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)  http://www.sciencemag.org/content/342/6156/373.long

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.”  http://www.sciencemag.org/content/340/6140/1529

Nedergaard describes the glymphatic system, or, less politely, the “Garbage Truck of the Brain”.  http://www.sciencemag.org/content/340/6140/1529

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 (http://videocast.nih.gov/summary.asp?Live=15718&bhcp=1 or, more efficiently, on YouTube (the NIH website frequently freezes; 821 views) https://www.youtube.com/watch?v=JmykxytFiGg

She also spoke at Cold Spring Harbor Laboratory on the Glymphatic System on 12/12/2014. https://www.youtube.com/watch?v=S-JXgPUmd3A . (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; http://www.nature.com/nrneurol/journal/v10/n2/full/nrneurol.2013.269.html ). 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.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351409/

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 (http://www.cbtforinsomnia.com/ ), 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. http://www.ncbi.nlm.nih.gov/pubmed/18681982
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.

A patient emailed me recently: he was going to a few countries in Europe. Could he take his medications with him? He was on a schedule II stimulant.

I think it’s a good idea, before visiting a new country, to check out a few websites:

The first is the US State Department’s Alerts and Warnings Page to see if anything really dangerous is happening where you’re going. http://travel.state.gov/content/passports/english/alertswarnings.html

Then, on the same page, check out the information for the individual country you’re going to: http://travel.state.gov/content/passports/english/country.html

Finally, check out the Center for Disease Control Website to see if there are any medical concerns where you’re going.

http://wwwnc.cdc.gov/travel/destinations/list

It turns out that taking a prescribed stimulant to Europe is legal (keep the medication in the original  prescription bottle).

But every country is different, and the laws in the United States are very different from those of other countries, in some surprising ways.

For example, taking a schedule II stimulant into Japan is illegal, with the exception of Concerta (the only schedule II stimulant allowed in Japan for the treatment of ADHD). Adderall, Vyvanse, dextroamphetamine, etc are illegal, even in the original bottle, with a copy of the prescription and a note from the prescribing physician. So are over the counter inhalers containing pseudoephedrine.

“However, it is illegal to bring into Japan some over-the-counter medicines commonly used in the United States, including inhalers and some allergy and sinus medications. Specifically, products that contain stimulants (medicines that contain pseudoephedrine, such as Actifed, Sudafed, and Vicks inhalers) or codeine are prohibited. You can generally bring up to one month’s supply of allowable prescription medicine into Japan. You must bring a copy of your doctor’s prescription as well as a letter stating the purpose of the drug. However, some U.S. prescription medications, such as Adderall, cannot be imported into Japan, even when accompanied by a customs declaration and a copy of the prescription.”  (my emphasis)

http://travel.state.gov/content/passports/english/country/japan.html  (under the heading: Local Laws and Special Circumstances, and sub-heading: Confiscation of Prescription Drugs and Other Medication

This is not a misprint. From another source:

Prescription Medications

“Heroin, cocaine, MDMA, opium, cannabis, stimulant drugs including some  prescription medications such as Adderall, and including some medications available over-the-counter in the U.S. are prohibited in Japan.  There are no exceptions in bringing these prohibited medications into Japan, even if the medication is legally obtained outside of Japan.  The import of stimulant drugs such as methamphetamines and amphetamines in particular are strictly prohibited, even when accompanied by a customs declaration and a copy of the prescription. Japanese customs officials or police can detain travelers importing prohibited items. Japanese customs officials do not make on-the-spot “humanitarian” exceptions for medicines that are prohibited in Japan.”

http://japan.usembassy.gov/e/acs/tacs-medimport.html

And another:

“When bringing prescription medications to Japan you may have items inspected and cleared upon arrival by the Customs Agency, and avoid further processing if the following conditions apply:…

Items are not prohibited drugs in Japan such as stimulants (i.e. Adderall)

There are no exceptions in the case of (stimulants), even if the medication is legally obtained outside of Japan. The import of stimulants such as methamphetamines or amphetamines, as well as precursors such as ephedrine or pseudoephedrine exceeding a certain concentration level, is prohibited by the Stimulants Control Law.

http://www.seattle.us.emb-japan.go.jp/about/import_restrictions.html

Even more curiously, if one had the illusion that the world is rational, while one cannot bring legally prescribed Adderall or Vyvanse into Japan, one can bring in the following with no problem

