Monday, November 24, 2014

In the Clutches of Depression

Oh, that this too, too sullied flesh would melt,
Thaw, and resolve itself into a dew,
Or that the Everlasting had not fixed
His canon ’gainst self-slaughter! O God, God!
How weary, stale, flat, and unprofitable
Seem to me all the uses of this world!
Fie on ’t, ah fie! ’Tis an unweeded garden
That grows to seed. Things rank and gross in nature
Possess it merely. That it should come to this.
Hamlet

I need not speak to him to know he is not well. A simple glance tells me all. The patient’s unshaven face wears no smile and, at once, no frown. His vapid gaze lingers longer than it should on various objects or people or nothing at all. The slippers, pajama pants, and torn t-shirt express the disposition of their owner, unkempt and exhausted. His visage is neither pale nor tan nor some variation on one of these — it is like a bare tree on a late and chilly fall day. His brow barely responds even when he speaks and his susurrant replies to our questions are scarcely audible over the ambient sounds in the room. In conversation he rests his hands on his knees, palms up as if hoping to receive something to make this all end. I can only claim that he exists in physical form.

We, the psychiatry team, confronted in this patient a true disease of the mind; unchecked and unmitigated depression, eating away at the soul and destroying its possessor. One doesn’t require the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association to diagnose this young father with depression. But if we wanted to, we could look through it for criteria on diagnosis and treatment of this disease. A diagnosis of Major Depressive Disorder requires five of nine specific symptoms, which include depressed mood, decreased pleasure, change in appetite, change in sleep, and others, present nearly every day for more than two weeks. This makes the diagnosis “official,” though the definition and the name of the diagnosis lack the descriptive power to characterize its severity (and perhaps also a crispness that one wants out of any definition). Algis Valiunas, a fellow at the Ethics and Public Policy Center and a contributing editor to this journal, points this out in a wonderful 2007 essay in The New Atlantis, “Melancholy’s Whole Physician.” He writes that the term “depression” was “never appropriately ferocious to begin with, suggesting a mere dip in the road rather than the sulfurous sinkhole that engulfs you and all you love and sends you into infernal freefall like the host of wicked angels, plummeting in terror with no end in sight, no hope of seeing the beautiful face of God again.”

Still, we’ve chosen “depression” as the name for it and unfortunately this gives a false sense of innocuousness to the whole experience. We also, frankly, overuse the term which may contribute to that perception. Whenever we feel down or something hasn’t gone our way we claim depression, as if getting a flat tire marks a trough in our lives. But to see someone truly depressed gives new meaning to the word.

There was no triggering factor for this particular patient. He had dealt with depression his whole life. He never attempted suicide but his illness waxed and waned, sometimes waxing so powerfully that he could not work, love, or live outside of the pseudo-security of a dark room under his blanket.

Nobody is sure about the exact pathophysiology of depression, but physicians suspect it has to do with an imbalance of neurotransmitters, small molecules that bind receptors in the brain affecting happiness, sadness, and desire. Specifically, depressed patients often lack the neurotransmitter called serotonin, which functions in many different biological activities including vomiting, memory, blood pressure, pain, and others. Therefore, psychiatrists often begin treating depression with an SSRI (Selective Serotonin Reuptake Inhibitor) as well as cognitive behavioral therapy, which in combination are better than either alone. SSRIs work by preventing neurons from absorbing serotonin after they have transmitted a neural impulse, which allows serotonin to remain active for a longer period of time. And there is a 60–70 percent response rate to initial therapy with antidepressants. Other medications can be tried if these fail, including multiple SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors, and others.

