Is The Joke On Me?

May 12, 2012

I recently returned from the American Psychiatric Association (APA) Annual Meeting in Philadelphia.  I had the pleasure of participating on a panel discussing “psychiatrists and the new media” with the bloggers/authors from Shrink Rap, and Bob Hsiung of dr-bob.org.  The panel discussion was a success.  Some other parts of the conference, however, left me with a sense of doubt and unease.  I enjoy being a psychiatrist, but whenever I attend these psychiatric meetings, I sometimes find myself questioning the nature of what I do.  At times I wonder whether everyone else knows something I don’t.  Sometimes I even ask myself:  is the joke on me?

Here’s an example of what I mean.  On Sunday, David Kupfer of the University of Pittsburgh (and task force chair of the forthcoming DSM-5) gave a talk on “Rethinking Bipolar Disorder.”  The room—a cavernous hall at the Pennsylvania Convention Center—was packed.  Every chair was filled, while scores of attendees stood in the back or sat on the floor, listening with rapt attention.  The talk itself was a discussion of “where we need to go” in the management of bipolar disorder in the future.  Dr Kupfer described a new view of bipolar disorder as a chronic, multifactorial disorder involving not just mood lability and extremes of behavior, but also endocrine, inflammatory, neurophysiologic, and metabolic processes that deserve our attention as well.  He emphasized the fact that in between mood episodes, and even before they develop, there are a range of “dysfunctional symptom domains”—involving emotions, cognition, sleep, physical symptoms, and others—that we psychiatrists should be aware of.  He also introduced a potential way to “stage” development of bipolar disorder (similar to the way doctors stage tumors), suggesting that people at early stages might benefit from prophylactic psychiatric intervention.

Basically, the take-home message (for me, at least) was that in the future, psychiatrists will be responsible for treating other manifestations of bipolar disorder than those we currently attend to.  We will also need to look for subthreshold symptoms in people who might have a “prodrome” of bipolar disorder.

A sympathetic observer might say that Kupfer is simply asking us to practice good medicine, caring for the entire person rather than one’s symptoms, and prevent development or recurrence of bipolar illness.  On the other hand, a cynic might look at these pronouncements as a sort of disease-mongering, encouraging us to uncover signs of “disease” where they might not exist.  But both of these conclusions overlook a much more fundamental question that, to me, remains unanswered.  What exactly is bipolar disorder anyway?

I realize that’s an extraordinarily embarrassing question for a psychiatrist to ask.  And in all fairness, I do know what bipolar disorder is (or, at least, what the textbooks and the DSM-IV say it is).  I have seen examples of manic episodes in my own practice, and in my personal life, and have seen how they respond to medications, psychotherapy, or the passage of time.  But those are the minority.  Over the years (although my career is still relatively young), I have also seen dozens, if not hundreds, of people given the diagnosis of “bipolar disorder” without a clear history of a manic episode—the defining feature of bipolar disorder, according to the DSM.

As I looked around the room at everyone concentrating on Dr Kupfer’s every word, I wondered to myself, am I the only one with this dilemma?  Are my patients “special” or “unique”?  Maybe I’m a bad psychiatrist; maybe I don’t ask the right questions.  Or maybe everyone else is playing a joke on me.   That’s unlikely; others do see the same sorts of patients I do (I know this for a fact, from my own discussions with other psychiatrists).  But nobody seems to have the same crisis of confidence that I do.  It makes me wonder whether we have reached a point in psychiatry when psychiatrists can listen to a talk like this one (or see patients each day) and accept diagnostic categories, without paying any attention to the fact that they our nosology says virtually nothing at all about the unique nature of each person’s suffering.  It seems that we accept the words of our authority figures without asking the fundamental question of whether they have any basis in reality.  Or maybe I’m just missing out on the joke.

As far as I’m concerned, no two “bipolar” patients are alike, and no two “bipolar” patients have the same treatment goals.  The same can be said for almost everything else we treat, from “depression” to “borderline personality disorder” to addiction.  In my opinion, lumping all those people together and assuming they’re all alike for the purposes of a talk (or, even worse, for a clinical trial) makes it difficult—and quite foolish—to draw any conclusions about that group of individuals.