“If you intend to import / export the psychotropics equal to or less than theamount indicated in the Table (excluding injection form), you don’t need a certificate written by your doctor nor the permission by authorities under the “Narcotics and Psychotropics Control Law”.

http://www.nco.go.jp/dl_data/keitai/keitai_guideh26.pdf

1. Secobarbital, up to 6 grams (a barbiturate, rarely used now due to narrow therapeutic index (too easy to overdose on)

2. Mecloqualone, up to 9 grams: per Wikipedia, “Mecloqualone is faster-acting but shorter-lasting than methaqualone and so was used only as a sleeping pill, in contrast to methaqualone, which was used as a general-purpose anxiolytic as well. Mecloqualone was never as widely used as methaqualone and is no longer prescribed because of concerns about its potential for abuse and overdose. In the United States it is a Schedule I non-narcotic (depressant) controlled substance with an ACSCN of 2572 and zero annual aggregate manufacturing quota. It is most often seen these days as a component in purported Quāāludes (resulting from incomplete synthesis of methaqualone) from underground labs.”

3. glutethimide, up to 15 grams: glutethimide is Doriden. Per Wikipedia, “Glutethimide is a hypnotic sedative that was introduced by Ciba in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms… Current production levels in the United States (the annual quota for manufacturing imposed by the DEA has been three grams, enough for six Doriden tablets, for a number of years) point to it only being used in small scale research.

So you’re allowed to bring 15 mg of this into Japan, with no problem: this is equivalent to 5 times the annual quota for the entire United States.

In overview, one is allowed to bring in a month of benzodiazepines (diazepam: 1200 mg (Valium), zolpidem (Ambien) 300 mg, and a variety of amphetamine like appetite suppressants (phendimetrazine 3.15 g, phentermine 1.125 g, benzfetamine 1.5 g)

Finally, meprobamate 18 grams: continuing our tour of pharmaceuticals popular in the Mad Men era, meprobamate (Miltown) was  “launched in 1955 and  rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining notoriety for its seemingly miraculous effects” (Wikipedia) in relieving anxiety. Like glutethimide, it soon became apparent that it was as dangerous as the barbiturates. “By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written” (Wikipedia). In 1965, the Medical Letter reported meprobamate was addictive; in 1970, it became a controlled substance; in 2012, the European Union withdrew its marketing authorization; in 2013, Canada did the same.

But I digress. Back to Japan and Adderall, with an example of what happens when one brings prescribed stimulants into Japan:

Carrie Russell was a 26 year old college graduate,  diagnosed with ADHD at the age of 7, whose mother, a physician, shipped her a 90 day supply of Adderall (prescribed by Carrie’s family practitioner), in a “care package”,  when she was in  South Korea. (Her mother removed her  Adderall from the prescription bottle and put them in a Tylenol bottle, because she was worried they might be stolen if properly labeled). Carrie mailed the box to Nagoya, Japan, where she planned to teach English. “At 11 p.m. on Feb. 20, according to Russell’s Portland-area family, five plain-clothed police officers in black suits burst into a Tokyo restaurant where the 26-year-old American was dining with friends. They took her into custody. She was taken 275 miles west to Nagoya, where she was incarcerated in a women’s detention center outside the city.” She was released after 18 days in custody after the Caroline Kennedy, the Ambassador to Japan, intervened.  She gave her Japanese prison experience a good review:

“Russell said that although her arrest was shocking, the detention center “was not anything terrifying,” Russell said. “The facility was clean. We had daily chores.”  Inmates were served bento meals, Russell said, each with rice as a staple and small portions of noodles, potatoes, vegetables and other food. She said she learned some more Japanese language, such as, “How to say, ‘open,’ how to say, ‘refill my water,’” and, ‘I’m finished with my meal.’”

http://www.oregonlive.com/pacific-northwest-news/index.ssf/2015/03/released_oregon_woman_says_in.html

Interestingly, amphetamine abuse in Japan is quite common: “According to police officials, 2.6 million Japanese had used between 15 and 18 tons of amphetamines in the late 1990′s. This is more than the use of all other illegal drugs combined. Officials state that amphetamines are their biggest challenge. The drugs are popular amongst truck drivers, gang members, partiers, housewives, salary men, people wanting to lose weight, and the rich of Japan. Amphetamines are 10 times the cost in Japan than the United States, but still remain the most favorable drug of choice.” http://www.thecabinchiangmai.com/archive/statistics_of_japan___s_rising_drug_use#.VZbl3vlVikp

