Sunday, March 24, 2013

The Heart is a Lonely Hunter

Carson McCullers wrote The Heart is a Lonely Hunter when she was 23. It became a literary sensation, though she was already suffering from rheumatic fever and would live most of her remaining life handicapped by a series of strokes. She wrote most often of love, loneliness, and empathy for the human condition.

I haven’t written a philosophical post in a while. Maybe because I’d done enough public searching for meaning in the first years. Maybe because so many read the blog now. And sometimes when I am busy, meaning is lost in the day to day of clinical medicine. In pain, addiction, success, coping, transcendence…but mostly pain, loss, and suffering. That is what people bring to me on a daily basis. And of all my elixirs to offer the most powerful is empathy.

Maybe when people longed for a thing that bad the longing made them trust in anything that might give it to them.
A psychiatrist’s job is a strange one. I sit with people as they cry. I try to sort out the influences of biological and psychologic pathology. I attempt to buttress the strengths and soothe and repair the weaknesses. And I never know what will happen, though I may have seen a similar patient walk through my door a hundred times, say a middle aged man drinking twelve beers a day. One of them gets worse, loses his family, the next one finds his path, quits drinking, and yet another sticks with six beers a day from here on out. Ten thousand variables walk in with every patient and we try to predict the possibilities.

It was funny, too, how lonesome a person could be in a crowded house.
I hate people, sometimes, their selfishness and my own. Our weakness and blindness. The mistakes we make over and over. And I love people, as they push through. It is a great gift that they will share with me all these daily despairs and victories. Sometimes I wish I could be more specific, but another part of my job is the vault of secrets, whether they are fantastic or heart wrenching.

One of the things I struggled with, initially, was a great sense of loneliness. Here I was with so many psychiatrists dismayed by my elixirs and not entirely sure the answer could be found by reading enough Kohut, Winnicot, or Freud. But the blogosphere is plentiful, the world of interested people almost limitless, despite the limitations of the medium and the egos and the foolishness.

I do not have any home. So why should I be homesick?
Our brittle weaknesses almost always come from places of pain. If someone is arrogant, outrageous, narcissistic, or lost, or too easily hurt…at the heart of it is insecurity and the ever-present pain. And where does the wish for finding some truth in the evolutionary medicine come from but dismay and pain? How many people have I seen die from heart disease or complications of diabetes? How many disabled from multiple sclerosis or lupus? And then the daily complaints of fatigue, depression, or constipation. I have few cures and far more questions to ask. 

The modern human race is a dysfunctional, limping family with awesome powers of energy and information. Here on the interweb we strike out and rant and rave and post pictures of our cats.

It was like they waited to tell each other things that had never been told before. What she had to say was terrible and afraid. But what he would tell her was so true that it would make everything all right.

When I sit with people who are dying, they tell me of their families. Their children and lives, and the people they meet on the street, and the color of the air at their favorite summer place. And when I sit with people who are living, they speak of the same, but hardly ever mention the color of the air.

Pain is the currency of my profession. For all doctors, perhaps, and all nurses. The rants, always, the raves, sometimes, and rarely, we hear about the cat pictures, which are, of course, the most important things. When you go out tomorrow try to remember to notice the colors in the sky and the crispness of the wind, because within those small details are serenity. The past is gone, the future is not here. The present is all we will ever hold and experience.

I’m a stranger in a strange land.
I am filled with stories, with sorrows and secrets. Carson McCullers knew these things at 23, and I am much older yet am still figuring them out. When do you call out the brutes, the proud, and the misguided? When do you succor their misery? What is the greater good? Is it silence and a smiling face, or a bitter cut, or perhaps manipulating a character weakness to serve a common end.

Some will benefit from the succor, others the cut. Some won’t learn, ever, and can only serve the good with the benign manipulation. All the terrible and glorious people and their ten thousand variables.

The most fatal thing a man can do is try to stand alone.
It seems like a long time ago that I wrote The Glorious Cause. And I still believe in it, that we have to move forward with open minds, honest skepticism, and a common respect for each other, for science, and for human health. But there are no seekers without flaws, no truths without pain, and no consensus without compromises. The question is are the compromises we make and the new friends we keep worth the cost? Each day those variables change, and the question differs, and the air carries a new scent and a new hue.

