The use of such outrageous
therapeutics did not end in that era. In an article
last month in the New York Review of
Books ("Neuroscience and the Law: Don't Rush In"), Jed S. Rakoff describes
the zealous, grotesque embrace of first eugenics and then lobotomies for the prevention
and treatment of mental illness in the first half of the twentieth century. He
states that more than 40,000 lobotomies were performed in the two and a half
decades after 1940, including on children and for the "treatment" of
homosexuality. These sorts of atrocities, it's worth noting, are not unique to
the field of psychiatry: They can be found throughout the history of medicine.

But then the story began
to change, which is where Kramer begins his book. In the 1950s, in Switzerland,
a psychiatrist named Roland Kuhn developed one of the first modern
antidepressant medications. Before that point, Kuhn had relied on a combination
of psychotherapy and existing therapeutics. For instance, with "insulin-shock
therapy," he would administer high doses of insulin to his patients, causing
their blood sugar to plummet to dangerously low levels, which would in turn
induce ostensibly therapeutic seizures. He would also sometimes turn to the old
uppers and downers, amphetamine and morphine.

But new drugs were
emerging. The first antipsychotic drug—what we call thorazine—became available
in this decade. However, after a brief trial period, Kuhn's hospital couldn't
afford any more thorazine, so Kuhn turned to a Swiss pharmaceutical company
named Geigy to see if it might provide a similar compound. Geigy gave him
substance G22355. However, Kuhn found that G22355, in contrast to thorazine,
wasn't very effective in treating the psychosis of his schizophrenic patients; it
did, however, improve their mood. So he proceeded to try it on dozens of his depressed
patients. He observed marked clinical improvements among these individuals, observations
he presented and published in 1957. Geigy, as it happened, only moved ahead
with the production of the drug, which would be called imipramine, after one
its key shareholders gave it to his wife with apparent benefit. Imipramine was
the first tricyclic drug—a class of antidepressants still in clinical use
today. Indeed, it has not yet been trumped by any drug since with respect to
efficacy.

And so the age of
antidepressants began.

The
story of Kuhn and imipramine, Kramer contends, is unique. Though Kuhn's study was
flawed, it was an "experiment ... of singular evidentiary value," one which can
never again be replicated, and because of this, it holds important lessons for
the interpretation of modern antidepressant drug studies, the central concern
of Kramer's book. In contrast to the participants of modern randomized trials
of antidepressants—who may have already been on several rounds of
antidepressants and who are studied in a somewhat artificial setting—Kuhn's
patients were antidepressant virgins treated in a real clinical environment. "He
had witnessed," Kramer writes, "the full power of an antidepressant," something
(he believes) that modern investigators can longer do. Whether this is as
important as Kramer suggests is something I'll return to later.

From there, Kramer
proceeds to tell, in a series of short chapters, the story of the other developments
that together brought about the modern era of psychopharmacology. One critical
advance was the development of the randomized clinical trial (RCT). Doctors, of
course, had already been studying the impact of drugs on disease since the
advent of medicine. They would administer a treatment, observe its effects, and
conclude from these observations whether it had been successful or unsuccessful.
That might sound, on face value, like a perfectly reasonable method for
determining efficacy. In truth, however, this approach has grossly misled the
medical profession from the time of Hippocrates to today. Based on their honest
clinical observations, physicians have become deeply, sincerely convinced of
the efficacy of treatments later shown to be useless and even deadly. The
reality is that the course of most diseases is quite variable: some will
improve with a useless treatment, while others will worsen even if they receive
a highly effective one. Distilling from these varied and contradictory
experiences the true "clinical effect" requires nothing less than the cold-blooded
rigor of statistical analysis.

Another problem: if the
decision to treat or not to treat is anything but entirely random, any effects
that are observed may reflect characteristics of the individuals, and not of
the drug. That is why—as Kramer emphasizes—RCT's were such a milestone in
medical history. An RCT is an experiment conducted on human beings, with
treatment determined by a coin flip (or something like it). When they are performed
correctly, they can bring us closer to the truth about a medicine's effect than
is possible through observation alone. Yet as crucial as RCTs are to the development
of medical therapeutics, they are a very recent innovation: as Kramer notes, the
age of the clinical trial only began in 1946, with the British Medical Research
Council's landmark trial of streptomycin for tuberculosis (notably, it worked).
The key element of this trial was that it randomized participants to treatment
or no-treatment; later trials, Kramer notes, would also include blinding as
well as placebos for the no-treatment group.