What we need to do is to figure out whether what we call “bipolar disorder” is a true disorder in the first place, rather than accept it uncritically and start looking for yet additional symptom domains or biomarkers as new targets of treatment.  To accept the assumption that everyone currently with the “bipolar” label indeed has the same disorder (or any disorder at all) makes a mockery of the diagnostic process and destroys the meaning of the word.  Some would argue this has already happened.

But then again, maybe I’m the only one who sees it this way.  No one at Kupfer’s talk seemed to demonstrate any bewilderment or concern that we might be heading towards a new era of disease management without really knowing what “disease” we’re treating in the first place.  If this is the case, I sure would appreciate it if someone would let me in on the joke.

54 Comments | bipolar, diagnostics, DSM-5, psychiatry | Tagged: , , , , | Permalink
Posted by stevebMD

The Unfortunate Therapeutic Myopia of the EMR

January 19, 2012

There’s a lot you can say about an electronic medical record (EMR).  Some of it is good: it’s more legible than a written chart, it facilitates billing, and it’s (usually) readily accessible.  On the other hand, EMRs are often cumbersome and confusing, they encourage “checklist”-style medicine, and they contain a lot of useless or duplicate information.  But a recent experience in my child/adolescent clinic opened my eyes to where an EMR might really mislead us.

David, a 9 year-old elementary school student, has been coming to the clinic every month for the last three years.  He carries a diagnosis of “bipolar disorder,” manifested primarily as extreme shifts in mood, easy irritability, insomnia, and trouble controlling his temper, both in the classroom and at home.  Previous doctors had diagnosed “oppositional defiant disorder,” then ADHD, then bipolar.  He had had a trial of psychostimulants with no effect, as well as some brief behavioral therapy.  Somewhere along the way, a combination of clonidine and Risperdal was started, and those have been David’s meds for the last year.

The information in the above paragraph came from my single interaction with David and his mom.  It was the first time I had seen David; he was added to my schedule at the last minute because the doctor he had been seeing for the last four months—a locum tenens doc—was unavailable.

Shortly before the visit, I had opened David’s EMR record to review his case, but it was not very informative.  Our EMR only allows one note to be open at a time, and I saw the same thing—”bipolar, stable, continue current meds”—and some other text, apparently cut & pasted, in each of his last 3-4 notes.  This was no big surprise; EMRs are full of cut & pasted material, plus lots of other boilerplate stuff that is necessary for legal & billing purposes but can easily be ignored.  The take-home message, at the time, was that David had been fairly stable for at least the last few months and probably just needed a refill.

During the appointment, I took note that David was a very pleasant child, agreeable and polite.  Mom said he had been “doing well.”  But I also noticed that, throughout the interview, David’s mom was behaving strangely—her head bobbed rhythmically side to side, and her arms moved in a writhing motion.  She spoke tangentially and demonstrated some acute (and extreme) shifts in emotion, at one point even crying suddenly, with no obvious trigger.

I asked questions about their home environment, David’s access to drugs and alcohol, etc., and I learned that mom used Vicodin, Soma, and Xanax.  She admitted that they weren’t prescribed to her—she bought them from friends.  Moreover, she reported that she “had just taken a few Xanax to get out the door this morning” which, she said, “might explain why I’m acting like this.”  She also shared with me that she had been sent to jail four years ago on an accusation of child abuse (she had allegedly struck her teenage daughter during an argument), at which time David and his brothers were sent to an emergency children’s shelter for four nights.

Even though I’m not David’s regular doctor, I felt that these details were relevant to his case.  It was entirely possible, in my opinion, that David’s home environment—a mother using prescription drugs inappropriately, a possible history of trauma—had contributed to his mood lability and “temper dysregulation,” something that a “bipolar” label might mask.

But I’m not writing this to argue that David isn’t “bipolar.”  Instead, I wish to point out that I obtained these details simply by observing the interaction between David and his mom over the course of ~30 minutes, and asking a few questions, and not by reading his EMR record.  In fact, after the appointment I reviewed the last 12 months of his EMR record, which showed dozens of psychiatrists’ notes, therapists’ notes, case manager’s notes, demographic updates, and “treatment plans,” and all of it was generally the same:  diagnosis, brief status updates, LOTS of boilerplate mumbo-jumbo, pages and pages of checkboxes, a few mentions of symptoms.  Nothing about David’s home situation or mom’s past.  In fact, nothing about mom at all.  I could not have been the first clinician to have had concerns about David’s home environment, but if such information was to be found in his EMR record, I had no idea where.