We learn so much when we go to those places that cause us pain, yet it sticks to us like glue, and we cannot be free, and we make the same foolish mistakes when we are beset by pain. I hope we can transcend and write and learn and move forward and break through. I hope we can do such a thing together, brute, nerd, narcissist, seeker, mother, warrior, and all the elements of the human family.

Perhaps we cannot get along. Perhaps the compromises we make are not honorable or worthy enough. Perhaps we are too small, too vulnerable, to make it work. That is the human condition, and it is not shameful.
I will not be hurried…kindly allow me to sit in peace a moment.
Every day we are dying. And every moment we live. Every moment there is an opportunity for weakness or triumph or love or serenity. Everything risks pain except perhaps serenity, and that may be why it is the nirvana of choice in lieu of happiness for the wise. The heart is a lonely hunter. We know so little, and expect so much.

Friday, March 22, 2013

Malnourishment in Infancy and Adult Personality Traits

I could have sworn I’d written about the Barbados long-term malnutrition follow-up study before, but I could not for the life of me remember the context or the name of the article. That’s the problem with having over 350 articles since 2010…I tried looking for the similarly-designed Mauritius study and found it at the bottom of this breezy post from last summer, Mainstreaming. In that study, poor nutrition in early childhood correlated with low IQ at age 12 and schizotypal personality traits at age 23. (Schizotypal traits in the Five Factor model include low self-directedness, introversion, and some distorted perceptions of reality, though an increased openness to new ideas).  It was felt the malnutrition resulted in poor development and functioning of the frontal lobes.

This week a new study came out from Barbados (1). 77 children who were admitted to the hospital at age 7 months for malnutrition were matched with 57 controls. All the malnourished children were subsequently enrolled in an interventional program from infancy until age 12. All 77 malnourished infants were otherwise healthy and achieved complete catch-up of growth by the end of puberty. The children and their matched classmates with no hospital admissions have been followed pretty much ever since. What is interesting about the original cohort is that malnutrition was a “reportable” disease in Barbados, so every child on the island who presented with malnutrition was subsequently enrolled in the same program. That means there is not extra "selection bias" in the malnourished cohort, besides the obvious that they were malnourished in the first place. In addition, on Barbados, education is compulsory until age 16, and 99% of the population is literate.

As children, the malnourished cohort had impaired IQ and poorer grades than their peers. They also had poorer attention and behavior, even after controlling for socioeconomics and family background. These problems persisted through adolescence, along with a greater tendency to be depressed. At age 40 years, both groups were given personality testing, measuring the tendency of the person to be open or withdrawn, altruistic or suspicious, angry, depressed, hopeful, and other measures such as whether the person tends to have irrational ideas, poor planning abilities, or brittle coping skills. All adults with IQ less than or equal to 70 were taken out of the sample, and a number of other measures that had been taken over the years, including questionnaires completed by their parents, were used to sort out other factors that might cause certain personality traits in mid-adulthood.

After all the data-crunching, the personality testing showed some significant differences between the previously malnourished cohort and their classmates. The malnourished cohort was more likely to have more negative feelings such as anxiety, anger and depression, seemed more vulnerable to stress, were less warm and gregarious, less trusting and less altruistic. They were less likely to consider new ideas and try to experience new things, and they also reported being less able to carry out plans, less punctuality and reliability. These significant differences remained after controlling for IQ and socioeconomic status in adulthood and childhood.

The malnourishment itself could have affected the brain, of course, particularly the frontal lobe and hippocampus, where it is known that early protein malnutrition can cause changes. In addition, maternal depression is associated with malnourishment in children, and maternal depression is known to affect childhood behavior and coping. Also, it is clear the early malnutrition was associated with other problems in childhood (behavioral issues, less ability to achieve in school) and these childhood experiences could have contributed to the adult personality differences as well.

Children born during the Dutch Famine in WWII were found to have an increased prevalence of antisocial and schizoid personality traits (which would include some of the traits studied here, such as decreased trust of others). In a Finnish study, children with slow growth in the first 6 months of life were more likely to be hospitalized later for personality disorders, particularly borderline and antisocial personality (2). No study had examined the personality particular traits in a Five Factor Personality questionnaire after 40 years of follow-up as was done in the Barbados cohort.

