Ordinarily Well: The Case for Antidepressants

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What We Know

DEPRESSION TREATMENT WILL change, and we have reason to hope that breakthroughs will come soon. In the meanwhile, we practice psychotherapy and prescribe our current antidepressants. We know, I am guessing, most of what conventional outcome trials will ever tell us about their efficacy.

More high-quality academic research, like the STAR*D and R&R studies, might conceivably inch us forward, but it’s not in the cards. In 2013, Thomas Insel, then director of the NIMH, signaled that the agency was done with that sort of effort. He was investing in basic brain sciences, on the theory that until we understand more about depression, improvements in treatment will likely remain incremental.

Meanwhile, the pharmaceutical industry has largely abandoned drug development in psychiatry. The drubbing, however well deserved, that Pharma took in the past decade must have played a role, but other reasons include the problems we have seen in randomized trials. Ever-rising placebo response rates make the arithmetic work against the enterprise. By chance, some effective antidepressants will test out poorly. And the conditions for vetting me-too drugs—variants of what’s already available—must be distressing even to industry. Finally, no one can think it’s right to scour homeless shelters for “volunteers.”

Despite the drop in research funding, psychiatrists are optimistic. One reason is ketamine, an anesthetic that is being repurposed as an antidepressant.

Although drug companies have taken an interest lately, the ketamine story developed independent of industry. For decades, researchers have sought new brain targets for depression treatment—receptors and nerve pathways involving chemicals other than serotonin or norepinephrine. A quarter century back, a team at Yale began looking at drugs that influence the brain’s handling of a neurotransmitter called glutamate. By 1994, John Krystal (we have discussed his research on trajectories of recovery) had begun working with low doses of ketamine, an anesthetic that affects a particular type of glutamate receptor. In 2000, Krystal and his colleagues reported that seven depressed patients had responded to an intravenous infusion of ketamine with quick relief—within hours or days—from core symptoms.

Ketamine is also a recreational drug and can cause hallucinations or a dissociative state, a sense of not being oneself. Research on ketamine abusers had raised red flags about risks to the brain from long-term exposure. Follow-up to Krystal’s study came slowly. In 2006, NIMH researchers—one, Dennis Charney, had migrated from Yale—reported on the response to ketamine, mostly favorable, of eighteen patients with treatment-resistant depression. This study is of the sort that can still be run well: it is always possible to recruit real patients who have proved unresponsive to available medications. Further confirmations followed. Meanwhile, in advance of additional research, many people have been treated in clinicians’ offices. It looks as if ketamine infusions end depressive episodes promptly.

Key clinical questions remain unanswered: how long the relief lasts, how often the treatment can be repeated, whether extended use has a downside. (Although ketamine has not been offered chronically to many patients, already colleagues have told me of two instances of serious tachyphylaxis to ketamine—dramatic loss of efficacy after repeated doses.) Meanwhile, researchers have tried to tame ketamine, looking for variants that can be given in pill form or as nose sprays and that avoid the transient unpleasant effects.

Some efforts have failed. Ketamine seems more effective than other drugs that target glutamate, a development that has caused researchers to wonder whether ketamine does after all work through its effects on glutamate receptors. Perhaps it acts via some other, distinctive means, so that the discovery of its usefulness for depression, if that pans out, will have been serendipitous. If so, ketamine may open the door to unexplored approaches to mood disorder.

It is the rule rather than the exception for proposed antidepressant drugs that work through novel mechanisms to fail in the late going. Because it has been around for fifty years, because many people have taken it recreationally or as an anesthetic, ketamine seems likelier than most to survive scrutiny, but you never know.

If ketamine or a near variant does succeed, we may wonder what role our current antidepressants will assume. As new medications become available, older drugs for the same indication have varied fates. With the advent of the SSRIs, imipramine faded into the background. In contrast, digitalis or close analogues survived decades of competition from newer heart medicines and have only lately fallen in rank.

Let’s take ketamine now as our word for an imagined drug, the next Prozac, the antidepressant that takes the field by storm. What happens to Zoloft and Lexapro will depend on what practicing doctors discover about ketamine. Writing about Prozac, I referred to its “personality.” Prescribing, observing, hearing from patients, clinicians learn whether a drug is harsh or mild, brash or subtle, difficult or easy to live with. These informal impressions contribute to experience, the observations that doctors add to lessons from the formal literature. The sum guides the application of treatments. Medication use is always crowdsourced, through crowds of experts. Not because of controlled trials, but through what emerged in the course of practice, doctors learned to reserve Serzone and trazodone for special purposes; Zoloft and Lexapro became go-to treatments for depression.

