Antipsychotics Might Cause Cognitive Impairment

Epistemic Statuspretty rough, a first pass

A friend of mine recounted a pretty terrifying description of his experience being on antipsychotics for years as a child:

Antipsychotics can make you dumber.  So can a lot of other medications.  But with antipsychotics it isn’t the normal sort of drug-induced dumbness – feeling tired, or distracted, or mentally sluggish, say.  It’s more qualitative than that.  It’s like your capacity for abstract thought is reduced.

And one of the consequences of this is that you may lose the ability to notice that you have lost anything.  You agree to give the new med a try, and you start taking it, and then when you see your prescriber again you don’t report any problems because you’ve lost the ability to form thoughtslike “my cognition has changed a lot recently, and the change coincided with the introduction of this new med.”

This can go on for years.  It did for me and for several people I know.

When I finally went off Risperdal – encouraged by my parents, I don’t remember really caring – it suddenly seemed obvious that I’d been cognitively altered for the past five years.  I didn’t remember the time before that very well (I had started Risperdal when I was about 10 years old), but there were objective indicators – for instance, I loved reading before Risperdal, and while on Risperdal I don’t think I read a single book cover-to-cover.

You’d think I would have noticed that I couldn’t read anymore.  Somehow I didn’t, for five years.  What did it feel like?  It’s hard to remember and also hard to describe.  Sort of a passivity.  The world acted upon me for mysterious reasons.  I did not draw correlations between present and past events, didn’t formulate ideas about the workings of things.  The present was simply given; I wasn’t frustrated when it refused to honor my theories.  “Reading is hard” was a datum, and was unpleasant, but I was not really surprised by it, or frustrated in the “this wasn’t supposed to happen!” way of abstract-reasoning-creatures.  It was a given datum and all I did was hope that given data would be pleasant and not unpleasant.

I think people should know that antipsychotics can do this.  They still may be worth trying, in certain situations.  But taking an antipsychotic is a special sort of decision, one that interferes with decision-making itself, like choosing to listen to the Sirens.

There are also cases of antipsychotics causing autistic catatonia, in which an autistic person, upon treatment with antipsychotics, suddenly loses speech and motor skills.  See examples: personal narrative,  case study, case study.

So, a natural question is: does this happen often? Do antipsychotics actually cause cognitive problems?

And here I’m referring to long-term cognitive problems. Many medications, including most atypical antipsychotics, are sedating; nobody thinks as clearly when they’re sleepy.  But when you stop taking a sedative, you generally become alert again. Do antipsychotics have any permanent effects?

Now, a major confounder is that schizophrenia causes cognitive impairment in itself, and antipsychotics seem to slightly relieve those problems.

Overall, atypical antipsychotics seem to help cognition in schizophrenia

One study of 533 patients having their first psychotic episode and randomized to either risperidone or haloperidol found that, on both drugs, there were slight but significant improvements in most cognitive tests after 3 months of treatment and patients did not significantly worsen on any tests.[1]

The CATIE trial, a randomized trial of 1460 schizophrenics given various antipsychotics, found significant (p < 0.001) improvement in a composite score consisting of speed, reasoning, working memory, verbal memory, and vigilance on all antipsychotic meds.[2]

There are dozens of studies like this. A meta-study found that various atypical antipsychotics were found to improve cognitive functioning in roughly half of studies, most of which were short-term (6 weeks).[3]

Typical Vs. Atypical Side Effects

“Typical” antipsychotics are older drugs, like haloperidol, whose primary effect is dopamine antagonism, while “atypical” antipsychotics are newer drugs, like risperidone, olanzapine, clozapine, and quetiapine, with a wider variety of targets including serotonin agonist, anticholinergic, and antihistamine effects.  The atypical drugs are often believed to be safer because they aren’t as likely to cause the motor disorders (extrapyramidal effects and tardive dyskinesia — that is, Parkinson’s-like stiffness and involuntary twitching movements) that the older drugs did, but the newer drugs often have other side effects (like sedation and large amounts of weight gain).

Clozapine is associated with an average of 14-25 pounds of weight gain over a period of several months of treatment; over 50% of patients become overweight when treated with clozapine.  A year of high-dose olanzapine causes an average of 26 pounds of weight gain.  Risperidone and quetiapine are associated with a weight gain of 4-5 pounds over the course of 5-6 weeks, and remaining stable over long-term use.[4] At the higher end of weight gain, this is no longer a cosmetic issue, but a serious diabetes risk.

Recently, it’s been observed that “atypical” antipsychotics can cause motor problems too, and their safety advantages have been overstated.

The CATIE study found that 8% of patients on olanzapine or risperidone had extrapyramidal symptoms. All agents, typical and atypical, had rates of tardive dyskinesias of 13-17% after a year of follow-up. Akasthisia rates for atypical antipsychotics are in the 10-20% range, compared to 20-52% with typical neuroleptics.[5]

While older studies found that atypical antipsychotics had lower rates of extrapyramidal effects than typical antipsychotics, these studies were comparing the new drugs to high-dose haloperidol, and the difference disappears when you compare to low-dose haloperidol or other typical antipsychotics (such as perphenazine, whose side effects are milder.)  The CATIE trial, which randomized schizophrenics to olanzapine, quetiapine, risperidone, perphenazine, or ziprasidone, found no differences in the incidence of extrapyramidal side effects. 12-month Parkinsonism rates were 37-44% for the four atypical antipsychotics and 37% for perphenazine. Akasthisia rates were 26-35% for the atypical antipsychotics and 35% for perphenazine.  Tardive dyskinesia was rarer, but also not different — 1.1%-4.5% for the atypical antipsychotics and 3.3% for perphenazine.[6]

In a meta-study, second-generation antipsychotics had significantly less use of antiparkinson medication than haloperidol (RR’s 0.17 for clozapine to 0.7 for risperidone), but not significantly less compared to low-potency typical antipsychotics (like perphenazine). Atypical antipsychotics caused significantly more weight gain than haloperidol, but not compared to low-potency typical antipsychotics.  Atypical antipsychotics caused the same amount of sedation as haloperidol and low-potency typical antipsychotics — except that clozapine causes more sedation than everything else.[7]

In other words, it’s definitely not true that the new drugs are safer than the old drugs across the board. Lower doses or better choices in the old drugs would have a comparable or strictly better side effect profile.

As a rough rule of thumb, the stronger the antihistamine effects, the more sedation and weight gain (that’s clozapine and olanzapine), and the stronger the dopamine-antagonist effects, the more movement disorders there are (that’s haloperidol and risperidone).

Evidence that Antipsychotics Impair Cognitive Abilities

While the majority of studies of antipsychotics find improvements or no change on cognitive tests, there are some exceptions, particularly on tests that have to do with spatial or procedural learning.

A study of 25 patients, after being on risperidone for 6 weeks, and throughout a 1-year follow-up period, found that risperidone worsened spatial working memory in first-episode schizophrenia. [8]

Procedural learning is impaired after months of treatment with haloperidol and risperidone — schizophrenic patients are slower to learn the Tower of Toronto task (though no difference is apparent after 6 weeks of treatment).  Olanzapine caused much less cognitive impairment (p < 0.001).[9]

A comparison of treatment-naive first-episode schizophrenics vs. schizophrenics treated with risperidone for six weeks found that the untreated patients were no worse at a procedural learning task than controls, while the treated patients were significantly worse.  This indicates that the medication, and not the schizophrenia, is responsible for the impairment.[10]

In a study of 35 schizophrenic and 45 control patients given a procedural learning task, the patients randomized to haloperidol performed worse than controls, while those randomized to risperidone or clozapine did not.[12]

In a study of 20 patients on haloperidol, 20 on risperidone, and 19 healthy controls tested on psychomotor tests related to driving ability, the medicated patients were significantly worse than controls on all tests, and haloperidol was worse than risperidone.[11]

Note that procedural learning — remembering how to complete a task, usually physical/motor, by practice — is associated with activity in the striatum and basal ganglia, the part of the brain that produces dopamine. This seems to fit with the fact that antipsychotics, in particular the most dopamine-inhibiting ones, particularly impair procedural learning.

Evidence that Tardive Dyskinesia Comes With Cognitive Impairment

Out of 28 studies identified in a meta-study, 22  reported patients with tardive dyskinesia to be more impaired along at least one cognitive measure.  The most common findings were an association with decreased orientation and memory (13 studies).  The finding persists even in studies that controlled for anticholinergic side effects.  Orofacial tardive dyskinesia seems to be especially associated with cognitive impairment (beta=0.23 of association with performance on the Trail Making Test, a measure of executive function and task switching).[13]

If cognitive dysfunction is a symptom of tardive dyskinesia, that supports the hypothesis that antipsychotic drugs cause cognitive dysfunction.

Animal Evidence that Antipsychotics Cause Cognitive Impairment

Animal studies give a usefully different perspective than human studies because you can ethically give antipsychotics to healthy animals. It may be that antipsychotics both remediate the cognitive problems caused by schizophrenia and cause additional cognitive problems of their own; with animals, you can see the latter in isolation.

Monkeys develop working memory deficits after 1-4 months of haloperidol administration (P = 0.0000004) and recover when given a D1 agonist.[15]

If you give a rhesus monkey haloperidol, it performs worse on a working-memory task (in which, if you can remember which window had a flashing light earlier, you get a treat when you stick your face in), and the higher the dose, the worse the accuracy.[16]

Haloperidol, olanzapine, risperidol, quetiapine, and clozapine all worsened marmosets’ performance at an object-retrieval task relative to baseline. Lurasidone, on the other hand, improved performance.[17]

Evidence that Antipsychotics Shrink Brains

A meta-study of longitudinal MRI effects of antipsychotics on brain volumes found that ventricular volumes increased 7.7-10.9% in treated patients, compared to 1.4% in controls; and that gray-matter or whole-brain volume decreased 1.2-2.9% per year in patients compared to 0.4 to 1% in controls.  [Note that ventricles are fluid-filled spaces in the skull cavity: growing ventricles means a shrinking brain.]

