(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.

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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.


What Psychiatrists Treat and Why

February 20, 2011

Do we treat diseases or symptoms in psychiatry?  While this question might sound philosophical in nature, it’s actually a very practical one in terms of treatment strategies we espouse, medications and other interventions we employ, and, of course, how we pay for mental health care.  It’s also a question that lies at the heart of what psychiatry is all about.

Anyone who has been to medical school or who has watched an episode of House knows that a disease has (a) an underlying pathology, often hidden to the naked eye but which is shared by all patients with that diagnosis, and (b) signs and symptoms, which are readily apparent upon exam but which may differ in subtle ways from patient to patient.  An expert physician performing a comprehensive examination can often make a diagnosis simply on the basis of signs and symptoms.  In some cases, more sophisticated tools (lab tests, scans, etc) are required to confirm the diagnosis.  In the end, once a diagnosis is obtained, treatment can commence.

(To be sure, sometimes a diagnosis is not apparent, and a provisional or “rule-out” diagnosis is given.  The doctor may initiate treatment on an empiric basis but will refine the diagnosis on the basis of future observations, responses to treatment, and/or disease course.)

In psychiatry, which is recognized as a branch of medicine and (should) subscribe to the same principles of diagnosis and treatment, the expectations are the same.  There are a number of diseases (or disorders) listed in the DSM-IV, each theoretically with its own underlying pathology and natural history, and each recognizable by a set of signs and symptoms.  A careful psychiatric evaluation and mental status exam will reveal the true diagnosis and suggest a treatment plan to the clinician.

It sounds simple, but it doesn’t always work out this way.  Psychiatrists may disagree about a given diagnosis, or make diagnoses based on “soft” signs.  Moreover, there are very few biological or biochemical tests to “rule in” a psychiatric diagnosis.  As a result, treatment plans for psychiatric patients often include multiple approaches that don’t make sense;  for example, using an antidepressant to treat bipolar disorder, or using antipsychotics to treat anxiety or insomnia symptoms in major depression.

The psychiatrist Nassir Ghaemi at Tufts has written about this before (click here for a very accessible version of his argument and here [registration required] for a more recent dialogue in which he argues his point further).  Ghaemi argues in favor of what he calls “Hippocratic psychopharmacology.” Specifically, we should understand and respect the normal course of a disease before initiating treatment.  He also emphasizes that we not treat symptoms, but rather the disease (this is also known as Osler’s Rule, in honor of Sir William Osler, the “founder of modern medicine”).  For example, Ghaemi makes a fairly compelling argument that bipolar disorder should be treated with a mood stabilizer alone, and not with an antidepressant, or an antipsychotic, or a sedative, because those drugs treat symptoms which should resolve as a person goes through the natural course of the disease.  In other words, we miss the diagnostic forest by focusing on the symptomatic trees.

The problem is, this is a compelling argument only if there is such a diagnosis as “bipolar disorder.”  Or, to be more specific, a clear, unitary entity with a distinct pathophysiological basis that gives rise to the symptoms that we see as mania and depression, and which all “bipolar” patients share.  And I don’t believe this assumption has been borne out.

My personal bias is that bipolar disorder does exist.  So do major depression, schizophrenia, panic disorder, anorexia nervosa, ADHD, and (almost) all the other diagnoses listed in the DSM-IV.  And a deeper understanding of the pathophysiology of each might help us to develop targeted treatments that will be far more effective than what have now.  But we’re not there yet.  In the case of bipolar disorder, lithium is a very effective drug, but it doesn’t work in everyone with “bipolar.”  Why not?  Perhaps “bipolar disorder” is actually several different disorders.  Not just formes frustes of the same condition but separate entities altogether, with entirely different pathophysiologies which might appear roughly the same on the outside (sort of like obesity or alcoholism).  Of course, there are also many diagnosed with “bipolar” who might really have no pathology at all– so it is no surprise that they don’t respond to a mood stabilizer (I won’t elaborate on this possibility here, maybe some other time).