Medical charts—particularly in psychiatry—are living documents.  To any physician who has practiced for more than a decade or so, simply opening an actual, physical, paper chart can be like unfolding a treasure map:  you don’t know what you’ll find, but you know that there may be riches to be revealed.   Sometimes, while thumbing through the chart, a note jumps out because it’s clearly detailed or something relevant is highlighted or “flagged” (in the past, I learned how to spot the handwriting of the more perceptive and thorough clinicians).  Devices like Post-It notes or folded pages provide easy—albeit low-tech—access to relevant information.  Also, a thick paper chart means a long (or complicated) history in treatment, necessitating a more thorough review.  Sometimes the absence of notes over a period of time indicates a period of decompensation, a move, or, possibly a period of remission.  All of this is available, literally, at one’s fingertips.

EMRs are far more restrictive.  In David’s case, the EMR was my only source of information—apart from David himself.  And for David, it seemed sterile, bland, just a series of “check-ins” of a bipolar kid on Risperdal.  There was probably more info somewhere in there, but it was too difficult and non-intuitive to access.  Hence, the practice (adopted by most clinicians) of just opening up the patient’s most recent note—and that’s it.

Unfortunately, this leads to a therapeutic myopia that may change how we practice medicine.  EMRs, when used this way, are here-and-now.  They have become the medical equivalent of Facebook.  When I log on to the EMR, I see my patient’s most recent note—a “status update,” so to speak—but not much else.  It takes time and effort to search through a patient’s profile for more relevant historical info—and that’s if you know where to look.  After working with seven different EMRs in the last six years, I can say that they’re all pretty similar in this regard.  And if an electronic chart is only going to be used for its most recent note, there’s no incentive to be thorough.

Access to information is great.  But the “usability” of EMRs is so poor that we have easy access only to what the last clinician thought was important.  Or better yet, what he or she decided to document.  The rest—like David’s home life, the potential impact of his mother’s behavior on his symptoms, and environmental factors that require our ongoing attention, all of which may be far more meaningful than David’s last Risperdal dose—must be obtained “from scratch.”  If it is obtained at all.

24 Comments | computers, diagnostics, EMR, psychiatry | Tagged: , , , , , | Permalink
Posted by stevebMD

Abilify for Bipolar Maintenance: More Hard Questions

May 31, 2011

Much attention has been drawn to a recent PLoS Medicine article criticizing the evidence base for the use of Abilify as maintenance treatment for bipolar disorder.  The major points emphasized by most critics are, first, that the FDA approved Abilify for this purpose in 2005 on the basis of flawed and scanty evidence and, secondly, that the literature since that time has failed to point out the deficiencies in the original study.

While the above may be true, I believe these criticisms miss a more important point.  Instead of lambasting the FDA or lamenting the poor quality of clinical research, we psychiatrists need to use this as an opportunity to take a closer look at what we treat, why we treat, and how we treat.

Before elaborating, let me summarize the main points of the PLoS article.  The authors point out that FDA approval of Abilify was based on only one “maintenance” trial by Keck et al published in 2007.  The trial included only 161 patients (only 7 of whom, or 1.3% of the total 567 who started the study, were followed throughout 26 weeks of stabilization and 74 follow-up weeks of maintenance).  It also consisted of patients who had already been stabilized on Abilify; thus, it was “enriched” for patients who had already shown a good response to this drug.  Furthermore, the “placebo failures” consisted of patients who were abruptly withdrawn from Abilify and placed on placebo; their relapses might thus be attributed to the researchers’ “randomized discontinuation” design rather than the failure of placebo.  (For more commentary, including follow-up from Bristol-Myers Squibb, Abilify’s manufacturer, please see this excellent post on Pharmalot.)

These are all valid arguments.  But as I read the PLoS paper and the ongoing discussion ever since, I can’t help but think, so what??  First of all, most psychiatrists probably don’t know about the PLoS paper.  And even if they did, the major questions for me would be:  would the criticism of the Keck et al. study change the way psychiatrists practice?  Should it?

Let’s think about psychiatric illness for a moment.  Most disorders are characterized by an initial, abrupt onset or “episode.”  These acute episodes are usually treated with medications (plus or minus psychotherapy or other psychosocial interventions), often resulting in rapid symptomatic improvement—or, at the very least, stabilization of those symptoms.

