What Adderall Can Teach Us About Medical Marijuana

June 19, 2012

An article in the New York Times last week described the increasing use of stimulant medications such as Adderall and Ritalin among high-school students.  Titled “The Risky Rise of the Good-Grade Pill,” the article discussed how 15 to 40 percent of students, competing for straight-As and spots in elite colleges, use stimulants for an extra “edge,” regardless of whether they actually have ADHD.  In this blog, I’ve written about ADHD.  It’s a real condition—and medications can help tremendously—but the diagnostic criteria are quite vague.  As with much in psychiatry, anyone “saying the right thing” can relatively easily get one of these drugs, whether they want it or not.

Sure enough, the number of prescriptions for these drugs has risen 26% since 2007.  Does this mean that ADHD is now 26% more prevalent?  No.  In the Times article, some students admitted they “lie to [their] psychiatrists” in order to “get something good.”  In fact, some students “laughed at the ease with which they got some doctors to write prescriptions for ADHD.”  In the absence of an objective test (some computerized tests exist but aren’t widely used nor validated, and brain scans are similarly circumspect) and diagnostic criteria that are readily accessible on the internet, anyone who wants a stimulant can basically get one.  And while psychiatric diagnosis is often an imperfect science, in many settings the methodology by which we assess and diagnose ADHD is particularly crude.

Many of my colleagues will disagree with (or hate) me for saying so, but in some sense, the prescription of stimulants has become just like any other type of cosmetic medicine.  Plastic surgeons and dermatologists, for instance, are trained to perform medically necessary procedures, but they often find that “cosmetic” procedures like facelifts and Botox injections are more lucrative.  Similarly, psychiatrists can have successful practices in catering to ultra-competitive teens (and their parents) and giving out stimulants.  Who cares if there’s no real disease?  Psychiatry is all about enhancing patients’ lives, isn’t it?  As another blogger wrote last week, some respectable physicians have even argued that “anyone and everyone should have access to drugs that improve performance.”

When I think about “performance enhancement” in this manner, I can’t help but think about the controversy over medical marijuana.  This is another topic I’ve written about, mainly to question the “medical” label on something that is neither routinely accepted nor endorsed by the medical profession.  Proponents of medical cannabis, I wrote, have co-opted the “medical” label in order for patients to obtain an abusable psychoactive substance legally, under the guise of receiving “treatment.”

How is this different from the prescription of psychostimulants for ADHD?  The short answer is, it’s not.  If my fellow psychiatrists and I prescribe psychostimulants (which are abusable psychoactive substances in their own right, as described in the pages of the NYT) on the basis of simple patient complaints—and continue to do so simply because a patient reports a subjective benefit—then this isn’t very different from a medical marijuana provider writing a prescription (or “recommendation”) for medical cannabis.  In both cases, the conditions being treated are ill-defined (yes, in the case of ADHD, it’s detailed in the DSM, which gives it a certain validity, but that’s not saying much).  In both cases, the conditions affect patients’ quality of life but are rarely, if ever, life-threatening.  In both cases, psychoactive drugs are prescribed which could be abused but which most patients actually use quite responsibly.  Last but not least, in both cases, patients generally do well; they report satisfaction with treatment and often come back for more.

In fact, taken one step further, this analogy may turn out to be an argument in favor of medical marijuana.  As proponents of cannabis are all too eager to point out, marijuana is a natural substance, humans have used it for thousands of years, and it’s arguably safer than other abusable (but legal) substances like nicotine and alcohol.  Psychostimulants, on the other hand, are synthetic chemicals (not without adverse effects) and have been described as “gateway drugs” to more or less the same degree as marijuana.  Why one is legal and one is not simply appears to be due to the psychiatric profession’s “seal of approval” on one but not the other.

If the psychiatric profession is gradually moving away from the assessment, diagnosis, and treatment of severe mental illness and, instead, treating “lifestyle” problems with drugs that could easily be abused, then I really don’t have a good argument for denying cannabis to patients who insist it helps their anxiety, insomnia, depression, or chronic pain.

Perhaps we should ask physicians take a more rigorous approach to ADHD diagnosis, demanding interviews with parents and teachers, extensive neuropsychiatric testing, and (perhaps) neuroimaging before offering a script.  But in a world in which doctors’ reimbursements are dwindling, and the time devoted to patient care is vanishing—not to mention a patient culture which demands a quick fix for the problems associated with the stresses of modern adolescence—it doesn’t surprise me one bit that some doctors will cut corners and prescribe without a thorough workup, in much the same way that marijuana is provided, in states where it’s legal.  If the loudest protests against such a practice don’t come from our leadership—but instead from the pages of the New York Times—we only have ourselves to blame when things really get out of hand.

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The Evidence of the Anecdote

June 8, 2012

The foundation of medical decision-making is “evidence-based medicine.”  As most readers know, this is the effort to use the best available evidence (using the scientific method) to make decisions and recommendations about how to treat individual patients.  “Evidence” is typically rated on four levels (1 to 4).  Level 1 represents high-quality evidence—usually the results of randomized clinical trials—while level 4 typically consists of case studies, uncontrolled observations, and anecdotal reports.

Clinical guidelines and drug approvals typically rely more heavily (or even exclusively) on level-1 evidence.  It is thought to be more valid, more authoritative, and less affected by variations among individuals.  For example, knowing that an antidepressant works (i.e., it gives a “statistically significant effect” vs placebo) in a large, controlled trial is more convincing to the average prescriber than knowing that it worked for a single depressed guy in Peoria.

But is it, really?  Not always (especially if you’re the one treating that depressed guy in Peoria).  Clinical trials can be misleading, even if their results are “significant.”  As most readers know, some investigators, after analyzing data from large industry-funded clinical trials, have concluded that antidepressants may not be effective at all—a story that has received extensive media coverage.  But lots of individuals insist that they do work, based on personal experience.  One such depression sufferer—who benefited greatly from antidepressants—wrote a recent post on the Atlantic Online, and quoted Peter Kramer: “to give the impression that [antidepressants] are placebos is to cause needless suffering” because many people do benefit from them.  Jonathan Leo, on the other hand, argues that this is a patently anti-scientific stance.  In a post this week on the website Mad In America, Leo points out (correctly) that there are people out there who will give recommendations and anecdotes in support of just about anything.  That doesn’t mean they work.

Both sides make some very good points.  We just need to find a way to reconcile them—i.e., to make the “science” more reflective of real-world cases, and use the wisdom of individual cases to influence our practice in a more scientifically valid way.  This is much easier said than done.

While psychiatrists often refer to the “art” of psychopharmacology, make no mistake:  they (we) take great pride in the fact that it’s supposedly grounded in hard science.  Drug doses, mechanisms, metabolites, serum levels, binding coefficients, polymorphisms, biomarkers, quantitative outcome measures—these are the calling cards of scientific investigation.  But when medications don’t work as planned (which is often), we improvise, and when we do, we quickly enter the world of personal experience and anecdote.  In fact, in the absence of objective disease markers (which we may never find, frankly), psychiatric treatment is built almost exclusively on anecdotes.  When a patient says a drug “worked” in some way that the data don’t support, or they experience a side effect that’s not listed in the PDR, that becomes the truth, and it happens far more frequently than we like to admit.