If our imagined ketamine is highly effective but hard to live with or liable to cause harm over time, it may be used to jump-start recovery from depression, with SSRIs retaining a role in maintenance. We halt an episode with nose spray; then we turn to Celexa.

Ketamine may come with so many adverse effects that its use is confined to severe depression. SSRIs might—this development would have its amusing aspect—become the treatment of choice for less symptomatic states. Why not? Our current medicines work well for low-level chronic conditions, stabilizing the emotionally fragile. The SSRIs’ effect on neuroticism might keep them in business.

Perhaps inhaled ketamine will handle the whole job. Patients employ it, find relief, and put the sprayer on the medicine-cabinet shelf, to be turned to as needed for “rescue.” In the face of this routine, recurrence loses its threat. Depression becomes intermittent, a nuisance treated as migraine headache sometimes is, through medication taken when an episode threatens.

Say that the relief is predictable, the effect size high. Will we have conquered an old foe, a disabling disease? Or changed what it is to be human? Those questions were ones I posed in Against Depression. How serious are we in our quest to vanquish mood disorders? I’d love to see that drama play out—to have access to a highly effective antidepressant drug in my lifetime—and perhaps I will have the chance.

Many interventions are vying for the role I have called ketamine. The NIMH is funding a program, titled Rapidly-Acting Treatments for Treatment-Resistant Depression, meant to offer prompt testing for medications that might interrupt depressive episodes quickly. Right now, academic centers are testing brief courses—under a week—of a “kappa-opioid receptor antagonist.” Some opium receptors in the brain affect pain perception, but others appear to regulate mood, and the new drug is meant to target them.

A quite different drug has shown promise in early tests. It is designed to influence the brain’s capacity to make new cells and new connections between cells in a region relevant to depression—and to do so without first affecting the brain’s use of serotonin or norepinephrine.

Researchers have been looking at nonstandard approaches to depression from the most superficial (Botox injections into forehead frown muscles) to the most profound (chemicals that alter the functioning of molecules within nerve cells). There’s early interest in pheromones, ultra-low-dose chemicals that work not through being absorbed into the bloodstream but by influencing receptors in the nose, unrelated to smell, that signal to mood centers in the brain. An area that has looked intriguing for decades, the use of anti-inflammatory drugs, such as Celebrex and Aleve, in depression treatment has gotten new play, although scattered findings also suggest that the drugs may interfere with the action of SSRIs. Groups interested in the brain effects of gut flora—bacteria in the bowel—are investigating their own approaches to depression. Natural herbal remedies have their advocates. That’s before we consider the many variants of magnetic or electrical influence on the brain, safer and less demanding variants of ECT. Ours may be the era of tinkerers and putterers—of garage-laboratory innovation in mental health care. The exit, however temporary or partial, of Big Pharma may have its upside. I am more confident now of seeing a truly novel effective medication for depression than I have been at any other time in my career, including the lead-up to the introduction of Prozac.

We may soon be able to select treatments more thoughtfully. I have mentioned the use of genetic profiles. More generally, extensive effort is going into the identification of biomarkers—indicators in cells or body fluids that may allow doctors to pair treatment and patient. It’s all very well to consider gross categories—anxious or lethargic. How much more useful it would be if a laboratory value gave direction: psychotherapy for this patient, ketamine for that one, and—unexpectedly, in the rare instance—stimulant medication for another.

For treatment outcomes, much of the new knowledge may come from research that forgoes randomization. We have learned that our standard trials can have disturbing downsides. The “blinding” requirement often means that treatments are not offered in their optimal form. The inclusion of placebos introduces problems with instruction effects and additivity. Recruitment issues are horrendous. After all that effort, we fail at the How much? question. It’s no wonder that researchers are looking beyond controlled trials.

Some are working to cull information from natural settings. A team at Massachusetts General Hospital is building a resource bank for fifty thousand “citizen scientists,” men and women with mood disorder who consent to serve as “data donors,” contributing the contents of their electronic medical records. Patients can volunteer while still taking guidance from their doctors, following what they consider the best course of treatment.

The MGH collection is the main mental health component of the Patient-Centered Outcomes Research Institute, a structure, created under the Obamacare legislation, that will include records on many millions of insurance subscribers. Scientists and patients alike will propose research topics.