But is this just the result of schizophrenia itself causing brain damage? The evidence suggests not. Two studies of drug-naive patients showed a decrease in brain volume after onset of antipsychotics; two showed no effect.  Studies of chronically ill, untreated patients in India show no difference in brain volume vs. controls.  There’s no difference in volume in the brains of “high-risk” (pre-psychosis) patients compared to controls, including in the subgroup that went on to develop psychosis.  It may be that the reduction in brain volume that has usually been associated with schizophrenia is instead caused by antipsychotic use.[14]

Longer-term and higher-dose use of antipsychotics is associated with more gray matter and white-matter shrinkage, even after adjusting for illness severity, substance abuse, and follow-up duration.[18]

Long-term (17-27 month) exposure to antipsychotics (olanzapine and haloperidol) in macaque monkeys resulted in an 8-11% reduction in brain weight.[19]

The fact that antipsychotic-naive schizophrenics do not show a progressive decline in brain volume, and the fact that treating macaques with antipsychotics does cause a decline in brain volume, has led psychiatrist Joanna Moncrieff to argue that antipsychotics do not exert a “neuroprotective” effect on schizophrenia, and that schizophrenia is not a degenerative brain disease — instead, she believes that antipsychotics treat symptoms and also cause much of the brain damage we observe in schizophrenics.[20]

Personal Views

Before I went to the literature on this, I had a pretty negative view on antipsychotics, heavily colored by the personal stories I’ve heard of them working out very badly, and the rare cases of severe side effects like neuroleptic malignant syndrome.  My view was also colored by the fact that they’re often used on children and psychiatric inpatients as a coercive mechanism, against the will of the patients, and whether or not they have any medically beneficial effect. My sympathies are always going to be with the victims of coercion who have, in many cases, pleaded eloquently to just be let alone.

On the other hand, schizophrenia is really bad. And, from what I can tell, we can be quite confident that antipsychotics reduce the positive symptoms (delusions and hallucinations).  I can believe there are situations where the benefits outweigh the costs.

I think the evidence that antipsychotics, including atypical antipsychotics, can cause cognitive impairment is pretty compelling.

Do they cause net cognitive impairment in schizophrenics? I don’t know.  Maybe they reduce negative symptoms enough to balance out the cognitive impairment.

Do they cause irreversible cognitive impairment? I don’t know.  I don’t think we have human evidence of what happens to brains when people go off antipsychotics, or take a dopamine agonist.

Is taking antipsychotics worse, or better, than leaving psychosis untreated? Can you split the difference by taking lower dosages or getting off meds sooner? I have no idea how I would even begin to answer this question, and the answer probably depends a lot on individual values.

Here’s stuff that I do think is sensible to do (keep in mind, I am not a doctor or any kind of psych professional):

  • Think about the tradeoffs of antipsychotics before you have a psychotic break. 
    • In some states, including California, you can write up a psychiatric advance directive in which you can specify what to do in the event you lose your mind, including medications you are not to be given.
  • Look up psychiatric meds that you’re prescribed and see what they do.
    • Sometimes antipsychotics will be prescribed for things besides psychosis, like depression or Tourette’s. Sometimes they work for those things! But they have the same kinds of side effect risks that they always do, and doctors don’t always tell you that.  Abilify? Is an antipsychotic! It can cause extrapyramidal side effects! It’s surprisingly common for people not to get told things like this.
  • Don’t take a judgmental, one-size-fits-all attitude unless you have correspondingly incredible data.
    • “Always meds!” and “Never meds!” are terrible oversimplifications. We don’t know what’s going on yet, so in the meantime, all anyone can do is to try to make the best judgments they can under conditions of colossal uncertainty (and often great stress).

References

[1]Harvey, Philip D., et al. “Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial.” American Journal of Psychiatry 162.10 (2005): 1888-1895.

[2]Keefe, Richard SE, et al. “Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial.” Archives of general psychiatry 64.6 (2007): 633-647.

[3]Meltzer, Herbert Y., and Susan R. McGurk. “The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.” Schizophrenia bulletin 25.2 (1999): 233-256.

[4]Nasrallah, H. “A review of the effect of atypical antipsychotics on weight.” Psychoneuroendocrinology 28 (2003): 83-96.

[5]Shirzadi, Arshia A., and S. Nassir Ghaemi. “Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome.” Harvard Review of Psychiatry 14.3 (2006): 152-164.

[6]Miller, Del D., et al. “Extrapyramidal side-effects of antipsychotics in a randomised trial.” The British Journal of Psychiatry 193.4 (2008): 279-288

[7]Leucht, Stefan, et al. “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.” The Lancet 373.9657 (2009): 31-41.

[8]Reilly, James L., et al. “Adverse effects of risperidone on spatial working memory in first-episode schizophrenia.” Archives of General Psychiatry 63.11 (2006): 1189-1197.

[9]Purdon, Scot E., et al. “Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol.” Psychopharmacology 169.3-4 (2003): 390-397.

[10]Harris, Margret SH, et al. “Effects of risperidone on procedural learning in antipsychotic-naive first-episode schizophrenia.” Neuropsychopharmacology 34.2 (2009): 468-476.

[11]Soyka, Michael, et al. “Effects of haloperidol and risperidone on psychomotor performance relevant to driving ability in schizophrenic patients compared to healthy controls.” Journal of psychiatric research 39.1 (2005): 101-108.

[12]Scherer, Hélene, et al. “Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.” Cognitive and behavioral neurology 17.1 (2004): 32-40.

[13]Waddington, J. L., et al. “Cognitive dysfunction in schizophrenia: organic vulnerability factor or state marker for tardive dyskinesia?.” Brain and cognition 23.1 (1993): 56-70.

[14]Moncrieff, J., and J. Leo. “A systematic review of the effects of antipsychotic drugs on brain volume.” Psychological medicine 40.09 (2010): 1409-1422

[15]Castner, Stacy A., Graham V. Williams, and Patricia S. Goldman-Rakic. “Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation.” Science 287.5460 (2000): 2020-2022.

[16]Bartus, Raymond T. “Short-term memory in the rhesus monkey: Effects of dopamine blockade via acute haloperidol administration.” Pharmacology Biochemistry and Behavior 9.3 (1978): 353-357.

[17]Murai, Takeshi, et al. “Effects of lurasidone on executive function in common marmosets.” Behavioural brain research 246 (2013): 125-131.

[18]Ho, Beng-Choon, et al. “Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia.” Archives of general psychiatry 68.2 (2011): 128-137.

[19]Dorph-Petersen, Karl-Anton, et al. “The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.” Neuropsychopharmacology 30.9 (2005): 1649-1661.

[20]Moncrieff, Joanna. “Questioning the ‘neuroprotective’hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?.” (2011): 85-87.

Dwelling in Possibility

Epistemic Status: Intuitive, Casual

One of the things I’ve noticed in people who are farther along in business or management than I am, usually men with a “leaderly” mien, is a certain comfort with uncertainty or imperfection.

They can act relaxed even when their personal understanding of a situation is vague, when the future is uncertain, when the optimal outcome is unlikely.  This doesn’t mean they’re not motivated to get things done.  But they’re cool with a world in which a lot of things remain nebulous and unresolved at any given moment.

They’re able to produce low-detail, high-level, positive patter for a general audience.  They’re able to remain skeptical, expecting that most new ideas won’t work, without seeming sad about that.

Talking to someone like that, it feels like a smooth layer of butter has been spread over the world, where everything is pretty much normal and fine most of the time — not a crisis, not a victory, just normalcy.

This isn’t me.  If something I care about is unclear to me, it’ll bother me. Either consciously (in which case I’ll try to learn more until I understand) or unconsciously (in which it’ll be an unpleasant blank spot on my map, that’ll nag at me uncomfortably.)

It also bothers me, as a radical, when I don’t see a path to my long-term goals being possible.  “Business as usual” feels not okay to me, much of the time.  I don’t like having a “forget about it, it’s Chinatown” attitude.  I don’t want to be a naive idiot, but I don’t want to be complacent either.

 

Being okay with vagueness seems to be a prerequisite to managing other people — after all, you can’t know every detail of everyone else’s job.  When I managed people, I struggled with that a lot. I couldn’t be sure a thing was done right unless I checked it for myself.  I’m pretty good at holding large systems in my head, but eventually organizations defeat even the most heroic attempt to micromanage them.

Being okay with uncertainty also seems to be a prerequisite for managing a portfolio of anything high-risk and high-reward — investments, sales leads, technologies to adopt, etc.  If you are elated every time an opportunity appears, and dejected every time it doesn’t work out, you’ll have a very hard time emotionally when dealing with a large volume of such opportunities. (My husband is a salesman and he’s long since stopped telling me about leads because I’ll get over-excited about every one of them.)

This reminds me of some of the stuff leadership coach Bryan Franklin says about paradox.  I don’t know if I can represent his ideas accurately, since he comes from a very different paradigm than mine, but I think he’s alluding to “both/and” thinking, the ability to simultaneously hold, for instance, the frame “this business is bound for incredible success” and “this business will fail unless we solve this problem.”

Consider the common example of a leader who needs to convince her followers that, while the team is experiencing significant challenges and there is a very real risk of failure, ultimately the team will prevail. There are two ways a lesser leader could falter in this moment. The first is to simply pander to neg activism: agreeing with everyone’s feeling that the current situation is rough or hopeless, without offering any vision, possibility, or credible plan. This would be a good display of empathy, but it won’t lead anyone to change. The second mistake would be to hold the opposite view, that the future is bright and the current setbacks are illusory or insignificant. This could be seen superficially as inspiring, but more likely it will backfire because it will be dismissed as being noncredible and unrelatable to the lived reality of the employees.

A superior leader learns how to hold paradox: to believe, at the same time, that the situation is dire and hopeful, meeting employees where they’re at, but also convincing them of the actions they can take that will lead to a brighter future. The evidence is that things are bad (anyone denying this will be seen as a Pollyanna); and also, the evidence is that things are good (anyone denying this would be seen as a weak leader, lacking creativity to produce a positive way forward). Followers need to feel met in the reality that they are scared, yet they also need to be given a realistic expectation of future success.

When you’re confronted with a paradox, you are presented with a choice. You can either ignore it and take a side (believe one side of the statement is true while the other is false), or you can do what we call hold paradox, which is to believe both contradictory statements or implications simultaneously. It’s an expression of faith in a greater truth that is currently invisible to you, but resolves the paradox and allows for the truth of both sides to harmoniously coexist. This is what great leaders do.

Holding paradox is the ability to literally hold in your mind the truth and acknowledge, for example, your utter insignificance on a cosmic scale, and then without allowing that experience to dissipate, add to it the unmistakable truth of your profound significance to those you love.

Believing a literal paradox is believing something that is logically impossible, and so, obviously, I don’t want to do it.  But believing in lots of different possibilities at the same time, believing that a thing can be viewed from lots of different points of view — there might be some purchase in that.

The real world is parti-colored. It doesn’t have a single theme or mood or color scheme.  But to really know in your bones that lots of different things are possible is a deeply scary option to me. It feels like letting go of things that are important to me, like commitment or ambition or rigor or even personal identity. If I care about something, how can I allow myself to chill out about it? How can I allow myself to fully enter into the worldview of someone with the opposite belief?  Wouldn’t that be a betrayal? Wouldn’t that mean losing myself?