It’s even more apparent in psychotherapy.  When a therapist asks a question like “What went through your mind when that woman rejected you?” the number of possible responses is infinite, unlike a serum lithium level or a blood pressure.  A good therapist follows the patient’s story and individualizes treatment based on the individual case (and only loosely on some theory or therapeutic modality).  The “proof” is the outcome with that particular patient.  Sure, the “N” is only 1, but it’s the only one that counts.

Is there any way to make the science look more like the anecdotal evidence we actually see in practice?  I think not.  Most of us don’t even stop to think about how UN-convincing the “evidence” truly is.  In his book Pharmageddon, David Healy describes the example of the parachute:  no one needs to do a randomized, controlled trial to show that a parachute works.  It just does.   By comparison, to show that antidepressants “work,” drug companies must perform large, expensive trials (and often multiple trials at that) and even then, prove their results through statistical measures or clever trial designs.  Given this complexity, it’s a wonder that we believe clinical trials at all.

On the other side of the coin, there’s really no way to subject the anecdotal report, or case study, to the scientific method.  By definition, including more patients and controls (i.e., increasing the “N”) automatically introduces heterogeneity.  Whatever factor(s) led a particular patient to respond to Paxil “overnight” or to develop a harsh cough on Abilify are probably unique to that individual.

But maybe we can start looking at anecdotes through a scientific lens.  When we observe a particular response or effect, we ought to look not just at the most obvious cause (e.g., a new medication) but at the context in which it occurred, and entertain any and all alternative hypotheses.  Similarly, when planning treatment, we need to think not just about FDA-approved drugs, but also patient expectations, treatment setting, home environment, costs, other comorbidities, the availability of alternative therapies, and other data points or “independent variables.”  To use a crude but common analogy, it is indeed true that every person becomes his or her own laboratory, and should be viewed as such.

The more we look at patients this way, the further we get from clinical trials and the less relevant clinical trials become.  This is unfortunate, because—for better or for worse (I would vote for “worse”)—clinical trials have become the cornerstone of evidence-based psychiatry.  But a re-emphasis on anecdotes and individual cases is important.  Because in the end, it’s the individual who counts.  The individual resembles an N of 1 much more closely than he or she resembles an N of 200, and that’s probably the most important evidence we need to keep in mind.


“Trainwrecks”

May 15, 2012

One of the highlights of the American Psychiatric Association (APA) Annual Meeting is the Exhibit Hall.  Here, under bright lights and fancy multimedia displays, sponsors get to show off their new wares.  If anyone wonders whether modern psychiatry isn’t all about psychopharmacology, one visit to the APA Exhibit Hall would set them straight.  Far and away, the biggest and glitziest displays are those of Big Pharma, promising satisfaction and success—and legions of grateful patients—for prescribing their products.

At the 2012 Annual Meeting last week, I checked out most of the Pharma exhibits, mainly just to see what was in the pipeline.  (Not much, it turns out.)  I didn’t partake in any of the refreshments—lest I be reported to the Feds as the recipient of a $2 cappuccino or a $4 smoothie—but still felt somewhat like an awestruck Charlie Bucket in Willie Wonka’s miraculous Chocolate Factory.

One memorable exchange was at the Nuedexta booth.  Nuedexta, as readers of this blog may recall from a 2011 post, is a combination of dextromethorphan and quinidine, sold by Avanir Pharmaceuticals and approved for the treatment of “pseudobulbar affect,” or PBA.  PBA is a neurological condition, found in patients with multiple sclerosis or stroke, and characterized by uncontrollable laughing and crying.  While PBA can be a devastating condition, treatment options do exist.  In my blog post I wrote that “a number of medications, including SSRIs like citalopram, and tricyclic antidepressants (TCAs), are effective in managing the symptoms of PBA.”  One year later, Nuedexta still has not been approved by the FDA for any other indication than PBA.

In my discussion with the Avanir salesman, I asked the same question I posed to the Avanir rep one year ago:  “If I had a patient in whom I suspected PBA, I’d probably refer him to his neurologist for management of that condition—so why, as a psychiatrist, would I use this medication?”  The rep’s answer, delivered in that cool, convincing way that can only emerge from the salesman’s anima, was a disturbing insight into the practice of psychiatry in the 21st century:

“Well, you probably have some patients who are real trainwrecks, with ten things going on.  Chances are, there might be some PBA in there, so why not try some Nuedexta and see if it makes a difference?”

I nodded, thanked him, and politely excused myself.  (I also promptly tweeted about the exchange.)  I don’t know if his words comprised an official Nuedexta sales pitch, but the ease with which he shared it (no wink-wink, nudge-nudge here) suggested that it has proven successful in the past.  Quite frankly, it’s also somewhat ugly.

First of all, I refuse to refer to any of my patients as “trainwrecks.”  Doctors and medical students sometimes use this term to refer to patients with multiple problems and who, as a result, are difficult to care for.  We’ve all used it, myself included.  But the more I empathize with my patients and try to understand their unique needs and wishes, the more I realize how condescending it is.  (Some might refer to me as a “trainwreck,” too, given certain aspects of my past.)  Furthermore, many of the patients with this label have probably—and unfortunately—earned it as a direct result of psychiatric “treatment.”

Secondly, as any good scientist will tell you, the way to figure out the inner workings of a complicated system is to take it apart and analyze its core features.  If a person presents an unclear diagnostic picture, clouded by a half-dozen medications and no clear treatment goals, the best approach is to take things away and see what remains, not to add something else to the mix and “see if it makes a difference.”

Third, the words of the Avanir rep demonstrate precisely what is wrong with our modern era of biological psychopharmacology.  Because the syndromes and “disorders” we treat are so vague, and because many symptoms can be found in multiple conditions—not to mention everyday life—virtually anything a patient reports could be construed as an indication for a drug, with a neurobiological mechanism to “explain” it.  This is, of course, exactly what I predicted for Nuedexta when I referred to it as a “pipeline in a pill” (a phrase that originally came from Avanir’s CEO).  But the same could be said for just about any drug a psychiatrist prescribes for an “emotional” or “behavioral” problem.  When ordinary complaints can be explained by tenuous biological pathways, it becomes far easier to rationalize the use of a drug, regardless of whether data exist to support it.

Finally, the strategy of “throw a medication into the mix and see if it works” is far too commonplace in psychiatry.  It is completely mindless and ignores any understanding of the underlying biology (if there is such a thing) of the illnesses we treat.  And yet it has become an accepted treatment paradigm.  Consider, for instance, the use of atypical antipsychotics in the treatment of depression.  Not only have the manufacturers of Abilify and Seroquel XR never explained how a dopamine partial agonist or antagonist (respectively) might help treat depression, but look at the way they use the results of STAR*D to help promote their products.  STAR*D, as you might recall, was a large-scale, multi-step study comparing multiple antidepressants which found that no single antidepressant was any better than any other.  (All were pretty poor, actually.)  The antipsychotic manufacturers want us to use their products not because they performed well in STAR*D (they weren’t even in STAR*D!!!) but because nothing else seemed to work very well.