One big, unanswered (and, unfortunately, under-asked) question in psychiatry is, then what?  Once a person is stabilized (which in some cases means nothing more than “he’s no longer a danger to himself or others”), what do we do?  We don’t know how long to treat patients, and there are no guidelines for when to discontinue medications.  Instead we hear the common refrain:  depression, schizophrenia, and bipolar disorder, are lifelong illnesses—”just like hypertension or diabetes”—and should be treated as such.

But is that true?  At the risk of sounding like a heretic (and, indeed, I’d be laughed out of residency if I had ever asked this question), are there some cases of bipolar disorder—or schizophrenia, or depression, for that matter—which only require brief periods of psychopharmacological treatment, or none at all?

The conventional wisdom is that, once a person is stabilized, we should just continue treatment.  And why not?  What doctor is going to take his patient off Abilify—or any other mood stabilizer or antipsychotic which has been effective in the acute phase—and risk a repeat mood episode?  None.  And if he does, would he attribute the relapse to the disease, or to withdrawal of the drug?  Probably to the disease.

For another example of what I’m talking about, consider Depakote.  Depakote has been used for decades and is regarded as a “prototypical” mood stabilizer.  Indeed, some of my patients have taken Depakote for years and have remained stable, highly functional, and without evidence of mood episodes.  But Depakote was never approved for the maintenance treatment of bipolar disorder (for a brilliant review of this, which raises some of the same issues as the current Abilify brouhaha, read this article by The Last Psychiatrist).  In fact, the one placebo-controlled study of Depakote for maintenance treatment of bipolar disorder showed that it’s no better than placebo.  So why do doctors use it? Because it works (in the acute phase.)  Why do patients take it?  Again, because it works—oh, and their doctors tell them to continue taking it.  As the old saying goes, “if it ain’t broke, don’t fix it.”

However, what if it is broke[n]?  Some patients indeed fail Depakote monotherapy and require additional “adjunctive” medication (which, BTW, has provided another lucrative market for the atypical antipsychotics).  In such cases, most psychiatrists conclude that the patient’s disease is worsening and they add the second agent.  Might it be, however, that after the patient’s initial “response” to Depakote, the medication wasn’t doing anything at all?

To be sure, the Abilify study may have been more convincing if it was larger, followed patients for a longer time, and had a dedicated placebo arm consisting of patients who had not been on Abilify in the initial stage.  But I maintain that, regardless of the outcome of such an “improved” trial, most doctors would still use Abilify for maintenance treatment anyway, and convince themselves that it works—even if the medication is doing absolutely nothing to the underlying biology of the disease.

The bottom line is that it’s easy to criticize the FDA for approving a drug on the basis of a single, flawed study.  It’s also easy to criticize a pharmaceutical company for cutting corners and providing “flawed” data for FDA review.  But when it comes down to it, the real criticism should be directed at a field of medicine which endorses the “biological” treatment of a disorder (or group of disorders) whose biochemical basis and natural history are not fully understood, which creates post hoc explanations of its successes and failures based on that lack of understanding, and which is unwilling to look itself in the mirror and ask if it can do better.

28 Comments | antipsychotics, bipolar, FDA, medications | Tagged: , , , , , | Permalink
Posted by stevebMD

Here’s A Disease. Do You Have It?

March 29, 2011

I serve as a consultant to a student organization at a nearby university.  These enterprising students produce patient-education materials (brochures, posters, handouts, etc) for several chronic diseases, and their mission—a noble one—is to distribute these materials to free clinics in underserved communities, with a goal to raise awareness of these conditions and educate patients on their proper management.

Because I work part-time in a community mental health clinic, I was, naturally, quite receptive to their offer to distribute some of their handiwork to my patients.  The group sent me several professional-looking flyers and brochures describing the key features of anxiety disorders, depression, PTSD, schizophrenia, and insomnia, and suggested that I distribute these materials to patients in my waiting room.

They do an excellent job at demystifying (and destigmatizing) mental illness, and describe, in layman’s terms, symptoms that may be suggestive of a significant psychiatric disorder (quoting from one, for example: “Certain neurotransmitters are out of balance when people are depressed.  They often feel sad, hopeless, helpless, lack energy, … If you think you may be depressed, talk to a doctor.”)  But just as I was about to print a stack of brochures and place them at the front door, I thought to myself, what exactly is our goal?