There’s a common thread between this notion, and people like Jonathan Haidt who believe in worldview diversity and people at the Integral Center who believe that higher human developmental stages involve the ability to move fluidly between frames, and who sometimes connect this to business through books like Tribal Leadership.

All of them share a view that the principled or systematic person — the person who believes in one truth according to one set of principles — is weaker or less spiritually advanced than the person who sees things through multiple points of view.

In particular, one idea I picked up from Tribal Leadership is that if you believe a particular thing as an individual, you’ll be a weaker leader, because you’re just saying what you personally believe (which is selfish, in a sense, or at least private, and thus taken less seriously by others).  The leader has to be not just John Smith but the voice of Acme Corp.  Expressing your own thoughts (speaking as John Smith) has value coming from an individual contributor, but there’s a different, more facilitator-like, skill where you try to encourage dialogue or distill a common thread between different people’s views, and encourage teamwork and unity — and that’s leadership.

What I worry about, in all these kinds of philosophies, is that if I gain this balance, this ability to stay cool in the face of uncertainty and ignorance, this ability to engage with multiple perspectives, then I’ll no longer be able to be an individual with a particular point of view and set of goals and detailed knowledge of my areas of expertise.

Is it possible to love something, or pursue something, without freaking out about it?  Doesn’t equanimity trade off against passion?  Wouldn’t a person who kept their cool all the time be boring?  Wouldn’t a person who tried to “diversify worldviews” be inherently an unprincipled pragmatist?  Doesn’t the chillness of leaders sometimes look uncomfortably like privilege or elitism?  Isn’t there a lot of potential for manipulativeness when people try to “facilitate” for others?

And yet, pretty much every book about business success counsels equanimity — to a very high standard, from what I can see.  Seriously, flip through something like Emotional Intelligence 2.0 the next time you’re in an airport bookstore. Apparently ordinary middle managers have to be unbelievably good at handling emotional stress just to scrape by.

I have definitely seen chillness coexist with strong technical skill; quite a few people with that relaxed, leaderly affect are also top-notch at engineering or data science.  Accepting that some information “lives” in the “collective mind” of a group clearly doesn’t preclude knowing some things very well in your own mind and being able to execute well individually.

I’ve even seen a certain kind of chillness coexist with radical commitment. Rick Doblin, the founder of MAPS, has been steadily working for forty years on trying to promote research into the therapeutic use of psychedelics.  He’s a pleasant, mild-mannered family man; despite his controversial mission, he seems to bear no ill will to anyone, including the regulators he’s been trying to persuade to ease up drug restrictions.  He’s willing to collaborate with anyone, from any perspective or background, if it’ll help psychedelic research.  He’s my role model for how someone can be profoundly committed to a cause without being an angry or rigid person.  His way is like water wearing down a stone.

But I definitely have heard people tell me that equanimity cost them something — that they lost the chance to have a personal perspective and to want things for themselves when they learned to see things from all possible angles and be a facilitator for others.  I’ve seen people who are very good at sparking “interesting” conversations complain that they have a hard time connecting personally rather than remaining a third-party observer.

I’ve had occasions myself when I deliberately “took myself out of the picture” in order to hold space for others — and it worked pretty well, and was fun in its own way, and people responded well to it, but I had a strong intuition that this wasn’t what I wanted to spend the majority of my life doing.  I have a self, and it’s not going to like being cooped up forever.

So I’m genuinely uncertain.  Maybe leadership is fundamentally incompatible with stuff I want to keep? Maybe I just have hangups about harmless stuff, or resistance against working on things I’m naturally not good at? I wonder what older and more accomplished people would think about this issue.

What’s Up With Minimum Wage?

Epistemic status: Super casual

Raising minimum wages is supposed to reduce employment, right? If you make something more expensive, people buy less of it.

So, if you ran a study, you’d think you’d actually see that.  If one state or city raises the minimum wage, employment should drop.

But the evidence actually seems pretty equivocal.

In 1994, the famous Card and Krueger study came out. New Jersey’s minimum wage rose; neighboring Pennsylvania’s didn’t. Yet, over a period of 8 months after the wage hike, full-time employment increased in New Jersey relative to Pennsylvania.  Instead, the fast-food employers passed on the extra costs to customers in the form of higher prices of meals.

This study is controversial and its results have been directly challenged, though even that challenge is itself controversial:

Because of concerns about the Card and Krueger data, the Employment Policies Institute examined payroll records for 71 fast-food restaurants and found significant discrepancies between the Card and Krueger data and payroll records for these firms. They found significantly different results when their revised data was used for estimation purposes. Critics of the EPI study argue that the selection process used to generate the Employment Policies Institute sample appears not to be random (all Pennsylvania observations are Burger King restaurants owned by a single franchise owner).

There are more recent studies finding that minimum wage increases do reduce employment, like a study of Seattle’s 2015 minimum-wage hike, which has found that (compared to economically-similar counties without the wage increase) Seattle saw low-wage employment drop slightly and wages rise slightly, for a net decrease in low-wage workers’ earnings.

The results seem to depend a lot on how the studies are conducted. The Economic Policy Institute observes that fixed-effects regression studies tend to show that minimum wage increases have negative employment effects, while matching locations with minimum wage increases with similar locations without them finds that minimum wages don’t harm employment.  The former is a more rigorous methodology (since minimum wage hikes may be correlated with economic downturns in some way.)

However, economist David Neumark writing for the WSJ claims that it matters how you match test and control jurisdictions; if you match geographically nearby locations, you find that minimum wage increases don’t cause reduced employment, but if you match locations which are subject to the same economic shocks, you do find a negative employment effect of minimum wage hikes.

This is all very confusing. Even if minimum wages do indeed reduce employment, if it were a huge and unequivocal effect, we wouldn’t find that it was so sensitive to statistical methodology.

What could be going on?

Some hypotheses:

  • Employment is sticky. When workers get more expensive, employers don’t fire them now, because high capital costs mean you still need about the same number of people to run your store/restaurant. Instead, what might happen is:
    • Firms eat the cost and go out of business (some evidence shows that this happens)
    • Firms invest in labor-saving equipment and don’t hire anyone later (some studies show that minimum wage hikes hurt long-term job growth)
    • Firms cut back on non-monetary compensation for workers (like AC or benefits)
  • People’s demand for goods produced by low-wage workers isn’t very elastic; we’ll still eat a sandwich even if it’s more expensive, so most of the cost of minimum wages gets passed on to consumers.
  • There’s massive data falsification in some direction
  • Economics is fake: people don’t really always try to get more stuff for less money

I don’t have a great way to find out what’s actually going on. I’d really appreciate more information if anyone has it!

Do Pineal Gland Extracts Promote Longevity? Well…Maybe.

Epistemic Status: Casual. I’m in a period of blogging more frequently so my posts represent only a few hours of thought.

I love ground-up organs.

Seriously — they’re where a lot of medical progress comes from. Long before we knew what “cortisol” did, we were treating autoimmune diseases with ground-up adrenal cortex extract. Long before we knew what thyroxine did, we were treating hypothyroid patients with ground-up thyroid extract.  And a lot of regenerative medicine is still at the stage of “put some mashed-up lymph node tissue or bone marrow on it and see if it grows.”

It’s primitive, but it’s a kind of prudent primitiveness. It is very hard to map out biochemical pathways and extract the precise chemical that binds to the precise receptor that does what you want. Given the messiness of evolution, it is not at all surprising when it turns out that there are many potentially relevant receptors and chemicals related to the disease you want to target.  If you just know the organ, you route around all that complexity.  You don’t have to know all the growth factors to know that bone marrow contains some kind of growth-y stuff.

So I was very interested, after having been linked to this database of putative life-extension drugs, that the top scorer was epithalamin, an extract of the pineal gland; it’s said to extend life by 31% in mice. The second item on the list was polypeptide pineal preparation, which is another name for epithalamin; and melatonin, the primary hormone produced by the pineal gland, is no slouch either, allegedly giving mice 18% longer lives.

So, I had to ask, is this for real?

First, let’s talk about melatonin.

Melatonin is the “sleep hormone” — it is produced at night much more than in the day, and its primary effect is to make humans and animals sleepy. The cyclical pattern of melatonin secretion provides the circadian rhythm.

The study linked in the database, by Walter Pierpaoli, finds that male mice (but not female mice) given melatonin at night (but not during the day) live 18% longer than control mice, and engrafting young pineal glands onto the thymuses of older mice increases lifespan by 27%.[1]

Unfortunately, this experiment is on strains of mice that happen to be deficient in melatonin already,[2] so it doesn’t tell us much about whether melatonin or pineal-gland transplants will extend the lifespans of normal-melatonin individuals.

A critical paper in 1995, called “Melatonin Madness,”[3] pointed out this mistake, and pointed out that in another study on a strain of mouse that does produce melatonin (C3H/He), the treated mice actually had shorter lifespans because they developed more tumors.

Pierpaoli is…rather problematic.  He’s the author of “The Melatonin Miracle: Nature’s Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone” and sells melatonin in his online store. So, a little skepticism is warranted here.

On the other hand, there’s been additional evidence that melatonin can extend life, even in melatonin-producing animals.

In C3H mice (which produce melatonin), melatonin in drinking water prolongs the life of male mice by about 20% (p < 0.01) but not female mice.[4]

In CBA mice, which also produce melatonin, those given melatonin in their night-time drinking water were significantly more likely than controls to get lung cancer and lymphoma, but their lifespan still was extended by 5% relative to controls.[5]

Moreover, a 1979 study by the Russian longevity researcher Vladimir N. Anisimov found that female rats given daily doses of epithalamin at 0.1 or 0.5 mg increased lifespan by 10% and 25% respectively, and aging-related disturbances in the estrus cycle were significantly (p < 0.05) reduced.[6]

Anisimov also found that female  C3H mice (a melatonin-producing strain) given daily epithalamin at 0.5 mg lived on average 40% longer than controls.[7]

However, he found that epithalamin given to old rats did not significantly increase lifespan.[8]

In another Russian experiment, by Vladimir Khavinson, a frequent collaborator of Anisimov’s,[9] 94 women aged 66-94 from the War Veterans Home in St. Petersburg were randomized to control, thymus extract (thymalin), pineal extract (epithalamin), or both.  At baseline, these elderly women had high B lymphocytes, low NK counts, high IgG levels, high cortisol, insulin, and TSH, and low estrogen and LH, compared to the “normal” levels.