If the most convincing argument we can make for a drug therapy is “well, nothing else has worked, so let’s try it,” this doesn’t bode well for the future of our field.  This strategy is mindless and sloppy, not to mention potentially dangerous.  It opens the floodgates for expensive and relatively unproven treatments which, in all fairness, may work in some patients, but add to the iatrogenic burden—and diagnostic confusion—of others.  It also permits Pharma (and the APA’s key opinion leaders) to maintain the false promise of a neurochemical solution for the human, personal suffering of those who seek our help.

This, in my opinion, is the real “trainwreck” that awaits modern psychiatry.  And only psychiatrists can keep us on the tracks.


Sleeping Pills Are Deadly? Says Who, Exactly?

March 1, 2012

As most readers know, we’re paying more attention than ever before to conflicts of interest in medicine.   If an individual physician, researcher, speaker, or author is known to have a financial relationship with a drug company, we publicize it.  It’s actually federal law now.  The idea is that doctors might be biased by drug companies who “pay” them (either directly—through gifts, meals, or cash—or indirectly, through research or educational grants) to say or write things that are favorable to their drug.

A recent article on the relationship between sedative/hypnotics and mortality, published this week in BMJ Open (the online version of the British Medical Journal) and widely publicized, raises additional questions about the conflicts and biases that individual researchers bring to their work.

Co-authors Daniel Kripke, of UC San Diego, and Robert Langer, of the Jackson Hole Center for Preventive Medicine, reviewed the electronic charts of over 30,000 patients in a rural Pennsylvania health plan.  Approximately 30% of those patients received at least one prescription for a hypnotic (a benzodiazepine like Klonopin or Restoril, or a sleeping agent like Lunesta or Ambien) during the five-year study period, and there was a strong relationship between hypnotics and risk of death.  The more prescriptions one received, the greater the likelihood that one would die during the study period.  There was also a specifically increased risk of cancer in groups receiving the largest number of hypnotic prescriptions.

The results have received wide media attention.  Mainstream media networks, major newspapers, popular websites, and other outlets have run with sensational headlines like “Higher Death Risk With Sleeping Pills” and “Sleeping Pills Can Bring On the Big Sleep.”

But the study has received widespread criticism, too.  Many critics have pointed out that concurrent psychiatric diagnoses were not addressed, so mortality may have been related more to suicide or substance abuse.  Others point out the likelihood of Berkson’s Bias—the fact that the cases (those who received hypnotic prescriptions) may have been far sicker than controls, despite attempts to match them.  The study also failed to report other medications patients received (like opioids, which can be dangerous when given with sedative/hypnotics) or to control for socioeconomic status.

What has not received a lot of attention, however, is the philosophical (and financial) bias of the authors.  Lead author Daniel Kripke has been, for many years, an outspoken critic of the sleeping pill industry.  He has also widely criticized the conventional wisdom that people need 8 or more hours of sleep per night.  He has written books about it, and was even featured on the popular Showtime TV show “Penn & Teller: Bullshit!” railing against drug companies (and doctors) who profit by prescribing sleep meds.  Kripke is also one of the pioneers of “bright light therapy” (using high-intensity light to affect circadian rhythms)—first in the area of depression, and, most recently, to improve sleep.  To the best of my knowledge, he has no financial ties to the makers of light boxes.  Then again, light boxes are technically not medical devices and, therefore, are not regulated by the FDA, so he may not be required to report any affiliation.  Nevertheless, he clearly has had a decades-long professional interest in promoting light therapy and demonizing sleeping pills.

Kripke’s co-author, Robert Langer, is an epidemiologist, a past site coordinator of the Women’s Health Initiative, and a staunch advocate of preventive medicine.  More importantly, though (and advertised prominently on his website), he is an expert witness in litigation involving hormone replacement therapy (HRT), and also in cancer malpractice cases.  Like Kripke, he has also found a place in the media spotlight; he will be featured in “Hot Flash Havoc,” a movie about HRT in menopausal women, to be released later this month.

[Interestingly, Kripke and Langer also collaborated on a 2011 study showing that sleep times >6.5 hrs or <5 hrs were associated with increased mortality.  One figure looked virtually identical to figure 1 in their BMJ paper (see below).  It would be interesting to know whether mortality in the current study is indeed due to sedative prescriptions or, if the results of their earlier paper are correct, simply due to the fact that the people requesting sedative prescriptions in the first place are the ones with compromised sleep and, therefore, increased mortality.  In other words, maybe the sedative is simply a marker for something else causing mortality—the same argument raised above.]

Do the authors’ backgrounds bias their results?  If Kripke and Langer were receiving grants and speakers’ fees from Forest Labs, and published an article extolling the benefits of Viibryd, Forest’s new antidepressant, how would we respond?  Might we dig a little deeper?  Approach the paper with more skepticism?  Is the media publicizing this study (largely uncritically) because its conclusion resonates with the “politically correct” idea that psychotropic medications are bad?  Michael Thase (a long-time pharma-sponsored researcher and U Penn professor) was put in the hot seat on “60 Minutes” a few weeks ago about whether antidepressants provide any benefit, but Kripke and Langer—two equally prominent researchers—seem to be getting a free ride, as far as the media are concerned.

I’m not trying to defend the drug industry, and I’m certainly not defending sedatives.  My own bias is that I prefer to minimize my use of hypnotics in my patients—although my opposition is not so much because of their cancer or mortality risk, but rather the risk of abuse, dependence, and their effect on other psychiatric and medical symptoms.  The bottom line is, I want to believe the BMJ study.  But more importantly, I want the medical literature to be objective, fair, and unbiased.

Unfortunately, it’s hard—if not impossible—to avoid bias, particularly when you’ve worked in a field for many years (like Kripke and Langer) and have a strong belief about why things are the way they are.  In such a case, it seems almost natural that you’d want to publish research providing evidence in support of your belief.  But when does a strongly held belief become a conflict of interest?  Does it contribute to a bias in the same way that a psychopharmacologist’s financial affiliation with a drug company might?

These are just a few questions that we’ll need to pay closer attention to, as we continue to disclose conflicts of interest among medical professionals.  Sometimes bias is obvious and driven by one’s pocketbook, other times it is more subtle and rooted in one’s beliefs and experience.  But we should always be wary of the ways in which it can compromise scientific objectivity or lead us to question what’s really true.


ADHD: A Modest Proposal

February 1, 2012

I’m reluctant to write a post about ADHD.  It just seems like treacherous ground.  Judging by comments I’ve read online and in magazines, and my own personal experience, expressing an opinion about this diagnosis—or just about anything in child psychiatry—will be met with criticism from one side or another.  But after reading L. Alan Sroufe’s article (“Ritalin Gone Wild”) in this weekend’s New York Times, I feel compelled to write.