"Listening to Prozac but Hearing Placebo" was "the opening
salvo" of today's still unfolding debate.  

This history is
important, because a good portion of Kramer's book, though interspersed with
interesting clinical anecdotes and poignant reflections, grapples with the
question of how we should interpret modern antidepressant clinical trials. A
few other developments, however, were also needed before our era of antidepressant
therapy could begin. In order to determine if antidepressants are effective in a
clinical trial, their effect must somehow be objectively quantified. Kramer describes
how, in the 1950s, a British psychiatrist with statistical expertise named Max
Hamilton formulated a depression scale—still employed in studies today as the "the
Hamilton Depression scale"—that quantified various symptoms of depression, with
a response defined as a reduction in one's score by half. By the 1970s, when
Kramer began his medical training, randomized trials of imipramine, relying on improvements
in Hamilton scores, had demonstrated positive results. Although, Kramer says,
an older guard trained in Freudian psychoanalytic therapy still resisted the
use of these medications, they were increasingly recognized and utilized, to—in
his eyes—often marvelous effect.

1987 was a final
milestone that he makes note of: this was the year when the FDA approved the
first selective serotonin reuptake inhibitor, Prozac. Prozac seemed to have similar
efficacy to imipramine, but a better side effect profile. If you or someone you
know is taking an antidepressant, it is most likely a drug of this or a similar
class. Kramer sees the introduction of antidepressant medications as altering
the very landscape of mental health in America. What he calls "end-of-the-line"
depression—severe, end-stage, intractable, hopeless depression—became a rarity
in his eyes, though he admits empirical evidence is lacking. "[M]y impression
is that end-of-the-line depression is less common in part because—haphazardly,
with many a case missed altogether—we treat depression early, generally with
antidepressants." Modern psychopharmacology had arrived.

Yet, it wasn't long
before the pendulum again began to swing. In 1998, without warning, two
researchers fired a shot across the bow of the psychiatric mainstream. This
came in the form of a paper
whose title echoed Kramer's own book from five years earlier. "Listening to Prozac but Hearing Placebo: A Meta-analysis
of Antidepressant Medication," was, according to Kramer, "the opening
salvo" of today's still unfolding debate about antidepressants.  

Clinical trials, I'd argue, touch on all of
our lives in profound ways, though elucidating the finer points of their
design, analysis and interpretation—as Kramer does—is not an easy task.
Optimally, clinical trials are both well-designed and massive, in which case
they sometimes produce definitive results. In such cases, repeating the trials
becomes worthless and often grossly unethical. However, psychiatry has few if
any of these "gold standard trials," as Kramer acknowledges, and for that reason,
the field relies on "meta-analyses." These are essentially studies that pool together
data from multiple smaller studies to produce more definitive results. "Listening
to Prozac But Hearing Placebo" was one such meta-analysis (albeit a highly
controversial one), performed by Irving Kirsch, a psychologist interested in placebo
science, then at the University of Connecticut, together with psychologist Guy
Sapirstein.

Now, as Kirsch has argued
in a 2014 review
("Antidepressants and the Placebo Effect"), the fact that placebos might have
an effect on depression should not be seen surprising. Depression, he contends,
is frequently characterized by a deep sense of hopelessness, and so "the mere
promise of an effective treatment" might help to replace "hopelessness with
hopefulness—the hope that one will recover after all." This was, in any event, he
and Sapirstein's thinking when they set out to investigate how placebos might affect
depression.

Their study was a
meta-analysis that combined the results of 19 placebo-controlled trials, each
of which looked at the effect of some drug on depression. In analyzing the data
from these varied studies, they found that those who took drugs had a 1.55 overall
standard deviation improvement in their depression scores (measuring
improvement in standard deviations is a way to standardize these changes), consistent
with a substantial response. However, those who took placebo also had a
substantial improvement, with a 1.16 standard deviation rise in scores. They
thus write:

Subtracting
mean placebo response rates [1.16] from mean drug response rates [1.55] reveals
a mean medication effect of 0.39 SDs [standard deviations]. This indicates that
75% of the response to the medications examined in these studies was a placebo
response, and at most, 25% might be a true drug effect ... [this] means that for
a typical patient, 75% of the benefit obtained from the active drug would also
have [been] obtained from an inactive placebo.

Now this is not, necessarily, as damning as it
might sound. As Kramer notes, from this result alone, we can not conclude that
there is a powerful (or indeed, any) placebo effect at work: it may simply be
that people improve over time for various reasons, including the natural
history of the illness. Antidepressants help those who don't otherwise improve.