After seeing multiple psychiatrists the patient had unsuccessfully tried many of these medications. Dr. Paul McHugh, former psychiatrist-in-chief at Johns Hopkins Hospital, describes the kind of hopelessness a patient like this feels when confronted with depression in a wonderful essay for Commentary Magazine. (A collection of his essays can be found in The Mind Has Mountains, a fascinating collection reviewed here in The New Atlantis). “You cannot choose for or against this disease. It chooses you, just as does epilepsy, cancer, or heart disease. It turns you into a stereotyped copy of every other person afflicted with it. You are not in charge of it, you are not to blame for it, and you can do little about it except seek the help that may enable you to escape its clutches.” When the medical help fails as it had for this patient, imagine the tightening of clutches, the sheer hopelessness compounded with the underlying pathology.

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The next option for this patient was Electroconvulsive Therapy (ECT). This is an effective last-ditch possibility for some patients with intractable depression as well as some patients with schizophrenia. (I will write about a schizophrenic patient in the next couple of posts.) The side effects of ECT include some ephemeral cognitive decline and memory loss. Anesthesiologists sedate the patient and the psychiatrist hooks the patient up to a machine and sends a series of electrical waves through the patient’s brain. The response to this therapy, which is relatively safe despite the possible conception of it as some barbaric torture method, depends on the individual. Some patients respond and feel better after one treatment. Others may need multiple treatments. Psychiatrists don’t fully understand why this works. Also, ECT does not always permanently fix depression; it often merely gives a brief respite, sometimes half a year, before the disease comes roaring back.

And this persistence of disease leads to even more problems, as Valiunas explains in his essay — it actually causes anatomical changes that further exacerbate depression, a vicious cycle. Examples of changes include destruction of glia, which supply nutrients to neurons and clean up their garbage, and atrophy of the hippocampus and amygdala, parts of the brain involved in memory and emotion.
This, of course, is why treatment of depression is so important and it explains why this disease, as Dr. McHugh points out, is not due to some “great personal or moral flaw, one that can be corrected if only [patients] would not let their emotions run amok.” No, the disease is very real and vicious.

I don’t know if ECT ever worked for this particular patient because, as seems to be so common a trope in this blog, I left the psychiatry service before I got to see the procedure performed on him. But I cross my fingers that when I run into him again I won’t recognize him at all.

Tuesday, November 18, 2014

On Evidence-Based Medicine

Physicians throw around the term “evidence-based medicine” a lot. Whether it’s an antibiotic, IV fluid, or blood-pressure pill, the decision about how to use a drug often comes down to the question: is the treatment evidence-based? But what does that mean? Evidence-based medicine is “the conscientious, explicit, and judicious use of current best evidence in making decisions” about patient care. This definition suggests that clinicians or researchers fastidiously tested and confirmed the effectiveness of an intervention with a robust, replicable, and accurate scientific study.

Designing a valid study, however, is difficult because there are many potential biases that can render its conclusions inaccurate. Here are some examples:

  • Selection bias occurs when subjects are assigned in a nonrandom manner to different study groups. If a physician runs a trial to test the efficacy of a drug he may put those who have a better prognosis in the treatment group, as opposed to the non-treatment group. Consequently, scientists can claim this new treatment is successful even though it was tested on those who were most likely to improve anyway.
     
  • Sampling bias, where subjects chosen for the study do not represent the general population, can mean that a study’s findings do not apply to the general population.
     
  • The Hawthorne effect arises when subjects change their behavior because they know they’re being watched by a researcher or physician.
     
  • Confounding bias describes a situation in which one factor can distort the effect of another. If a researcher studies the effects of alcohol on health but ignores the fact that many people who drink alcohol also smoke, alcohol will appear to have a worse effect on one’s health due to the consequences of smoking.
     
Another kind of bias has been in the news a lot recently with regard to prostate-cancer screening. Here’s how Dr. Michael S. Cookson, a urologist at Vanderbilt University, describes this kind of bias:

Lead-time bias suggests that the natural history of the disease is not truly affected by screening. For example, a patient may be diagnosed with prostate cancer at 50 years of age through ... screening. He then undergoes treatment but ultimately progresses and dies at 60 years of age. Accordingly, the same patient without screening develops symptomatic bony metastases [late stage cancer] at age 58, undergoes treatment with androgen deprivation therapy, and dies at age 60. Thus, in this theoretical scenario, even though he was diagnosed 8 years prior through screening, his death was not affected by screening or early detection.