If you have not read the article, I encourage you to do so.  Personally, I agree with every word (well, except for the comment about “children born into poverty therefore [being] more vulnerable to behavior problems”—I would remind Dr Sroufe that correlation does not equal causation).  In fact, I wish I had written it.  Unfortunately, it seems that only outsiders or retired psychiatrists can write such stuff about this profession. The rest of us might need to look for jobs someday.

Predictably, the article has attracted numerous online detractors.  For starters, check out this response from the NYT “Motherlode” blog, condemning Dr Sroufe for “blaming parents” for ADHD.  In my reading of the original article, Dr Sroufe did nothing of the sort.  Rather, he pointed out that ADHD symptoms may not entirely (or at all) arise from an inborn neurological defect (or “chemical imbalance”), but rather that environmental influences may be more important.  He also remarked that, yes, ADHD drugs do work; children (and adults, for that matter) do perform better on them, but those successes decline over time, possibly because a drug solution “does nothing to change [environmental] conditions … in the first place.”

I couldn’t agree more.  To be honest, I think this statement holds true for much of what we treat in psychiatry, but it’s particularly relevant in children and adolescents.  Children are exposed to an enormous number of influences as they try to navigate their way in the world, not to mention the fact that their brains—and bodies—continue to develop rapidly and are highly vulnerable.  “Environmental influences” are almost limitless.

I have a radical proposal which will probably never, ever, be implemented, but which might help resolve the problems raised by the NYT article.  Read on.

First of all, you’ll note that I referred to “ADHD symptoms” above, not “ADHD.”  This isn’t a typo.  In fact, this is a crucial distinction.  As with anything else in psychiatry, diagnosing ADHD relies on documentation of symptoms.  ADHD-like symptoms are extremely common, particularly in child-age populations.  (To review the official ADHD diagnostic criteria from the DSM-IV, click here.)  To be sure, a diagnosis of ADHD requires that these symptoms be “maladaptive and inconsistent with developmental level.”  Even so, I’ve often joked with my colleagues that I can diagnose just about any child with ADHD just by asking the right questions in the right way.  That’s not entirely a joke.  Try it yourself.  Look at the criteria, and then imagine you have a child in your office whose parent complains that he’s doing poorly in school, or gets in fights, or refuses to do homework, or daydreams a lot, etc.  When the ADHD criteria are on your mind—remember, you have to think like a psychiatrist here!—you’re likely to ask leading questions, and I guarantee you’ll get positive responses.

That’s a lousy way of making a diagnosis, of course, but it’s what happens in psychiatrists’ and pediatricians’ offices every day.  There are more “valid” ways to diagnose ADHD:  rating scales like the Connors or Vanderbilt surveys, extensive neuropsychiatric assessment, or (possibly) expensive imaging tests.  However, in practice, we often let subthreshold scores on those surveys “slide” and prescribe ADHD medications anyway (I’ve seen it plenty); neuropsychiatric assessments are often wishy-washy (“auditory processing score in the 60th percentile,” etc); and, as Dr Sroufe correctly points out, children with poor motivation or “an underdeveloped capacity to regulate their behavior” will most likely have “anomalous” brain scans.  That doesn’t necessarily mean they have a disorder.

So what’s my proposal?  My proposal is to get rid of the diagnosis of ADHD altogether.  Now, before you crucify me or accuse me of being unfit to practice medicine (as one reader—who’s also the author of a book on ADHD—did when I floated this idea on David Allen’s blog last week), allow me to elaborate.

First, if we eliminate the diagnosis of ADHD, we can still do what we’ve been doing.  We can still evaluate children with attention or concentration problems, or hyperactivity, and we can still use stimulant medications (of course, they’d be off-label now) to provide relief—as long as we’ve obtained the same informed consent that we’ve done all along.  We do this all the time in medicine.  If you complain of constant toe and ankle pain, I don’t immediately diagnose you with gout; instead, I might do a focused physical exam of the area and recommend a trial of NSAIDs.  If the pain returns, or doesn’t improve, or you have other features associated with gout, I may want to check uric acid levels, do a synovial fluid analysis, or prescribe allopurinol.

That’s what medicine is all about:  we see symptoms that suggest a diagnosis, and we provide an intervention to help alleviate the symptoms while paying attention to the natural course of the illness, refining the diagnosis over time, and continually modifying the therapy to treat the underlying diagnosis and/or eliminate risk factors.  With the ultimate goal, of course, of minimizing dangerous or expensive interventions and achieving some degree of meaningful recovery.

This is precisely what we don’t do in most cases of ADHD.  Or in most of psychiatry.  While exceptions definitely exist, often the diagnosis of ADHD—and the prescription of a drug that, in many cases, works surprisingly well—is the end of the story.  Child gets a diagnosis, child takes medication, child does better with peers or in school, parents are satisfied, everyone’s happy.  But what caused the symptoms in the first place?  Can (or should) that be fixed?  When can (or should) treatment be stopped?  How can we prevent long-term harm from the medication?

If, on the other hand, we don’t make a diagnosis of ADHD, but instead document that the child has “problems in focusing” or “inattention” or “hyperactivity” (i.e., we describe the specific symptoms), then it behooves us to continue looking for the causes of those symptoms.  For some children, it may be a chaotic home environment.  For others, it may be a history of neglect, or ongoing substance abuse.  For others, it may be a parenting style or interaction which is not ideal for that child’s social or biological makeup (I hesitate to write “poor parenting” because then I’ll really get hate mail!).  For still others, there may indeed be a biological abnormality—maybe a smaller dorsolateral prefrontal cortex (hey! the DLPFC!) or delayed brain maturation.

ADHD offers a unique platform upon which to try this open-minded, non-DSM-biased approach.  Dropping the diagnosis of “ADHD” would have a number of advantages.  It would encourage us to search more deeply for root causes; it would allow us to be more eclectic in our treatment; it would prevent patients, parents, doctors, teachers, and others from using it as a label or as an “excuse” for one’s behavior; and it would require us to provide truly individualized care.  Sure, there will be those who simply ask for the psychostimulants “because they work” for their symptoms of inattentiveness or distractibility (and those who deliberately fake ADHD symptoms because they want to abuse the stimulant or because they want to get into Harvard), but hey, that’s already happening now!  My proposal would create a glut of “false negative” ADHD diagnoses, but it would also reduce the above “false positives,” which, in my opinion, are more damaging to our field’s already tenuous nosology.

A strategy like this could—and probably should—be extended to other conditions in psychiatry, too.  I believe that some of what we call “ADHD” is truly a disorder—probably multiple disorders, as noted above; the same is probably true with “major depression,” ”bipolar disorder,” and just about everything else.  But when these labels start being used indiscriminately (and unfortunately DSM-5 doesn’t look to offer any improvement), the diagnoses become fixed labels and lock us into an approach that may, at best, completely miss the point, and at worst, cause significant harm.  Maybe we should rethink this.


Whatever Works?