Thymalin normalized the NK levels. Epithalamin normalized NK levels as well as ACTH, TSH, cortisol, and insulin. Thymalin significantly reduced the rate of acute respiratory diseases (from 58% to 25%) and epithalamin significantly reduced the rate of ischemic heart disease. In 6 years, 81.8% of the control patients died, compared to 41.7% of the thymalin patients, 45.8% of the epithalamin patients (both applied for 2 years) and 20.0% of the patients given epithalamin and thymalin for 6 years.  The effect on mortality was significant at p<0.001.

This is a pretty small study for a measurement of all-cause mortality, but something might be going on here.

It’s also possible that pineal extract reverses aging-related insulin resistance (which is associated with many aging-related diseases, like heart disease, cancer, and diabetes.)

Old rhesus monkeys have lower melatonin levels than young monkeys. Pineal gland extract, but not placebo, raises old rhesus monkeys’ melatonin levels to that of young monkeys.  Old monkeys also have higher blood glucose levels (at baseline and in response to glucose challenge) than young monkeys; pineal gland extract significantly reduces glucose in old monkeys (but not young monkeys.) Old monkeys have a delayed and flatter curve of insulin response to glucose challenge than young monkeys; pineal gland extract reverses this.  This suggests that pineal gland extract improves insulin sensitivity in monkeys.[10]

There is a lot of uncontroversial evidence that melatonin has something to do with aging. Mammals and humans secrete less melatonin as they age.

The pineal gland’s melatonin secretion rhythm becomes less regular with age (smaller amplitude) in both rats and hamsters. In hamsters and humans, the pineal gland develops “concretions” of calcium with age.  Older animals lose beta-adrenergic receptors on the pineal gland with age.  Food-restricted rats, on the other hand, continue to produce more melatonin in old age — and that’s suggestive, because food-restricted animals also live longer.[11]

Old rats had neurons in their pineal glands fire at lower frequencies than young rats, and produced less melatonin.[12]

Food-restricted rats at 28 months (old age) had twice the melatonin levels of ad-lib fed rats.  Food-restricted rats were smaller, and had no tumors or cataracts, unlike ad-lib fed rats.[13]

The pineal gland also seems to be associated with insulin sensitivity and other markers associated with aging.

Pinealectomy (the removal of the pineal gland) increases blood pressure in rats, suspected to be caused by an increase in adrenal steroid levels.  Melatonin in the drinking water reduces blood pressure to normal levels.[14]

Pinealectomy causes glucose intolerance and insulin insensitivity in rats.  At 8 AM, glucose and insulin are normal in response to glucose challenge; but at 4 PM, pinealectomized rats have way higher of a glucose spike and way less insulin production.  The pancreas responds less to pinealectomized rats, both morning and afternoon. Pinealectomized rats have significantly less GLUT-4 (glucose transporter) in their adipose tissues.[15]

Pinealectomized rats have higher glucose levels, lower insulin levels, and higher glucagon levels than control rats; treatment of pinealectomized rats with melatonin increases insulin and reduces glucagon. Pinealectomized rats have glucose intolerance. Melatonin supplementation partially recovers glucose tolerance.[16]

Corticosterone (the primary corticosteroid in rodents, serving similar functions to cortisol in humans) rises in rats as they age; two-month-old pinealectomized rats had the same corticosterone levels as 24-month-old aged rats.[17]

So, if you remove the pineal gland, you get higher levels of corticosteroids, higher blood pressure, and more metabolic-syndrome-like changes, just like people and animals do as they age. Pinealectomy also causes “pro-gonadal” effects — higher sex hormones and larger sex organs.

Pinealectomizing rats causes ovarian, pituitary, and adrenal hypertrophy (p < 0.001). Adding bovine pineal extract to the rats reverses this.[18]

Melatonin reduces prostate weight in rats as a fraction of total body weight (p < 0.02) and prostate fructose (p < 0.05); being kept in darkness drops testosterone levels to 1/8th their usual levels; pinealectomy increases prostate weight (p < 0.05) and triples testosterone levels (p < 0.01).[19]

The testes of rats produce more testosterone after pinealectomy, and administering melatonin reverses the effect.[20]

Blinding female rats retards the development of their ovaries and uterus. Pinealectomy recovers the normal size of the ovaries and uterus.[21] (Note that blinding animals or keeping them in darkness is kind of like making it perpetually night for them — the conditions under which melatonin is usually secreted. So that’s also consistent with the “melatonin = less sex hormones” pattern.)

Nighttime, but not continuous, administration of melatonin causes delayed puberty and delayed reproductive senescence in mice.  That is, mice given melatonin are slower to reach puberty and slower to become infertile with age.[22]

So this pattern is starting to make sense. Remember how most mutations that increase lifespan have something to do with the GH/IGF pathway that promotes growth and insulin release and sex hormones?  And how caloric restriction increases lifespan, improves insulin sensitivity, but impairs fertility?  And how higher levels of IGF, sex hormones, and obesity are risk factors for cancer, especially reproductive-organ cancers like breast and prostate?  Almost as though there’s an evolutionary toggle between “growth and reproduction” and “surviving through famine”?  Well, melatonin and the pineal gland seem to tie into this story; if you take away the pineal gland you get high sex hormone levels and metabolic syndrome, while if you add melatonin or pineal extract you can reverse those phenomena.

But does it really connect to longevity? It’s not clear. The only study I found that measured the lifespan of pinealectomized rats was by Walter Pierpaoli, and found that rats pinealectomized at 3 to 5 months have 20% shorter lifespan (p = 0.014) but that pinealectomy does not alter lifespan in 7 to 9 month rats.  Pinealectomy at 14 months actually increases lifespan (by 12.5%) but at 18 months it has no effect.  Pierpaoli speculates that there’s a precise age at which the pineal gland promotes aging, but I think this study is nowhere near enough evidence to conclude that.[23]

At any rate, there’s a simple evolutionary story for why we’d have a toggle between “eat, grow, reproduce” and “survive”, and why that would be connected to the circadian rhythm: SEASONS.

Summer has longer days and more food. Winter has shorter days (more melatonin at night!) and less food. You want to grow fat in the summertime and have babies; you want to survive the winter. A lot of species (though not humans) have a seasonal mating pattern.

And, accordingly, you see the effects of the pineal gland on seasonal mating.

Short-day Siberian hamsters (kept under conditions that are dark longer than they are bright), compared to long-day hamsters, have later puberty, more ovarian follicles, and longer fertility.  Pinealectomize the hamsters and even the short-day ones lose fertility quickly.  (Siberian hamsters in the wild reproduce in spring and summer.)  Long-days have higher body mass than short-days, and pinealectomized short-days are the largest of all.  This is because short-day hamsters eat 16% fewer calories.  The basic bottom line is consistent: darkness = melatonin = less gonadal/growth processes going on = slower reproductive aging.[24]

Siberian hamsters are very cute:

but they have an extremely seasonal pattern of gonadal growth; Google Image Search “siberian hamster testicles” if you dare. Those are summertime testicles. In winter the male Siberian hamster loses thirty percent of his body mass.

Testosterone also rises upon pinealectomy in white-tailed deer at baseline, but it prevents them from having the annual “autumn rut” spike in testosterone that usually peaks in November.  Testicular size also rises in the fall in normal white-tailed deer, but in pinealectomized deer it rises steadily throughout the year.  In other words, pinealectomy flattens out the seasonal breeding rhythm.[25]

So, the pineal gland maintains a regular seasonal and daily cycle of “growth/sex” vs “rest/survival”, with nighttime and winter being the more “rest/survival” oriented periods. If you destroy the pineal gland, you can keep animals shifted towards “growth/sex” all the time (which doesn’t actually make them more fertile overall, it makes them use up their fertility faster).  It’s annoyingly unclear whether pinealectomy makes animal lifespans shorter, and somebody should check that.

It’s also not that clear whether you can get normal animals into more of a “rest/survival” oriented mode by administering extra melatonin or pineal extract. You definitely can’t get them to be in permanent “rest/survival” by administering melatonin 24/7 — continuous melatonin (as opposed to nighttime melatonin) has no effect on longevity or delaying puberty or aging.  But there are some apparently okay mice and rat studies that show that melatonin or pineal extract has a longevity-promoting effect. If it pans out, it would be the biggest-effect-size longevity intervention I’ve seen that isn’t a highly restrictive diet (caloric restriction or low-methionine) or obviously very dangerous (high-dose rapamycin).

I might also speculate from all this that getting a good night’s rest is good for you (I know, shocking), and that having artificial light that doesn’t get any shorter in the winter than the summer may be messing with modern people’s metabolisms in some way.

References

[1]Pierpaoli, Walter, and William Regelson. “Pineal control of aging: effect of melatonin and pineal grafting on aging mice.” Proceedings of the National Academy of Sciences 91.2 (1994): 787-791.

[2]Kasahara, Takaoki, et al. “Genetic variation of melatonin productivity in laboratory mice under domestication.” Proceedings of the National Academy of Sciences 107.14 (2010): 6412-6417.

[3]Reppert, Steven M., and David R. Weaver. “Melatonin madness.” Cell 83.7 (1995): 1059-1062.

[4]Oxenkrug, G., P. Requintina, and S. Bachurin. “Antioxidant and Antiaging Activity of N‐Acetylserotonin and Melatonin in the in Vivo Models.” Annals of the New York Academy of Sciences 939.1 (2001): 190-199.

[5]Anisimov, Vladimir N., et al. “Melatonin increases both life span and tumor incidence in female CBA mice.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56.7 (2001): B311-B323.

[6]Dilman, V. M., et al. “Increase in lifespan of rats following polypeptide pineal extract treatment.” Experimentelle Pathologie 17.9 (1979): 539-545.

[7]Anisimov, V. N., V. Khavinson, and V. G. Morozov. “Twenty years of study on effects of pineal peptide preparation: Epithalamin in experimental gerontology and oncology.” Annals of the New York Academy of Sciences 719.1 (1994): 483-493.

[8]Anisimov, V. N., L. A. Bondarenko, and V. Kh Khavinson. “Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin level in old rats.” Annals of the New York Academy of Sciences 673.1 (1992): 53-57.

[9]Khavinson, Vladimir Kh, and Vyacheslav G. Morozov. “Peptides of pineal gland and thymus prolong human life.” Neuroendocrinology Letters 24.3-4 (2003): 233-240.

[10]Goncharova, N. D., et al. “Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas.” Experimental gerontology 40.1 (2005): 51-57.

[11]Reiter, Russel J. “The ageing pineal gland and its physiological consequences.” Bioessays 14.3 (1992): 169-175.