Experiencing symptoms of anxiety, depression, or insomnia doesn’t necessarily indicate mental illness or a need for medications or therapy; they might reflect a stressful period in one’s life or a difficult transition for which one might simply need some support or encouragement.  I feared that the questions posed in these materials may lead people to believe that there might be something “wrong” with them, when they are actually quite healthy.  (The target audience needs to be considered, too, but I’ll write more about that later.)

It led me to the question: when does “raising awareness” become “disease mongering”?

“Disease-mongering,” if you haven’t heard of it, is the (pejorative) term used to describe efforts to lead people to believe they have a disease when they most likely do not, or when the “disease” in question is so poorly defined as to be questionable in and of itself.  Accusations of disease-mongering have made in the area of bipolar disorder, fibromyalgia, restless legs syndrome, female sexual arousal disorder, “low testosterone,” and many others, and have mainly been directed toward pharmaceutical companies with a vested interest in getting people on their drugs.  (See this special issue of PLoS One for several articles on this topic.)

Psychiatric disorders are ripe for disease-mongering because they are essentially defined by subjective symptoms, rather than objective signs and tests.  In other words, if I simply recite the symptoms of depression to my doctor, he’ll probably prescribe me an antidepressant; but if I tell him I have an infection, he’ll check my temperature, my WBC count, maybe palpate some lymph nodes, and if all seems normal he probably won’t write me a script for an antibiotic.

It’s true that some patients might deliberately falsify or exaggerate symptoms in order to obtain a particular medication or diagnosis.  What’s far more likely, though, is that they are (unconsciously) led to believe they have some illness, simply on the basis of experiencing some symptoms that are, more or less, a slight deviation from “normal.”  This is problematic for a number of reasons.  Obviously, an improper diagnosis leads to the prescription of unnecessary medications (and to their undesirable side effects), driving up the cost of health care.  It may also harm the patient in other ways; it may prevent the patient from getting health insurance or a job, or—even more insidiously—lead them to believe they have less control over their thoughts or behaviors than they actually do.

When we educate the public about mental illness, and encourage people to seek help if they think they need it, we walk a fine line.  Some people who may truly benefit from professional help will ignore the message, saying they “feel fine,” while others with very minor symptoms which are simply part of everyday life may be drawn in.  (Here is another example, a flyer for childhood bipolar disorder, produced by the NIH; how many parents & kids might be “caught”?)  Mental health providers should never turn away someone who presents for an evaluation or assessment, but we also have an obligation to provide a fair and unbiased opinion of whether a person needs treatment or not.  After all, isn’t that our responsibility as professionals?  To provide our honest input as to whether someone is healthy or unhealthy?

I almost used the words “normal” and “abnormal” in the last sentence.  I try not to use these words (what’s “normal” anyway?), but keeping them in mind helps us to see things from the patient’s perspective.  When she hears constant messages touting “If you have symptom X then you might have disorder Y—talk to your doctor!” she goes to the doctor seeking guidance, not necessarily a diagnosis.

The democratization of medical and scientific knowledge is, in my opinion, a good thing.  Information about what we know (and what we don’t know) about mental illness should indeed be shared with the public.   But it should not be undertaken with the goal of prescribing more of a certain medication, bringing more patients into one’s practice, or doling out more diagnoses.  Prospective patients often can’t tell what the motives are behind the messages they see—magazine ads, internet sites, and waiting-room brochures may be produced by just about anyone —and this is where the responsibility and ethics of the professional are of utmost importance.

Because if the patient can’t trust us to tell them they’re okay, then are we really protecting and ensuring the public good?

(Thanks to altmentalities for the childhood bipolar flyer.)

13 Comments | diagnostics, mental health | Tagged: , , , , | Permalink
Posted by stevebMD

Are Your Thoughts Still Racing, Jiefang?

March 10, 2011

A recent Vanity Fair article described the trend by American pharmaceutical companies to conduct more clinical trials outside of the United States and Western Europe.  The writer and bioethicist Carl Elliott also detailed this trend in his book White Coat, Black Hat, and it has recently received increasing scrutiny in the media.  While much attention has focused on the ethical concerns of overseas clinical trials, I’m avoiding that hot topic for now and arguing that we should pay some attention to questions of clinical relevance.