January 29, 2012

My iPhone’s Clock Radio app wakes me each day to the live stream of National Public Radio.  Last Monday morning, I emerged from my post-weekend slumber to hear Alix Spiegel’s piece on the serotonin theory of depression.  In my confused, half-awake state, I heard Joseph Coyle, professor of psychiatry at Harvard, remark: “the ‘chemical imbalance’ is sort of last-century thinking; it’s much more complicated than that.”

Was I dreaming?  It was, admittedly, a surreal experience.  It’s not every day that I wake up to the voice of an Ivy League professor lecturing me in psychiatry (those days are long over, thank Biederman god).  Nor did I ever expect a national news program to challenge existing psychiatric dogma.  As I cleared my eyes, though, I realized, this is the real deal.  And it was refreshing, because this is what many of us have been thinking all along.  The serotonin hypothesis of depression is kaput.

Understandably, this story has received lots of attention (see here and here and here and here and here).  I don’t want to jump on the “I-told-you-so” bandwagon, but instead to offer a slightly different perspective.

A few disclaimers:  first and foremost, I agree that the “chemical imbalance” theory has overrun our profession and has commandeered the public’s understanding of mental illness—so much so that the iconic image of the synaptic cleft containing its neurotransmitters has become ensconced in the national psyche.  Secondly, I do prescribe SSRIs (serotonin-reuptake inhibitors), plus lots of other psychiatric medications, which occasionally do work.  (And, in the interest of full disclosure, I’ve taken three of them myself.  They did nothing for me.)

To the extent that psychiatrists talk about “chemical imbalances,” I can see why this could be misconstrued as “lying” to patients.  Ronald Pies’ eloquent article in Psychiatric Times last summer describes the chemical-imbalance theory as “a kind of urban legend,” which no “knowledgeable, well-trained psychiatrist” would ever believe.  But that doesn’t matter.  Thanks to us, the word is out there.  The damage has already been done.  So why, then, do psychiatrists (even the “knowledgeable, well-trained” ones) continue to prescribe SSRI antidepressants to patients?

Because they work.

Okay, maybe not 100% of the time.  Maybe not even 40% of the time, according to antidepressant drug trials like STAR*D.  Experience shows, however, that they work often enough for patients to come back for more.  In fact, when discussed in the right context, their potential side effects described in detail, and prescribed by a compassionate and apparently intelligent and trusted professional, antidepressants probably “work” far more than they do in the drug trials.

But does that make it right to prescribe them?  Ah, that’s an entirely different question.  Consider the following:  I may not agree with the serotonin theory, but if I prescribe an SSRI to a patient with depression, and they report a benefit, experience no obvious side effects, pay only $4/month for the medication, and (say) $50 for a monthly visit with me, is there anything wrong with that?  Plenty of doctors would say, no, not at all.  But what if my patient (justifiably so) doesn’t believe in the serotonin hypothesis and I prescribe anyway?  What if my patient experiences horrible side effects from the drug?  What if the drug costs $400/month instead of $4?  What if I charge the patient $300 instead of $50 for each return visit?  What if I decide to “augment” my patient’s SSRI with yet another serotonin agent, or an atypical antipsychotic, causing hundreds of dollars more, and potentially causing yet more side effects?  Those are the aspects that we don’t often think of, and constitute the unfortunate “collateral damage” of the chemical-imbalance theory.

Indeed, something’s “working” when a patient reports success with an antidepressant; exactly why and how it “works” is less certain.  In my practice, I tell my patients that, at individual synapses, SSRIs probably increase extracellular serotonin levels (at least in the short-term), but we don’t know what that means for your whole brain, much less for your thoughts or behavior.  Some other psychiatrists say that “a serotonin boost might help your depression” or “this drug might act on pathways important for depression.”   Are those lies?  Jeffrey Lacasse and Jonathan Leo write that “telling a falsehood to patients … is a serious violation of informed consent.”  But the same could be said for psychotherapy, religion, tai chi, ECT, rTMS, Reiki, qigong, numerology, orthomolecular psychiatry, somatic re-experiencing, EMDR, self-help groups, AA, yoga, acupuncture, transcendental meditation, and Deplin.  We recommend these things all the time, not knowing exactly how they “work.”

Most of those examples are rather harmless and inexpensive (except for Deplin—it’s expensive), but, like antidepressants, all rest on shaky ground.  So maybe psychiatry’s problem is not the “falsehood” itself, but the consequences of that falsehood.  This faulty hypothesis has spawned an entire industry capitalizing on nothing more than an educated guess, costing our health care system untold millions of dollars, saddling huge numbers of patients with bothersome side effects (or possibly worse), and—most distressingly to me—giving people an incorrect and ultimately dehumanizing solution to their emotional problems.  (What’s dehumanizing about getting better, you might ask?  Well, nothing, except when “getting better” means giving up one’s own ability to manage his/her situation and instead attribute their success to a pill.)

Dr Pies’ article in Psychiatric Times closed with an admonition from psychiatrist Nassir Ghaemi:  “We must not be drawn into a haze of promiscuous eclecticism in our treatment; rather, we must be guided by well-designed studies and the best available evidence.”  That’s debatable.  If we wait for “evidence” for all sorts of interventions that, in many people, do help, we’ll never get anywhere.  A lack of “evidence” certainly hasn’t eliminated religion—or, for that matter, psychoanalysis—from the face of the earth.

Thus, faulty theory or not, there’s still a place for SSRI medications in psychiatry, because some patients swear by them.  Furthermore—and with all due respect to Dr Ghaemi—maybe we should be a bit more promiscuous in our eclecticism.  Medication therapy should be offered side-by-side with competent psychosocial treatments including, but not limited to, psychotherapy, group therapy, holistic-medicine approaches, family interventions, and job training and other social supports.  Patients’ preferences should always be respected, along with safeguards to protect patient safety and prevent against excessive cost.  We may not have good scientific evidence for certain selections on this smorgasbord of options, but if patients keep coming back, report successful outcomes, and enter into meaningful and lasting recovery, that might be all the evidence we need.


(Mis)informed Consent

December 20, 2011

Over the years, the practice of medicine has become less of an art, and more a process of crossing T’s and dotting I’s.  “Treating the chart” has become, in many ways, more important than treating the patient, and it seems that the pen—or, rather, the electronic medical record—has emerged as a more valuable tool than the stethoscope or reflex hammer.

For psychiatrists, one of the pesky little details of any office visit is obtaining “informed consent.”  Most commonly, this is the document—signed by the patient—stating that he/she has been fully informed of the reason they’re being prescribed a medication, the potential risks of taking said medication, and any possible alternatives.  Most private insurers and hospitals, and all Medicaid programs, require this documentation in the charts of patients seeing mental health specialists, and (at least in my experience) these documents are frequently sought in chart audits.

