To prevent lost time: on using the most effective medication first, not last

Joseph Goldberg has written an important article for clinicians who treat patients with mood disorders. Goldberg JF. Should we reserve big gun antimanic drugs for only big gun manias? Bipolar Disord. 2018; 20:7–8.

He suggests, writing primarily about olanzapine, that following the guidelines (use the big gun drugs last, because of their side effects) can harm patients, while using the big guns first can rapidly improve them, even for patients with “mild or moderate symptom severity on a baseline mania rating scale”.

In my outpatient practice, using it primarily for patients with treatment-resistant or “mixed features” depression (most of whom failed to respond to several previous antidepressant trials of adequate dose and duration), it is amazing how fast it works, often within 3 days. (Antidepressants usually take 2-3 weeks to begin to work, and 4-6 weeks to have their full effect).

The big side effect with olanzapine is weight gain. But this is slow to develop, taking weeks to months. And there are ways to combat it, such as using low carbohydrate diets, and metformin.

As an “atypical” or “second generation” antipsychotic, or “serotonin dopamine antagonist”, olanzapine has the usual list of antipsychotic side effects, including tardive dyskinesia: again, slow to develop.

In the meantime, the patient and physician get a quick answer to the question of ‘does this medication work?’

Here’s some key points Dr Goldberg makes in his paper:

1. He cites the paper by Samara et al, which used “individual participant-level data” to determine that “high baseline symptom severity strongly moderated treatment outcome” (i.e. the sickest patients did the best, a common finding in psychiatric drug trials, since most trials have placebo response rates around 30%; “High baseline severity typically lowers placebo responsivity.”). In a fascinating aside, he notes that using mildly ill patients helped delay recognition of lamotrigine’s efficacy, since it appeared ineffective due to the high placebo response rate.
2. But “side effect burden was unsparing of lower severity patients”. So, Samara et al and the treatment guidelines recommend use of olanzapine mainly in severe presentations of mania.
3. Goldberg notes that “the concept of examining participant-level data is more than just a data analytic nuance; as a practical strategy for transforming group-based findings into more tailored, individualized treatment, it is a quantum leap toward the goal of personalized medicine.” This is the holy grail of psychopharmacology: customizing the treatment to the patient, and the psychopharmacologist’s work with a patient resembles a Savile Row tailor creating a bespoke suit. Goldberg suggests that at present, participant level data is more helpful in this endeavor than pharmacogenomics. One can use “individual participant-level data to broker a more bespoke fit”
4. One can also use “pairwise post hoc comparisons—statistical power permitting—between clinical subgroups of interest. For example, post hoc analyses have demonstrated olanzapine’s comparable antimanic efficacy in men and women, psychotic and nonpsychotic patients, manic and mixed episode patients, rapid cyclers and non-rapid
cyclers, patients with early and later age at onset, and subjects with and without comorbid substance use disorders.” These comparisons usually suggest, however, what patient characteristics worsen response rather than telling us who will respond. What is striking here is olanzapine’s broad spectrum of efficacy.
5. Goldberg argues that we may be mistaking a mistake by withholding big gun drugs like olanzapine from all but the most severely ill patients. “Because some high-risk/
high-gain medications have fast onset and robust breadth of spectrum, even their short-term use at potentially low doses has been shown to reliably temporize an evolving subsyndromal deterioration” (I recently saw this in a treatment-resistant depression patient, who had a dramatic response after 2 days of 2.5 mg olanzapine, which has persisted for several weeks after he discontinued it.) “Brief initial pulsed dosing with a “big gun”/high-risk agent might thus forestall hospitalization or prevent work or other role functions being jeopardized.”
6. Finally, often the alternative to using one high-risk, high gain medication is to cobble together, over time, a multi-drug combination, which combines limited efficacy with additive side effects. “Given that about 20% of “real world” bipolar patients receive extensive polypharmacy regimens (at least four medications)…. consider the potential hazards that low-efficacy/low-risk agents may pose with respect to incomplete remissions, relapse risk, cumulative adverse effects and poorer adherence in complex multi-drug regimens, and prolonged morbidity with psychosocial sequelae—despite the presence of only mild or moderate symptom severity on a baseline mania rating scale.”

Goldberg is writing about olanzapine use for manic patients. But I think the same arguments hold for patients with treatment-resistant depressions (who often turn out to have mixed states, or some form of bipolar disorder).