In other words, early detection of cancer makes it seem as if your lifespan is increased simply because you know that you have cancer for a longer period of time. But you don’t necessarily live longer because of that.

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There are many other kinds of bias but the descriptions above give a sense of how difficult it is to design experiments without it. The most powerful studies account for bias with a double-blindedrandomized, and controlled trial. Participants and researchers are both blind in that they do not know who is getting the placebo treatment and who is getting the trial treatment. Participants must also be randomized to the treatment group or the placebo group — that way, there is no selection bias and there is less confounding bias. Controlled just means that there must be a control group, which is a group that does not receive the disease therapy or that receives the current best therapy for the disease. Researchers can then compare the effectiveness of the newest therapy to the current best available therapy. Another way to avoid confusing results is to use crossover studies, where a patient serves as his or her own control. The patient receives the real therapy for a given period of time and then receives the placebo for a given period of time thereby eliminating confounding bias.

A statue of Avicenna in Tajikistan
Nikita Maykov / Shutterstock.com
Interestingly, this approach to scientific studies, albeit a much less sophisticated version, dates back to the eleventh-century Islamic philosopher and physician, Avicenna. In his Canon of Medicine, a multivolume medical encyclopedia, Avicenna expanded upon the work of Galen, the ancient Greek physician. In her 2008 article “Islamic Pharmacology in the Middle Ages: Theories and Substances,” Danielle Jacquart explains that Avicenna endorsed the concept of using drugs based on past results of experiments:

As for the powers only known through experiment, these were not deduced from the qualities or the appearance of pharmaceutical ingredients, but they rather acted through their whole form or substance. Their action could only be revealed by an experimental test. Yet this did not mean that ordinary physicians themselves had to undertake such experiments. Rather, they relied upon experiments carried out by their predecessors.

Similarly, when today’s physicians choose, say, an antibiotic for a bacterial infection, they rely upon experiments carried out by their predecessors.

When I started medical school, I assumed that everything in medicine was evidence-based; that scientists rigorously studied and validated every treatment. After all, we should not treat a patient with a drug unless we know it works. But it turns out that there is not always evidence to support every decision physicians make. Perhaps a study has simply not been done or the evidence collected was equivocal or inconclusive. Or perhaps some real-life situation has arisen that is complicated in ways that could not possibly have been tested in an experiment. In these cases, physicians must base their decisions on experience.

Let’s take the example of IV fluids, which are a basic staple of medical care, as I’ve mentioned in multiple posts. One would think that the data would be fairly clear on which types of IV fluids are best. Unfortunately, it’s not at all evident. Some background: there are two major types of IV fluids, colloids and crystalloids. Crystalloids contain water and electrolytes that are similar to those circulating in the blood. Some examples of these are Lactated Ringer’s and Normal Saline. Colloid fluids contain water and electrolytes, too, but they also contain osmotic substances like albumin, which draw fluid into the vascular space. Fluid in the body can be inside the blood vessels or outside the blood vessels, and colloids keep fluids in the vessels.

Ostensibly, colloid fluids ought to work better in certain situations. For instance, when a patient has very low blood pressure, the way to increase blood pressure is to increase fluid within the vasculature. However two studies, one in the New England Journal of Medicine in 2004, and one in the Annals of Internal Medicine in 2001, concluded that there were no significant differences in mortality in various medical situations when using one type of fluid versus the other. So, barring significant differences in cost, which fluids does one use in the hospital when patients need hydration or increased blood pressure?
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Given that the evidence is unclear, we use what our mentors use. During surgery rounds, for example, I asked “why are we using Lactated Ringer’s (LR)?” A resident replied that the evidence was inconclusive and the attending used LR so he used LR. Until we have better evidence, this seems completely legitimate even if it makes us uneasy because there’s no clear consensus. Furthermore, this demonstrates that though certain ideas may make sense in theory, they fail when standing against the test of scientific rigor. Thus, evidence-based medicine also requires open-mindedness.