These are interesting studies and fascinating cohorts, and I think it is very plausible that early malnutrition would affect personality development and coping skills. It is also plausible that other kinds of maltreatment in early infancy could be factors as well. 

Monday, March 11, 2013

Folate and Negative Symptoms in Schizophrenia

The psychiatric symptoms of schizophrenia are defined in two major categories, "positive" and "negative." So-called positve symptoms are called so because they are an addition that people without psychosis don't experience, such as hallucinations and delusions and disorganized behavior. The negative symptoms represent functions being taken away from the brain and can be apathy, social withdrawal, and loss of motivation and emotional expressiveness.

Earlier today, a paper (free full text) was released from JAMA Psychiatry detailing a multi-center trial of placebo vs 2 mg folate and 400 micrograms of B12 for folks diagnosed with schizophrenia.  All the patients (140, aged 18-68)  had residual symptoms but were stabilized on antipsychotic medications for at least 6 months and on a stable dose for at least 6 weeks.

All the patients had genetic evaluations of their folate systems and measurements of red blood cell levels of folate. Red blood cell levels of folate don't necessarily correlate with levels in the central nervous system, which is just something to keep in mind. However, in other studies, folate metabolite measurements in the central nervous system seem to flatten and be maintained at a relatively moderate level of red blood cell folate, and levels correlate more closely at lower levels of folate.

The folate cycle is complicated. Please see this article and several articles linked from that one for more detail. However, in short, folate is an important nutrient necessary to make neurotransmitters, DNA, and also to help with the activation or deactivation of DNA via a process called methylation (which is basically just adding groups of -CH3 molecules).

Folate deficiency has long been linked to schizophrenia. Certain groups of people with hereditary deficits in their folate cycle metabolism are more likely to be schizophrenic than the general population, and cohorts of babies born during famines are more likely to develop schizophrenia a few decades later.  A few of the particular genes include the C77T variant of the MTHFR gene (the young man in the case study of B12 deficiency and psychosis had this variation of this gene). MTHFR is needed to make folate from food into the kinds of folate we use in the body, and many of us have a less efficient version of this enzyme. Each copy (we have two) of the C77T version (rather than C77C, the more typical version) reduces MTHFR activity by 35%. Other missense variants in genes coding for FOLH1 (a peptide that sits on the intestinal brush border and helps dietary folate be absorbed into the body), COMT, and methionine synthase also confer a higher risk of schizophrenia. More interestingly, problems with these genes will predict a greater negative symptom burden in schizophrenia but seem to have no relationship to the positive symptoms.

Back to the current study. Folate (in rather large doses, 2mg) and B12 were used together as the B12 would facilitate the action of the folate in helping the folate cycle… cycle through. In more biochemical terms, B12 is a cofactor for methionine synthase (MTR), which remethylates homocysteine into methionine, which is then converted into the universal methyl donor S-adenosylmethionine (SAMe). 

The long and the short of it…supplementation failed to separate from placebo for the general study group. HOWEVER, among those with the (more efficient) version of the FOLH1 gene and to a lesser degree among other folate cycle genetic variants, folate and B12 supplementation did seem to significantly help negative symptoms in schizophrenia, but not the positive ones.

An important point to make is that negative symptoms are extremely difficult to treat. It is, relatively speaking, fairly straightforward to decrease positive symptoms of hallucinations and disorganized behavior with medications in most people with psychosis. Apathy, social withdrawal, and flattened emotions tend to remain and be very debilitating. (In addition, the medicine can also cause a flattened affect). Therefore finding any intervention, particularly one with presumably far fewer side effects than antipsychotic medication that might help the negative symptoms is an exciting finding.

Genetic testing in psychiatry is still in its infancy. In many cases (such as finding if someone is a rapid metabolizer of certain antidepressants) the tests have modest usefulness in the Real World where such tests are generally paid for out of pocket. But with this study we are really starting to unlock some real clinical utility, and as genetic testing becomes cheaper and more readily available, it might help us design personalized treatments. 