The committee in charge of writing the DSM-5 is almost certainly facing this conundrum.  One of the “holy grails” of 21st century psychiatry (which I wrote about here) is to identify biochemical or genetic markers that predict or diagnose psychiatric disease, and it was hoped that the next version of the DSM would include these markers amongst its diagnostic criteria.   Unfortunately, this isn’t happening, at least not with DSM-5.  In fact, what we’re likely to get is a reshuffling and expansion of diagnostic criteria.  Which just makes matters worse:  how can we follow Osler’s advice to treat the disease and not the symptom when the definition of disease will change with the publication of a new handbook?

As a practicing psychiatrist, I’d love to be able to make a sound and accurate diagnosis and to use this diagnosis to inform my treatment, practicing in the true Hippocratic tradition and following Osler’s Rule, which has benefited my colleagues in other fields of medicine.  I also recognize that this approach would respect Dr Ghaemi’s attempt at bringing some order and sensibility to psychiatric practice.  Unfortunately, this is hard to do because (a) we still don’t know the underlying cause(s) of psychiatric disorders, and (b) restricting myself to pathophysiology and diagnosis means ignoring the psychosocial and environmental factors that are (in many ways) even more important to patients than what “disease” they have.

It has frequently been said that medicine is an art, not a science, and psychiatry is probably the best example of this truism.  Let’s not stop searching for the biological basis of mental illness, but also be aware that it may not be easy to find.  Until then, whether we treat “diagnoses” or “symptoms” is a matter of style.  Yes, the insurance company wants a diagnosis in order to provide reimbursement, but the patient wants management of his or her symptoms in order to live a more satisfying life.


Cognitive Therapy in Schizophrenia: Worth Another Look

February 15, 2011

While writing my recent post on the placebo effect in schizophrenia (and while reviewing some of the comments I received on this post), I started to think about what aspects of the patients’ experience are most susceptible to change, which might account for the “placebo effect” seen in clinical studies of antipsychotics.  As one commenter correctly pointed out, the placebo effect should not be viewed as a mysterious consequence of ingesting some inert drug, but rather a reflection of the patient’s inherent ability to heal.  Unfortunately we know very little about the mechanisms involved, and we are devoting even less effort to understanding how to capitalize (no pun intended) on this process in the long-term management of psychotic disorders.

I realized, however, that I didn’t acknowledge the fact that psychotherapy does have a place in the treatment of schizophrenia.  Psychosocial treatment approaches, for instance, are routinely employed, with varying degrees of success, and some groups have used cognitive behavioral therapy techniques as well.  Cognitive therapy, in a nutshell, is based on the assumption that early experiences and social environment can give rise to “schemas” about the self, other people, and the world.  These beliefs then lead to cognitive distortions, negative styles of thinking, and misinterpretations of events in the world (or in one’s own mind).  Cognitive therapy aims to question or challenge these distortions and misinterpretations to engender a healthier, more functional view of oneself and one’s ability to master his surroundings.

At first glance, cognitive therapy seems like it would be ineffective in a psychotic patient, who may not be able to appreciate the discrepancy between his subjective experiences and objective reality.  Nevertheless, it has shown some promise, and a classic paper in this field is the 1994 article “Cognitive Behaviour Therapy of Schizophrenia” by Kingdon, Turkington, and John, in the British Journal of Psychiatry.  It is a fascinating, and eye-opening, read.

