Ordinarily Well: The Case for Antidepressants

29

Elaboration

I HAVE MENTIONED the theory that antidepressants restore resilience and permit recovery to proceed. Much of the support for this view comes from animal studies and parallel research on human brains. Depression seems to hamper the brain’s ability to generate new nerve cells or elaborate connections between existing ones. Antidepressants reverse these impediments. But how does that renewed flexibility translate into people’s becoming “unstuck”? What happens in the person?

For years, the official line was that antidepressants take two to four weeks to bring relief. Clinicians knew better. Kuhn spotted improvements in the first days of treatment. When I prescribed imipramine, I started with tiny doses and inched up to realistic levels; patients might notice nothing for some time. But with drugs such as Zoloft, where the initial dose can be the final, therapeutic dose, patients will report an immediate, if vague, response. The foreboding recedes. They’re not slogging through molasses.

Thanks to the work of researchers such as Philip Cowen, an Oxford University psychiatrist, we know now that medications have a quick impact. In an experiment whose results appeared in 2009, Cowen gave either a placebo pill or a half dose of an antidepressant to patients with mild-to-moderate depression. Asked to assess emotional expressions in images of faces, patients on placebo had difficulty recognizing happiness. They were also slow to recall positive events in their lives. Patients on medication recognized happiness and recalled positive events—and the normalization was apparent three hours after the administration of the first pill. The early improvement predicted a fuller response down the road.

If their helpful effects can be detected immediately, why do medicines take weeks to calm depression? Cowen finds that antidepressants act right away to correct flawed emotional processing, counteracting negative slants in perception. Long before the depression remits, patients on antidepressants see themselves and their surroundings in a warmer light. Part of what happens next may be social and psychological. Cowen writes:

According to this view, effects of antidepressants on emotional bias are seen rapidly, but the translation of these changes into improved subjective mood takes time as the patient learns to respond to this new, more positive social and emotional perspective of the world. An increased tendency to interpret social signals as positive may not immediately lead to improved mood but could reinforce social participation and social functioning, which over repeated experience improve mood and the other symptoms of depression.

This psychological sequence may not tell the whole story. Sometimes, antidepressants seem to act directly, ending a bout of illness. Occasional patients follow the “unique” pattern that Fred Quitkin observed. Three weeks in, they feel better abruptly and stay well. And as we shall see, certain medicines still being tested for depression seem to reverse the syndrome in hours or days.

Also, even where our current antidepressants act as catalysts, the change that they bring about goes beyond attitude. The medications induce actual resilience to stress—protecting cells from certain forms of biological injury—and allow for greater possibility of learning. Probably, antidepressants work on two levels, lifting despair and making the brain more responsive.

Either way, there’s a multiplier effect. Antidepressants allow the adoption of new beliefs and behaviors, so that the drug action is enhanced by gains in social functioning and the benefit of what often follows, a more supportive environment.

If, sometimes against the evidence, I believe in the special virtues of combined treatment, antidepressants and psychotherapy, it’s because when medication breaks the ice, patients become open to insight and productive activity.

Cowen’s model raises questions about the “inherent efficacy” of medication. When it works promptly, freeing the brain, has an antidepressant been effective? We may be inclined to say no, not yet. Only if a patient does, in practice, elaborate early change into substantial symptom loss will we give credit.

Recently, researchers have reported that Botox, injected to paralyze frown muscles, can combat depression, especially in patients already on antidepressants. Probably the cure involves neurological feedback—the brain reads the relaxed forehead as an indicator of favorable circumstance. Social responses may play a role, too. People are friendlier to people who look relaxed. We would not applaud the nerve toxin (as an augmenter for antidepressants) if it only smoothed out wrinkles. The subsequent steps must occur and result in mood improvement.

It is not enough for us, then, that antidepressants alter emotional perception. Paradoxically, when we speak of inherent efficacy, inherent means immanent—unpacked, elaborated, present. Changed brain biology is only the beginning of a sequence. The patient’s new willingness to phone a friend represents the drug’s action. So does the friend’s encouraging response. But we measure change only through diminished scores on the Hamilton scale. Analogously, we might give antihypertensives credit only if they prevent stroke; lowering blood pressure is not enough.