His article gives the clinician the intellectual rationale for trying the most efficacious intervention first, in appropriately selected patients, rather than last. Time is important, and a rapid response diminishes the time a patient remains ill.

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ADHD, Accidents, and Premature Death

Occasionally insurance companies make doctors fill out forms for  medications  not on their formularies, and on the form will be  a statement that asks the doctor to check a box if a ‘standard review timeline’ of 72 hours might seriously ‘jeopardize the life or health of the enrollee’.

In the past, I paused to wonder if such a delay would really matter.

Then I read “Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study” by Soren Dalsgaard et al, in the Lancet in 2015.

This study (with no pharmaceutical industry funding) followed 1.92 million Danish individuals for 24.9 million person-years, and found a mortality risk ratio of 2.07 for individuals with ADHD. Accidents were the most common cause of death. The rates were far higher in those diagnosed after the age of 18 than in those diagnosed from   6 to 17. The mortality risk, surprisingly, was higher in girls and women than in boys and men.

This was the first study to show that ADHD doubled a patient’s risk of death. As Stephen Faraone put it in his accompanying editorial: “Although no single study can be definitive, this one comes close. The data come from the medical registers of Denmark, where diagnoses of ADHD are conservative. The sample was large—1·92 million people, of whom 32 061 had ADHD—and the follow-up was long, with little missing data. Most importantly, the authors adjusted for potential confounders.”

Why the increased accidents? One possibility is that people with ADHD have increased sensation seeking (SS). “SS refers to a personality trait marked by the proclivity to seek out experiences that are novel, varied, complex, and intense” (page 180). Another is that they have problems with “effortful control” processes that result in lapses of concentration or working memory.

A patient recently told me a story that brought the concept of ADHD-induced accidents  to life for me. He had started Adderall close to the age of 30, after his previous physician had advised him to take a low dose consistently. On the routine Adderall, he had  been able to finish his thesis, get married, and obtain a job, all in rapid succession. (He previously had used  Adderall intermittently to cram for exams.) When he tried to taper off Adderall, his list of incomplete chores grew, producing more anxiety and frustration.  He went back on it and has stayed on the same low dosage for the last 6 years.

At our first visit, about six years ago, he reported he had had surgeries on  both knees, his wrist, and his hand, due to accidents suffered doing vigorous outdoor sports such as  surfing, rockclimbing, and mountain biking.

I saw him again in early June, 2017. He continued to do well, and the Adderall continued to be helpful, at the same modest dosage: “If I don’t stay on it, work won’t happen”.

But, he reported, there had been a remarkable change in the frequency of his accidents and surgeries. “I had about one orthopedic surgery/year from my teens to my late twenties:  both knees, both elbows, multiple broken wrists, and multiple concussions, because of my risk-taking behavior. Now I’m less apt to carelessly throw myself off something”. His last major injury had occurred one year before he started Adderall,  when he broke his wrist.

He ascribes the difference to his ability to perceive risk.

“Wow,” I said. “That’s an amazing change. It’s really impressive. But please,” I begged, “please wear your helmet when you ride your bike.”



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How lithium helps prevent suicide: one patient’s experience

How lithium helps prevent suicide: a patient’s experience


Lithium is one of the most effective anti-suicide medications psychiatrists have to treat patients with mood disorders.


How it works is unknown. [i]


Recently, a patient of mine with recurrent major depression had increasingly intense suicidal ideation.  She was already taking lurasidone (Latuda), escitalopram (Lexapro) 10 mg/day, and trazodone 50 mg at bedtime, but they weren’t helping.  She reported she was “terrible…desperately depressed…I can’t get out of this dark place…I go to bed early to escape the day…It would be easier if I wasn’t here.” She told me she was thinking of overdosing several times a day.


I started her on lithium 300 mg/day and met with her two weeks later. She reported she had been feeling so unsafe she had asked a series of family members to stay with her.


One week after she started the lithium, she was at home with her sister, standing in her living room, next to her couch, watching golf on television, when “it felt like a switch flipped, and the suicidal thoughts left me. It felt like a weight had been lifted. I knew it immediately.”


“Before this, the suicidal thoughts had been constant: how can I do it (which pills can I take), when can I do it, where should I do it (should I got go a hotel, so no one has to find me in the house?). It was overwhelming and very scary.”


“I still have the depression, I’m still feeling sluggish and sad, but I don’t have the suicidal thoughts. Things don’t seem as catastrophic. Before, everything seems like a dead end, hopeless”.