Tuesday, March 5, 2013

The Grand Theory

Last week there was a bit of hubbub as a new paper was printed in The Lancet, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

The paper is a dense discussion of the higher maths of a large genome-wide association study. There’s all sorts of statistical wizardry going on with triple pseudocontrols and a number of things that are a bit above my pay grade, with my single statistics class from medical school and my genetics knowledge from the 20th century. But the gist of the paper is the following: after hacking the genome (using variations in genome markers, called SNPs, or “snips” to use the genetic parlance, meaning “genome-wide single nucleotide polymorphisms”) of many tens of thousands of cases and controls for people with autistic spectrum disorders, schizophrenia, bipolar disorder, major depressive disorder, and attention deficit hyperactivity disorder, several gene clusters were found that seemed to increase the risk of ALL FIVE of those disorders. Most of the genes found to increase the risk of these disorders were located within the coding for two L-type voltage-gated calcium channel subunits.

What? Okay, so we know that psychiatric diagnosis is a mess. We have the DSM (soon to be in its 5th iteration) which is basically a recipe list of symptoms. Find enough of your symptoms on the list, and voila, a diagnosis. The DSM is atheoretical ON PURPOSE. They make no pretensions at looking for pathology or brain chemistry issues or whatnot because, for the most part, back in 1980 when the DSMIII came out no one knew what the heck the actual pathology was. The earlier renditions did have some “causes” which led to some gems like the “schizophrenogenic mother,” and so instead of making horrible gaffes, the psychiatrists writing the DSMIII (and IV and V) really strove to see if there were clusters of symptoms that seemed to have some diagnostic validity without venturing into causes at all, so that researchers and clinicians and everyone could more or less speak the same language when talking about patients and trying to come up with evidenced-based treatments. The first MRI was built in 1977, and it’s only been since then (and really, since the invention of functional MRIs, advanced genetics with rapid PCR and PET scans and SPECT scans and the like) that we’ve really been able to see a bit more what is going on in a human brain in a living, thinking subject.

One of the frustrating (and great) things about psychiatry (and, frankly, medicine in general) is that you will almost never see a textbook case of anything. Most of my patients who show up at my office for the first time meet criteria for several diagnoses simultaneously. It’s easier to use symptoms as a benchmark rather than the full diagnoses, though for FDA purposes, treatments are researched based on diagnosis, not symptom. More recently genetic studies have shown links between various diagnoses (most notably, I think, bipolar disorder and schizophrenia, and schizophrenia and autism). While the diagnostic categories are quite clear, sometimes it can be quite difficult in practice to distinguish schizophrenia from bipolar disorder (so much so that there is a midway in between diagnosis called schizoaffective disorder), and many antipsychotic medications are approved for both treating the psychosis of schizophrenia and treating the manic episodes of bipolar disorder.

So what the new paper tells us is that these 5 different disorders of adult and childhood-onset diseases may well all be related. Voltage-gated calcium channels are little places in the cell membrane that decide, based on the voltage of the membrane at the time, whether to let a parade of positively charged calcium ions through the membrane. We need the particular calcium channel subunits coded by the genes found in the study for many brain processes, including functions involved with memory, planning, emotional processing and regulation, and attention. Another one of the calcium channels identified by the study helps other calcium channel subunits be turned on and off, whether by helping them travel to the membrane to set up shop, assist in their regulation by other molecules, or increase their function in other ways. 

A commentary on the study published at the same time in The Lancet spoke to the methods used in the study (and some of the weaknesses, geneticists, by all means, pull the papers and have a look). But it also tried to make some sense of the overall picture here. Basically we have many, many interacting factors that convey risk for psychiatric disorders.  

Prenatally, we have infectious disease, drugs, alcohol, nicotine, nutritional deficiencies, maternal stress and disease interacting with the genetic make-up of the baby. The postnatal environment of trauma, living conditions, nutrition, disease, etc can effect epigenetic changes which interact with brain plasticity to influence, along with the genetic make-up, disease vulnerability. So someone with an abnormal calcium channel gene in the wrong place at the wrong time (along with some other genetic and environmental issues) will get symptoms of ADHD. Another person (with the same calcium channel gene issue but different other genes, environment, etc.) will end up with schizophrenia.  Some with the gene will have no psychiatric disorder at all, I’m sure. 

Are we getting closer to upending the DSM? To define disease from the pathology upwards rather from the symptoms down? I hope so.