However, Kirsch and
Sapirstein had some other findings that suggested that there was indeed a real
placebo effect at play, at least in their view. For instance, they found that
the effect was basically the same regardless of the type of drug used, meaning there
was no major difference whether subjects received traditional antidepressants
(e.g. imipramine or Prozac) or "other medications" (e.g. thyroid hormones,
benzodiazepines, barbiturates, or lithium) that are not considered
antidepressants. Whereas it could be true that these latter drugs actually had
an antidepressant effect, it could also be that they caused side effects that
made the individuals taking them come to
believe they were taking active drugs. This, in turn, would boost the intrinsic
hope-inducing effect of the placebo. This is what is referred to as an "active
placebo," a paradoxical-sounding concept that is rather fascinating. (As a side
note, it's worth stressing that for "harder" outcomes, like the growth of a
tumor, there is no placebo effect, active or otherwise. Where they exist, placebo
effects are, by and large, confined to subjective outcomes). But in short, Kirsch
and Sapirstein hypothesized that the relatively modest effect seen by
antidepressants—which have side effects that can be detected by the patient—might
actually be nothing more than the incremental effect of an active placebo over
an inactive placebo.

Kramer
rebuts these highly provocative claims with a wide range of arguments. The "active
placebos" used in the studies all have potential antidepressant effects of
their own, he argues (especially when, as in one study, they were combined with
an antidepressant). Moreover, the placebo arm of clinical trials, as he
describes across a number of chapters, is not a real placebo effect, but is
instead reflective of a host of benefits that accompany the experience of participating
in a clinical trial. To document this, Kramer visits a for-profit clinical
trial testing center that is frequently used in modern randomized trials of
psychiatric drugs. He understandably finds the experience rather disconcerting.

As he notes, it is
considered unethical to pay people too much to participate in a clinical trial
(as this is considered coercive). As a result, the relatively modest
reimbursements for participation in these trials winds up attracting only
economically disadvantaged individuals. In addition to the money, he describes how
the host of fringe benefits that come from participation—like transportation to
and from the center in the company of others—confers real quality-of-life
improvements for these individuals (if only temporarily):

For
the duration of a trial, participants enjoy higher income, richer social
contracts, attention from doctors and nurses, access to transportation, time in
an attractive setting, structured days, and a sense of purpose. In the bus,
talk turns to cash gifts given to adult children. That's a luxury the extra
income affords, the ability to be generous. Even on placebo, these patients
ought to get better.

Collectively, he argues, these benefits amount to
a weak form of psychotherapy, and as a result, the placebo arm is not really a
placebo arm: "In antidepressant trials as they are run today," he writes, "the
contrast is not between dummy pills and active pills. It is between
psychotherapy plus dummy pills and psychotherapy plus medication."

The point is, I suppose,
reasonable, but then again, does it really matter? In Kramer's own practice, he
generally doesn't prescribe drugs outside of the confines of psychotherapy. In
my mind, what matters is the additive effect of antidepressant drugs to some
sort of therapy: if the drugs have no added
effect, then why shouldn't the money we spend on antidepressants instead go
towards more talk therapy and social support for disadvantaged people? Still,
even in Kirsch and Sapirstein's 1998 study (and later studies by Kirsch and
others), antidepressants do have some
"added" effect: it's just far more modest than what Kramer believes he sees in
clinical practice.

At the end of the day, Kramer
had thought that the Kirsch and Sapirstein study would prove to be one quirky,
quickly forgotten study. "I had seen it as a rearguard action," he notes. On the
contrary, "[i]t was in the vanguard, the start of a resurgence of doubt about
antidepressants."

This "resurgence of doubt,"
however, would ultimately stem less from concern over the placebo effect, and
more from revelations about the corrupting influence of corporate greed.

Imagine,
for a moment, a friend who boasts successes—whether in cards or in love, in
stock picks or in sport fishing—while leaving out the losses and the lonely
nights, the busts and empty buckets. Depending on how well you know him or her,
you might come to a rather inflated sense of your friend's talents. Now imagine
that this individual is actually an enormous multi-billion dollar business
running clinical trials on antidepressants, and that it was selectively
publishing successful trials, while kicking the less-successful ones under the
carpet. You might similarly come to have an inflated sense of the potency of
the drugs it was producing.