This is no small matter.  The VF article reports that one-third of clinical trials by the 20 largest US-based pharmaceutical companies are conducted exclusively at foreign sites, and medications destined for use in the U.S. have been tested in almost 60,000 clinical trials in 173 countries since 2000.  The reasons for “outsourcing” clinical trials are not surprising:  cheaper costs, less restrictive regulations, more accessible subjects, and patients who are less likely to have taken other medications in the past, thus yielding a more “pure” population and, hopefully, more useful data.

At first glance, overseas clinical trials really shouldn’t be much of a problem.  The underlying biology of a disease should have nothing to do with where the diseased person lives.  Hypertension and hepatitis are probably quite similar, if not identical, whether the patient is in Boston or Bangalore.  An article in this month’s Archives of General Psychiatry appears to reinforce this concept, showing that rates of bipolar disorder—as well as its “severity” and “impact”—are similar in a variety of different international settings.  Hence, if you were to ask me where I’d do a clinical trial for a new bipolar medication, I’d probably go where it would cost less to do so (i.e., overseas), too.

But is this appropriate?  Just because we can find “bipolar disorder” in the U.S. and in Uganda, does this mean we should we treat it the same way?  Over at the blog 1boringoldman, Mickey has uncovered data showing that trials of Seroquel (an atypical antipsychotic) for bipolar depression are being conducted in 11 Chinese provinces.  You can search the data yourself at clinicaltrials.gov (a truly fantastic tool, BTW) and find that many other psychiatric drugs are being tested worldwide, for a wide range of indications.

To a lowly community psychiatrist like me, this raises a few red flags.  As I learned in my transcultural psychiatry lectures in med school and residency, the manifestations of disease—and the recommended treatment approaches—can vary dramatically based on the culture in which the disease appears.  Even in my own practice, “bipolar disorder” varies greatly from person to person:  a bipolar patient from a wealthy San Francisco suburb experiences her disease very differently from the patient from the poverty-stricken neighborhoods of East Oakland.  A good psychiatrist must respect these differences.  Or so I was taught.

In his book Crazy Like Us, author Ethan Watters gives numerous examples of this phenomenon on a much larger scale.  He argues that the cultural dimensions that frame a disease have a profound impact on how a patient experiences and interprets his or her symptoms.  He also describes how patients’ expectations of treatments (drugs, “talk” therapy) differ from culture to culture, and can determine the success or failure of a treatment.

Let’s say you asked me to treat Jiefang, a young peasant woman with bipolar disorder from Guangdong Province.  Before doing so, I would want to read up on her community’s attitudes towards mental illness (and try to understand what “bipolar disorder” itself means in her community, if anything), learn about the belief systems in place regarding her signs and symptoms, and understand her goals for treatment.  Before prescribing Seroquel (or any other drug, for that matter), I’d like to know how she feels about using a chemical substance which might affect her feelings, emotions, and behavior.  I imagine it would take me a while before Jiefang and I felt comfortable proceeding with this approach.

There’s just something fishy about scientists from a multinational Contract Research Organization hired by Astra-Zeneca, flying into Guangdong with their white coats and clipboards, recruiting a bunch of folks with (western-defined) bipolar disorder just like Jiefang, giving them various doses of Seroquel, measuring their responses to bipolar rating scales (developed by westerners, of course), and submitting those data for FDA approval.

I sure hope I’m oversimplifying things.  Then again, maybe not.  When the next me-too drug is “FDA approved” for schizophrenia or bipolar depression (or, gasp, fibromyalgia), how can I be sure that it was tested on patients like the ones in my practice?  Or even tested at all on patients who know what those diagnoses even mean?   There’s no way to tell anymore.

The “pathoplastic” features of disease—what Watters calls the “coloring and content”—make psychiatry fascinating.  But they’re often more than just details; they include the ways in which patients are influenced by public beliefs and cultural ideas, the forces to which they attribute their symptoms, and the faith (or lack thereof) they put into medications.  These factors must be considered in any attempt to define and treat mental illness.

Clinical trials have never resembled the “real world.”  But designing clinical trials that resemble our target patients even less—simply for the sake of bringing  a drug to market quickly and more cheaply—is not just unreal, but deceptive and potentially dangerous.

9 Comments | clinical trial, FDA, medications | Tagged: , , , , , , , , | Permalink
Posted by stevebMD

How Lithium Works (Maybe)

February 17, 2011

“Half of what we have taught you is wrong.  Unfortunately, we don’t know which half.”