[12]Stokkan, Karl-Arne, et al. “Food restriction retards aging of the pineal gland.” Brain research 545.1 (1991): 66-72.

[13]Stokkan, Karl-Arne, et al. “Food restriction retards aging of the pineal gland.” Brain research 545.1 (1991): 66-72.

[14]Holmes, S. W., and D. Sugden. “Proceedings: The effect of melatonin on pinealectomy-induced hypertension in the rat.” British journal of pharmacology 56.3 (1976): 360P.

[15]Lima, Fabio B., et al. “Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats.” American Journal of Physiology-Endocrinology and Metabolism 275.6 (1998): E934-E941.

[16]Diaz, Beatriz, and E. Blazquez. “Effect of pinealectomy on plasma glucose, insulin and glucagon levels in the rat.” Hormone and metabolic research 18.04 (1986): 225-229.

[17]Oxenkrug, Gregory F., Iain M. McIntyre, and Samuel Gershon. “Effects of pinealectomy and aging on the serum corticosterone circadian rhythm in rats.” Journal of pineal research 1.2 (1984): 181-185.

[18]Wurtman, Richard Jay, Mark D. Altschule, and Uno Holmgren. “Effects of pinealectomy and of a bovine pineal extract in rats.” American Journal of Physiology–Legacy Content 197.1 (1959): 108-110.

[19]Kinson, G. A., and Frances Peat. “The influences of illumination, melatonin and pinealectomy on testicular function in the rat.” Life Sciences 10.5 (1971): 259-269.

[20] “Effects of melatonin on Leydig cells in pinealectomized rat: an immunohistochemical study.” Acta histochemica 104.1 (2002): 93-97.

[21]Reiter, Russel J., Peter H. Rubin, and John R. Richert. “Pineal-induced ovarian atrophy in rats treated neonatally with testosterone.” Life sciences 7.5 (1968): 299-305.

[22]Meredith, S., et al. “Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles☆.” Experimental gerontology 35.3 (2000): 343-352.

[23]PIERPAOLI, WALTER, and DANIELE BULIAN. “The Pineal Aging and Death Program: Life Prolongation in Pre‐aging Pinealectomized Mice.” Annals of the New York academy of sciences 1057.1 (2005): 133-144.

[24]Place, Ned J., et al. “Short Day Lengths Delay Reproductive Aging 1.” Biology of reproduction 71.3 (2004): 987-992.

[25]Plotka, E. D., et al. “Early effects of pinealectomy on LH and testosterone secretion in white-tailed deer.” Journal of endocrinology 103.1 (1984): 1-7.

Update on Sepsis

Dr. Marik’s home university, EVMS, is currently raising money for an RCT of his sepsis treatment.

You can donate as a private individual here.

Remember, the whole thing only costs $250,000 — a few people can make a significant dent in that.  The response from my preliminary survey was great, and we clearly have a lot of generous people interested in the sepsis issue.

For my own record-keeping, I’d appreciate it if people who saw this blog post and donated would fill out this form; I’d like to be able to congratulate my blog readers on our total amount raised.

 

How Much Work is Real?

Epistemic Status: Casual, just framing things

Some work is clearly “productive.” If you plant things in a garden, you put in work, and you get out plants.  If you cook a meal, your family gets fed. If you build a building where people want to live or work, they get shelter. If you treat a patient, the patient gets better. If you carry goods to the place that they’re sold, people get their stuff. If you invent a labor-saving machine, people get to free up their time for other things.

Productive work creates value, in the sense of “doingstuffness”, mana, usefulness-to-humans, etc. It’s not just effort expended, or an accounting formalism like dollars, it’s an increase in the “real wealth” of humanity. That’s not a well-defined concept, but it’s worth pointing at, so we know what we’re complaining about when we see deviations from this.

In the standard capitalist story, you get paid for work because you created value for somebody; they wanted your stuff so much that they were willing to give you something in exchange for it.

In this world, all productive work is honorable.  Work is fair — on average, you get what it’s worth — and it’s a contribution, however small, to the wellbeing of humankind, the fire that beats back against the blackness of hard vacuum.

But there are ways that things called “work” can fail to be productive work.

Fraud or crime obviously are not productive. If you get money from people by tricking or terrifying them, you’re not getting it by providing them with value. You’re not a maker.

Enforced monopoly power is also not entirely productive. If people are required by law — on pain of punishment — to buy your product, then at least some of your revenue is driven by fear, not desire.

Regulations can be a form of enforced monopoly power. If only people who meet certain criteria are allowed to sell, then people are buying from you and not your competitors not because they like you better, but because your competitors are driven out by fear of punishment. Once again, you’re profiting partly off fear, not just desire.

A job that is funded by taxpayer money, or by the fact that the product sold is mandatory to buy, or by the fact that nobody knows whether it would be illegal to get rid of that job and they want to play it safe, doesn’t need to be useful at all.

And there are still more indirect ways that a job can fail to be useful.  If you sell to people who don’t do anything useful, then your job would not have been necessary in a sensibly organized world, even if you do nothing dishonest yourself and genuinely add value to your customers.

This is what it means to live in a “mixed economy.”  Not everything that everyone does for a living is genuinely useful.

If there are bullshit jobs, as anthropologist David Graeber claims, then that’s a shame, from the perspective of human well-being. If we have enough real wealth, enough mana, to support even people who aren’t making mana, then why not just allow leisure, instead of forcing people to go through the motions of dull and unnecessary work?

This is largely the position of left-libertarians like the people at Center for a Stateless Society.  They make the empirical claim that most of the present economy in developed countries is coercive and unproductive, the result of crony capitalism and regulatory capture rather than honest, useful work.  As such, a “freed market” without such corruption would actually be more egalitarian than our current economy.   Since government promotes monopoly, Big Business wouldn’t be sustainable without coercion.  Since highly regulated and positional goods like housing and education are essentially mandatory for participating in much of modern life, if those mandates were abolished, socioeconomic inequality would drop.

On the other hand, this empirical claim could be false. Nobody denies that some corruption exists, but it might be the exception rather than the rule. We might not, in fact, be in post-scarcity conditions.  So-called “bullshit” jobs may actually be valuable, just easy to dismiss by outsiders like Graeber.  Growing wealth inequality may be largely the result of winner-take-all phenomena, as Tyler Cowen thinks — in his model, the working rich really are more productive than ever, thanks to the amplifying effects of technology.  Love it or hate it, says Cowen, capitalism works the way it says on the tin.

There is some evidence that economic rents are on the rise in the US. Wealth inequality has risen over recent decades, but labor productivity has declined. Economic dynamism — the number of people changing jobs and starting new businesses — has also declined.

One important piece of evidence that rents are on the rise in the United States is the divergence of rising returns to capital and declining real interest rates. In the absence of economic rents, the return on corporate capital should generally follow the path of interest rates, which reflect the prevailing return to capital in the economy. But over the past three decades, the return to productive capital generally has risen, despite the large decline in yields on government bonds.

Other firm-side evidence points to an increased prevalence of supranormal returns over time. Between 1997 and 2012, market concentration increased in 12 out of 13 major industries for which data are available, and a range of micro-level studies of sectors including air travel, telecommunications, banking, and food-processing have all produced evidence of greater concentration.

The fact that variations in the rate of return to capital have increased enormously across firms may also at least partially reflect increased concentration and the role of economic rents. Finally, there is evidence that land-use regulation may also play a role in the presence of increased economic rents, decreasing housing affordability, and reducing nationwide productivity and growth by restricting supply.

There’s also Matt Rognlie’s paper showing that the long-term rise of capital’s share of wealth (compared to labor’s) is almost entirely a result of increased housing prices — literal rents, kept high by land-use restrictions.

And there’s the phenomenon that S&P 500 firms are now 5/6ths “dark matter” — that is, things that a new entrant to the field can’t copy.

Imagine that you wanted to create a new firm to compete with one of these big established firms. So you wanted to duplicate that firm’s products, employees, buildings, machines, land, trucks, etc. You’d hire away some key employees and copy their business process, at least as much as you could see and were legally allowed to copy.

Forty years ago the cost to copy such a firm was about 5/6 of the total stock price of that firm. So 1/6 of that stock price represented the value of things you couldn’t easily copy, like patents, customer goodwill, employee goodwill, regulator favoritism, and hard to see features of company methods and culture. Today it costs only 1/6 of the stock price to copy all a firm’s visible items and features that you can legally copy. So today the other 5/6 of the stock price represents the value of all those things you can’t copy.

“Intangibles” would certainly include rent-seeking forms of favoritism.

It also includes patents, which arguably do not increase innovation on the margin (according to natural experiments between different countries with different patent regimes or changes in patent laws.) Copyright and patent lengths have gotten longer in the US, and patent applications have grown at an accelerating rate; the growth of intellectual property is another example of our economy becoming more monopolistic.

How much of our economy consists of rent-seeking would be hard to detect, and I’m not sure anybody has attempted it. “Spikiness” in wealth between firms or individuals could be either due to monopolistic privileges or variance in productivity.  Concentration of growth in highly regulated industries points towards rent-seeking being prominent, especially if the measured outcomes of those industries don’t improve (e.g. healthcare), but it doesn’t tell us what percent of the value of healthcare is due to rents.

And, of course, even such estimates don’t tell us what to do, because of path-dependency effects. Even if we discovered with high confidence that an industry was mostly corrupt, that doesn’t guarantee that “anti-corruption” efforts will actually make it less so.  (Sometimes the increased administrative demands of making sure nobody gives bribes cost more than the bribes themselves did.)

But the question is relevant, to those of us who want to know “where can I find productive work?” and “how much misdirection is going on under the surface of today’s world?”

I work at a biotech company. I made a special effort to find a job that was as honest as possible, while still being in my field.  And I think we are honest here; the official purpose of the company (to find new promising drugs) is also the implicitly endorsed goal that people actually work towards.  We’re a bunch of scientists, with scientific sensibilities. But we’re still in an industry defined by grants, patents, regulations, and other monopolistic practices.  There are still, I think, pockets of inefficiency that result from being in that industry.  Bigger, older businesses often get flummoxed when their startup partners move too fast.  And those of us who don’t work in the lab don’t really need to work 8 hours a day every day in order to meet our planned goals.  My job isn’t bullshit, by any means, but I sometimes suspect that it isn’t maximally productive.

I don’t believe in being so obsessed with personal purity that you never get anything done — that’s not useful and it’s not the point. It’s more about trying to figure out what kind of world you live in.

Chronic Fatigue Syndrome

Epistemic Status: moderately confident. Spent several weeks on this in an effort to be more complete and careful than most of my lit reviews.