What do I mean by “pesky”?  Put briefly, the process of obtaining informed consent can be time-consuming, and some doctors worry that it might actually interfere with treatment.  In a 2004 survey, for instance, 44% of psychiatrists reported that “informed consent … increases patients’ anxiety.”  With respect to antipsychotics, nearly 20% of psychiatrists in the same study admitted “it is good practice to withhold information about tardive dyskinesia from some patients.”  As a result, patients are often poorly informed about the meds they take.  In a 2001 study of psychiatric inpatients in Scotland, fewer than half knew the reason they were receiving medication, the side effects of those medications, or even remembered getting an explanation from staff.  (But, according to the survey, far more than half were “happy to take all medications”!!)

I was recently asked for some suggestions on how to improve the medication-consent process in my outpatient clinic.  I must admit, the current process is atrocious.  Our forms are 10+ years old, with general descriptions of each class of medication (and, of course, they lack any drug introduced in the last decade); and they have that “photocopy of a photocopy” appearance, with faded margins and text at a crooked angle.  But hey, no big deal—they’re just papers to sign and stick in the chart, basically.  In the community clinic where I work part-time, the process is even more rudimentary: we have one generic form with no drug names or descriptions; the front-desk staff asks each patient to sign the form before each visit, and afterward I simply write in the name of the medication(s) I’ve prescribed.

In thinking of ways to improve the process, I’ve come to realize that it may provide an opportunity for some meaningful change in our treatment approach.

First of all, there’s no excuse for not describing the potential adverse effects of the drugs we use, but we must be cautious not to trivialize this process.  Most psychiatrists I know, for example, have a readymade “speech” about the potential for rash with Lamictal, or weight gain with Zyprexa, or sedation with Seroquel.  (See this post at Shrink Rap—and its comments—for more on this perspective.)  But if the patient hears this as just a “speech,” it’s less likely to be meaningful, just like the pre-flight safety lectures you hear on airplanes.  I advise my students and residents to pretend they’re prescribing to their spouse, parent, or child, and give all the information they would want to hear about each new drug.  (This includes how to stop the medication, too.)

Second, just as important as the potential adverse effects, I believe that patients need to hear more specific explanations of how the drug might actually provide some benefit.  All too often we give a feeble explanation like “this Prozac should make you feel better in a few weeks” or ” Valium might calm your nerves a bit” or “since you haven’t responded to your antidepressant, here’s some Abilify to help it along.”  We owe it to our patients (and to ourselves) to provide more detailed explanations.  To be sure, most patients don’t need to hear a molecular mechanism, complete with pKa values or details of CYP450 metabolism, but we ought to have this information in our heads, and we must know how we’re using this information to treat the patient in front of us.  When a patient asks how an antipsychotic might help their depression, or why an anticonvulsant might help stabilize their mood, we must give an answer.  (And if no good answer is possible, we need to rethink our treatment plan.)

Third, it is equally important to discuss treatment options with a patient.   When patients ask “is there anything else I can do or take?” the ensuing discussion might extend the appointment by a few minutes, but it always leads to a more collaborative dialogue (unless, of course, the patient is fishing for a Xanax prescription or a month’s supply of Seroquel to sell for cash).  A discussion of alternatives often gives an indication of what the patient wants, what the patient values, and how we can best promote the patient’s recovery.

Finally, the informed consent process really should be extended to non-psychiatrists who prescribe these agents.  Primary-care docs routinely prescribe antidepressants, benzodiazepines, psychostimulants, and mood stabilizers (and, of course, my personal favorite, “Seroquel for sleep”), without a discussion of risks, benefits, and alternatives, or (in most cases) a signed consent form.  Heck, even gastroenterologists prescribe Reglan, which is as likely to cause tardive dyskinesia as many of the antipsychotics we use in psychiatry, and pain specialists are fond of Cymbalta (an SNRI with some potentially nasty withdrawal effects) for “chronic pain.”  These providers should recognize the potential risks (and mechanisms) of psychotropics, just as psychiatrists do, and share them with their patients.

So even though we might look at obtaining informed consent as a “necessary evil,” we should instead look at it as a way to enhance treatment.  If nothing else, this would force us to think about what we do and why we do it.  It would enable us to honestly evaluate the true benefits and risks of what we prescribe, and maybe steer us in a different—and healthier—direction.


Latuda-Palooza: Marketing or Education?

October 2, 2011

In my last blog post, I wrote about an invitation I received to a symposium on Sunovion Pharmaceuticals’ new antipsychotic Latuda.  I was concerned that my attendance might be reported as a “payment” from Sunovion under the requirements of the Physicians Payment Sunshine Act.  I found it a bit unfair that I might be seen as a recipient of “drug money” (and all the assumptions that go along with that) when, in fact, all I wanted to do was learn about a new pharmaceutical agent.

As it turns out, Sunovion confirmed that my participation would NOT be reported (they start reporting to the feds on 1/1/12), so I was free to experience a five-hour Latuda extravaganza yesterday in San Francisco.  I was prepared for a marketing bonanza of epic proportion—a la the Viagra launch scene in “Love And Other Drugs.”  And in some ways, I got what I expected:  two outstanding and engaging speakers (Dr Stephen Stahl of NEI and Dr Jonathan Meyer of UCSD); a charismatic “emcee” (Richard Davis of Arbor Scientia); an interactive “clicker” system which allowed participants to answer questions throughout the session and check our responses in real time; full lunch & breakfast, coffee and snacks; all in a posh downtown hotel.  (No pens or mugs, though.)

The educational program consisted of a plenary lecture by Dr Stahl, followed by workshops in which we broke up into “teams” and participated in three separate activities:  first, a set of computer games (modeled after “Pyramid” and “Wheel Of Fortune”) in which we competed to answer questions about Latuda and earn points for our team; second, a “scavenger hunt” in which we had 5 minutes to find answers from posters describing Latuda’s clinical trials (sample question: “In Study 4 (229), what proportion of subjects withdrew from the Latuda 40 mg/d treatment arm due to lack of efficacy?”); and finally, a series of case studies presented by Dr Meyer which used the interactive clicker system to assess our comfort level in prescribing Latuda for a series of sample patients.  My team came in second place.

I must admit, the format was an incredibly effective way for Sunovion to teach doctors about its newest drug.  It reinforced my existing knowledge—and introduced me to a few new facts—while it was also equally accessible to physicians who had never even heard about Latuda.

Moreover, the information was presented in an unbiased fashion.  Unbiased?, you may ask.  But wasn’t the entire presentation sponsored by Sunovion?  Yes, it was, but in my opinion the symposium achieved its stated goals:  it summarized the existing data on Latuda (although see here for some valid criticism of that data); presented it in a straightforward, effective (and, at times, fun) way; and allowed us doctors to make our own decisions.  (Stahl did hint that the 20-mg dose is being studied for bipolar depression, not an FDA-approved indication, but that’s also publicly available on the clinicaltrials.gov website.)  No one told us to prescribe Latuda; no one said it was better than any other existing antipsychotic; no one taught us how to get insurance companies to cover it; and—in case any “pharmascold” is still wondering—no one promised us any kickbacks for writing prescriptions.