Apparently, the illegal amphetamine trade is controlled by criminal organizations, such as the Yakuza, whose profits might suffer if these medications could be legally prescribed by physicians, as is the case  in the United States and the European Union. Thus economics helps us understand what appears irrational at first glance. Why would Japan allow in dangerous sedatives without restriction and forbid a medication commonly and safely  used for ADHD in other countries? Apparently because it would interfere with the profits of the criminal elements who control the amphetamine market. Another factor is that mental illness is stigmatized in Japan.

This surprising  article will probably  change the way clinicians view and assess adult ADHD and the way DSM-6 conceptualizes it.

DSM-5 considers ADHD a “neurodevelopmental disorder” (page 32) and states that “ADHD begins in childhood” (page 61). Diagnostic Criterion B requires that  “Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years.”

This study presents surprising, almost shocking, evidence to the contrary.

It’s a “prospective longitudinal study of a representative birth cohort”,  namely “all infants born between April 1972 and March 1973 in Dunedin, New Zealand (N=1,037, 52% male, 7% non-Caucasian). Assessments “were carried out at birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and, most recently, 38, when 95% of the 1,0007 study members still alive took part.”

Childhood ADHD was diagnosed in 61 children, for a cohort prevalence of 6%; adult ADHD was diagnosed at age 38 in 3%.

This is the mind-blowing part: “Unexpectedly, childhood and adult diagnoses comprised virtually non-overlapping sets of individuals. Follow-forward from childhood ADHD to adult ADHD revealed that only 3 (5%) of the cohort’s 61 childhood cases still met diagnostic criteria at age 38.”

The follow-forward result is not that surprising. Other follow-up  studies have shown that the great majority of childhood ADHD patients no longer meet the full ADHD diagnostic criteria in adult life, although they experience substantial life difficulties (few got a university degree, many struggled financially, suicide attempts, criminal convictions, etc).  A meta-analysis reported that “only 16% of childhood ADHD cases continue to meet diagnostic criteria into their 20s”.

It’s the “follow-back” that is surprising. Of the 31 cases of adult ADHD at age 38, only 3 had ADHD in childhood.

So those with  childhood ADHD (79% male, IQs 10 points below normal) did not continue to have adult ADHD, and those with adult ADHD (61% male, normal IQ) did not have childhood ADHD.

Amusingly, among “childhood ADHD cases, only 23% had parents who recalled that their child had core ADHD symptoms or was diagnosed with ADHD. Thus, 77% of documented childhood ADHD cases were forgotten 20 years later.” So, 77% false negatives.

So much for obtaining an accurate history of childhood ADHD from parental informants. In addition, 4% of the comparison subjects’ parents (35 in all) “recalled evidence their child had ADHD”. So, 4% false positives.

Why so high? Perhaps because none of the children received medication, “as prescribing medication for ADHD was rare in New Zealand in the 1970s and 1980s.”

Specific medication treatment was also rare for ADHD in adults: only 4 of the diagnosed adults (13%) had taken appropriate drugs (Ritalin, Dexedrine, Strattera).

The adult ADHD patients had elevated (48%)  rates of substance dependence on alcohol, cannabis and other drugs and persistent tobacco dependence (39%). 70% of them saw a mental health professional, and 48% were prescribed psychotropic medications, primarily for depression and anxiety.

What makes this study special is that it is “the first follow-back prospective study of the childhood origins of individuals diagnosed with DSM-5 adult ADHD”, and it revealed that “the adult syndrome did not represent a continuation from a child-onset neurodevelopmental disorder”.

This suggests that adult ADHD and childhood ADHD are two different disorders. Adult ADHD, in this study, appears not to have a childhood onset.