Chronic fatigue syndrome is something of a medical mystery. Some doctors question whether it’s a real disease at all. There are no well established treatments. We don’t know what causes it.

There’s a lot of evidence that CFS has something to do with immune and hormonal dysfunction, and is frequently associated with infectious diseases, particularly the Epstein-Barr virus and other herpes viruses (not all of which are sexually transmitted.)  There are also some immunotherapy options that seem to be effective in a subset of CFS patients, in particular corticosteroids.

Bottom Lines

Corticosteroids seem to help for a sub-population of CFS patients.  Rituximab, bacterial therapy, and intravenous immunoglobulin may also help for some CFS patients, but the evidence base is smaller or less consistent for those.

Chronic Fatigue and the HPA Axis

The hypothalamus/pituitary/adrenal (HPA) axis is a system of interconnected hormone signaling processes involved in the body’s response to stress. Cortisol, the “stress hormone”, is produced by the adrenal glands in response to signals from the pituitary gland and hypothalamus.

Cortisol suppresses inflammation, which is why it’s often used as a treatment in autoimmune diseases. It also promotes alertness and increases blood sugar, to ready the body for action.

There’s evidence that patients with chronic fatigue syndrome have lower cortisol levels, or are less able to produce cortisol in response to the appropriate stimuli.

There are a number of small studies showing that CFS patients have lower cortisol than healthy people.  14 CFS patients had significantly lower salivary cortisol levels compared to 26 cases of depression and 131 controls.[2]  In 15 CFS patients and 20 controls, mean salivary cortisol levels were significantly lower for CFS patients.[3] Urinary free cortisol was significantly lower in 121 CFS patients compared to 64 control patients.[4]  10 melancholic depressives had higher urinary free cortisol than 15 controls, while 21 CFS patients had lower urinary free cortisol.[5]  In 10 patients with CFS, 15 patients with major depression, and 25 healthy controls, baseline serum cortisol levels were highest in the depressives, lowest in the CFS patients, moderate in the controls.[6]

However, not all studies replicate the finding. In 22 CFS patients and 22 healthy controls, one study found no difference in urinary or salivary cortisol.[7] In another study of 10 CFS patients vs 10 controls, patients were slightly but significantly higher in salivary cortisol.[8]

One possible explanation for the discrepancy is that cortisol levels fluctuate greatly throughout the day, and in response to conditions that vary from day to day (food intake, stress, etc).  All these studies sampled patients over the course of a day or less. It’s not surprising that small studies should find discordant results, especially given the possibility that not all CFS patients are alike.

One finding that does seem consistent is that chronic fatigue patients have a blunted cortisol response to ACTH, the hormone produced by the pituitary that normally stimulates cortisol release, and they have an exaggerated drop in cortisol levels in response to challenge with corticosteroids (cortisol and its molecular analogues reduce ACTH levels in a negative feedback loop.)  So, even if cortisol is not always lower in CFS patients, it may be more sluggish to rise and quicker to decline.  In 21 CFS patients vs. 21 healthy controls, patients with CFS had normal baseline salivary cortisol but showed enhanced and prolonged suppression of salivary cortisol in response to dexamethasone challenge.[9]  Prednisolone challenge suppresses both salivary and urinary cortisol more in CFS patients (n=15) than controls (n=20).[11]

Upon challenge with ACTH, the increase in plasma cortisol was significantly less for 20 CFS subjects vs. 20 controls.[10]  In 22 CFS patients vs 14 controls, CFS patients also had a blunted DHEA response to ACTH; DHEA is a steroid hormone and androgen precursor, which is generally produced in response to exercise. In other words, the steroid-promoting effects of ACTH are weaker in CFS patients, while the cortisol-reducing negative feedback effects of corticosteroids are stronger.

Perhaps relatedly, CFS patients have blunted salivary cortisol response to awakening compared to healthy volunteers.[1]  Another study compares that female CFS patients have lower lower morning salivary cortisol than controls.[8] This may be related to the unrefreshing sleep and constant fatigue that CFS patients experience.

Finally, when there are hormonal differences in CFS patients, there are also clear anatomical differences. 8 CFS patients who had a subnormal cortisol response to ACTH challenge were found to have adrenal glands less than 50% the size of normal subjects’ adrenal glands.  In each case, the symptoms of fatigue were preceded by a viral infection.[12]  So in at least some cases, CFS patients have smaller glands than healthy people, which indicates that at least some of the time, CFS is associated with a damaged endocrine system.

Chronic Fatigue and Impaired NK Function

Studies find a variety of abnormalities in white blood cells in CFS patients, but the only really consistent results are impairment of NK (natural killer) cells’ function.  NK cells are cytotoxic (cell-killing) white blood cells involved in the innate immune response; they attack tumor cells and infected cells.

A study of 30 CFS patients and 69 controls found that NK cell cytotoxicity was 64% lower against tumor cell lines.[13]  In a family with 8 relatives with chronic fatigue syndrome, affected individuals had 62% lower NK activity levels (p = 0.008) against a tumor cell line than normal controls; unaffected relatives had intermediate NK activity levels.[14]  In a study of 41 CFS patients and 23 matched controls, the patients had significantly lower cytotoxic activity against EBV-infected cell lines and tumor cell lines, and patients also had significantly lower levels of NKH1+ NK cells, a subtype which comprises most of the NK cells in healthy people.[15]  A review article [16] explained that there are conflicting results in most immunological abnormalities in CFS; most studies, however, found reduced NK activity and reduced lymphoproliferative activities in response to antigens.  Of 17 studies that evaluated NK activity in CFS patients, 15 found reduced NK cytotoxicity in the CFS patients compared to controls, and a greater decrease in activity was associated with greater symptom severity.[17]

This suggests that CFS is characterized by a weakened immune system.

In general, NK deficiencies or reduced NK activity are associated with greater susceptibility to herpesviruses.[18] Reduced NK activity has also been found in major depression [19],  stress[20][21][22], bereavement [23], and sleep deprivation[24][25].

Chronic Fatigue and Herpesviruses

A number of studies have found that CFS is associated with elevated antibodies to viruses, particularly herpesviruses. It’s also often been found that CFS occurs with rapid onset, after a viral illness, and that there are outbreaks of CFS in locations where there have been disease outbreaks.  However, results are not entirely consistent between studies.

Negative Results

In a study of 548 CFS patients vs 30 healthy controls, CFS patients did not have significantly higher rates of positive titers on antibodies to HSV1, HSV2, Rubella, CMV, EBV, HHV-6, or Coxsackie.  This was a study of consecutive patients at a chronic fatigue clinic in Washington State.[26]

In another study of 100 CFS patients referred to the lab by doctors and 92 healthy controls, there were significantly higher rates in patients than controls of prevalence of antibodies to EBV viral capsid antigen, and prevalence of antibodies to EBV early antigen, but not to antibodies to EBV nuclear antigen; there was also no significant difference between patients and controls in who had high titers of antibodies.[27]

In a study of 26 patients from Atlanta with CFS and 50 healthy controls, there were no significant differences in the rate of prevalence of antibodies to any viruses, including HHV-6; the prevalence of antibodies in the controls was nearly 100% for all viruses tested.  Also, there was no significant difference in the antibody titers for any EBV antibodies (early antigen, nuclear antigen, or viral capsid.)[28]

In a study of four clusters of outbreaks of CFS in the Nevada/California area in the 1980’s, with 31 patients and 105 controls in total, there was no significant difference in the mean antibody titer to HHV-6, EBV-VCA, or EBV-EA.  Mean VCA GMT level for cases was 239.7 vs. 254.0 for controls, a non-significant difference.[29]

In 88 patients with CFS compared to 76 healthy blood donors in the Netherlands, there was no significant difference in geometric mean titer for EBV EA antibodies or EBV VCA antibodies. Mean VCA GMT level for patients was 39.5 vs. 38.0 for controls.[33]

For identical twin pairs discordant for CFS, the twin with CFS was no more likely to have serological evidence of virus than the twin without (including EBV and HHV-6).[39]

In 14 patients with CFS compared to 14 controls, there was no significant difference in EBV antibody titer.[40]

Positive Results

In a study of 259 patients associated with the Lake Tahoe outbreak in 1984, compared to 40 healthy controls, found active replication of HHV-6 in cell cultures from blood in 70% of patients compared to 20% of controls.  The reciprocal geometric mean titers for EBV VCA were significantly higher in the patient than control group (138.0 +/- 2.6 for the cases vs. 67.6 +/- 4.4 for the controls) but not for early antigen or nuclear antigen.  There was no significant difference in antibody titers for HHV-6, though.  Mean HHV-6 ELISA densities were 1905 for cases and 1288 for controls, a nonsignificant difference.[30]

In a study comparing 15 patients from the Lake Tahoe outbreak who had been sick for more than 2 months to 119 patients with less severe symptoms and 30 matched controls found that a significantly higher fraction of cases than non-case patients had EBV VCA antibodies at 160 or greater, and 320 or greater.  Reciprocal geometric mean titers for VCA were higher in case-patients than controls (254 vs. 115.)  After retesting across 3 laboratories, the only significant difference between case-patients and control-patients was EBV EA titer, with reciprocal geometric mean titers of 22 in cases vs. 9 in controls; VCA levels were not significantly different.[31]

In 58 CFS patients and 68 matched controls, 33 CFS patients (57%) had positive EBV VCA IgM titers, compared to 7% of controls.[32]  IgM titers to EBV are rare, are more likely to indicate active infection, and most studies find none at all.