In a post about the Research Domain Criteria (RDoC), Thomas Insel notes  “that symptoms alone rarely indicate the best choice of treatment” and that “mental disorders are biological disorders involving brain circuits”. [ii]


In this case, a symptom (increasing suicidal ideation) suggested a treatment (lithium) that appeared to cause my patient’s suicidal ideation (and hopelessness) to turn off like a switch turning off an electrical circuit.



[i] UpToDate lists the following under mechanisms of action: “Traditionally thought to alter cation transport across cell membranes in nerve and muscle cells, influence the reuptake of serotonin and/or norepinephrine, and inhibit second messenger systems involving the phosphatidylinositol cycle (Ward, 1994). May also provide neuroprotective effects by increasing glutamate clearance, inhibiting apoptotic glycogen synthase kinase activity, increasing the levels of antiapoptotic protein Bcl-2 and, enhancing the expression of neurotropic factors, including brain-derived neurotrophic factor.”


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Psychopharmacology Made Simple: What’s it like when an SSRI[i] works?

Psychopharmacology Made Simple: What’s it like when an SSRI[1] works?

What benefit can one expect from a medication? While it’s easy enough to find information online about side effects and diagnostic indications (approved uses), it’s much more difficult to learn how it feels, from the patient’s point of view, when a medication works well.

Numerically, there are drops in rating scales, like the GAD-7 or the PHQ-9. [2] But it’s more useful (and certainly more interesting) to hear a patient’s experience directly.

This patient had started on Lexapro (escitalopram) [3] three months earlier. Her primary

complaint was her irritability, which led her to make harsh, critical comments to coworkers that she always regretted.

She returned 3 months later for a follow-up visit and noted she felt much less stressed.

“Things don’t bother me nearly as much; it’s like water off a duck’s back”. [4]For example, “previously my husband would say things I found very irritating and I would debate with him to try to change his mind. Now, I realize we don’t have to feel the same way about everything. I’m much better about letting things go.” “It’s much easier to talk with people and care about how they feel, because I care less about how I’m feeling, because I feel less upset about things. It’s amazing. Everything seems so much easier.”

Annoying things are still annoying, but the annoyance doesn’t last as long, it’s easier to put it aside, and the pain caused is not as great.

Is a medication worth taking? No one knows before trying a new one. One weighs the benefits and the side effects, and decides.




[1] SSRIs are selective serotonin reuptake inhibitors.

[2] The GAD-7 and PHQ-9 are commonly used patient rated scales that give the clinician a rough sense of the level of  anxiety and depression the patient is dealing with.

[3] Lexapro is a one of the 6 SSRIs (selective serotonin reuptake inhibitors, the others being, in rough order

of their release, fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and

citalopram (Celexa)). It is approved for major depression and generalized anxiety disorder, and, like the

other members of its class, tends to work particularly well for anxiety, which often manifests in the form of

looping negative thoughts, and irritability.

[4] This is the most frequent simile patients use to describe their experience.

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Psychopharmacology Made Simple: What’s it like when Wellbutrin works?

Wellbutrin (bupropion) works quite differently from SSRIs such as Lexapro (escitalopram), the subject of a previous blog post.

How does it work? Per UpToDate[1], “like other antidepressants the mechanism of bupropion’s activity is not fully understood”. [2]


Clinically, it’s useful to think of it as a selective norepinephrine reuptake inhibitor, or SNRI. It helps depressed mood, low energy level, hypersomnia (sleeping too much), and anhedonia. [3] It’s quite different from the SSRIs, which help anxiety, rumination, and irritability.

Here is one patient’s experience with it. He reported chronic depression for many years that worsened in the last 12 months since he became clean and sober, and got even worse when he quit his lifelong smoking habit, which  increased his irritability. “I want to sleep all day. I have no passion to do anything I used to love doing. I’m not interested or excited by anything.” He had been attending AA meetings daily, then decreased for the last couple of months to 1 or 2 meetings/week. He had no sponsor. He hadn’t progressed beyond the third step because “I feel worn out when I think about picking up a book”.

He started Wellbutrin XL 150 mg/day for one week, and then increased to 300 mg/day, but after 3 days on the higher dosage, he called me to report he was “waking up at 4 AM, ready to go, with a lot of energy. I started to get racy, I felt like I couldn’t breathe, I had  little shocks, “air hiccups”, like I was out of breath. Last night I felt a lot of anxiety, panicky, my heart was heart racing.”


