, and his psychiatric medication was slowly withdrawn over the next several months. Repeat sleep studies showed normalized sleep. Since rapid release melatonin lasts 60-90 minutes, it was felt it was not a suitable replacement for the absent pineal gland - thus the controlled release formulation.
Interestingly enough, the patient discontinued his melatonin in 2009 and remained symptom free, with a stable sleep-wake cycle. The authors of the letter speculated that his bipolar symptoms arose from lack of restorative sleep, and with the help of exogenous melatonin, the patient was able to somehow use other signals to synchronize his sleep wake times, preventing relapse.
Lesson - sleep is exceedingly important (more on this fact in future posts). Also, all my first episode psychotic patients get an MRI and a full medical work-up.
The patient was started on melatonin (a controlled release formulation), his sleep cycle stabilized, and his psychiatric medication was slowly withdrawn over the next several months. Repeat sleep studies showed normalized sleep. Since rapid release melatonin lasts 60-90 minutes, it was felt it was not a suitable replacement for the absent pineal gland - thus the controlled release formulation.
Interestingly enough, the patient discontinued his melatonin in 2009 and remained symptom free, with a stable sleep-wake cycle. The authors of the letter speculated that his bipolar symptoms arose from lack of restorative sleep, and with the help of exogenous melatonin, the patient was able to somehow use other signals to synchronize his sleep wake times, preventing relapse.
Lesson - sleep is exceedingly important (more on this fact in future posts). Also, all my first episode psychotic patients get an MRI and a full medical work-up.
Sunday, January 16, 2011
The Neurobiology of Sleep
There is quite a bit going on, and I'm not always capable of doing it all with one hand behind my back, especially when sleep-deprived. One of my colleagues had a baby recently, and she asked us when our kids began sleeping through the night. Another colleague, mother of three, said "never." And to some extent it is true - sure, the newborn every 3-4 hour torture phase passes, but then you get teething, and then nightmares/fear of the dark, and beyond that I wouldn't know from personal experience, but let's just say I've got one teething and one afraid of the dark, and I am thoroughly sleep-deprived.
Which wouldn't bother me too much, except that I put on a couple of pounds (darn cortisol) and vanity is a failing of mine. From medical training I'm an old hand at sleep deprivation. Now there are actually laws against the amount of work I did back in the day. Not that I disagree with those laws as a rule - I happened to do my psych consultation service on some of the same floors where the medicine interns wore EEG leads post-call (meaning after being up all day and all night, and rounding on patients in the morning) as part of a study on resident work hours. Turns out they spent a good deal of those post-morning rounds in phase I sleep. Since I'm sure most of you don't care for sleepwalking doctors in charge of communicating vital information about your admission and hospital course, I imagine you are probably in favor of laws controlling medical residents' work hours. You might be surprised by the response within the medical community. They want residents to suffer - they think it makes better doctors. And working crazy hours does build confidence and experience faster than anything. However, I hope it is not terribly controversial to suggest that we not make new doctors at the expense of safety (too much).
Well, sleep! Which I am sorely missing. I'm not young anymore, after all. I have at hand a basic reference for the neurobiology of the circadian rhythms. It is from the supplements from the Journal of Clinical Psychiatry (which I normally throw away, as they are generally thinly-gilded advertisements for the pharmaceutical industry. And this supplement is no different- it came out in 2005, which was right about when Ambien CR and Rozerem were being marketed, and if you read the entire supplement you get statements about how cheap, long-used sleeping pills aren't FDA approved (of course they are not - they were generic long before the current FDA approval process, and who would bother to spend the several gazillion dollars needed for the current FDA approval process for generic medicines?) But, pharmaceutical advertising notwithstanding, the paper I'm referencing is rather too basic to be dangerous, and it is free (with free registration) for everyone, so let's call it egalitarian.
The Human Circadian System and Normal and Disordered Sleep
The neurobiology of sleep is nearly as simple as light and dark. We have, in our brains, right in the middle a bit above our eyes, a little area called the superchiasmatic nucleus. It is an area of about 10,000 neurons that runs our circadian rhythms. Without light stimulus, it tends to fire in a rhythmic pattern in a cycle of a bit more than 24 hours. Light stimulus will reign it in and keep it correlated with our natural light/dark cycles.