A data donor can ask, “If I add Advil to a full dose of Effexor, what are the odds that my depression will respond? Might it worsen? What is the risk that I will suffer serious bleeding?” Researchers will locate records of depressed patients who tried a given strategy, define a rough control group, and compare outcomes. Statisticians are scrambling to develop data-mining techniques that give valid answers. If the effort succeeds, psychiatry research will have what it lacks now, large numbers representing the experience of patients in routine care.

One paper along these lines has already appeared, on weight gain in more than nineteen thousand patients started on antidepressants. After a year, patients on Wellbutrin gained less than did patients on Celexa—and so on. The results were not impressive, but the size of the research sample was.

Weight is low-hanging fruit. Doctors weigh patients regularly. Researchers have looked at how doctors encode mental health visits in electronic records and found material that statisticians can work with, indirect indicators of the severity of mood disorders. Our next insights into antidepressants’ risks and benefits—our tests of clinical wisdom—may well come from analyses of massive data sets.

Or it may be that we will come to understand antidepressants better when we arrive at a clearer understanding of what depression is. That’s the NIMH method, to start with brain biology. The leading theory has it that depression will turn out to be many discrete conditions.

The model is autism, which seems to arise from a variety of genetic abnormalities. It needs to be said that we don’t know what autism is either. Different causes may lead to a common downstream effect that then produces problems with empathy, intimacy, and language use. But autism is looking diverse—like cancer. Almost certainly, there will be many autisms.

In Against Depression, I took a position contrary to the prevailing view. My thought was that the diagnosis—depression—might prove reasonably coherent. I was influenced by the failure of past attempts to subdivide the category into more biological and more psychological variants. I still think that depression may have a coherent core, that many upstream causes will pass through a biological bottleneck, a limited set of abnormalities that cause the syndrome. Perhaps all mood disorders entail an impairment of resilience functions in the brain. That’s why there’s hope for ketamine, the real and ideal forms—because depression looks like one thing, a painful form of stasis.

I may be wrong. There may be many depressions, each in need of targeted treatment. We will come to know—and then, incidentally, we will understand what contribution the SSRIs and, before them, the tricyclics made when they were the drugs of choice.

I doubt that there will be great surprises. Through diverse sorts of research, through extensive clinical experience, we know our current antidepressants well. They alleviate depression. The level of efficacy sits in the territory bounded on the bottom by the numbers generated in imperfect trials and on the top by the absolute response rates encountered in practice—likely in the middle ground, with numbers needed to treat in the 3-to-6 range, where most medical interventions fall. Those figures sound right to me, based on how I see depression respond to medication, based on how I’ve seen it respond to psychotherapy, thyroid treatment, and the rest. My bet is that the higher—less favorable—numbers in some trials reflect bad research design and execution.

The How do we know? question turns out to be immensely complicated and reassuringly familiar. Knowing embraces a history and a heritage. It comes from seeing depression resolve faster than it once did, and from seeing patients lead fuller lives. It comes from research that has access to realistic groups of patients—early (1950s and ’60s) research, research in cardiology and neurology, research in psychiatry that takes on all comers.

The notion that there’s some grander take on reality strikes me as delusion. Our statistics are skewed by confounds. The results require interpretation. And what better perspective to bring to bear than the clinical?

Evidence-based medicine is not without its own downside. In the case of my good friend Alan, the influence was informal. A general impression—antidepressants’ reach is limited—had made its way from shaky meta-analysis into popular reporting and then a neurologist’s practice.

But EBM has been institutionalized. Exponents publish guidelines, and they constrain practice. Insurance companies decline reimbursement for treatment at odds with the rules. Hospitals create standards and punish doctors who fail to color within the lines. Training programs use the guidelines for teaching and testing medical students and residents.

We’ve run into one case where this sequence made mischief—when the British oversight group NICE recommended that for nonsevere depression, including mild and moderate major depression, doctors forgo further prescribing in favor of alternatives like exercise.

That directive was based on the results of meta-analyses like those we have looked at together, but it is hard not to think that taste played a role as well—that, in a broad sense, the quality standard reflected Doris Mayer’s sentiment about preferred ways for meeting life’s challenges. Meanwhile, the group ignored the confounds that plague research on exercise. Regarding NICE’s directive, critics writing in the BMJ noted “a lack of high quality evidence to support such a recommendation.”