Dosing of Wellbutrin has to be individualized. Some people need 300 mg, some can’t tolerate it and do better on 150 mg. I told him to stop it for a day or two until his symptoms resolved, and then to restart on 150 mg/day.


I saw him one month after he reported the side effects.  “The Wellbutrin is doing good; I feel pretty normal, not elated. Before, I couldn’t get out of bed, I had very low energy, I wanted to sleep 18 hours/day, be horizontal, I felt worn out all the time”. Now, he reported he was going to more meetings, 2-3/day, and working his program.


For depression, one of the  most common conditions seen in outpatient practice, either the SSRIs or the SNRI bupropion are probably the most common first medications tried. [4]



[1] UpToDate is an evidence based, peer reviewed medical information resource.

[2] Wikipedia notes that it is characterized as a weak norepinephrine-dopamine reuptake inhibitor (NDRI). Bupropion is converted into several active metabolites that “are present in much higher concentrations in the body compared to bupropion itself. The most important example is the major metabolite of bupropion, hydroxybupropion, a selective norepinephrine reuptake inhibitor (and likely releasing agent) and nicotinic acetylcholine receptor (nAChR) antagonist … which, with oral bupropion treatment, can reach area under the curve (AUC) plasma concentrations that are as much as 16–20 times greater than those of bupropion itself.”

[3] Anhedonia, or the inability to experience pleasure, is one of the cardinal symptoms of depression. I ask, “Is there stuff you enjoyed doing before (exercising, being with friends, reading, watching movies) that you don’t do now?”

[4] Somewhat analogous to e4 and d4, probably the two most common  first moves in chess, and, like chess, there are infinite variations after these simple beginnings.

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What does hypomania look like?

Hypomanic states are rarely observed by the psychiatric clinician. Bipolar  patients are much more commonly depressed  (according to Judd et al, bipolar II patients spent only 1.3% of the time in hypomania over 13 years of follow-up).  accessed 1/14/17


The manifestations of hypomania are often quite subtle. By definition, in hypomania the patient is not psychotic, does not need hospitalization, and has no marked impairment in social or occupational functioning.


I am indebted to a patient, whom I have treated for 10 years, and who takes several mood-stabilizing medications, for providing a vivid example of hypomania, and the damage that can result.

Her hypomanic states are infrequent, once every 3 months. They occur 3 days before her period, and end when she gets her menses. First she has extra energy, then she stops sleeping for 1-2 days, then feels “light, happy, like I can do no wrong” for one day, and then crashes and goes back to normal.

She only recognizes her hypomania after the episode has ended. When her partner tries to point it out to her, she becomes irritable and can’t hear her. Earlier in her life, she went shopping when hypomanic.

Unfortunately, considerable damage can result from the impaired judgment typical of hypomanic states. In this case, the patient was involved in litigation. She decided to edit and “improve” a document which had already been submitted to opposing counsel “because I thought it didn’t look professional enough”, without  informing her attorney or asking his opinion. The unfortunate result was that her lawsuit, from which she was likely to get a substantial award, was thrown out, and she was fined a large sum for altering the document.

It is much easier for patients to recognize their depressions than their hypomanias. In hypomania, they feel good and often become irritable when others try to inform them something is not right. Perhaps the best approach is to learn what your hypomanic symptoms look like and to work out in advance what your significant others can say or do to get through to you.

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Trans-Atlantic differences on drinking in pregnancy, and the pleasures of literary fiction

The English have a somewhat more relaxed attitude towards drinking in pregnancy than we do in the States.

From the RCOG:

“It is recommended that you do not drink alcohol during the first three months of pregnancy. Drinking small amounts of alcohol after this time does not appear to be harmful for the unborn baby, but you should not:

• drink more than one or two units, and then not more than once or twice per week

• binge drink (which for a woman is when she has six units or more of alcohol on any one occasion).”

Vs the CDC:

“Every woman who is pregnant or trying to get pregnant – and her partner – want a healthy baby. But they may not be aware that drinking any alcohol at any stage of pregnancy can cause a range of disabilities for their child,” said Coleen Boyle, Ph.D., director of CDC’s National Center on Birth Defects and Developmental Disabilities. “It is critical for healthcare providers to assess a woman’s drinking habits during routine medical visits; advise her not to drink at all if she is pregnant, trying to get pregnant or sexually active and not using birth control; and recommend services if she needs help to stop drinking.”