This standard (for what counts as inherent efficacy) is exacting, and it explains why the number needed to treat is never as low as we hope. At the level of brain cells, the medicine may do its job, and still we will not arrive at a result we call efficacy.

In this context, the placebo can do harm. Awareness that a study uses dummy pills may induce uncertainty and dissuade patients on active medication from capitalizing on the early improvement. Irving Kirsch has contributed important papers on this subject. Again, to my mind it is in this effort, elaborating the theory of the placebo, that he excels.

In 1993, Kirsch ran an experiment that involved lying to participants. He divided one hundred undergraduates into three groups. To one, he said that everyone would get coffee, the real thing, caffeinated. To another, he promised decaf. Students in the third group learned that they were in a double-blind study and might be given either caf or decaf. Each subject was then served strong coffee, once with and once without caffeine. One outcome measured was tension.

Among those told that they were getting caffeine, regular coffee produced high levels of tension and decaf did nothing.

For those told that they were getting decaf, the tension effect disappeared; even high-test did not give the jitters.

The interesting condition was the one where the students had been told that they were in a controlled trial. Those students, too, felt no rise in tension. When it came to tension, being told that you were in a trial was the equivalent of being told you were on decaf.

This result demonstrates an instruction effect. What an experimenter said shaped what subjects experienced. Their awareness that they might be on placebo (decaf) made an outcome based on chemistry and neurobiology—caffeine’s inherent ability to arouse tension—disappear.

Kirsch commented that this result cast doubt on the “validity of current double-blind methods.” If instruction—mere awareness that placebos are in play—matters, drug effects reported in controlled trials may be lower than real inherent drug effects enjoyed by patients treated through their doctor’s prescribing.

Instruction’s power to mask efficacy has been encapsulated in the coinage lessebo, a wince-inducing Teutonic-Latin mash-up that has the virtue of being memorable. According to the word’s originators, lessebo refers to a reduced medication benefit “because the patient is uncertain as to whether his or her randomly assigned compound is truly active or not.” Hopeful expectancy drives the classic placebo effect. With the lessebo effect, the motive force is corrosive doubt.

Researchers first made note of this phenomenon in the 1990s. A 2010 study confirmed that patients in a trial comparing two medications were more likely to respond than patients in a trial comparing one of those medications and placebo. Similar results have been found in the treatment of Parkinson’s disease: drug trials with placebos showed lower efficacy. In the face of uncertainty, drug responses are muted.

Doubt is a major topic in psychology today. Studies in behavioral economics, conducted via game playing, show that humans dislike ambiguity. Even when an overall situation is unthreatening, uncertainty activates the amygdala, a part of the brain involved with fear and vigilance. Introduce doubt, and you produce change in the brain and then in perception and behavior.

In the case of depression, we can turn to Cowen’s theory of elaboration. A patient takes an antidepressant. Three hours in, he feels stirrings of change. Knowing that he might be on a placebo, he mistrusts the sensation. He does not pick up the phone and so does not receive the encouragement a friend would offer. An instruction or lessebo effect prevents the full expression of the drug’s powers, blocking the part that extends beyond the initial change in brain and body.

This point is important conceptually. If recovery from depression depends partly on elaboration of early changes in perspective, and if doubt interferes with elaboration, then placebo-controlled trials (by their nature, because of their design, and regardless of how well they are conducted) will be liable to a confound. They will produce overly conservative—spurious—results. Just as prescribing doctors have no easy way to tease out the influence of hopeful expectancy, so researchers cannot see past lessebo effects. They arise from the structure of these trials—from the use of placebo arms, informed consent, and blinding, which introduce uncertainty and weaken medication responses.

As Austin Bradford Hill warned, strict reliance on randomized trials can cause the field to underestimate the worth of treatments like antidepressants. Studies (like Lisa Ekselius’s) that forgo placebos supply a useful counterbalance. Even the clinical setting has its advantages. In a doctor’s office, like our imagined Viola’s, there is no suggestion that drugs are not drugs. Patients freed up in the early going by antidepressants will think and do things that consolidate those gains. The doctor will take note and refine her estimate of the medications’ worth. Her informal observation can serve as a partial corrective to distortions inherent in conventional outcome research.



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!