That's
basically what happened over the last few decades, though it took a Freedom of
Information Request to figure it all out. Kramer discusses two studies, both
published in 2008, that used data from studies that had never been published to
shed light on the real efficacy of antidepressants. Kirsch was the lead author
of one
("Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data
Submitted to the Food and Drug Administration"), published in the journal PLOS One. The other, by Erick H.
Turner and colleagues, ("Selective Publication of Antidepressant Trials and Its
Influence on Apparent Efficacy"), was published in the New England Journal of Medicine. The Turner study explicitly examined
the extent to which publication bias affected the "apparent efficacy" of
antidepressants, and it made headlines.
Briefly, these investigators obtained trial data submitted to the FDA for 12
antidepressants approved between 1987 and 2004. Overall, of the 74 studies they
found, almost one third had never been published. They then classified the
studies based on how the FDA had reviewed them: "positive" (the drug worked),
"negative" (it didn't), or "questionable" (somehow mixed). They found that the
vast majority of positive studies—37 out of 38—were published. On the contrary,
of the 36 negative and questionable studies, "3 were published as not positive,
whereas the remaining 33 either were not published (22 studies) or were published,
in our opinion, as positive (11) and therefore conflicted with the FDA's
conclusion." This is disturbing, to say the very least. Selective publication
fundamentally distorts our perception of whether the drugs work at all, much
less how they work. Still—and as Kramer underscores—the study still found, at the end of the day, that
the drugs were effective, just substantially less so than what one would believe
on the basis of the published literature.

The 2008 study by Kirsch
and colleagues didn't compare unpublished and published study, but instead
simply included both together in order to determine, more accurately, the actual
effect of antidepressants. Ultimately, what they found (again, drawing on study
data arrived at through a Freedom of Information Request) was that there was a statistically
significant effect of antidepressants but that it wasn't very impressive
(indeed, it was below the standard considered to be of "clinical significance"
by the British National Health Service), though this depended on the severity
of depression. This last finding—that the effect of antidepressants depended on
the severity of depression—was confirmed in another widely-reported meta-analysisby Jay C. Fournier and colleagues that appeared in
2010 in the Journal of the American
Medical Association (also discussed and critiqued by Kramer). In this
study, whereas evidence for efficacy was "nonexistent to negligible" for
patients with more moderate forms of depression, there was evidence that the
drugs were fairly potent for those with "very severe symptoms." (Kramer cites
other studies that he contends dispel this so-called "severity hypothesis").

It
was in the context of the unfurling of these somewhat scandalous studies that the
debate over antidepressants burst onto the public stage. In 2011, Marcia
Angell, physician and former editor-in-chief of the New England Journal of Medicine, wrote a two–part,
wide-ranging essay in the New York Review
of Books that reviewed several critical books about mental illness, one of
which was a book by Kirsch that built on his 2008 study. Angell, however, went beyond a discussion of
antidepressant efficacy to excoriate the diffuse corruption of the psychiatric
field by industry money, the expansion of psychiatric diagnostic categories to
encompass ever-larger numbers of people, and the downgrading of non-drug
therapies. "[B]y emphasizing drug treatment," she notes, "psychiatry became the
darling of the pharmaceutical industry, which soon made its gratitude tangible."
The same year, Kramer issued something of a rebuttal, a long article headlined "In Defense of Antidepressants" that
appeared in the New York Times.

Kramer,
I should be clear, is in no way defensive of Pharma's dishonesty. Indeed, he
describes no financial conflict of interests with the industry, and he
disclaims their chicanery in no uncertain terms. It is clear that his support
for antidepressants comes from a combination of his clinical experience and his
reading of the literature. Additionally, he himself prescribes the drugs
conservatively (he calls them his "cotherapists"). His belief that the drugs
are improving the lives of countless millions is, in other words, genuine. However,
though his central assertion, contained in the book's title, is that
antidepressants simply work "ordinarily well"—that is to say, like other
effective medications—he makes them out to work extraordinarily well. "I find antidepressants useful up and down
the line," he notes. Similarly: "There are utterly untreatable depressions—but today, few." And with the right approach, he notes, "over three-quarters of
those who start treatment enjoy substantial improvement." In short, he sees
them as highly effective in bringing relief to the majority of treated
individuals with basically every size and shape of depression. That's no
ordinary drug—that's a wonder drug.

Kramer sees antidepressants as highly effective for basically every size and shape of depression. That's no
ordinary drug—that's a wonder drug.