Ian McEwan’s latest novel, Nutshell (“Oh God, I could be bounded in a nutshell and count myself a king of infinite space – were it not that I have bad dreams.” Shakespeare, Hamlet), is told from the point of view of a rather sophisticated fetus 2 weeks prior to a full-term birth, during an English summer, using the plot of Hamlet as a frame: his mother Trudy (Queen Gertrude in Hamlet), and his uncle, Claude (King Claudius in Hamlet) are scheming to murder his father (a poet, in the novel).

Here are 3 excerpts from the novel portraying the fetus’s view of drinking:

“I like to share a glass with my mother. You may never have experienced, or you will have forgotten, a good burgundy (her favorite) or a good Sancerre (also her favorite) decanted through a healthy placenta. Even before the wine arrives – tonight, a Jean-Max Roger Sancerre – at the sound of a drawn cork, I feel it on my face like the caress of a summer breeze. I know that alcohol will lower my intelligence. It lowers everyone’s intelligence. But oh, a joyous, blushful Pinot Noir, or a gooseberried Sauvignon, sets me turning and tumbling across my secret sea, reeling off the walls of my castle, the bouncy castle that is my home. Or it did so when I had more space. Now I take my pleasures sedately, and by the second glass my speculations bloom with that license whose name is poetry. My thoughts unspool in well-sprung pentameters, end-stopped and run-on lines in pleasing variation. But she never takes a third, and it wounds me.

“I have to think of baby,” I hear her say as she covers her glass with a priggish hand. That’s when I have it in mind to reach for my oily cord, as one might a velvet rope in a well-staffed country house, and pull sharply for service. What ho! Another round here for us friends!

But no, she restrains herself for love of me.”

Ian McEwen, Nutshell, pages 6-7, 2016, Nan A. Talese/Doubleday

“A few minutes ago the radio told us it was four o’clock. We’re sharing a glass, perhaps a bottle, of Marlborough Sauvignon Blanc. Not my first choice, and for the same grape and a less grassy taste, I would have gone for a Sancerre, preferably from Chauvignol. A degree of flinty mineral definition would have mitigated the blunt assault of direct sunlight and oven blast of heat reflected off the cracked façade of our house.

But we’re in New Zealand, it’s in us, and I’m happier than I’ve been in two days. Trudy cools our wine with plastic cubes of frozen ethanol.”

Nutshell, page 31.

And finally (and best of all):

“Trudy and I are getting drunk again and feeling better, while Claude, starting later and with greater body mass, has ground to cover. She and I share two glasses of the Sancerre, he drinks the rest, then returns to his plastic bag for a burgundy. The grey plastic bottle of glycol (which will later be used to poison his father) stands next to the empty, sentinel to our revels. Or memento mori. After a piercing white, a Pinot Noir is a mother’s soothing hand. Oh, to be alive while such a grape exists! A blossom, a bouquet of peace and reason. No one seems to want to read aloud the label so I’m forced to make a guess, and hazard an Echezeaux Grand Cru. Put Claude’s penis or, less stressful, a gun to my head to name the domaine, I would blurt out la Romanee-Conti, for the spicy cassis and black cherry alone. The hint of violets and fine tannins suggests that lazy, clement summer of 2005, untainted by heatwaves, though a teasing, next-room aroma of mocha, as well as more proximal black-skinned banana, summon Jean Grivot’s domaine in 2009. But I’ll never know. As the brooding ensemble of flavours, formed at civilisations’s summit, makes its way to me, through me, I find myself, in the midst of horror, in reflective mood.”

Nutshell, pages 51-52.

But, beyond illustrating trans-Atlantic cultural differences, I have one other reason for sharing these excerpts with you. A patient lamented yesterday that the pressures of her work for a famous tech company  left her longing for a break, which she wouldn’t have until an island vacation that was months away. And likewise we doctors need to have a  healthy way to relieve the pressures of our work. I  would argue that, for those who love and appreciate great writing, literary fiction can provide a break from the stress of work and daily life that is more readily available, more mentally refreshing, and more spiritually rejuvenating than even the banal pleasures of a resort holiday.

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How long to give an SSRI to work ?

An important review article and meta-analysis, Early Treatment Responses of Selective Serotonin Reuptake Inhibitors (SSRIs) and clomipramine in pediatric OCD was published in the Journal of the American Academy of Child and Adolescent Psychiatry (October, 2016, p 851-859).