Light hits the retina of our eyeballs, which then sends a signal up through our optic nerve directly to the superchiasmatic nucleus. There a dimer of two proteins is made in response to the light - CLOCK+BMAL1 (let me suggest that the scientist who named the CLOCK protein was a tad more poetic than the namer of BMAL1). BMAL1/CLOCK starts the day running by binding the per/cry promoter regions in the nucleus, leading to the creation of the PER/CRY protein complex (there are in fact 2 pers and 3 crys, but let's just call it per/cry for simplicity's sake.)
From here, PERs and CRYs have to bond with other PERs and CRYs to form dimers, or else they are broken down very readily. The dimer of PER/CRY is then translocated from the nucleus to the cytoplasm for daytime cellular activity. All right! Throughout the night, when no new PERs or CRYs are made, the dimers already in the cytoplasm slowly degrade, until light comes again and more new ones are made. Thus the cycle of life and light and dark. That, in a nutshell, is the circadian rhythm.
Under conditions of sleep deprivation, our circadian clock will keep us from getting too far out of whack from light/dark cycles. We will readily sleep in the wee hours of the morning (and in fact major industrial accidents such as the Exxon Valdez crash and the Three Mile Island radiation leak happened at 3-4 am - at least according to my book on chaos and sleep), and yet even if sleep deprived and given ample opportunity, we have a hard time sleeping during the "forbidden zones" of 9am and 9pm.
And what of that famous pineal gland hormone, melatonin? It is secreted in response to dark, and light stimulus (such as checking the twitter feed on the ipad at 3am, or turning the hall light on to quell the 3 y/o's fear of the dark) will diminish melatonin secretion immediately. The human superchiasmatic nucleus (SCN) has a bunch of melatonin receptors (there are very few in the human brain outside this region). Melatonin signals the SCN to cool it and settle down for the night. Melatonin seems to sharpen the natural SCN response to light and dark. Without proper melatonin signaling, light and dark signals to sleep or wake up are attenuated, leading to night wakefulness and daytime sleepiness.
So what to do if you have insomnia? The first thing is to cut out any late night retina stimulators - like TV or internet. Music or low-light reading is probably okay. Our retinas were never designed for HDTV at midnight streaming so much signal straight into our brains (I'm reminded of when my oldest as a baby was awake at night, and my husband, trying to spare me, dutifully took her downstairs and began watching "Three Kings" with her at 2am - well, that Iraqi sun on the big screen TV at 2am did nothing for our baby's ability to sleep, and she was WIRED for several hours.) Do not turn on the lights for a midnight visit to the refrigerator or the restroom. I'm not entirely convinced that complete, black darkness is necessary given our ancestral propensity to sleep under the moon and stars, but as little light as possible is likely ideal.
Get rid of the clocks, too. I don't use an alarm and haven't for many years. If you need an alarm to wake up, you aren't getting nearly enough sleep in the first place.
There is an online resource called "CBTforInsomnia.com" that has an inexpensive program to help with insomnia (I have no connections to this resource and receive no money from promoting it).
Failing that, if you have a condition such as depression, anxiety, or bipolar disorder, sleep is exceedingly important. I'll focus more on these individual conditions in separate blog posts. In these cases I often feel it is prudent to prescribe sleep medicines (in fact, with an escalating mania, especially a psychotic mania, sleep medicines will nip it in the bud as quickly as anything else), but it is obviously not the ideal and is not a long term solution.
My own preferred sleep remedy is magnesium supplementation. I take magnesium oxide (low bioavailability, but easy to find at any drugstore) 250-500mg (depending on how many nights in a row I forget to take it), a lower dose of magnesium citrate, or a low dose of magnesium gel meant to spread on the skin, and I sleep well, right up until one of the children wakes me up. Maybe I should coat them with magnesium too.