Research testing of the NICE policy found that “facilitated physical activity” had no measurable effect on depression at any point in a year. What if instead of attention to exercise—or in addition—NICE had recommended attempts to optimize prescribing, the sort of enhanced care shown to help cardiac and neurologic patients? Participants in the study, many of them, might have enjoyed a year of good life.

We’re left with the suspicion that NICE’s recommendation, to postpone further attention to prescribing, caused suffering and harm, to brain, mind, patient, family. As for the many more patients not in the study but in the clinics of Britain’s National Health Service, the guideline does allow for them to be treated with further medication or psychotherapy once low-intensity treatments fail. But how much failure should we tolerate? And how ironic for EBM to postpone treatments for which evidence is strong in favor of one for which it is lacking. Today, that quality standard is still in place, although NICE has signaled that it is revisiting its recommendations for depression treatment.

More generally, it seems to me that when it passes into policy, evidence-based medicine risks hubris. EBM’s methods have rarely been subjected to its own standard: proof of efficacy. When we rein doctors in, do patients benefit? Think of the Canadian study of operating-room checklists. To cite one from a short list of statistically significant outcomes, when teams used the checklist, ambulatory patients experienced more complications. Perhaps there’s a cost to upsetting surgeons’ established routines. I don’t want to put weight on an incidental finding—except to say that it’s not obvious that we always do worse when we leave doctors to their own devices.

These examples—exercise, checklists—are the most innocuous. I ask my patients to exercise, although I am careful not to shame those too apathetic to begin. And I am sympathetic to experts who point to well-run small trials that contradict the conclusions of the Ontario checklist study. Perhaps surgical “time-out” should be enshrined through rules. The problem then becomes, where does the rule-making end? Based on EBM experts’ reading of the meta-analyses, shall we have a policy: no antidepressants for mild and moderate major depression? We would fail our patients.

The damage would extend beyond the effects of that one guideline. Because our symptom-based diagnoses are imprecise and antidepressants are imperfect, prescribing is an art. When I consult colleagues, what I hope for is a special expertise, one that allows them, as Jonathan Cole did, to reach out of category and match drug to patient, never mind the diagnosis. As applied by insurers and health-care systems, evidence-based medicine punishes that skill. When I prescribe a medication and a drug plan denies authorization—Why is this depressed person on Ritalin?—I am rarely convinced that my patient has been afforded protection.

It’s not just that EBM can get questions wrong and then make the answers into a rule. Like medication, EBM may have side effects. Will training young physicians to follow a guideline lead to better medicine than training them to read critically, observe closely, choose strong mentors, and aim to adapt treatments to cases? I would respect EBM more if its guidance included this requirement for trainees: Make note of what you see.

As for the antidepressant controversy, in retrospect it can be understood as one of those social phenomena that arise when long-standing grievance meets an opportunity for pushback. For partisans of psychotherapy, openings to resistance arose in the form of flawed outcome studies and the drug industry’s egregious overreaching. Pharma’s missteps came in the context of stalled drug development and—a factor easily underestimated—the culture’s discomfort with technical approaches to problems of mind. These same circumstances primed journalists and the public for the antidepressant-as-placebo reports, however implausible.

If we get new and highly effective antidepressants—our “ketamine”—the debate will lose urgency. Before it does, I feel impelled to say that in its late phases, the debunking of antidepressants assumed an unattractive tenor. In the early going, the opposition felt like counterculture pushback. Later, it became triumphalist—and implausible.

Think of what imipramine and Prozac and the others achieve. In primary-care patients who stay on the first drug they’re offered, the response rate may be 90 percent. No one—almost no one—believes that hopeful expectancy and the natural waning of symptoms produce anything like that level of improvement. If depression were that placebo responsive, every civilization should have had access to effective remedies, and we in our time would have more types than we do.

Smug implausibility has a bad track record in psychiatry and psychology. The professions’ stumbles often involve ideas that are at once unlikely and in accord with the zeitgeist. I am thinking of castration anxiety and penis envy, understood, in the time of Freud’s dominance, as deep motive forces producing personality traits and mental illnesses. I wrote about those concepts in my brief Freud biography. They arrived in a Vienna proud of its new openness about sexuality. Freud’s constructs were at once outrageous and complicit, stirringly counterintuitive and cozily conventional. Danger arises when the implausible becomes the obvious. Think of the offhand ease with which a Chestnut Lodge doctor said, of Ray Osheroff’s career, “This business that he created was a giant breast.”