The authors make several interesting points:

1. “Ubiquitous comorbidity for adults with ADHD has been reported before, suggesting the hypothesis that ADHD symptoms in adults in their 30s might be the psychiatric equivalent of fever, a syndrome that accompanies many different illnesses and is diagnostically nonspecific but signals treatment need.” (my emphasis)
2. “A third intriguing possibility is that adult ADHD is a bona fide disorder that has unfortunately been mistaken for the neurodevelopmental disorder of ADHD because of surface similarities, and given the wrong name.”
3. “Ironically, by requiring childhood onset and neurodevelopmental origins, DSM-5 leaves these impaired adults out of the classification system.”
4. “If our finding of no childhood-onset neurodevelopmental abnormality for the majority of adult ADHD cases is confirmed by others, then the etiology for adults with an ADHD syndrome will need to be found.”
5. “We suspect that, like us, clinicians often ignore the childhood-onset criterion for adult patients needing treatment.” (my emphasis)

This paper has huge implications.

In order to analyze Davis’ fresh approach to the translation, I would like to compare her work in a famous passage from the novel …. The passage ends with a beautiful and often quoted simile in which Flaubert compares human speech to a cracked kettle. It marks a turning point in Emma Bovary’s first affair, when Rodolphe begins to grow tired of her and her overwrought expressions of love.

From Lydia Davis’ 2010 translation:

He had heard these things said to him so often that for him there was nothing original about them. Emma was like all other mistresses; and the charm of novelty, slipping off gradually like a piece of clothing, revealed in its nakedness the eternal monotony of passion, which always assumes the same forms and uses the same language. He could not perceive—this man of such broad experience—the differences in feeling that might underlie similarities of expression. Because licentious or venal lips had murmured the same words to him, he had little faith in their truthfulness; one had to discount, he thought, exaggerated speeches that concealed commonplace affections; as if the fullness of the soul did not sometimes overflow in the emptiest of metaphors, since none of us can ever express the exact measure of our needs, or our ideas, or our sorrows, and human speech is like a cracked kettle on which we beat out tunes for bears to dance to, when we long to inspire pity in the stars. (Flaubert, trans. Davis, 167)

http://readingintranslation.com/2013/07/21/lydia-davis-brings-her-concision-and-ironic-sensibilities-to-a-new-translation-of-madame-bovary/

• “I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the sea-shore, and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.”
  • Memoirs of the Life, Writings, and Discoveries of Sir Isaac Newton (1855) by Sir David Brewster (Volume II. Ch. 27). Compare: “As children gath’ring pebbles on the shore”, John Milton, Paradise Regained, Book iv. Line 330

The pricing of generic medications for uninsured patients is irrational and counter-intuitive.

Because of this, the uninsured patient can pay far too much for a generic drug.

One might expect that the price of a generic medication to be “low”, and to not vary much from pharmacy to pharmacy.

This is often not the case.

What inspired me to write this post is hearing from several different patients that they had paid exorbitant prices for their generic meds.

Consider lamotrigine, the generic name for Lamictal, which is increasingly admired for its ability to prevent depression in bipolar II patients.

A typical initial prescription for lamotrigine would be for 60 25 mg pills.

Without insurance, the estimated cash price would be (from the Goodrx website, accessed 5/16/15: https://www.goodrx.com/lamotrigine/price#/?distance=6&filter-location=&coords=&label=lamotrigine&form=tablet&strength=25mg&quantity=60.0&qty-custom=&language=&store-chain=

Walgreens       $149

CVS                $134

Rite Aid          $127.

This is far too much to pay. How to pay less:

Method 1:

1.         Go to the Goodrx website  http://www.goodrx.com/ (It is unnecessary to sign in or register)

2.         Enter the name of the drug you’re interested in.

3.         At the lamotrigine page, enter your zip code (so you can see the pharmacies closest to you), the dosage of lamotrigine you’re interested in, and the number of pills you’d like to buy

4.         In the example above, I’d enter 90403 (my office zipcode), lamotrigine 25 mg, quantity 60.

5.         The cheapest price ($13.98) is from “membership warehouse, name cannot be shown” (presumably Costco).

6.         There is no need to battle traffic in the Costco parking lot, however, because of these prices (which require printing the free coupon from the Goodrx website):

Ralph’s            $13.98

Pharmaca         $14.08

Walgreen’s      $14.38 (a 90% savings over the cash price)

Von’s              $14.63

But note, even with the coupon

CVS                $79.39

Rite Aid          $107.33

7.         If you prefer your small, neighborhood, independently owned pharmacy (as I do), Goodrx will allow you to print out a coupon which you can take to your pharmacy. For the lamotrigine example, the cost is

independent pharmacy: $13.20

Example 2: sertraline 50 mg # 30 (generic for Zoloft, a commonly prescribed selective serotonin reuptake inhibitor, useful for anxiety and irritability)

Cash price:                              GoodRx coupon price

Ralph’s            $42                  $7.02

Vons                $24                  $8.45

Rite Aid          $55                  $9.99

Walgreens       $36                  $10.58

CVS                $31                  $24.93

Independent pharmacy           $9.89

Example 3: in the above examples, the supermarket pharmacies (Von’s, Ralph’s) are often  less expensive than the retail pharmacies (Walgreen’s, Rite Aid, CVS).