Let’s also look at an example of how evidence-based medicine changes medical practice rapidly on a day-to-day basis. This past summer, the treatment for Parkinson’s disease (PD), a disease of certain neurons in the brain, underwent a change. Previously, movement disorder neurologists recommended dopamine agonists as a first-line treatment for the disease. The alternative is carbidopa-levodopa, a medication that is more effective at controlling PD symptoms. However, carbidopa-levodopa causes more side effects, such as dyskinesias, or compulsive and uncontrollable movements (some of these can be irreversible), the longer one takes the medication. And, given that patients with PD can live a long time, neurologists wanted to put off using it so that patients would not experience these effects so soon after starting medication.

But this past June, a study in The Lancet compared starting a dopamine agonist with starting carbidopa-levodopa in patients with newly diagnosed, early PD. And the researchers found that there is not a significant difference in patient-rated mobility scores (a fancy way of saying movement difficulties as well as quality of life) when starting with levodopa rather than dopamine agonists. I observed the direct practice changes as a result of this study. In the neurology clinic, the attending, after reading this article, changed the way he spoke to patients with newly diagnosed PD. Instead of saying that it is better to avoid carbidopa-levodopa first, he told patients that it was their choice what drug they wanted to start taking. This is a wonderful example of why evidence-based medicine and research is so important and how it can affect the practice of medicine — very concretely, very directly, and very soon after the research is published.

Monday, November 3, 2014

Pregnancy and Awkward Realities

I can’t think of a more awkward social situation for a single, twenty-six-year-old male to be in. A previous experience as the only Jew in a room full of Catholics singing songs about Jesus didn’t hold a candle to this. I was observing a group of fifteen pregnant women discussing pregnancy and getting pregnancy screening tests. Nurse practitioners run this group to aid and educate pregnant women who do not have enough money to pay for individual physician visits or are uninsured or even undocumented. Some of the screening tests, which occur at specified times during pregnancy, include maternal blood pressures and weights, labs to identify low blood counts, tests for sexually transmitted diseases that are a danger both to the mother and the fetus, ultrasounds of the fetus, dopplers of fetal heartbeats, fundal heights (a measurement of the top of the pelvic bone to the top of the uterus) to assess fetal growth, and more.

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These tests provide obstetricians with abundant information about the health of the mother and the fetus. For example, a test for gestational diabetes determines whether the pregnant mother may have insulin resistance — a state in which she is unable to store sugar properly, which could cause the fetus to receive excessive sugar and grow too large, resulting in shoulder dystociahyperinsulinemia, and hypoglycemia at birth. Screening tests help physicians to identify these sorts of problems early enough to prevent complications.

Obstetricians also examine the cervix, which is the lower part of the uterus. It may be most helpful to think about it as the passageway between the vagina and the uterus. As females progress through childbirth the cervix dilates up to 10 centimeters to allow for passage of the baby from the uterus. The cervix effaces as well; that is, it shortens. Obstetricians check for fetal station, too, an assessment of how far down the fetal head lies in the pelvis — the range is -3 to +3, where +3 indicates imminent birth. They use monitors with probes to assess the fetal heart rate and uterine contractions. The fetal heart rate gives the physician a sense of the baby’s health status. If the baby’s heart slows down too much, the baby lacks oxygen, necessitating immediate delivery.