Which wouldn't bother me too much, except that I put on a couple of pounds (darn cortisol) and vanity is a failing of mine. From medical training I'm an old hand at sleep deprivation. Now there are actually laws against the amount of work I did back in the day. Not that I disagree with those laws as a rule - I happened to do my psych consultation service on some of the same floors where the medicine interns wore EEG leads post-call (meaning after being up all day and all night, and rounding on patients in the morning) as part of a study on resident work hours. Turns out they spent a good deal of those post-morning rounds in phase I sleep. Since I'm sure most of you don't care for sleepwalking doctors in charge of communicating vital information about your admission and hospital course, I imagine you are probably in favor of laws controlling medical residents' work hours. You might be surprised by the response within the medical community. They want residents to suffer - they think it makes better doctors. And working crazy hours does build confidence and experience faster than anything. However, I hope it is not terribly controversial to suggest that we not make new doctors at the expense of safety (too much).
Well, sleep! Which I am sorely missing. I'm not young anymore, after all. I have at hand a basic reference for the neurobiology of the circadian rhythms. It is from the supplements from the Journal of Clinical Psychiatry (which I normally throw away, as they are generally thinly-gilded advertisements for the pharmaceutical industry. And this supplement is no different- it came out in 2005, which was right about when Ambien CR and Rozerem were being marketed, and if you read the entire supplement you get statements about how cheap, long-used sleeping pills aren't FDA approved (of course they are not - they were generic long before the current FDA approval process, and who would bother to spend the several gazillion dollars needed for the current FDA approval process for generic medicines?) But, pharmaceutical advertising notwithstanding, the paper I'm referencing is rather too basic to be dangerous, and it is free (with free registration) for everyone, so let's call it egalitarian.
The Human Circadian System and Normal and Disordered Sleep
The neurobiology of sleep is nearly as simple as light and dark. We have, in our brains, right in the middle a bit above our eyes, a little area called the superchiasmatic nucleus. It is an area of about 10,000 neurons that runs our circadian rhythms. Without light stimulus, it tends to fire in a rhythmic pattern in a cycle of a bit more than 24 hours. Light stimulus will reign it in and keep it correlated with our natural light/dark cycles.
Light hits the retina of our eyeballs, which then sends a signal up through our optic nerve directly to the superchiasmatic nucleus. There a dimer of two proteins is made in response to the light - CLOCK+BMAL1 (let me suggest that the scientist who named the CLOCK protein was a tad more poetic than the namer of BMAL1). BMAL1/CLOCK starts the day running by binding the per/cry promoter regions in the nucleus, leading to the creation of the PER/CRY protein complex (there are in fact 2 pers and 3 crys, but let's just call it per/cry for simplicity's sake.)
From here, PERs and CRYs have to bond with other PERs and CRYs to form dimers, or else they are broken down very readily. The dimer of PER/CRY is then translocated from the nucleus to the cytoplasm for daytime cellular activity. All right! Throughout the night, when no new PERs or CRYs are made, the dimers already in the cytoplasm slowly degrade, until light comes again and more new ones are made. Thus the cycle of life and light and dark. That, in a nutshell, is the circadian rhythm.
Under conditions of sleep deprivation, our circadian clock will keep us from getting too far out of whack from light/dark cycles. We will readily sleep in the wee hours of the morning (and in fact major industrial accidents such as the Exxon Valdez crash and the Three Mile Island radiation leak happened at 3-4 am - at least according to my book on chaos and sleep), and yet even if sleep deprived and given ample opportunity, we have a hard time sleeping during the "forbidden zones" of 9am and 9pm.
And what of that famous pineal gland hormone, melatonin? It is secreted in response to dark, and light stimulus (such as checking the twitter feed on the ipad at 3am, or turning the hall light on to quell the 3 y/o's fear of the dark) will diminish melatonin secretion immediately. The human superchiasmatic nucleus (SCN) has a bunch of melatonin receptors (there are very few in the human brain outside this region). Melatonin signals the SCN to cool it and settle down for the night. Melatonin seems to sharpen the natural SCN response to light and dark. Without proper melatonin signaling, light and dark signals to sleep or wake up are attenuated, leading to night wakefulness and daytime sleepiness.