But this is only the case for non-controlled substances. For certain controlled substances, the retail pharmacies are less expensive

Adderall XR 20 mg # 30, in its generic form:

Cash price:                              GoodRx coupon price

Rite Aid          $200                $81.08

CVS                $175                $102.12

Walgreen’s                              $75.62

Von’s                                      $132.75

Ralph’s                                    $133

Independent pharmacy           $133-133.50

Method 2:

Go to the Costco website http://www.costco.com/Pharmacy/home-deliveryb?storeId=10301&catalogId=10701&langId=-1  (You do not have to be a Costco member to use the pharmacy, due to a California state law).

Enter lamotrigine.

Notice that this website is less informative, because you cannot customize the results.

A second weakness of the Costco site is that it will not give pricing information on controlled substances, such as stimulants (commonly prescribed for ADHD) or benzodiazepines (sometimes prescribed, cautiously, for anxiety).

In our case, looking for 25 mg lamotrigine, we find only the orally disintegrating tab, not the tablet, in amounts of 30 ($10.27), 50 ($13.10), and 100 ($18.26). The price is roughly comparable to the Goodrx coupon price at Ralph’s, Pharmaca, Walgreen’s, and Von’s.

Lithium induced subclinical hypothyroidism

Definition: elevated TSH (thyroid stimulating hormone) in a lithium treated patient, with normal T4 and T3

Prevalence: 6-52% in 11 reports (UptoDate Lithium and the Thyroid, accessed 3.8.2015), average 20-30%

Odds ratio for hypothyroidism on lithium: 5.78

TSH should be tested for every 6-12 months

When does it occur? “usually within the first 6-18 months of treatment” (Managing the Side Effects of Psychotropic Medications, Joseph Goldberg, MD, Carrie Ernst, MD, APP, 2012, page 185)

May be more common in patients with circulating thyroid antibodies (ie, underlying chronic autoimmune thyroiditis; measure antiperoxidase and antithyroglobulin
More common in women

When should supplemental thyroid hormone be added?
Opinions differ
1. One option is to monitor TSH more often (every 3 months) but not treat unless TSH levels “exceed 10 mU/L or clinical manifestations emerge”
2. Typical manifestations are “fatigue, anergia, weight gain, poor concentration, depression, cold intolerance, and brittle hair.” (Clinician’s Guide to Bipolar Disorder, David Miklowitz, PhD and Michael Gitlin, MD, Guilford Press, 2014, p. 123)
3. Another option: add thyroid hormone whenever TSH is high (eg, 4-10), especially if there are mood symptoms, or complaints of lethargy and fatigue

How to add:
1. Start with T4 (eg Synthroid, levothyroxine) 0.025 mg/day .
2. Recheck TSH in 6 weeks.
3. If still low, continue to increase by 25 micrograms every 6 weeks, rechecking TSH, until levels have normalized.

Lithium, hypercalcemia (increased serum calcium), and hyperparathyroidism
or
What to do when you’re stable on lithium and your calcium level is high?

Lithium therapy increases the prevalence of hypercalcemia and hyperparathyroidism (http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2013.13081057):
1. 10% absolute risk in 730 lithium-treated patients compared with 730 unexposed
2. Recent case-control study of 112 patients with bipolar disorder found 8.6% prevalence hyperparathyroidism and 24.1% hypercalcemia
3. General population rate: from 0.1-0.7%

Mechanisms:
1. Lithium stimulates calcium reabsorption form renal tubules and bowel
2. Lithium stimulates parathyroid hormone release
3. lithium may affect the set point at which the parathyroid gland slows parathyroid hormone release in response to increasing serum calcium levels
4. Increase in parathyroid gland mass correlates with the duration of lithium therapy, and may lead to “lithium-induced ‘primary’ hyperparathyroidism”, which becomes independent of lithium.