The most important finding was that “more than 85% of the improvement observed on SSRI compared to placebo in pediatric OCD trials was observed by week 2”. The current guidelines state that an 8 to 12 week trial of SSRIs is necessary, for both children and adults, although adults have a similarly rapid response.


Also, in answer to patients’ common question, “which SSRI is the best?”, there was no “significant differences among individual SSRI agents” (fluoxetine, fluvoxamine, sertraline, paroxetine).


There was no effect of maximum SSRI dosing (previously, it has been posited that OCD response required higher dosages, than, say, depression, and previous adult meta-analyses showed greater therapeutic response with higher SSRI dosages).


Clomipramine, a tricyclic antidepressant, also showed a rapid response (75% of benefit by week 2), and was more effective than SSRIs, compared to placebo (there were no direct drug-drug comparisons). However, clomipramine is not viewed as the first choice, due to its higher side effect burden of “weight gain, anticholinergic side effects, and arrhythmias”.


The major clinical implication of this article is that if there is no or minimal response after 2 weeks of SSRI treatment  in pediatric OCD, one should start seriously thinking about changing medications. It also suggests that the follow-up visit should be 2 weeks after starting the new medication, and not 4.


Apparently this is the case not only in OCD, but in major depression, and in both children and adults.

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J shaped risk curves versus linear risk curves: drinking versus smoking

Too often, when I ask patients if they smoke cigarettes, I hear, “Oh, only 2 or 3 a day”, as if, not a problem, no big deal, like saying, “when I play Russian roulette, there’s only one bullet in the gun”.

There was a nice little article in JAMA recently explain why sometimes even a little bit matters.

If you plot relative risk of mortality on the y-axis, and number of cigarettes/day on the x-axis, you see a simple linear association. Each cigarette smoked increases mortality risk. So with  1-4 cigarettes/day, the relative risk is 1.5, 5-9 cigarettes 2.0, 20-24, 3.0.

In contrast, alcohol, measured in drinks/day, has a j shaped curve. “Consumption of up to 2 drinks/day in women and 4 drinks/day in men was associated with lower mortality than zero consumption, with about one-half drink per day associated with the lowest mortality risk.”

So, better not to smoke.

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Thinking about sleep: Maiken Nedergaard and the function of deep sleep

All animals sleep, even flies (research with the fruit fly Drosophila revealed the presence of clock genes).  All mammals have REM (rapid eye movement) and non-REM sleep. Human infants sleep 16 hours/day (if their parents are lucky); adults sleep 8 hours/day; elderly adults 5.5 hours/day. (S Lockley and R Foster: Sleep: A Very Short Introduction, Oxford University Press, 2012, pages 48-49).

Continuous sleep deprivation kills rodents and flies within days to weeks.

But why do we sleep? It would seem to be an evolutionary disadvantage. We are more vulnerable to predators when asleep. We could be working instead of sleeping. Korean secondary-school students attend hagwons (private cram academies) for five hours after school, then go home at 10 PM to study until past midnight (The Economist, September 19-25, 2015). If they didn’t have to sleep, they could study all night.

So sleep must perform some very important functions. But what?

Maiken Nedergaard, a neuroscientist at the University of Rochester (more specifically, an astroglial biologist), appears to have answered the non-REM portion of this question, in her paper “Sleep Drives Metabolic Clearance from the Adult Brain” (Science Vol 342, 10/18/2013, p. 373-377)

Other bodily organs rid themselves of waste protein products by using bulk flow of fluid between cells to wash them into the blood or lymphatic system, which carry them to the liver, where they are metabolized.

The brain uses 20% of the body’s energy supply. Yet it has no lymphatic system. How does it get rid of its waste products, such as beta-amyloid (Alzheimer’s), alpha-synuclein (Parkinson’s disease, Lewy body dementia), and tau (Alzheimer’s), to name a few, all of which are present in the interstitial fluid surrounding brain cells.

This question becomes more interesting when one considers that “essentially all neurodegenerative diseases are associated with misaccumulation of cellular waste products. Of these, misfolded or hyperphosphorylated proteins are among the most difficult for the brain to dispose of. For example tau and beta-amyloid can accumulate as stable aggregates that are neurotoxic in conditions such as Alzheimer’s disease.”

Nedergaard describes the glymphatic system, or, less politely, the “Garbage Truck of the Brain”.

