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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.

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The Mythology of “Treatment-Resistant” Depression

February 27, 2011

“Treatment-resistant depression” is one of those clinical terms that has always been a bit unsettling to me.  Maybe I’m a pessimist, but when I hear this phrase, it reminds me that despite all the time, energy, and expense we have invested in understanding this all-too-common disease, we still have a long way to go.  Perhaps more troubling, the phrase also suggests an air of resignation or abandonment:  “We’ve tried everything, but you’re resistant to treatment, and there’s not much more we can do for you.”

But “everything” is a loaded term, and “treatment” takes many forms.  The term “treatment-resistant depression” first appeared in the literature in 1974 and has been used widely in the literature.  (Incidentally, despite appearing over 20 times in the APA’s 2010 revised treatment guidelines for major depression, it is never actually defined.)  The phrase is often used to describe patients who have failed to respond to a certain number of antidepressant trials (typically two, each from a different class), each of a reasonable (6-12 week) duration, although many other definitions have emerged over the years.

Failure to respond to “adequate” trials of appropriate antidepressant medications does indeed suggest that a patient is resistant to those treatments, and the clinician should think of other ways to approach that patient’s condition.  In today’s psychiatric practice, however, “treatment-resistant” is often a code word for simply adding another medication (like an atypical antipsychotic) or to consider somatic treatment options (such as electroconvulsive therapy, ECT, or transcranial magnetic stimulation, TMS).

Seen this way, it’s a fairly narrow view of “treatment.”  The psychiatric literature—not to mention years and years of anecdotal data—suggests that a broad range of interventions can be helpful in the management of depression, such as exercise, dietary supplements, mindfulness meditation, acupuncture, light therapy, and literally dozens of different psychotherapeutic approaches.  Call me obsessive, or pedantic, but to label someone’s depression as “treatment resistant” without an adequate trial of all of these approaches, seems premature at best, and fatalistic at worst.

What if we referred to someone’s weight problem as “diet-resistant obesity”?  Sure, there are myriad “diets” out there, and some obese individuals have tried several and simply don’t lose weight.  But perhaps these patients simply haven’t found the right one for their psychological/endocrine makeup and motivational level; there are also some genetic and biochemical causes of obesity that prevent weight loss regardless of diet.  If we label someone as “diet-resistant” it means that we may overlook some diets that would work, or ignore other ways of managing this condition.

Back to depression.   I recognize there’s not much of an evidence base for many of the potentially hundreds of different “cures” for depression in the popular and scientific literature.  And it would take far too much time to try them all.  Experienced clinicians will have seen plenty of examples of good antidepressant response to lithium, thyroid hormone, antipsychotics (such as Abilify), and somatic interventions like ECT.  But they have also seen failures with the exact same agents.

Unfortunately, our “decision tree” for assigning patients to different treatments is more like a dartboard than an evidence-based flowchart.  “Well, you’ve failed an SSRI and an SNRI, so let’s try an atypical,” goes the typical dialogue (not to mention the typical TV commercial or magazine ad), when we really should be trying to understand our patients at a deeper level in order to determine the ideal therapy for them.

Nevertheless, the “step therapy” requirements of insurance companies, as well as the large multicenter NIH-sponsored trials (like the STAR*D trial) which primarily focus on medications (yes, I am aware that STAR*D had a cognitive therapy component, although this has received little attention and was not widely chosen by study participants), continue to bias the clinician and patient in the direction of looking for the next pill or the next biological intervention, instead of thinking about patients as individuals with biological, genetic, psychological, and social determinants of their conditions.

Because in the long run, nobody is “treatment resistant,” they’re just resistant to what we’re currently offering them.


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