How does parathyroid hormone work? :
1. It regulates the concentration of serum ionized calcium
2. It stimulates the kidneys to reabsorb calcium.
3. It stimulates the gut to reabsorb calcium
4. parathyroid hormone secretion is regulated by a very sensitive calcium sensing receptor on the parathyroid cell surface.
5. Increasing serum ionized calcium inhibits parathyroid hormone secretion.

Classic hypercalcemia/primary hyperparathyroidism presents with “stones, bones, thrones, abdominal groans and psychiatric moans”
1. stones represents kidney stones, diabetes insipidus (polyuria and polydipsia)
2. bones represents bone problems: bone pain, pathological fractures, osteoporosis.
3. abdominal groans represents nausea, vomiting, constipation, peptic ulcers, acute pancreatitis
4. Thrones refers to constipation and polyuria
5. psychiatric moans refers to lethargy, fatigue, and depression

Good news is that “up to 80% of cases (of hypercalcemia and primary hyperparathyroidism have no symptomatic manifestations” (Am J Psychiatry 172: 1, January 2015 p. 13) and go by the name of “asymptomatic primary hyperparathyroidism”.

Female/male prevalence is 2.5/1
Three times more common in patients over age 80 vs patients 20-29

Lithium-associated hypercalcemia/ hyperparathyroidism is different from primary hyperparathyroidism:
1. serum calcium levels are less elevated
2. phosphate levels are normal rather than low.
3. magnesium levels are increased, rather than normal .
4. calcium in the urine is decreased rather than increased (hypocalciuria), so there are lower rates of kidney stones
5. parathyroid hormone levels are lower
6. lithium protects bone
The evidence to date (albeit uncontrolled) suggests that lithium induced calcium elevations cause less risk of damage to the kidney and the bones. However, there are “numerous case reports” of “classical symptomatic hypercalcemic states in lithium treated patients” (AJP page 14)

What are the options?
1. Surgical referral (the standard of care for primary hyperparathyroidism is parathyroidectomy)
2. discontinue lithium (the condition is often reversible)
3. continue lithium and monitor it (“Monitored lithium continuation in asymptomatic cases may be a prudent option for many patients, modeled on commonly practiced asymptomatic primary hyperparathyroidism surveillance. ..Monitored surveillance should proceed cautiously and with an appreciation for nuance. Subtle signs of hypercalcemia/ hyperparathyroidism may mimic underlying psychiatric disorders, with disturbances in mood, energy, and cognition in patients who are otherwise classified as asymptomatic.” )
4. calcimimetic therapy (Cinacalcet, FDA approved has “reversed lithium-associated hypercalcemia/ hyperparathyroidism in…five cases to date”
“In consultation with an endocrinologist, cinacalcet represents an important additional treatment option in symptomatic patients for whom lithium discontinuation poses substantial psychiatric risks, for whom surgical intervention has failed, or for whom surgery is contraindicated.”)
5. cinacalcet problems: high rates of gastrointestinal side effects, high cost
6. Get baseline calcium testing in all patients and follow-up testing at 6 months and annually thereafter

This superb summary of ADHD is likely to be of interest to several different types of reader. First, the physician who wants a brief (the entire book, including index, is 125 pages) overview; second, the therapist whose patients have ADHD and wants to learn more about it; third, the parent who wonders if their child has ADHD, and whether they should treat it, and how; fourth, the curious layperson.

Dr. McGough, a professor of psychiatry at UCLA, and one of the top researchers in the ADHD field, is a forceful lecturer, and his book is also pithy and powerful. Every sentence counts; there is not a wasted word. The person who likes to highlight the text will often be confronted with entire pages of yellow.

His book, the first in a new series, the “Oxford American Psychiatric Library”, by Oxford University Press (other volumes are bipolar disorder by Stephen Strawkowski, MD and Schizophrenia, by Stephen Marder, MD) captures the state of the art of ADHD knowledge and treatment in 2014.

Let’s take a brief tour through this book.

In the Introduction, Dr. McGough notes that ADHD “is a frequently occurring, brain-based, neurodevelopmental disorder with substantial negative consequences for individual and public health. Once viewed as a childhood condition, , it is now recognized that a majority of cases persist throughout adolescence and adulthood.”