— attributed to a Harvard Medical School dean at commencement, sometime in the 20th century

The above, possibly apocryphal, statement is often invoked to illustrate how dynamic the field of medicine can be, and how what we thought we once knew beyond a shadow of a doubt, sometimes turns out to be dead wrong.  It’s also a celebration of scientific progress; as we revise our pathophysiological models, we can develop more targeted therapeutics.

In this regard, psychiatry is no different from any other field of medicine.  We don’t know (yet) what we don’t know, but once we do, our treatments will improve.  At the same time, we need to be careful how we use this new information, lest it give us a false sense that we “know” something we don’t.

I thought of this question when I encountered a headline earlier today at psychcentral.com:  “How Lithium Works Finally Explained.” Talk about a tantalizing headline!  First used clinically in the late 1800s (and later “rediscovered” in the 1940s), and still used extensively as a mood stabilizer in bipolar disorder and as adjunctive treatment for major depression, lithium is one of the most widely prescribed medications in all of medicine.  Many patients report a very good response to lithium, and its efficacy has not been surpassed by the multitude of other mood stabilizing agents introduced in the last 40 years.

But there’s just one problem.  Nobody really knows how lithium works.  It’s an ion (similar to sodium), so it doesn’t bind to a receptor or transporter, like most other psychiatric drugs.  It doesn’t seem to affect membrane potential (and therefore neuron excitability), and it doesn’t seem to target any particular region of the brain, much less those thought to be involved in mood disorders.  It may inhibit intracellular messengers (the phosphatidylinositol pathway) or it might inhibit cellular differentiation (via the Wnt signaling pathway).  Maybe it blocks sodium ion transport.  Maybe it interacts with nitric oxide.  No one knows.  And yet it works.

So it was with great interest that I read the original paper cited in the Psychcentral article.  It’s a “mega-analysis,” published in the February 15 issue of Biological Psychiatry, of 321 bipolar patients in 11 centers worldwide who underwent MRI scans and were compared to non-bipolar controls.  Half of the bipolar patients were taking lithium.  To summarize the results, patients taking lithium had larger hippocampal and amygdala volumes than those not taking lithium, and patients with a longer history of bipolar disorder had reduced cerebral volumes.

The data, then, seem to be consistent with the idea of lithium as having a “trophic” effect—i.e., as a promoter of neuronal growth, at least in some brain structures.  But that’s about all we can say.  Whether this has anything to do with intracellular signaling or the Wnt pathway, or with any known nerve growth factors, is beyond the scope of this study.

So despite the exciting headline claiming to identify the “mechanism of lithium,” this is simply an observation, much like the observation about how antipsychotics may decrease brain volumes, about which I wrote last week.  It suggests further research to understand lithium’s effect on these regions.  But it may not be clinically relevant.

Lithium is a widely used drug because it works.  Period.  These new data add to our knowledge about bipolar disorder, but to assume that they help us understand bipolar patients any better than we did before, is incorrect.  Moreover, it may lead us to draw false conclusions about our patients (i.e., “he’s not responding to lithium so his hippocampus must be atrophied”) or, worse, reject or disregard data that don’t fit with our hypothesis.  I’d much rather prescribe a drug because I have years of experience using it, and have heard hundreds of patients endorse its benefit, rather than adhere to an incorrect theory, even a theory with “face validity” like lithium promoting nerve cell growth and differentiation.  In fact it’s not too hard to find arguments against this theory:  for starters, consider lithium’s teratogenic effects during human embryonic development.

Anyone who wants an accurate explanation for how a psychiatric drug works is, unfortunately, out of luck.  The serotonin hypothesis is a perfect example:  SSRIs work in a lot of patients, and the serotonin hypothesis helps to guide treatment, but it might be absolutely incorrect.  How many alternate explanations have we ignored because we want to believe that our model must be right?

We can, and should, continue to use SSRIs to treat depression, and lithium to treat bipolar disorder.  But we should be aware that our explanations of their mechanisms are mere hypotheses—nothing more.  And, moreover, that these hypotheses may be contradicted or proven wrong.  Because we don’t know which half of our knowledge is the correct half.

3 Comments | bipolar, medications | Tagged: , , , , , | Permalink
Posted by stevebMD