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.


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  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.

Do Antipsychotics Treat PTSD?

August 23, 2011

Do antipsychotics treat PTSD?  It depends.  That seems to be the best response I can give, based on the results of two recent studies on this complex disorder.  A better question, though, might be: what do antipsychotics treat in PTSD?

One of these reports, a controlled, double-blinded study of the atypical antipsychotic risperidone (Risperdal) for the treatment of “military service-related PTSD,” was featured in a New York Times article earlier this month.  The NYT headline proclaimed, somewhat unceremoniously:  “Antipsychotic Use is Questioned for Combat Stress.”  And indeed, the actual study, published in the Journal of the American Medical Association (JAMA), demonstrated that a six-month trial of risperidone did not improve patients’ scores in a scale of PTSD symptoms, when compared to placebo.

But almost simultaneously, another paper was published in the online journal BMC Psychiatry, stating that Abilify—a different atypical antipsychotic—actually did help patients with “military-related PTSD with major depression.”

So what are we to conclude?  Even though there are some key differences between the studies (which I’ll mention below), a brief survey of the headlines might leave the impression that the two reports “cancel each other out.”  In reality, I think it’s safe to say that neither study contributes very much to our treatment of PTSD.  But it’s not because of the equivocal results.  Instead, it’s a consequence of the premises upon which the two studies were based.

PTSD, or post-traumatic stress disorder, is an incredibly complicated condition.  The diagnosis was first given to Vietnam veterans who, for years after their service, experienced symptoms of increased physiological arousal, avoidance of stimuli associated with their wartime experience, and continual re-experiencing (in the form of nightmares or flashbacks) of the trauma they experienced or observed.  It’s essentially a re-formulation of conditions that were, in earlier years, labeled “shell shock” or “combat fatigue.”

Since the introduction of this disorder in 1980 (in DSM-III), the diagnostic umbrella of PTSD has grown to include victims of sexual and physical abuse, traumatic accidents, natural disasters, terrorist attacks (like the September 11 massacre), and other criminal acts.  Some have even argued that poverty or unfortunate psychosocial circumstances may also qualify as the “traumatic” event.

Not only are the types of stressors that cause PTSD widely variable, but so are the symptoms that ultimately develop.  Some patients complain of minor but persistent symptoms, while others experience infrequent but intense exacerbations.  Similarly, the neurobiology of PTSD is still poorly understood, and may vary from person to person.  And we’ve only just begun to understand protective factors for PTSD, such as the concept of “resilience.”

Does it even make sense to say that one drug can (or cannot) treat such a complex disorder?  Take, for instance, the scale used in the JAMA article to measure patients’ PTSD symptoms.  The PTSD score they used as the outcome measure was the Clinician-Administered PTSD Scale, or CAPS, considered the “gold standard” for PTSD diagnosis.  But the CAPS includes 30 items, ranging from sleep disturbances to concentration difficulties to “survivor guilt”:

It doesn’t take a cognitive psychologist or neuroscientist to recognize that these 30 domains—all features of what we consider “clinical” PTSD—could be explained by just as many, if not more, neural pathways, and may be experienced in entirely different ways, depending upon on one’s psychological makeup and the nature of one’s past trauma.

In other words, saying that Risperdal is “not effective” for PTSD is like saying that acupuncture is not effective for chronic pain, or that a low-carb diet is not an effective way to lose weight.  Statistically speaking, these interventions might not help most patients, but in some, they may indeed play a crucial role.  We just don’t understand the disorders well enough.

[By the way, what about the other study, which reported that Abilify was helpful?  Well, this study was a retrospective review of patients who were prescribed Abilify, not a randomized, placebo-controlled trial.  And it did not use the CAPS, but the PCL-M, a shorter survey of PTSD symptoms.  Moreover, it only included 27 of the 123 veterans who agreed to take Abilify, and I cannot, for the life of me, figure out why the other 96 were excluded from their analysis.]

Anyway, the bottom line is this:  PTSD is a complicated, multifaceted disorder—probably a combination of disorders, similar to much of what we see in psychiatry.  To say that one medication “works” or another “doesn’t work” oversimplifies the condition almost to the point of absurdity.  And for the New York Times to publicize such a finding, only gives more credence to the misconception that a prescription medication is (or has the potential to be) the treatment of choice for all patients with a given diagnosis.

What we need is not another drug trial for PTSD, but rather a better understanding of the psychological and neurobiological underpinnings of the disease, a comprehensive analysis of which symptoms respond to which drug, which aspects of the disorder are not amenable to medication management, and how individuals differ in their experience of the disorder and in the tools (pharmacological and otherwise) they can use to overcome their despair.  Anything else is a failure to recognize the human aspects of the disease, and an issuance of false hope to those who suffer.