A particularly striking aspect of the paper (and keep in mind that I received my psychiatric training within the last 10 years, firmly in the atypical antipsychotic era) is that it says nothing about eliminating psychotic symptoms.  The current literature, in contrast, starts with the assumption that hallucinations, delusions, and cognitive deficits of schizophrenia are biochemical entities (which they are, of course, like any other mental phenomenon), but they are deviant and/or undesirable, and biological interventions (i.e., drugs) abolish or “correct” them.  The Kingdon article assumes that schizophrenic thought content lies on a continuum with “normal” cognition, and in fact some of the same cognitive processes are employed, albeit improperly or deficiently.  The authors claim that “abnormal beliefs” can be more or less “amenable to reason” (as with any cognitive distortion in CBT) and a key element of therapy is to “identify meaning in delusional material and then assess alternative explanations.”  In other words, it emphasizes the patient’s subjective experience, rather than the symptoms witnessed by the clinician.

Another surprising feature of the Kingdon article is its implicit acknowledgment that certain delusions or hallucinations may be entirely acceptable.  Schizophrenic patients, they claim, often do not have the ability to “meta-think”– i.e., to think about thinking– so they frequently are not aware that their unusual sensory or perceptual experiences differ from normal thought.  As a result, they cannot usually be “argued out of” a belief, even with the most skilled cognitive behavioral approach, and we must accept that they’ll find their own personal meaning for their experience.  “It may be,” the authors write, “that the reassurance of finding a meaningful explanation, however improbable, in a distressing and perplexing situation is sufficient to explain why the delusion is reached for and clung to, so energetically and with such certainty.”

Newer applications of CBT-based techniques, reviewed in an excellent 2009 article by Tai and Turkington in Schizophrenia Bulletin, have taken advantage of this viewpoint and start with the belief that “it is the individual’s personal meaning, understanding, and coping with symptoms that are the focus of treatment” – not the mere presence or absence of hallucinations or delusions.  In particular, mindfulness-based approaches, acceptance and commitment therapy (ACT), and compassionate mind training (CMT), are therapeutic techniques that involve awareness of one’s experience, acceptance of internal events, and minimization of shame and self-criticism that can arise from paranoid or persecutory thoughts, respectively.

Schizophrenia is probably not a single disease; in fact it is likely to comprise many different cognitive, developmental, physiological, and externally mediated disruptions, all of which lie on a spectrum with the “normal” state.  (The Kingdon article, in fact, goes to great lengths to point out how even non-psychotic individuals can experience “psychotic” beliefs in the form of superstitious thought, overvalued ideas, or psychosis induced by sleep deprivation or hallucinogenic drugs.)  To be sure, some psychotic symptoms in some patients will respond best to a dopamine antagonist, but it is imperative that we employ other tools at our disposal to help patients overcome them, amend them, or just accept them.  Unfortunately, too few psychiatrists in my generation have learned those tools—all we have is the antipsychotic hammer, and “schizophrenia” is the proverbial, monolithic nail.


The Placebo Effect: It Just Gets Better and Better

February 13, 2011

The placebo response is the bane of clinical research.  Placebos, by definition, are inert, inactive compounds that should have absolutely no effect on a patient’s symptoms, although they very frequently do.  Researchers compare new drugs to placebos so that any difference in outcome between drug and placebo can be attributed to the drug rather than to any unrelated factor.

In psychiatry, placebo effects are usually quite robust.  Trials of antidepressants, antianxiety medications, mood stabilizers, and other drugs typically show large placebo response rates.  A new paper by Bruce Kinon and his colleagues in this month’s Current Opinion in Psychiatry, however, reports that placebos are also show some improvement in schizophrenia.  Moreover, placebos seem to have become more effective over the last 20 years!

Now, if there’s any mental illness in which you would not expect to see a placebo response, its schizophrenia.  Other psychiatric disorders, one might argue, involve cognitions, beliefs, expectations, feelings, etc.—all of which could conceivably improve when a patient believes an intervention (yes, even a placebo pill) might make him feel better.  But schizophrenia, by definition, is characterized by a distorted sense of reality, impaired thought processes, an inability to grasp the differences between the external world and the contents of one’s mind, and, frequently, the presence of bizarre sensory phenomena that can only come from the aberrant firing of the schizophrenic’s neurons.  How could these symptoms, which almost surely arise from neurochemistry gone awry, respond to a sugar pill?