Denying the efficacy of antidepressants may begin well enough, with a love of psychotherapy and a respect for human complexity. But in time, the position becomes stigmatizing, too much in accord with the notion that depression is something other, something less than what research and practice find it to be: a progressive, destructive multisystem disorder fully worthy of medical attention. Denial becomes forgetting—of Paula J.F., Irma, Robert Liberman, and endless others, Troys and Moiras, exposed to depression without antidepressants as a remedy.

Antidepressants don’t look to be placebos. Consider the research on maintenance, with fifty-four trials all favoring medication. Only in psychiatry would there still be debate about whether the treatment is protective—whether the drugs are glorified dummy pills. Yes, there are concerns about a genial confound (antidepressants’ possible benefits for various aspects of health), but finally the psychosomatic literature, the trials that find antidepressant efficacy for patients with stroke or heart disease or exposure to interferon, should put paid to the placebo canard.

Consider—how bold, how transgressive, in the era of straitlaced EBM, it feels to put this item on the list—consider what patients say: On medication, they have come back to life. Oh, we are mistrustful, but that testimony is not wholly without evidentiary value. To dismiss it, research results to the contrary would need to be solid. We would need to see that antidepressants do little and that depression is highly placebo responsive. Instead, our studies show drug efficacy for depression—mild, moderate, and severe—while the placebo story is suspect.

We have not—not yet—moved beyond our current classes of antidepressants, but we have come this far: achieving the ability, unique in human history, to treat depression reasonably well with medication. At the start of this journey, I asked, Do antidepressants work, and how do we know? It may be time to ask, How do we embrace our answers?

It’s wondrous for humankind to have the use of treatments for that antique scourge, melancholy. Wondrous for a time, until the good news is absorbed and we turn our focus to the bad. Not everyone is helped, and not everyone helped is helped fully.

Perhaps an equal problem is that medications succeed and make melancholy look medical. Antidepressants can assume the role of partisans in an old struggle, about mind and brain, meaning and symptoms. Must that contest persist? Antidepressants and psychotherapy mesh so well.

Still, it’s true: we discount the miracle because sometimes antidepressants fail; and then sometimes we discount it because they succeed.

A treatment that tests out as well as treatments in the rest of medicine is not enough. A treatment that works on the wrong basis—without prior growth in self-understanding—is too much.

We long for more and better—until we take perspective. As when the end of treatment nears, there comes a time to say, Look how far we’ve traveled.

Certainly, I have enjoyed the journey. The company has been good. I mean my patients, of course, and my teachers, ones you’ve met here and others I’ve thanked in prior books and more yet unnamed, and colleagues I consult and socialize with, along with those I know through their writing. But it would be wrong not to tip a hat in the direction of imipramine, the SSRIs, and lithium and the rest. Think of the difference between practicing in the course of my career and practicing in other eras—any, besides that heady one when modern psychotherapeutic drugs first came into use. To get to meet Prozac and then to work in concert—what unexpected reach, for a clinician trained exclusively, all but exclusively, in psychotherapy. I am conscious of the privilege.

How wrong, too, it would be to conclude on a solemn note. Practicing doctors live amid anecdote.

Just yesterday, I had a follow-up visit with a patient troubled by chronic mild depression. Zach is serious, deliberate, and painstaking. He had preferred to work with me in psychotherapy and then—some weeks ago—finally asked me to prescribe. Presently, the antidepressant kicked in. He functioned, he thought, somewhat better at work. Then Zach made note of an additional improvement, changed perspective:

“I’ll tell you what was absent in the bad months: appreciation of what I have. I’d lost touch with what a good person my wife is. She’d sensed my dissatisfaction and turned resentful.”

He said, “I must have been more depressed, and for longer, than I’d known. It’s been since forever that I appreciated winter. I felt the oppression of the darkness. I missed the sunlight on the snow.”

Over time, in session I’ve heard repeatedly how depression dampens responses to love and beauty. When medication works, the world does its bit. Patients are freed to notice what’s precious in their lives. That’s why doctors prescribe. They see how symptomatic relief adds dimensions to patients’ consciousness. In retrospect, doctors—no, I—regularly I discover that I had failed to appreciate the extent of my patients’ impairment.

In ways large and small, depression burdens lives. Combating it, psychiatry has been in stasis. But it would be shameful not to show gratitude for our imperfect tools. We’re lucky to have them. Progress in mental health care may be slow, but make no mistake: for clinicians, for depressed patients, ours are still extraordinary times.



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