Psychiatry, Homeostasis, and Regression to the Mean

July 20, 2011

Are atypical antipsychotics overprescibed?  This question was raised in a recent article on the Al Jazeera English website, and has been debated back and forth for quite some time on various blogs, including this one.  Not surprisingly, their conclusion was that, yes, these medications are indeed overused—and, moreover, that the pharmaceutical industry is responsible for getting patients “hooked” on these drugs via inappropriate advertising and off-label promotion of these agents.

However, I don’t know if this is an entirely fair characterization.

First of all, let’s just be up front with what should be obvious.  Pharmaceutical companies are businesses.  They’re not interested in human health or disease, except insofar as they can exploit people’s fears of disease (sometimes legitimately, sometimes not) to make money.  Anyone who believes that a publicly traded drugmaker might forego their bottom line to treat malaria in Africa “because it’s the right thing to do” is sorely mistaken.  The mission of companies like AstraZeneca, Pfizer, and BMS is to get doctors to prescribe as much Seroquel, Geodon, and Abilify (respectively) as possible.  Period.

In reality, pharmaceutical company revenues would be zero if doctors (OK, and nurse practitioners and—at least in some states—psychologists) didn’t prescribe their drugs.  So it’s doctors who have made antipsychotics one of the most prescribed classes of drugs in America, not the drug companies.  Why is this?  Has there been an epidemic of schizophrenia?  (NB:  most cases of schizophrenia do not fully respond to these drugs.)  Are we particularly susceptible to drug marketing?  Do we believe in the clear and indisputable efficacy of these drugs in the many psychiatric conditions for which they’ve been approved (and those for which they haven’t)?

No, I like to think of it instead as our collective failure to appreciate that patients are more resilient and adaptive than we give them credit for, not to mention our infatuation with the concept of biological psychiatry.  In fact, much of what we attribute to our drugs may in fact be the result of something else entirely.

For an example of what I mean, take a look at the following figure:

This figure has nothing to do with psychiatry.  It shows the average body temperature of two groups of patients with fever—one who received intravenous Tylenol, and the other who received an intravenous placebo.  As you can easily see, Tylenol cut the fever short by a good 30-60 minutes.  But both groups of patients eventually reestablished a normal body temperature.

This is a concept called homeostasis.  It’s the innate ability of a living creature to keep things constant.  When you have a fever, you naturally perspire to give off heat.  When you have an infection, you naturally mobilize your immune system to fight it.  (BTW, prescribing antibiotics for viral respiratory infections is wasteful:  the illness resolves itself “naturally” but the use of a drug leads us to believe that the drug is responsible.)  When you’re sad and hopeless, lethargic and fatigued, you naturally engage in activities to pull yourself out of this “rut.”  All too often, when we doctors see these symptoms, we jump at a diagnosis and a treatment, neglecting the very real human capacity—evolutionarily programmed!!—to naturally overcome these transient blows to our psychological stability and well-being.

There’s another concept—this one from statistics—that we often fail to recognize.  It’s called “regression to the mean.”  If I survey a large number of people on some state of their psychological function (such as mood, or irritability, or distractibility, or anxiety, etc), those with an extreme score on their first evaluation will most likely have a more “normal” score on their next evaluation, and vice versa, even in the absence of any intervention.  In other words, if you’re having a particularly bad day today, you’re more likely to be having a better day the next time I see you.

This is perhaps the best argument for why it takes multiple sessions with a patient—or, at the very least, a very thorough psychiatric history—to make a confident psychiatric diagnosis and to follow response to treatment.  Symptoms—especially mild ones—come and go.  But in our rush to judgment (not to mention the pressures of modern medicine to determine a diagnosis ASAP for billing purposes), endorsement of a few symptoms is often sufficient to justify the prescription of a drug.

Homeostasis and regression to the mean are not the same.  One is a biological process, one is due to natural, semi-random variation.  But both of these concepts should be considered as explanations for our patients “getting better.”  When these changes occur in the context of taking a medication (particularly one like an atypical antipsychotic, with so many uses for multiple nonspecific diagnoses), we like to think the medication is doing the trick, when the clinical response may be due to something else altogether.

Al Jazeera was right: the pharmaceutical companies have done a fantastic job in placing atypical antipsychotics into every psychiatrist’s armamentarium.  And yes, we use them, and people improve.  The point, though, is that the two are sometimes not connected.  Until and unless we find some way to recognize this—and figure out what really works—Big Pharma will continue smiling all the way to the bank.

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.

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