“The high community prevalence of ADHD suggests that there are affected patients in virtually every clinical practice in every medical specialty. Nevertheless, comprehensive education about ADHD is largely limited to specialized programs in child and adolescent psychiatry and behavioral pediatrics.”

“MIsinformation about ADHD abounds. Some assert that ADHD is not real….that childhood inattention and hyperactivity are normal, the diagnosis is subjective….older student fake symptoms to obtain academic advantages….adults are similarly drug seeking….or that the condition represents a conspiracy by pharmaceutical companies and organized psychiatry to increase medication sales.”

“ADHD…is among the most scientifically validated psychiatric disorders”, with diagnostic reliability “on par with many conditions in general medicine”,and well demonstrated biological underpinnings….”the accumulated evidence base for its clinical management is of the strongest in mental health. Medications for ADHD have been used for over 70 years in millions of patients annually, creating an indisputable record of real-world safety and positive benefit….Treatment effect sizes are double those typically seen with more widely prescribed medications for depression and schizophrenia.”

Chapter 2, Historical Perspectives, reviews the history of ADHD (first mentioned in an 18th century medical text) and follows it through the various iterations of the DSM, including the DSM-5.

Chapter 3, Epidemiology and Burden, notes how common the condition is, with an estimated 5.3% worldwide mean. Male/female ratios, 9/1 in school age clinic samples, are 1/1 in adult clinic samples. This implies that boys are treated as children because they are more likely to disrupt the classroom, while quietly inattentive girls are ignored. The late Dennis Cantwell, MD, one of my best teachers, used to describe boys as having “garlic symptoms” (which bother the environment), while girls have “onion symptoms”, and suffer internally.

Chapter 3 also notes the extensive co-morbidity of ADHD, Mood disorders and anxiety disorders are quite common, and often the underlying ADHD is missed. Chapter 4 reviews etiology and neurobiology. Chapter 5 reviews diagnostic criteria, especially the different forms the criteria take in children and adults.

Chapter 6 reviews the various aspects of a thorough assessment. “ADHD is a clinical syndrome….ADHD is not diagnosed on the basis of any distinct neuropsychological profile. There is no scientific justification for claiming to diagnose ADHD on the basis of other laboratory studies, computerized tests of attention, electroencephalography (EEG), or other brain imaging methods.” A careful reading of this chapter could save a parent thousands of dollars, and spare a child needless radiation exposure.

Chapter 7 and 8 review Treatment Planning in Children and Adolescents, and in Adults.

Chapter 9 reviews basic pharmacology.Here are a few of the pearls strewn though its pages. “It is commonly stated that 70% of patients respond favorably to stimulants. In fact, approximately 70% respond favorably to the first stimulant prescribed, whether a methylphenidate or amphetamine. Of those who fail, an additional 70% respond favorably to the alternative class. As such, more that 90% of patient have satisfactory clinical improvement with stimulants, at least during acute treatment.”

Is my child/spouse/partner being overmedicated by their physician? Tables 9-2, 9-3, and 9-4 and the associated text show the reader how the meds are commonly used, ie what are the usual standards of care.

OK, so should I start my ADHD patients on amphetamine or methyphenidate? “Some patients respond preferentially to one or another stimulant class, but there is no method other than clinical trial and error to predict whether MPH or AMPH is the optimal choice.”

OK, so what is the difference between how methyphenidate and amphetamine work at the cellular level? “Both AMPH and MPH inhibit catecholamine reuptake into presynaptic neurons by blocking norepinephrine and dopamine transporters. AMPH further directly displaces norepinephrine and dopamine from presynaptic storage vesicles, and it inhibits monoamine oxidase and subsequent neurotransmitter breakdown.”

OK, so how do these drugs work at the level of brain circuits? This is fascinating, and a little complicated, and still being worked out, but here goes (pages 74-75): “Recent research suggests that ADHD treatment response is not a direct effect of increased catecholamine release, but that increased levels of norepinephrine and dopamine have indirect modulating effects on glutaminergic signaling in the the prefrontal cortex (PFC).”