Yet respond they do.  And not only do subjects in clinical trials get better with placebo, but the placebo response has been steadily improving over the last 20 years!  Kinon and his colleagues summarized placebo response rates from various antipsychotic trials since 1993 and found a very clear and gradual improvement in scores over the last 15-20 years.

Very mysterious stuff.  Why would patients respond better to placebo today than in years past?  Well, as it turns out (and is explored in more detail in this article), the answer may lie not in the fact that schizophrenics are being magically cured by a placebo, but rather that they have greater expectations for improvement now than in the past (although this is hard to believe for schizophrenia), or that clinical researchers have greater incentives for including patients in trials and therefore inadequately screen their subjects.

In support of the latter argument, Kinon and his colleagues showed that in a recent antidepressant trial (in which some arbitrary minimum depression score was required for subjects to be included), researchers routinely rated their subjects as more depressed than the subjects rated themselves at the beginning of the trial—the “screening phase.”  Naturally, then, subjects showed greater improvement at the end of the trial, regardless of whether they received an antidepressant or placebo.

A more cynical argument for why antipsychotic drugs don’t “separate from placebo” is because they really aren’t that much better than placebo (for an excellent series of posts deconstructing the trials that led to FDA approval of Seroquel, and showing how results may have been “spun” in Seroquel’s favor, check out 1BoringOldMan).

This is an important topic that deserves much more attention.  Obviously, researchers and pharmaceutical companies want their drugs to look as good as possible, and want placebo responses to be nil (or worse than nil).  In fact, Kinon and his colleagues are all employees of Eli Lilly, manufacturer of Zyprexa and other drugs they’d like to bring to market, so they have a clear interest in this phenomenon.

Maybe researchers do “pad” their studies to include as many patients as they can, including some whose symptoms are not severe.  Maybe new antipsychotics aren’t as effective as we’d like to believe them to be.  Or maybe schizophrenics really do respond to a “placebo effect” the same way a depressed person might feel better simply by thinking they’re taking a drug that will help.  Each of these is a plausible explanation.

For me, however, a much bigger question arises: what exactly are we doing when we evaluate a schizophrenic patient and prescribe an antipsychotic?  When I see a patient whom I think may be psychotic, do I (unconsciously) ask questions that lead me to that diagnosis?  Do I look for symptoms that may not exist?  Does it make sense for me to prescribe an antipsychotic when a placebo might do just as well?  (See my previous post on the “conscious” placebo effect.)  If a patient “responds” to a drug, why am I (and the patient) so quick to attribute it to the effect of the medication?

I’m glad that pharmaceutical companies are paying attention to this issue and developing ways to tackle these questions.  Unfortunately, because their underlying goal is to make a drug that looks as different from placebo as possible (to satisfy the shareholders, you know) I question whether their solutions will be ideal.  As with everything in medicine, though, it’s the clinician’s responsibility to evaluate the studies critically—and to evaluate their own patients’ responses to treatment in an unbiased fashion—and not to give credit where credit isn’t due.


“That’s OK, I Didn’t Need That Brain Anyway”

February 10, 2011

Long-term treatment with antipsychotic medication apparently causes a decrease in brain volume, according to a new report by Nancy Andreasen’s group at the University of Iowa in this month’s Archives of General Psychiatry. In the study, over 200 schizophrenic patients, treated with antipsychotics, underwent MRI scans of their brains at various intervals over a 5-14 year period. The results showed that the “intensity” of antipsychotic treatment (i.e., doses and lengths of treatment) correlated with the reduction in brain tissue.

Instead of just looking at an overall “snapshot” of the brain, researchers calculated the volumes of several brain regions (from the whole-brain MRI scans) and found, on average, subtle decreases in both gray matter and white matter volumes, as well as enlargement of the ventricles (the “spaces” in the normal brain). The changes were more pronounced with longer time periods of treatment and, in particular, when higher doses of antipsychotics were used for extended periods of time.