So what to do if you have insomnia? The first thing is to cut out any late night retina stimulators - like TV or internet. Music or low-light reading is probably okay. Our retinas were never designed for HDTV at midnight streaming so much signal straight into our brains (I'm reminded of when my oldest as a baby was awake at night, and my husband, trying to spare me, dutifully took her downstairs and began watching "Three Kings" with her at 2am - well, that Iraqi sun on the big screen TV at 2am did nothing for our baby's ability to sleep, and she was WIRED for several hours.) Do not turn on the lights for a midnight visit to the refrigerator or the restroom. I'm not entirely convinced that complete, black darkness is necessary given our ancestral propensity to sleep under the moon and stars, but as little light as possible is likely ideal.
Get rid of the clocks, too. I don't use an alarm and haven't for many years. If you need an alarm to wake up, you aren't getting nearly enough sleep in the first place.
There is an online resource called "CBTforInsomnia.com" that has an inexpensive program to help with insomnia (I have no connections to this resource and receive no money from promoting it).
Failing that, if you have a condition such as depression, anxiety, or bipolar disorder, sleep is exceedingly important. I'll focus more on these individual conditions in separate blog posts. In these cases I often feel it is prudent to prescribe sleep medicines (in fact, with an escalating mania, especially a psychotic mania, sleep medicines will nip it in the bud as quickly as anything else), but it is obviously not the ideal and is not a long term solution.
My own preferred sleep remedy is magnesium supplementation. I take magnesium oxide (low bioavailability, but easy to find at any drugstore) 250-500mg (depending on how many nights in a row I forget to take it), a lower dose of magnesium citrate, or a low dose of magnesium gel meant to spread on the skin, and I sleep well, right up until one of the children wakes me up. Maybe I should coat them with magnesium too.
Wednesday, January 12, 2011
Autism and Interpregnancy Interval
A paper came out earlier this week: Closely Spaced Pregnancies are Associated with Increased Odds of Autism in California Sibling Births.
In short, the researchers matched every single sibling birth in California from 1992-2002 with reports of getting services for autism, spent a good deal of time on the statistics and did a secondary case-controlled study to make sure they weren't missing anything. And turns out that the odds of a second child born within 12 months of a first child (*actually I messed this up a little - it is an interpregnancy interval of less than 12 months - so a second child born less than 18 months after the first. sorry!) have a little more than a 3 fold risk of having autism than a second child born more than 3 years after the first one. Risk for second children born at interpregnancy intervals of between 12 and 36 months were middling, but risk rose abruptly between 12-18 and "0"-12 months.
Unfortunately, the researchers spent so much time in the paper reviewing the statistics and making sure every last variable was accounted for that the discussion as to why was about one paragraph. They thought it might be folate depletion, omega 3 depletion, or stress (it is, obviously, very stressful to have a young baby and to be pregnant at the same time.) In a number of posts on autism I have speculated as to some nutritional and genetic causes:
Diet and Autism1
Diet and Autism 2
Autism and Vitamin D
Autism 4 - Inflammation Speculation
Brain Efficiency, Pediatric Edition
Since, during pregnancy, a baby will tend to suck whatever nutrients are needed straight from mama, whether she can spare them or not, it would make sense that a nutritional explanation could account for the increased risk of autism in second children when the pregnancies are closely spaced.
Here is a free, online, up to date, and comprehensive review of pregnancy, nutrition, and birth outcomes - if you are interested.
My ultimate preventative solution is, of course, to make sure that moms-to-be out there are consuming nutrient rich diets with plenty of folate, phospholipids, minerals, omega 3s, etc. etc. etc.
Also, it is snowing. A lot.
In short, the researchers matched every single sibling birth in California from 1992-2002 with reports of getting services for autism, spent a good deal of time on the statistics and did a secondary case-controlled study to make sure they weren't missing anything. And turns out that the odds of a second child born within 12 months of a first child (*actually I messed this up a little - it is an interpregnancy interval of less than 12 months - so a second child born less than 18 months after the first. sorry!) have a little more than a 3 fold risk of having autism than a second child born more than 3 years after the first one. Risk for second children born at interpregnancy intervals of between 12 and 36 months were middling, but risk rose abruptly between 12-18 and "0"-12 months.