Astrocytes express a water channel, the aquaporin 4 water channel (AQP4). Penetrating arteries which end in the brain are covered by astrocytic endfeet which express AQP4. This perivascular space around the arteries is a “highway for fast influx”, which can be observed with radiolabeled tracer.

In a three-step process, first cerebrospinal fluid (CSF) passes from the para-arterial space, through the aquaporin 4 (AQP4) water channels, into the interstitial space, where “vectorial convective fluxes drive waste products away from the arteries and toward the veins”, and CSF exchanges with interstitial fluid (ISF). Then the ISF and its waste products enter the paravenous space, eventually reaching lymphatic vessels in the neck, and later the systemic circulation, where the proteins travel to the liver, where they are metabolized. The brain has better things to do than chopping up the garbage.

The AQP4 water channels in the astroglial endfeet are crucial to this process (AQP4- knockout mice have a 65% reduction in beta amyloid clearance). In traumatic brain injury and stroke, AQP4 gets “mislocated to the cell body of astrocytes or to astrocytic processes that do not abut the vasculature”, and protein clearance “declines substantially”.

The interstitial concentration of beta amyloid is higher in awake rodents and humans than it is in sleeping ones. One possibility is that “wakefulness is associated with increased beta amyloid production”.

Nedergaard tested “the alternative hypothesis that beta amyloid clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance”.

Her group found that CSF influx into the brain was decreased by 95% in awake mice, compared to  sleeping mice or mice anaesthetized with ketamine/xylazine. (Ketamine has recently been discovered to be a very rapidly acting treatment for bipolar depression, but its antidepressant effect lasts only 1-2 weeks. One wonders if its short duration of action suggests that it clears the brain of garbage, which soon returns, leading to relapse.)

CSF influx into the brain  is “in part driven by arterial pulse waves that propel the movement of CSF inward along periarterial spaces”.

“Convective glymphatic fluxes of cerebrospinal fluid (CSF) and interstitial fluid propel the waste products of neuronal metabolism (proteins, peptides, lactate, ammonia, amyloid) into the paravenous space from which they are directed into lymphatic vessels and ultimately returned to the general circulation for clearance by the kidney and the liver.” This is analogous to garbage removal by “street sweeping” with liquid.

To manipulate the glymphatic system (the garbage highway from the glial endfeet lining the arteries, through the extracellular space, to the paravenous spaces, and the lymph channels), 4 methods were employed, all of which decreased efflux:

1.        AQP40 knockout mice: decreased fluid influx

2.        Cisternotomy: this opening eliminated the low-pressure system

3.        Acetazolamide: blocked CSF fluid production

4.        Sleep deprivation

After traumatic brain injury, increased protein markers are noted in plasma; but all 4 of the above interventions blocked the increase.

(Footnote: This glymphatic process calls to mind both the first sentence of James Joyce’s novel of sleep, Finnegans Wake:  “riverrun, past Eve and Adam’s, from swerve of shore to bend of bay, brings us by a commodius vicus of recirculation back to Howth Castle and Environs.”, and Steven Dedalus’s comment in Ulysses: “All Ireland is washed by the gulfstream.”)

Nedergaard points out that this process was first discovered by Patricia Grady in the early 1980’s, when she observed the movement of horseradish peroxidase into the brain. Attempts by others to replicate her work failed because the replicators used a “cranial window” cut into the skull, which destroyed the low pressure which drives the system. She left science and is now director of nursing at the NIH.

If pulse were the driving force behind the diurnal variation, one would expect to see greater influx during the day, when arterial blood pressure is higher than when asleep. Instead, one sees the opposite.

This system, Nedegaard reasoned, is like plumbing: all that matters is pressure and resistance. Pulse pressure is bigger when one is awake and alert. Yet influx is less. So therefore there must be less resistance while asleep.

“An alternative possibility is that the awake brain state is linked to a reduction in the volume of the interstitial space because a constricted interstitial space would increase resistance to convective fluid movement and suppress CSF influx”.

Nedegaard used techniques developed by Charles Nicholson to assess the volume and tortuosity of the interstitial space in awake, sleeping, and anaesthetized  mice, and found that the interstitial space volume fraction averaged 23.4% in sleeping mice, and 14.1% in awake mice. Both sleeping and anaesthetized mice had  higher levels of slow (delta) wave sleep. “Thus, the cortical interstitial volume fraction is 13  to 15% in the awake state as compared to 22 to 24% in sleeping or anaesthetized mice.” There was no change in tortuosity.