As expected, this finding has generated a great deal of interest– if not concern– and more than a touch of “I-told-you-so” from certain camps (see “Antipsychotics Shrink the Brain” by Robert Whitaker). Indeed, at first blush, it is quite shocking to think that the first-line treatment for such a devastating brain disease might cause damage to the very organ we are trying to treat.

But is it really “damage”? All joking aside, I think the title of this post needs to be taken seriously. Does the observed loss in brain tissue loss mean that a person is incapacitated in any way? That he can no longer think, feel, see, taste, or make plans for the future? Moreover, despite the headlines, the tissue loss was not incredibly dramatic. In other words, we’re not talking about a healthy, robust brain turning into a moth-eaten mass of Swiss cheese. In fact, by my read of the data, the largest individual change in frontal gray matter volume was from about 330 cm3 to 290 cm3 over a 10-year period (yes, that’s >10%, but who knows what else was happening in that patient?). Other changes were much smaller, and many patients actually showed increases in brain volumes.

There were slight correlations with disease severity (more symptomatic disease was associated with a greater decrease in brain volume), and different classes of antipsychotics affected some regions of the brain differently than others. Interestingly, there seemed to be no independent effect of substance abuse on brain volume changes, despite the oft-heard warning that drugs and alcohol “kill brain cells.”

So what does this all mean? Obviously, some will say that this provides evidence that antipsychotics are toxic to brain cells. But there’s no clear evidence that neurons are actually dying; in some studies in monkeys taking antipsychotic medication, the number of neurons remains constant, but they increase in density because support cells (called glia) decrease in number– resulting in the macroscopic appearance of a “smaller brain.”

Moreover, it is quite possible that the disease process itself already leads to a decrease in brain volume (actually, we know this already) and effective treatment helps to further “prune” dysfunctional areas of the brain. In fact, an editorial accompanying the article claims that “strategic reductions in brain volume” might actually be therapeutic, and reminds us that gray matter volume decreases significantly during human adolescence, a process thought to underlie the organization and refinement of brain cells, and elimination of redundancy. (No wonder you have to tell your teenage son six times to clean his room.)

The best way to tackle this question, of course, is to take two groups of schizophrenics, treat one “as usual” with antipsychotics and the other with no medication at all, and perform brain scans at regular intervals. For ethical reasons, we can’t do this (it’s unethical not to treat a psychotic patient with an antipsychotic– although some would argue differently). Another way is to take advantage of the fact that many non-schizophrenic patients are now taking antipsychotics for OTHER diagnoses– bipolar disorder, depression, anxiety, insomnia, PTSD (just to name a few)– and we could compare those on antipsychotics to those on other drugs. If we see brain tissue loss across a wide spectrum of diagnoses, it suggests that this effect may be a direct result of antipsychotic treatment, even though the mechanism remains unknown.

Regardless of what’s actually happening in the brains of treated schizophrenics– and whether it’s “good” or “bad,” or whether it resembles the brain loss observed in birds living near Chernobyl– two things must be kept in mind. First, the patient’s well-being is of utmost importance; it would be inappropriate to withhold antipsychotic treatment from a patient who is clearly tormented and disabled from his paranoia, his delusional preoccupations, and his absolute lack of insight, particularly when we know that such medications do, in most cases, result in dramatic improvement. At the same time, we must also consider the other side of the coin, namely that if antipsychotics might cause an unexplained loss in brain tissue—or any other anatomic defect elsewhere, for that matter—we must seriously consider our rationale for these drugs. In particular, brain development in children is an ongoing process, not complete until late adolescence or early adulthood.

Hopefully this finding will stimulate research to determine how antipsychotics affect brain cells over time. Perhaps then we can find ways to preserve brain structure – or, at least, essential brain structure—while still treating the symptoms of mental illness. In other words, avoiding harm, while still doing good.


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