Yet meta-analyses for
major depression, in contrast, including the ones discussed, consistently show
"effect sizes" that are modest. Kramer disputes these effect sizes with a wide
range of detailed criticisms, some of which I've already mentioned, and which
can only be briefly and incompletely listed here: he argues that these studies over-account
for the placebo effect; that their patient populations are atypical; that the
clinical trial setting is artificial; that the scoring system (the Hamilton) is
flawed; that the choice of trials included in meta-analyses are problematic; that
the individual trials relied on by these meta-analyses have shortcomings of
their own (insufficient doses of drugs, the wrong drugs); and that the doubt
implanted in people's mind by the fact that they could receive a placebo
results in a psychological "lessebo" effect that lessens the actual effect of
the drug. Moreover, he points to areas where he considers the evidence more robust—for
instance, for a form of chronic, low-level depression called dysthymia and for the
prevention of relapses—to support his overall position.

Yet
though he offers a host of objections as to why effects in clinical trials
unfairly represent what happens in actual clinical practice, one can come up with
a variety of counterpoints as to why effects in clinical trials could also inflate
real-world effects (which is often the case in other fields). For instance,
compliance with medication regimens may be higher in a clinical trial, given
the structure and support provided: this would make them look better in trials than they actually are
in real life.

Kramer also argues that
drug trials include individuals who are not typical of most depressed people.
He calls these people "immensely disadvantaged" patients, meaning that they
tend to be poor or lacking in resources. They do not have an "uncomplicated
depression" and so may be unusually difficult to treat. We are left to wonder where
along the economic spectrum, exactly, these "immensely disadvantaged" people actually
land. Not at the top, for sure, but are they true outliers, or do they account
for a substantial portion of the populace in our age of rising economic
inequality? And should "uncomplicated depression" necessarily be considered the
benchmark?

We are witnessing, for
instance, a historic opioid epidemic. A widely reported study last year demonstrated
that mortality is rising among middle-aged whites, in part driven by the fact
that they are abusing alcohol and drugs and killing themselves at higher rates.
Racial and ethnic minorities, meanwhile, contend with unique
threats to physical and mental health of their own. It's not clear to me
that the sort of non-disadvantaged people with "uncomplicated depression" Kramer
is referring to are necessarily representative of nation's mentally ill.

We
do not live in Kuhn's clinic: the efficacy of antidepressants should be judged
based on their ability to improve the health of the complexly depressed, often
previously treated, and frequently disadvantaged individuals of our day.

All things considered, we
live in a different era than that of the eighteenth-century phlebotomists and
the twentieth-century lobotomists. As compared to the therapies of the past, antidepressants
are—at the very least—gentle. They have real side effects, to be sure, but they
are reasonably safe and well tolerated by most. If they can effectively lessen
the great distress inflicted by depression, they should be employed.

But here we are, a full
half-century after Kuhn's experiment with G22355, debating whether they
actually work. Where do things stand when all is said and done? It's important
to emphasize that—at the end of the day, and even if we put aside many of
Kramer's criticisms—the prominent meta-analyses, published in top medical
journals, still show modest benefits for antidepressants, even when these
studies account for publication bias, and even when assembled by antidepressant
skeptics like Kirsch. Kirsch may argue that this is nothing more than the
effect of an active placebo over an inactive placebo. This could be true, but
it is an unproven theory. Moreover, effect sizes increase in those with more
severe depression, and so there does seem to be a more unambiguous role of the
drugs for these patients.

More broadly, whatever we
conclude about the efficacy of antidepressants, we should be doing more, not
less, for the alleviation of depression. Unmet needs are rampant. Kramer notes
that a third of those with major depression are entirely untreated. Real universal
health care—inclusive of comprehensive mental health benefits like
psychotherapy—remains a shamefully unrealized goal in the United States, something
that we should continue to pursue notwithstanding shrill protestations
from the liberal commentariat that it is unaffordable or impossible. Perhaps we
should even consider new trials of old antidepressants. These would be large,
publicly-financed, trials devoid of Pharma influence, conducted in more real
world settings, perhaps including a real "active placebo" arm, so as to more
clearly understand the real impact of these drugs. Finally, more attention
should be paid to the social determinants of mental health—the political and economic
structural factors that contribute to depression, even if by no means their
only cause.

It is a rare—perhaps
imaginary—individual whose life has not been negatively touched, either
directly or indirectly, by depression. Neither nihilism nor complacency is
acceptable in the struggle against its ravages.