PFC circuits regulate lots of stuff (attention, executive functioning, etc, etc). “One subset .. mediates active attention to “preferred” inputs or “signals”, while another subset mediates attention to “nonpreferred” inputs or noise.”

so “ADHD treatment can be viewed as a rebalancing of “signal” to “noise” ratios….Ideally, individuals should appropriately focus on important tasks (signal), while retaining some awareness of background activity (noise) and the ability to shift attention flexibly when required. Optimal balancing of signal to noise ratios in the PFC is dependent on a narrow range of catecholaminergic activity. If catecholamine levels are excessively elevated, perhaps from too high medication doses or stress, PFC networks collapse with concomitant deteriorations in cognitive or motor control. Dopamine increases that might be useful for tasks requiring highly focused attention could also cause problems with overfocus, cognitive rigidity, and a loss of personality and spontaneity.”

This is, in my opinion, a brilliant and succinct summary of a very complicated area, and it suggests what a delicate touch is required in adjusting a patient’s medication.

Chapter 10 is clinical medication management. Dr McGough has developed a method (which in my notes I label the McGough titration) to quickly (within 2 weeks) and efficiently (with one prescription) answer 2 questions: is this medication helpful or harmful to my patient, and what is the optimal dosage ? (pages 81-83, and table 10-1). When to use combination pharmacotherapy, and how to handle various common side effects are also discussed.

My psychiatrist wants to see me every month to give me refills. Is this really necessary? (see page 82)

Patients are often dealt more than one diagnostic card, and chapter 11 shows how to deal when a patient has comorbid diagnoses.

Chapter 12 reviews medication controversies Do ADHD meds stunt growth or cause sudden death? Should one get an EKG before starting a stimulant? What if the patient is using alcohol or marijuana? Do ADHD meds cause birth defects? Do patients fake symptoms to get stimulants? Do ADHD meds stop working?

Chapter 13, Complementary and Alternative Medicine Therapies, covers the evidence base, and the quality of the research, for restriction/elimination diets, dietary supplements, neuropsychological treatments, and mind-body therapies. Careful reading of this chapter could help parents avoid wasting a lot of money on treatments with scant evidence to support their efficacy. The treatments with the strongest evidence base are the addition of essential fatty acids, and the removal of artificial colors.

This is a book that the practicing psychiatrist will want to read from cover to cover, and then read again. It may be of even more benefit to the parent or the adult patient.

I’ve been impressed by James D. Watson, the co-discoverer of DNA, ever since I read his  account of the discovery of the structure of DNA,  The Double Helix  and used his Molecular Biology of the Gene to study biology as an undergraduate  (first published 1965; 7th edition, 2014). I like the quality of his writing and the clarity and simplicity  of his thought.

Dr Watson, now 86, gave an interesting and provocative lecture at UCLA in January, 2013 on  “Oxidants, anti-oxidants and the curing of cancer”

http://www.imedseminar.com/seminars/oxidants-antioxidants-and-the-curing-of/video

and published an article on the same subject  “Oxidants, antioxidants and the current incurability of metastatic cancers”  http://rsob.royalsocietypublishing.org/content/3/1/120144.

In his lecture and his article, he makes 3 assertions that are worth considering.

First, anti-inflammatory agents such as aspirin (low dose, eg 81 mg, used daily) “lead to much less cancer in those human beings who regularly take them”, probably because aspirin inhibits the “pushing by cytokines of otherwise quiescent mesenchymal cancer cells to grow and divide.” (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61720-0/fulltext )

Second, metformin is a relatively non-toxic, well-tested drug that preferentially kills mesenchymal stem cells. “This most widely used anti-diabetic drug’s heightened ability to kill late-stage mesenchymal cancer cells probably explains why those humans who use it regularly have reduced incidences of many cancers”. (http://www.pnas.org/content/110/3/972, and other papers by Kevin Struhl of Harvard, who discovered this “in a still much unappreciated article published three years ago in Cancer Research” in 2009).

Thirdly, free-radical-destroying antioxidative nutritional supplements may cause more cancers than they prevent. Humans kill cancer cells largely by  oxidizing them. Late stage cancer cells are hard to kill, in part, because they can make too many anti-oxidants. There have been numerous trials using anti-oxidants to prevent cancer which not only have failed to demonstrate benefit, but have led to an increased risk of cancer in those taking them. (http://www.ctu.dk/media/8831/Bjelakovic-Nikolova-and-Gluud-JAMA-2013.pdf ) “In light of the recent data strongly hinting that much of late-stage cancer’s untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.”

So, bottom line:

1. Daily aspirin, low dose, 81 mg
2. metformin works synergistically with cancer chemotherapy to kill the most dangerous cells
3. anti-oxidants in food, not as pills