Unfortunately, the researchers spent so much time in the paper reviewing the statistics and making sure every last variable was accounted for that the discussion as to why was about one paragraph. They thought it might be folate depletion, omega 3 depletion, or stress (it is, obviously, very stressful to have a young baby and to be pregnant at the same time.) In a number of posts on autism I have speculated as to some nutritional and genetic causes:
Diet and Autism1
Diet and Autism 2
Autism and Vitamin D
Autism 4 - Inflammation Speculation
Brain Efficiency, Pediatric Edition
Since, during pregnancy, a baby will tend to suck whatever nutrients are needed straight from mama, whether she can spare them or not, it would make sense that a nutritional explanation could account for the increased risk of autism in second children when the pregnancies are closely spaced.
Here is a free, online, up to date, and comprehensive review of pregnancy, nutrition, and birth outcomes - if you are interested.
My ultimate preventative solution is, of course, to make sure that moms-to-be out there are consuming nutrient rich diets with plenty of folate, phospholipids, minerals, omega 3s, etc. etc. etc.
Also, it is snowing. A lot.
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| Mailbox and Snow Bank |
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| Grill |
Tuesday, January 11, 2011
Snowpocalypse II Beef Stew
We're supposed to get another 14-21 inches of snow starting after midnight tonight, and despite several unseasonably warm days, we still have 8-10 inches of snow on the ground from the Christmas storm plus some additional snow last week. Needless to say clinic will be closed, and I'm cooking up some stew for a warm and cozy snowed-in day tomorrow. With that amount of snow, the plows can push up banks 4-6 feet high at the end of the driveway - they probably won't melt completely until late April or May! Well, here's the recipe of the evening (as usual, thrown together):
*Carton of beef broth
*Glug glugX 30 or so of red wine
*A pound of grassfed stew meat (usually I would brown this but I was feeling "slow and gentle cooking methods" today, or perhaps "lazy.")
* one onion (chopped)
* three small potatoes, peeled and chopped
* 2 carrots, chopped
* 1/4 cup cooked rice (to thicken - leftover excess from fried rice in the fridge)
* 4 marrow bones, roasted at 350 in the oven on a cookie sheet for half an hour, then put with tongs into the stew
* 2-3 stalks of celery, chopped
* a bit of baby spinach, chopped
* Celtic Sea Salt®, Light Grey, By The Grain & Salt Society, Coarse Ground, 1 lb
, pepper, kelp flakes (that's just the amazon link - of course I don't use a pound of salt!)
Boil on high for a bit, then set to low and boil for a long time. Toward the end I will add some chunks of pasture butter and maybe even some olive oil. Remove the bones before you eat! I usually use 2 bones, but I found a source of grassfed marrow bones not 2 miles from the house, so now I don't have to wait for my (infrequent) 50 pound orders of grassfed beef + marrow bones from my home state. This will feed four of us several times for a couple of days, so I don't sweat the rice and potatoes.
Here's a picture from a previous winter - maybe I will have some new ones tomorrow!
*Carton of beef broth
*Glug glugX 30 or so of red wine
*A pound of grassfed stew meat (usually I would brown this but I was feeling "slow and gentle cooking methods" today, or perhaps "lazy.")
* one onion (chopped)
* three small potatoes, peeled and chopped
* 2 carrots, chopped
* 1/4 cup cooked rice (to thicken - leftover excess from fried rice in the fridge)
* 4 marrow bones, roasted at 350 in the oven on a cookie sheet for half an hour, then put with tongs into the stew
* 2-3 stalks of celery, chopped
* a bit of baby spinach, chopped
* Celtic Sea Salt®, Light Grey, By The Grain & Salt Society, Coarse Ground, 1 lb
, pepper, kelp flakes (that's just the amazon link - of course I don't use a pound of salt!)Boil on high for a bit, then set to low and boil for a long time. Toward the end I will add some chunks of pasture butter and maybe even some olive oil. Remove the bones before you eat! I usually use 2 bones, but I found a source of grassfed marrow bones not 2 miles from the house, so now I don't have to wait for my (infrequent) 50 pound orders of grassfed beef + marrow bones from my home state. This will feed four of us several times for a couple of days, so I don't sweat the rice and potatoes.
Here's a picture from a previous winter - maybe I will have some new ones tomorrow!
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