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The nurse practitioner performed these tests and more for each member of the group over the course of nine months. After some brief screening tests in this particular session, the women sat in a circle and played games. As the only male in the room, I had a difficult time participating in some of these. One game consisted of suggesting an object to bring to the hospital when it was time to have the baby and then listing all the objects the previous patients had come up with — one had to propose something new and remember what others had proposed. Some objects included: a fluffy pillow, baby clothes, a stuffed animal, an R&B CD, a scented candle (cinnamon), and others that I can’t recall. When it came around to being my turn, although I appreciated not being treated as just a fly on the wall I couldn’t help but feel at this moment like a knight in those scenes in Monty Python and the Holy Grail: “Run away! Run away!” I had the eyes of fifteen pregnant women on me. Some of them giggled, either with anticipation or, more likely, because my face turned red and I sheepishly grinned, declaring, “I shouldn’t be here.” I blurted out: “I feel like Arnold Schwarzenegger in Junior.” The reference was lost on every single person in that room; too young, I guess — or too terrible a movie to bother with. So I started to name the objects they had chosen, things that I probably would not take anywhere even if I did own them. I stumbled a bit but managed, with some help, to claw my way through it. When I then had to suggest an object I would bring if I were expecting, I said food. This was met with nods of approval. A love of food is one of those things that certain pregnant women and I share in common.

We next took a short break, during which the conversations mostly covered topics I couldn’t relate to: potential baby names (my only reference for that is this Seinfeld episode but after my previous pop-culture reference fell flat, I knew better than to mention it), pregnancy clothes, car seats, baby clothes, nail polish, and past episodes of morning sickness. I excused myself to “go to the bathroom,” which really meant “avoid the conversations and wander the halls until the break was over.” What else is a twenty-six-year-old male to do in this situation? This was so far removed from any of my experiences or thoughts. After the break, we watched a corny video about the process of giving birth — the acting was so bad that all the actors convinced me that they felt opposite what they claimed to feel. It was a nice time for me to check out mentally.

As ridiculous as this experience seemed at times, there is a deeper, more serious matter worth thinking about here. Many of these women were young enough to be in high school and needed a doctor’s note to excuse them from school. Some of them did not know who the baby’s father was; all except for two were unmarried; and many could not rely on anyone but a single parent for help. Sociologists have thoroughly studied the deleterious effects of these kinds of social situations. As Derek Thompson asserts in The Atlantic:

Among what you might consider “modern families” (e.g. the 61 million people married and living together, both working), there is practically no poverty. None. Among marriages where one person works and the other doesn’t (another 36 million Americans) the poverty rate is just under 10 percent. But take away one parent, and the picture changes rather dramatically. There are 62 million single-parent families in America. Forty-one percent of them (26 million households) don't have any full-time workers. This is something beyond a wage crisis. It’s a jobs crisis, a participation crisis — and it’s a major driver of our elevated poverty rate.

Indeed, Kay Hymowitz, the William E. Simon Fellow at the Manhattan Institute, writes in the Wall Street Journal that homes without married parents put children “at an enormous disadvantage from the very start of life.” Additionally, teen pregnancy itself causes a range of harmful consequences for both children and their mothers. The National Institutes of Health points out here that teen mothers are more likely to live in poverty, have infants with developmental problems, have baby girls who grow up to be teen mothers and have baby boys who grow up to be arrested and jailed. Furthermore, teen pregnancies have higher rates of illness and death for both the mother and the infant. Though the rates of teen pregnancy are dropping, the problem and its manifestations are evidently very real.

It is difficult to know what exactly the physician’s role should be in this process. How much should physicians encroach on the job of parents, who ought to address this issue with their children? When there are no stable parental figures in a child’s life, how much paternalism does the physician offer? Will such paternalism backfire? At what age is it appropriate to start speaking to teenagers (or preteens) about sexuality, reproduction, and parenting? And what is the best way to do it? Here’s the CDC’s anodyne take on it: “Make your clinic teen-friendly. Provide your adolescent patients with confidential, private, respectful and culturally competent services, convenient office hours, and complete information.” It’s not that easy, nor is it that benign.

The medical profession is unusual in that the private lives of patients are relevant to nearly every visit. Consequently, no matter how uncomfortable or awkward or humorous it may be for physicians, these issues inevitably come up. Undoubtedly, then, medical practitioners will play a role in this deeply significant sociological quandary — how large that role is depends on the physician and the specialty.