Interestingly, other studies have shown that the interstitial volume declines by 1/3 in aged mice compared to young mice. “The smaller space during wakefulness increases tissue resistance to interstitial fluid flux and inward movement of CSF.” The smaller space in aged animals (and humans) would make it harder to clear out the garbage/amyloid; neurodegenerative diseases are more common in the elderly.

Beta amyloid was cleared twice as fast in sleeping as in awake mice. Before the streets of the brain are swept, they are widened, not by removal of parked cars, as in Santa Monica, but by shrinkage of brain cells into their quiet, resting state.

Nedergaard next asked “what drives the brain state-dependent changes of the interstitial space volume?” Her observation that anesthesia increases glymphatic influx and efflux led her to hypothesize that it is not circadian rhythm but the sleep wake state itself.

Since noradrenergic neurons in the locus coeruleus drive cortical networks into the awake state, Nedergaard administered a cocktail of adrenergic antagonists (prazosin (α1 adrenergic receptor antagonist, which improves sleep in patients with PTSD), atipamezole (α2 adrenergic receptor antagonist), and propranolol (non-selective beta adrenergic receptor blocker) and found that they induced an increase in CSF tracer influx comparable to the sleep state, and increased the interstitial volume fraction from 14.3 to 22.6%.  The antagonists also increased the prevalence of slow, delta waves. “Norepinephrine is the master regulator of ISS volume”, she notes.

Nedergaard can be seen talking about “The Nightlife of the Brain” at the National Institute of Health (2/11/2015) at the NIH website (534 views ( or, more efficiently, on YouTube (the NIH website frequently freezes; 821 views)

She also spoke at Cold Spring Harbor Laboratory on the Glymphatic System on 12/12/2014. . (1043 views).

So, clearance of brain garbage occurs primarily during slow wave, or deep (N3, formerly called stage 3-4) sleep.

Now, sleep problems occur very early in the course of Alzheimer’s disease (AD), even during mild cognitive impairment, often an Alzheimer’s precursor, with less slow wave sleep (SWS). (Ju, Lucey, Holtzman: Sleep and Alzheimer disease pathology-a bidirectional relationship. Nature Reviews Neurology 10: February 2014, 115-119; ). Alzheimer’s pathology begins 10-15 years before cognitive symptoms appear, when soluble beta amyloid becomes insoluble and aggregates into amyloid plaques.  Amyloid accumulation disrupts sleep; disrupted sleep “increases the risk of beta amyloid accumulation in mice, as well as dementia due to Alzheimer’s disease in humans”.

While chronic sleep deprivation “accelerates beta amyloid deposition into insoluble amyloid plaques”, improving sleep “through treatment with an orexin inhibitor antagonist decreased beta amyloid plaque deposition” in mice. “One obvious approach is to investigate whether improving the quality of sleep in humans can either reduce the risk of AD or delay the progression of preclinical to symptomatic AD.”

In a more recent paper, Holtzman suggests that “considering the profound protective effect of almorexant on beta amyloid plaque burden in mice, the orexin system is a high priority target. The recent approval of suvorexant, the first Food and Drug Administration approved orexin receptor antagonist, provides an excellent opportunity to evaluate orexin-targeted therapeutics on Aβ dynamics and cognitive endpoints in early-stage or presymptomatic AD.”

So, in summary:

  1. The brain rids itself of garbage during deep sleep (n3, non-REM, slow wave), by expanding interstitial fluid volume (due to neuronal cell shrinkage?), and washing away detritus in a slow moving stream of extracellular fluid. Failure to remove amyloid leads to amyloid plaque deposition and cognitive impairment.
  2. Treatments that can enhance stage N3 sleep (deep, non-REM, slow wave), whether medication or behavioral ( ), might help clear garbage such as amyloid and prevent or delay the onset of neurodegenerative disease. Medication possibilities that increase slow wave sleep include gabapentin, trazodone, prazosin, and suvorexant. Interestingly, very low carbohydrate diets increased the percentage of deep, slow wave, stage 4 (n3) sleep, in young males.
  3. Things that decrease slow wave sleep (alcohol, medications, poor sleep habits, sleep apnea, benzodiazepines, opiates) would impair garbage clearance, and increase the risk of neurodegenerative disease.
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