In a study of 154 CFS patients and 165 controls from Flint and Boston, patients were significantly more likely than controls (p < 0.001) to have the presence of IgG and IgM antibodies to HHV-6, but not to have EBV-EA antibodies.[34]

In a study of 10 CFS patients with acute mononucleosis onset, 10 CFS patients without, and 42 healthy controls found significantly higher EBV IgG VCA antibody titers in all CFS patients relative to controls, as well as HHV-6 antibody titers.[35]

In 21 MS patients, 35 CFS patients, and 28 healthy controls, 75% of MS patients had elevated IgM titers to HHV-6 antibodies compared to 6.7% of healthy controls, and 71.4% elevated IgM titers to HHV-6 virus compared to 15% of controls.  However 60-80% of everyone had HHV-6 by PCR. CFS patients were more likely to have IgG responses to early HHV-6 antibodies than controls (65.2% vs 20%) and IgM responses to early HHV-6 antibodies than controls (54.3% vs. 8.0%).  This suggests a high level of HHV-6 reactivation in CFS and MS patients.[36]

In 13 patients with CFS and 13 healthy controls, serum antibodies for HHV-6 were significantly higher in the patients; 7 of the patients and none of the controls had HHV-6 DNA, as measured by PCR.[37]

A study of 36 CFS patients and 24 controls found that HHV-6A DNA was significantly more prevalent in CFS patients, while HHV-6B DNA was the same.[38]

Tables

HHV-6 High IgG levels

Study Cases (number) Controls (number)
Buchwald 1996 13% (295) 7% (30)
Patnaik 1995 40% (154) 8% (165)
Sairenji 1995 100% (20) 88% (26)
Ablashi 2000 71% (35) 0% (25)


HHV-6 High IgM levels

Patnaik 1995 60% (154) 4% (165)
Ablashi 2000 54% (35) 8% (25)


HHV-6 DNA

Yalcin 1994 53% (13) 0% (13)
Di Luca 1995 22% (36) 4% (24)
Koelle 2002 36% (22) 27% (22)


EBV-VCA High IgG levels

Buchwald 1996 8% (308) 3% (30)
Sumaya 1991 11.9% (42) 18% (100)
Swanink 1995 32% (88) 32% (76)
Sairenji 1995 20% (20) 0% (26)


EBV-VCA High IgM Levels

Lerner 2004 100% (33) 8% (50)


EBV-EA High IgG levels

Buchwald 1996 18% (308) 23% (30)
Sumaya 1991 47.6% (42) 69% (100)
Lerner 2004 79% (33) 30% (50)
Swanink 1995 8% (88) 8% (76)
Patnaik 1995 25% (154) 15% (15)
Sairenji 1995 45% (20) 0% (26)

 

EBV-NA positive

Buchwald 1996 95% (308) 93% (30)
Sumaya 1991 97.6% (42) 88% (100)
Swanink 1995 16% (88) 32% (76)

 

EBV-IgM elevated

Buchwald 1996 0.6% (310) 3% (30)


EBV-VCA GMT

Sumaya 1991 182.5 (42) 181.2 (100)
Mawle 1995 89.0 (26) 83.6 (50)
Buchwald 1992 138 (134) 67.6 (27)
Holmes 1987 169 (15) 113 (30)
Levine 1992 239.7 (24) 254.0 (49)


EBV-EA GMT

Sumaya 1991 9.5 (42) 21.1 (100)
Mawle 1995 57.5 (26) 35.2 (50)
Buchwald 1992 40.7 (134) 12.6 (27)
Holmes 1987 22 (15) 9 (30)
Levine 1992 6.0 (24) 2.1 (49)


EBV-NA GMT

Sumaya 1991 21.7 (42) 13.8 (100)
Mawle 1995 26.4 (26) 21.1 (50)
Holmes 1987 53 (15) 36 (30)


HHV-6 IgG GMT

Mawle 1995 1460 (26) 1715 (50)
Buchwald 1992 1905 (134) 1288 (27)
Levine 1992 132.6 (27) 87.9 (89)

The only serological differences that are consistently significantly different between CFS and normal patients are HHV-6 DNA (except for the twin study), HHV-6 IgM, and EBV-VCA IgM levels.  IgM, as opposed to IgG, levels, indicate active infection, as do viral DNA levels. This suggests that chronic fatigue patients are more likely than controls to have reactivated herpesviruses, but may not be more likely than controls to have had past exposure to herpesviruses.

Chronic Fatigue and Other Infections

There are some studies that have found associations between chronic fatigue syndrome and other types of bacterial and viral infection.

Mycoplasma

Mycoplasma bacterial species can survive for a long time inside cells, evade immune response, and resist treatment with antibiotics. They can cause a form of pneumonia and a sexually transmitted disease, and have been associated with various types of cancer.

In a study of 200 CFS patients and 100 controls, 52% of CFS patients had Mycoplasma infections compared to 7% of controls, and 30.5% of CFS patients had HHV-6 infections compared to 9% of controls, as measured by forensic PCR.[41]

In 100 CFS patients and 50 controls, 52% of CFS patients had PCR results positive for Mycoplasma genus, compared to 14% of controls (p < 0.0001).[42]

Other viruses

In 258 patients from Dubbo in rural Australia, exposed to Epstein-Barr virus, Ross River virus, or Q fever, 35% had a post-infective fatigue syndrome at 6 weeks and 12% at 6 months, at which point 11% (28 patients) met criteria for chronic fatigue syndrome. [43]

Out of 51 patients infected with acute Parvovirus B19, 5 went on to meet criteria for CFS.  Those with prolonged fatigue and CFS had significantly higher rates of serum B19 DNA.[44]

In 50 patients with postviral fatigue, 6 were associated with a local epidemic of Coxsackie virus, and 9 from a different viral epidemic of unknown cause; 30 had high antibody titers to Coxsackie virus, but none to other viruses.[45]

Chronic fatigue syndrome seems to frequently follow acute infections, and it is associated with high DNA levels of pathogens, often ones (like viruses or Mycoplasma bacteria) that can persist in the body indefinitely.

Corticosteroids Relieve CFS In A Sub-Population of Patients

In a study of 37 patients with chronic fatigue syndrome and 28 healthy controls, the CFS group had higher baseline cortisol levels but weaker cortisol responses to CRH and fenfluramine, and lower urinary cortisol levels.  In a subset of responders (8 out of 23 patients) treated with low-dose hydrocortisone for 28 days, the blunting of the cortisol response recovered, and CRH again caused a strong cortisol spike.  In these patients, fatigue dropped to the same level as the normal population.[46]

In a randomized trial of 32 CFS patients with no comorbid disorders, self-reported fatigue scores fell by 7.2 points in treatment group vs. 3.3 points in placebo group (p = 0.009), and 28% of treated patients reached normal levels of fatigue, compared to 9% of the placebo patients. This was a crossover study: patients received either hydrocortisone or placebo for one month, and then the reverse.[50]

Patients with CFS have higher DHEA levels than controls; there is a correlation between higher DHEA and more disability; untreated CFS patients have a blunted DHEA response to CRH challenge compared to controls and hydrocortisone-treaded CFS patients; basal levels of DHEA also went down after treatment with hydrocortisone.[47]

In a much older study from 1948, 53 patients with chronic mononucleosis, with “infectious mononucleosis cells” in the blood, presenting with weakness or ease of fatigue, responded only to a preparation of adrenal cortical extract (“cortalex”). “There was but little subjective improvement during the first week, but a definite feeling of well being developed during the second week and was quite definite during the third week. After this the medication was discontinued and the improvement usually continued. In a few patients it was necessary to increase the dose, or resume it after its discontinuance. Associated with the subjective improvement, there was a decrease in the size of the spleen.”[48]

However, when patients are not selected for having a blunted cortisol response, sometimes trials of corticosteroids on CFS don’t show positive results.

A crossover study of 80 patients given hydrocortisone and fludrocortisone found no significant difference from placebo in reported fatigue.  Note that the treatment group here did not see a larger response than placebo to an ACTH injection. So this negative result would still be consistent with the hypothesis that steroids work only when they recover the cortisol response to CRH or ACTH.[49]

A controlled study of 63 patients given low-dose hydrocortisone vs. placebo found no significant difference in wellness score over a period of 3 months, but significantly more patients  (53% vs 29%, p =0.04) experiencing an improvement of >5 points on the wellness score, which could be consistent with the drug being effective on a sub-population.[51]

Corticosteroids in Autoimmune Neurological Disorders

Chronic fatigue syndrome has similar symptoms and may have similar causes to other autoimmune neurological disorders such as multiple sclerosis and inflammatory neuropathies. Fatigue, muscle weakness, and brain fog, as well as high antibody titers for viruses, are found in these diseases. Corticosteroids are often standard treatments. This suggests that analogous treatment may be useful in CFS.

Corticosteroids (particularly methylprednisone) decreased by 63% the probability of the patient failing to recover from an exacerbation of multiple sclerosis, according to a Cochrane Review.[52]

IVIG and/or corticosteroids are standard treatment for chronic inflammatory demyelinating polyradiculoneuropathy.  Both significantly reduce disability scores.[53][54]

Demyelinating peripheral neuropathy responded to corticosteroids in six children, who regained strength and ability to walk.[55]

Corticosteroids (prednisolone) have significant positive effects on muscle strength and ability to function in daily life for patients with myasthenia gravis, an autoimmune neurological disorder.[56]

However, corticosteroids are ineffective in Guillain-Barre syndrome, another autoimmune demyelinating disease causing weakness and numbness. Standard treatment for Guillain-Barre is plasmapheresis and/or IVIG.[57]

Corticosteroids suppress inflammation, so they are often effective on autoimmune disorders which damage the nervous system through inflammatory damage. While it is not known what causes CFS, if it is an autoimmune disorder, it may respond to similar treatment.

IVIG Is Not Consistently Effective in CFS

Intravenous immunoglobulin is the practice of treating immunodeficiency disorders with a variety of antibodies via injection.

A 30-person randomized trial of IVIG in CFS, with a dose of 1 gm/kg, found no significant differences in symptoms between treatment and control by the 5-month follow-up point.[58]

A 99-patient controlled trial of IVIG vs. placebo infusion on CFS patients found no significant treatment effect on any self-reported symptom scores.[59]

A 71-patient randomized controlled trial of IVIG vs. placebo infusion found a barely-significant (p = 0.04) difference between placebo and IVIG on symptom scores.[64]

However, a 49-person study of patients with CFS treated with a dose of 2 gm/kg of IVIG, 40 of which had reduced T-cell counts or reduced response to skin-test antigens, found  43% of the treated group compared to 12% of controls noticed major reductions in their symptoms at the 3-month follow-up point after treatment.  The responders also noticed recovery of their cell-mediated immunity findings.[60]

It’s possible that for a sub-population of CFS patients with abnormally low T-cell counts or T-cell subtype counts, IVIG can be helpful; but it doesn’t seem to be helpful for CFS patients across the board.

Staphylococcus Toxin May Help CFS

In a randomized trial treating 100 fibromyalgia or CFS patients with staphylococcus toxin or placebo found that the treatment group had 65% responders (reduction of >50% of symptoms on a comprehensive rating scale) compared to 18% for placebo, p < 0.001. There was improvement at a p < 0.01 level in fatiguability, reduced sleep, failing memory, concentration difficulties, and sadness.[61]

Rituximab May Help CFS

Rituximab, an immunosuppressant drug that targets B cells, was found to improve fatigue scores in 67% of 30 patients in a randomized trial, compared to 13% of placebo. (p = 0.003). There were no adverse effects except a worsening of psoriasis in two patients.[62]

In an open-label follow-up from the same lab, 18 out of 29 patients on maintenance rituximab therapy for 15 months had clinically significant responses.[63]

Speculations

Reduced NK activity and viral reactivations naturally go together, and stress can cause both.  Cortisol usually inhibits NK activity, so long-term hypocortisolism might result in NK cells that become more sensitive to cortisol[65], a possible mechanism for how an impaired HPA axis could result in NK dysfunction and thence viral reactivation.  The picture that seems to be emerging is that prolonged stress and/or an acute viral infection can result in fatigue and immunocompromise. This would explain why there are often psychological comorbid factors.