(Note:  I did speak with Dr Stahl personally after his lecture.  I asked him about efforts to identify patient-specific factors that might predict a more favorable response to Latuda than to other antipsychotics.  He spoke about current research in genetic testing, biomarkers, and fMRI to identify responders, but he also admitted that it’s all guesswork at this point.  “I might be entirely wrong,” he admitted, about drug mechanisms and how they correlate to clinical response, and he even remarked “I don’t believe most of what’s in my book.”  A refreshing—and surprising—revelation.)

In all honesty, I’m no more likely to prescribe Latuda today than I was last week.  But I do feel more confident in my knowledge about it.  It is as if I had spent five hours yesterday studying the Latuda clinical trials and the published Prescribing Information, except that I did it in a far more engaging forum.  As I mentioned to a few people (including Mr Davis), if all drug companies were to hold events like this when they launch new agents, rather than letting doctors decipher glossy drug ads in journals or from their drug reps, doctors would be far better educated than they are now when new drugs hit the market.

But this is a very slippery slope.  In fact, I can’t help but wonder if we may be too far down that slope already.  For better or for worse, Steve Stahl’s books have become de facto “standard” psychiatry texts, replacing classics like Kaplan & Sadock, the Oxford Textbook, and the American Psychiatric Press books.  Stahl’s concepts are easy to grasp and provide the paradigm under which most psychiatry is practiced today (despite his own misgivings—see above).  However, his industry ties are vast, and his “education” company, Neuroscience Education Institute (NEI), has close connections with medical communications companies who are basically paid mouthpieces for the pharmaceutical industry.  Case in point: Arbor Scientia, which was hired by Sunovion to organize yesterday’s symposium—and similar ones in other cities—shares its headquarters with NEI in Carlsbad, CA, and Mr Davis sits on NEI’s Board.

We may have already reached a point in psychiatry where the majority of what we consider “education” might better be described as marketing.  But where do we draw the line between the two?  And even after we answer that question, we must ask, (when) is this a bad thing?  Yesterday’s Sunovion symposium may have been an infomercial, but I still felt there was a much greater emphasis on the “info-” part than the “-mercial.”  (And it’s unfortunate that I’d be reported as a recipient of pharmaceutical money if I had attended the conference after January 1, 2012, but that’s for another blog post.)  The question is, who’s out there to make sure it stays that way?

I’ve written before that I don’t know whom to trust anymore in this field.  Seemingly “objective” sources—like lectures from my teachers in med school and residency—can be heavily biased, while “advertising” (like yesterday’s symposium) can, at times, be fair and informative.  The end result is a very awkward situation in modern psychiatry that is easy to overlook, difficult to resolve, and, unfortunately, still ripe for abuse.


“Dollars For Docs” – What It Really Means

September 25, 2011

A few weeks ago I received an invitation to an October 1 symposium on Latuda, a new antipsychotic from Sunovion (formerly known as Sepracor).  Latuda (lurasidone) was released about six months ago amidst much fanfare—and very aggressive marketing—as a new atypical antipsychotic with, among other advantages, pro-cognitive properties.

I have only prescribed Latuda to three patients, so I have only limited experience with it.  (In case you’re wondering:  one success, one failure, one equivocal.)  However, I have read several papers about Latuda, and I am interested in learning more about it.  The symposium’s plenary speaker is Stephen Stahl from the Neuroscience Education Institute.  Dr Stahl has received money from Sunovion (which is obvious from his publications and disclosures) but he is also a very knowledgeable neuroscientist.  I figured he would be able to describe the differences between Latuda and the other atypical antipsychotics currently on the market.  So I accepted the invitation.

However, upon further thought, I wondered whether my attendance might represent a “payment” from the Sunovion Corporation.  I was not offered any money from Sunovion to attend this event (in fact, you can see my invitation here: page1, page2).  Nevertheless, according to the Physician Payment Sunshine Act, which was passed as part of PPACA (i.e., “Obamacare”), all pharmaceutical companies and medical device manufacturers, as of 2013, are required to report payments to physicians, including direct compensation as well as “food, entertainment, research funding, education or conference funding,” and so forth.

Despite the mandatory 2013 reporting date, several companies have already started reporting.  Other major drug firms to self-report thus far include AstraZeneca, Eli Lilly, Merck, and Pfizer.  Their reports have been widely publicized at sites such as “Dollars For Docs,” which “allows the public to search for individual physicians to see whether they’ve been on pharma’s payroll.”  Several other sites encourage patients to use this site to ask “Does your doc get money from drug companies?”

A quick search of my own name reveals that I received $306 from Pfizer in the year 2010.  Wow!  I had no idea!  What exactly does this mean?  Am I a Pfizer slave?  Did my Pfizer rep walk up to me on 12/31/10, hand me a personal check for $306 and say, “Thank you, Dr. Balt, for prescribing Geodon and Pristiq this year—here’s $306 for your work, and we look forward to more in 2011″?

The answer is no.  I received no money from Pfizer (and, to be frank, I didn’t prescribe any Pristiq last year, because it’s essentially Effexor).  As it happens, during 2010 I worked part-time at a community mental health clinic.  The clinic permitted drug reps to come to the office, bring lunch, and distribute information about their products.  We had lunches 1-2 days out of the week, consisting of modest fare:  Panera sandwiches, trays of Chinese food, or barbecued ribs.  Most of the doctors didn’t have time to eat—or if we did, we scarfed it down in between patients—but we would often talk to the reps, ask questions about their drugs, and accept product literature (which virtually always went straight into the trash), reprints, and educational materials from them.

We were visited by most of the major drug companies in 2010.  (BTW, this continued into 2011, but we are no longer allowed—under our contract with the County mental health department—to accept free samples, and we no longer accept lunches.  Interestingly, my Pfizer rep told us that payments would be reported only as of 1/1/11 and NOT earlier; obviously that was untrue.)  All of the lunches were generally the same, and consisted of inexpensive, modest food, mainly consumed by the clinic staff—secretaries, administrators, assistants—since the doctors were actually working through the lunch hour.  I have since learned that the formula for calculating doctors’ payouts was to take the full cost of the lunch (including all staff members, remember), divide it by the number of doctors in the office, and report that sum.   That’s where you get my $306.00.

[In the interest of full disclosure, in my four years of practice post-residency, I have only been offered one "material" non-food gift: about three years ago, Janssen gave me a $100 voucher for a textbook; I used it to purchase Glen Gabbard's psychodynamic psychotherapy text.]

Anyway, back to the Latuda symposium.  Knowing what I now know about drug companies, I wouldn’t be surprised if Sunovion reports a $1000+ payout to me if I attend this half-day symposium.  (Facility rental + A/V costs + Xeroxing/handouts + coffee service + refreshments, all divided by the # of docs in attendance.)  I frankly don’t want my future patients searching my name on Dollars For Docs and finding I received a huge “payment” from Sunovion in Q3 2011.  On the other hand, I would like to learn more about Latuda and whether/how it differs from other antipsychotics on the market (including generic first-generation agents).  If possible, I would also like to question Steve Stahl directly about some of what he’s written about this drug (including his Sunovion-funded articles).  What better forum to do this than in a public symposium??

[Note: please see ADDENDUM below.]  I have contacted two different Sunovion sales reps to ask whether my attendance will be “reported” as a payment, and if so, how much.  I have not received a response.  I also called the RSVP number for the symposium.  The registration is being managed by Arbor Scientia, a medical communications company contracted by Sunovion to manage these events.  I was directed to Heather of Arbor Scientia; I left her a message but have not yet received a return call.

So at this point, I am looking forward to attending an event to learn more about a new drug—and the opportunity to challenge the experts on the advantages (if any) of this drug over others—but in doing so, I might also be reported as having “received” a large payment from Sunovion, perhaps even larger than what Pfizer reported they paid me in 2010.

Patients should recognize that sometimes the only way for their doctors to learn about new drugs is to attend such events (assuming they can remain objective, which can be hard when the wine is freely flowing!).  Admittedly, there are doctors who accept much larger sums as speakers or “key opinion leaders,” but organizations like ProPublica should differentiate those doctors (with whom I, personally, have an ethical gripe) from those who are simply workaday folks like me who want to get as much information as they can, provide effective and cost-efficient care—and maybe inhale a free sandwich every once in a while.

ADDENDUM Sept. 26:  Today I received a phone call from Arbor Scientia (from a number that is actually registered as NEI’s main number—as it turns out, they are located in the same building) to assure me that Sunovion adheres to the Physician’s Sunshine Act provision: namely, that they’ll report “payments” to doctors only after January 1, 2012.  (See also here.)  Interestingly, my local Sunovion rep had told me 1/1/11.  (This is only somewhat reassuring: my Pfizer rep had told me they would start reporting as of 1/1/11, but clearly my “payments” from 2010 were reported.)


How Abilify Works, And Why It Matters

September 13, 2011

One lament of many in the mental health profession (psychiatrists and pharmascolds alike) is that we really don’t know enough about how our drugs work.  Sure, we have hypothetical mechanisms, like serotonin reuptake inhibition or NMDA receptor antagonism, which we can observe in a cell culture dish or (sometimes) in a PET study, but how these mechanisms translate into therapeutic effect remains essentially unknown.

As a clinician, I have noticed certain medications being used more frequently over the past few years.  One of these is Abilify (aripiprazole).  I’ve used Abilify for its approved indications—psychosis, acute mania, maintenance treatment of bipolar disorder, and adjunctive treatment of depression.  It frequently (but not always) works.  But I’ve also seen Abilify prescribed for a panoply of off-label indications: “anxiety,” “obsessive-compulsive behavior,” “anger,” “irritability,” and so forth.  Can one medication really do so much?  And if so, what does this say about psychiatry?

From a patient’s perspective, the Abilify phenomenon might best be explained by what it does not do.  If you ask patients, they’ll say that—in general—they tolerate Abilify better than other atypical antipsychotics.  It’s not as sedating as Seroquel, it doesn’t cause the same degree of weight gain as Zyprexa, and the risk of contracting uncomfortable movement disorders or elevated prolactin is lower than that of Risperdal.  To be sure, many people do experience side effects of Abilify, but as far as I can tell, it’s an acceptable drug to most people who take it.

Abilify is a unique pharmacological animal.  Like other atypical antipsychotics, it binds to several different neurotransmitter receptors; this “signature” theoretically accounts for its therapeutic efficacy and side effect profile.  But unlike others in its class, it doesn’t block dopamine (specifically, dopamine D2) or serotonin (specifically, 5-HT1A) receptors.  Rather, it’s a partial agonist at those receptors.  It can activate those receptors, but not to the full biological effect.  In lay terms, then, it can both enhance dopamine and serotonin signaling where those transmitters are deficient, and inhibit signaling where they’re in excess.

Admittedly, that’s a crude oversimplification of Abilify’s effects, and an inadequate description of how a “partial agonist” works.  Nevertheless, it’s the convenient shorthand that most psychiatrists carry around in their heads:  with respect to dopamine and serotonin (the two neurotransmitters which, at least in the current vernacular, are responsible for a significant proportion of pathological behavior and psychiatric symptomatology), Abilify is not an all-or-none drug.  It’s not an on-off switch. It’s more of a “stabilizer,” or, in the words of Stephen Stahl, a “Goldilocks drug.”

Thus, Abilify can be seen, at the same time, as both an antipsychotic, and not an antipsychotic.  It’s both an antidepressant, and not an antidepressant.  And when you have a drug that is (a) generally well tolerated, (b) seems to work by “stabilizing” two neurotransmitter systems, and (c) resists conventional classification in this way, it opens the floodgates for all sorts of potential uses in psychiatry.

Consider the following conditions, all of which are subjects of Abilify clinical trials currently in progress (thanks to clinicaltrials.gov):  psychotic depression; alcohol dependence; “aggression”; improvement of insulin sensitivity; antipsychotic-induced hyperprolactinemia; cocaine dependence; Tourette’s disorder; postpartum depression; methamphetamine dependence; obsessive-compulsive disorder (OCD); late-life bipolar disorder; post-traumatic stress disorder (PTSD); cognitive deficits in schizophrenia; alcohol dependence; autism spectrum disorders; fragile X syndrome; tardive dyskinesia; “subsyndromal bipolar disorder” (whatever that is) in children; conduct disorder; ADHD; prodromal schizophrenia; “refractory anxiety”; psychosis in Parkinson’s disease; anorexia nervosa; substance-induced psychosis; prodromal schizophrenia; trichotillomania; and Alzheimers-related psychosis.

Remember, these are the existing clinical trials of Abilify.  Each one has earned IRB approval and funding support.  In other words, they’re not simply the fantasies of a few rogue psychiatrists; they’re supported by at least some preliminary evidence, or at least a very plausible hypothesis.  The conclusion one might draw from this is that Abilify is truly a wonder drug, showing promise in nearly all of the conditions we treat as psychiatrists.  We’ll have to wait for the clinical trial results, but what we can say at this point is that a drug which works as a “stabilizer” of two very important neurotransmitter systems can be postulated to work in virtually any way a psychopharmalogist might want.

But even if these trials are negative, my prediction is that this won’t stop doctors from prescribing Abilify for each of the above conditions.  Why?  Because the mechanism of Abilify allows for such elegant explanations of pathology (“we need to tune down the dopamine signal to get rid of those flashbacks” or “the serotonin 1A effect might help with your anxiety” – yes, I’ve heard both of these in the last week), that it would be anathema, at least to current psychiatric practice, not to use it in this regard.

This fact alone should lead us to ask what this says about psychiatry as a whole.  The fact that one drug is prescribed so widely—owing to its relatively nonspecific effects and a good deal of creative psychopharmacology on the part of doctors like me—and is so broadly accepted by patients, should call into question our hypotheses about the pathophysiology of mental illness, and how psychiatric disorders are distinguished from one another.  It should challenge our theories of neurotransmitters and receptors and how their interactions underlie specific symptoms.  And it should give us reason to question whether the “stories” we tell ourselves and our patients carry more weight than the medications we prescribe.


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