If this is what’s going on, then the obvious intervention points would be to increase cortisol (particularly the phasic cortisol response to stress) and to increase NK activity.  Administering low dose corticosteroids seems to do reasonably well at the former. It’s not clear how to do the latter, but cytokines like IL-15 might work[66] and so might bacterial therapies like the staphylococcus toxin mentioned above.

References

[1]Roberts, Amanda DL, et al. “Salivary cortisol response to awakening in chronic fatigue syndrome.” The British Journal of Psychiatry 184.2 (2004): 136-141.

[2]Strickland, Paul, et al. “A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls.” Journal of Affective Disorders 47.1 (1998): 191-194.

[3]Jerjes, W. K., et al. “Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.” Journal of affective disorders 87.2 (2005): 299-304.

[4]Cleare, Anthony J., et al. “Urinary free cortisol in chronic fatigue syndrome.” American Journal of Psychiatry 158.4 (2001): 641-643.

[5]Scott, Lucinda V., and Timothy G. Dinan. “Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers.” Journal of Affective Disorders 47.1 (1998): 49-54.

[6]Cleare, Anthony J., et al. “Contrasting neuroendocrine responses in depression and chronic fatigue syndrome.” Journal of affective disorders 34.4 (1995): 283-289.

[7]Wood, Barbara, et al. “Salivary cortisol profiles in chronic fatigue syndrome.” Neuropsychobiology 37.1 (1998): 1-4.

[8]Nater, Urs M., et al. “Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls.” The Journal of Clinical Endocrinology & Metabolism 93.3 (2008): 703-709.

[9]Gaab, Jens, et al. “Low-dose dexamethasone suppression test in chronic fatigue syndrome and health.” Psychosomatic Medicine 64.2 (2002): 311-318.

[10]Scott, Lucinda V., Sami Medbak, and Timothy G. Dinan. “The low dose ACTH test in chronic fatigue syndrome and in health.” Clinical endocrinology 48.6 (1998): 733-737.

[11]Jerjes, Walid K., et al. “Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome.” Psychoneuroendocrinology 32.2 (2007): 192-198.

[12]Scott, Lucinda V., et al. “Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study.” Psychoneuroendocrinology 24.7 (1999): 759-768.

[13]Klimas, Nancy G., et al. “Immunologic abnormalities in chronic fatigue syndrome.” Journal of clinical microbiology 28.6 (1990): 1403-1410.

[14]Levine, Paul H., et al. “Dysfunction of natural killer activity in a family with chronic fatigue syndrome.” Clinical immunology and immunopathology 88.1 (1998): 96-104.

[15]Caligiuri, M. I. C. H. A. E. L., et al. “Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome.” The Journal of Immunology 139.10 (1987): 3306-3313.

[16]Patarca-Montero, Roberto, et al. “Immunology of chronic fatigue syndrome.” Journal of Chronic Fatigue Syndrome 6.3-4 (2000): 69-107.

[17]Strayer, D., V. Scott, and W. Carter. “Low NK cell activity in Chronic Fatigue Syndrome (CFS) and relationship to symptom severity.” J Clin Cell Immunol 6 (2015): 348.

[18]Orange, Jordan S. “Natural killer cell deficiency.” Journal of Allergy and Clinical Immunology 132.3 (2013): 515-525.

[19]Nerozzi, Dina, et al. “Reduced natural killer cell activity in major depression: neuroendocrine implications.” Psychoneuroendocrinology 14.4 (1989): 295-301.

[20]Sieber, William J., et al. “Modulation of human natural killer cell activity by exposure to uncontrollable stress.” Brain, behavior, and immunity 6.2 (1992): 141-156.

[21]Irwin, Michael, et al. “Reduction of immune function in life stress and depression.” Biological psychiatry 27.1 (1990): 22-30.

[22]Glaser, Ronald, et al. “Stress depresses interferon production by leukocytes concomitant with a decrease in natural killer cell activity.” Behavioral neuroscience 100.5 (1986): 675.

[23]Irwin, Michael, et al. “Plasma cortisol and natural killer cell activity during bereavement.” Biological psychiatry 24.2 (1988): 173-178.

[24]Irwin, Michael, et al. “Partial night sleep deprivation reduces natural killer and cellular immune responses in humans.” The FASEB journal 10.5 (1996): 643-653.

[25]Moldofsky, Harvey, et al. “Effects of sleep deprivation on human immune functions.” The FASEB Journal 3.8 (1989): 1972-1977.

[26]Buchwald, Dedra, et al. “Viral serologies in patients with chronic fatigue and chronic fatigue syndrome.” Journal of medical virology 50.1 (1996): 25-30.

[27]Sumaya, Ciro V. “Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic fatigue syndrome.” Review of Infectious Diseases 13.Supplement 1 (1991): S19-S25.

[28]Mawle, Alison C., et al. “Seroepidemiology of chronic fatigue syndrome: a case-control study.” Clinical Infectious Diseases 21.6 (1995): 1386-1389.

[29]Levine, Paul H., et al. “Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome.” Archives of internal medicine 152.8 (1992): 1611-1616.

[30]Buchwald, Dedra, et al. “A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.” Annals of internal medicine 116.2 (1992): 103-113.

[31]Holmes, Gary P., et al. “A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause?.” JAMA 257.17 (1987): 2297-2302.

[32]LERNER, A. MARTIN, et al. “IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome.” in vivo 18.2 (2004): 101-106.

[33]Swanink, Caroline MA, et al. “Epstein-Barr virus (EBV) and the chronic fatigue syndrome: normal virus load in blood and normal immunologic reactivity in the EBV regression assay.” Clinical infectious diseases 20.5 (1995): 1390-1392.

[34]Patnaik, Madhumita, et al. “Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome.” Journal of Infectious Diseases 172.5 (1995): 1364-1367.

[35]Sairenji, Takeshi, et al. “Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome.” Intervirology 38.5 (1995): 269-273.

[36]Ablashi, D. V., et al. “Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients.” Journal of Clinical Virology 16.3 (2000): 179-191.

[37]Yalcin, Safak, et al. “Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome.” Microbiology and immunology 38.7 (1994): 587-590.

[38]Di Luca, D. A. R. I. O., et al. “Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome.” Journal of clinical microbiology 33.6 (1995): 1660-1661.

[39]Koelle, David M., et al. “Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome.” Clinical Infectious Diseases 35.5 (2002): 518-525.

[40]Whelton, C. L., I. Salit, and H. Moldofsky. “Sleep, Epstein-Barr virus infection, musculoskeletal pain, and depressive symptoms in chronic fatigue syndrome.” The Journal of rheumatology 19.6 (1992): 939-943.

[41]Nicolson, G. L., R. Gan, and J. Haier. “Multiple co‐infections (Mycoplasma, Chlamydia, human herpes virus‐6) in blood of chronic fatigue syndrome patients: association with signs and symptoms.” Apmis 111.5 (2003): 557-566.

[42]Vojdani, A., et al. “Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome.” FEMS Immunology & Medical Microbiology 22.4 (1998): 355-365.

[43]Hickie, Ian, et al. “Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.” Bmj 333.7568 (2006): 575.

[44]Kerr, Jonathan R., et al. “Chronic fatigue syndrome and arthralgia following parvovirus B19 infection.” The Journal of Rheumatology 29.3 (2002): 595-602.

[45]Hickie, Ian, et al. “Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.” Bmj 333.7568 (2006): 575.

[46]Cleare, A. J., et al. “Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.” The Journal of Clinical Endocrinology & Metabolism 86.8 (2001): 3545-3554.

[47]Cleare, A. J., V. O’Keane, and J. P. Miell. “Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome.” Psychoneuroendocrinology 29.6 (2004): 724-732.

[48]Isaacs, Raphael. “Chronic infectious mononucleosis.” Blood 3.8 (1948): 858-861.

[49]Blockmans, Daniel, et al. “Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study.” The American journal of medicine 114.9 (2003): 736-741.

[50]Cleare, Anthony J., et al. “Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.” The Lancet 353.9151 (1999): 455-458.

[51]McKenzie, Robin, et al. “Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial.” Jama 280.12 (1998): 1061-1066.

[52]Citterio, Antonietta, et al. “Corticosteroids or ACTH for acute exacerbations in multiple sclerosis.” The Cochrane Library (2000).

[53]Hughes, R. A. C., et al. “European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.” European journal of neurology 13.4 (2006): 326-332.

[54]Hughes, Richard, et al. “Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.” Annals of neurology 50.2 (2001): 195-201.

[55]Sladky, John T., Mark J. Brown, and Peter H. Berman. “Chronic inflammatory demyelinating polyneuropathy of infancy: A corticosteroid‐responsive disorder.” Annals of neurology 20.1 (1986): 76-81.

[56]Schneider‐Gold, Christiane, et al. “Corticosteroids for myasthenia gravis.” The Cochrane Library (2005).

[57]Hughes, Richard AC, et al. “Corticosteroids for Guillain‐Barré syndrome.” The Cochrane Library (2006).

[58]Peterson, Phillip K., et al. “A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome.” The American journal of medicine 89.5 (1990): 554-560.

[59]Vollmer-Conna, Ute, et al. “Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome.” The American journal of medicine 103.1 (1997): 38-43.

[60]Lloyd, Andrew, et al. “A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome.” The American journal of medicine 89.5 (1990): 561-568.

[61]Zachrisson, Olof, et al. “Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome—a randomised controlled trial.” European Journal of Pain 6.6 (2002): 455-466.

[62]Fluge, Øystein, et al. “Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.” PloS one 6.10 (2011): e26358.

[63]Fluge, Øystein, et al. “B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. an open-label phase II study with rituximab maintenance treatment.” PLoS One 10.7 (2015): e0129898.

[64]Rowe, Katherine S. “Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents.” Journal of psychiatric research 31.1 (1997): 133-147.

[65]Gatti, Giovanni, et al. “Inhibition by cortisol of human natural killer (NK) cell activity.” Journal of steroid biochemistry 26.1 (1987): 49-58.

[66]Childs, Richard W., and Mattias Carlsten. “Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens.” Nature Reviews Drug Discovery 14.7 (2015): 487-498.