Saturday, April 01, 2000

Reaching for the Happiness Throttle

The Science of Happiness: Unlocking the Mysteries of Mood

By: Kristin Leutwyler

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Despite the title of Stephen Braun’s new book, there just isn’t much to “the science of happiness,” which may be why the book is mostly about depression and the race among drug companies to find a successful treatment. It may also be because Braun, an award-winning medical writer, has focused much of his past work on mood-boosting drugs. His 1996 book, Buzz, explored the effects and fame of alcohol and caffeine. Yet another possible reason is that his interest in happiness, as he admits in the epilogue to this recent book, arose in part from his efforts to temper his own “microbursts”of bad moods. In any case, The Science of Happiness: Unlocking the Mysteries of Mood offers readers some fascinating ideas about Darwinian psychiatry, modern neuroscience, and the future of psychopharmacology.

The book does at least kick off with happiness—and the now old news that it cannot be bought. Chapter 2 neatly sums up what has been discovered about the “enduring sense of positive well-being,” as happiness expert David G. Myers defines it. Studies by Alex Michalos and Ronald Inglehart conducted during the 1980s were the largest ever to look for a correlation between money and happiness. Sixteen countries and 170,000 subjects later, Michalos and Inglehart found no evidence that people in wealthier countries were any more content. Ed Diener at the University of Illinois discovered the same trend within borders: the rich Americans he surveyed were, on average, only marginally happier than their poor neighbors—and many were, in fact, much less buoyant. Other investigators searched for, but could not find, greater happiness among lottery winners, young people, men, Caucasians, and the more highly educated. 

What scientists did find, Braun tells us, is that our personal happiness is, on average, fairly constant throughout our life. That idea comes from the National Health and Nutrition Examination Survey, which interviewed some 7,000 men and women in the mid-70s and again in the mid-80s and found that the happiest people remained so over time. Even subjects who had suffered life changes such as losing a job, a spouse, or both, were on the whole no less happy a decade later. Diener reports that most people return to their normal mood within three months after good news lifts them up or bad news gets them down. In other words, we all have a built-in happiness “set point” around which our moods fluctuate —much as we have a fixed, normal weight. 

This may sound like bad news for depressives and dieters alike, but it is this concept—the happiness set point—that makes Braun’s book interesting. Since we all strive to be happy, he asks, what does it mean if people begin the race from different starting lines, lines determined not by effort or accomplishment but by biology? Is trying to be happier as futile as trying to be taller? Or if our set point is inborn—seated somehow in our brain circuitry—is it possible to change it? Are there psychopharmacological drugs that can adjust the happiness set point as easily as we adjust a thermostat? If so, how will such drugs differ from the dreaded Soma that Aldous Huxley described in Brave New World some 70 years ago? 

ROSE-COLORED GLASSES AND OVERACTIVE WARNING LIGHTS

It is tempting to take the easy way out and avoid that controversy by simply challenging the accuracy of self-reported accounts of “subjective well-being,” the scientific term for happiness. Are not people likely to exaggerate how happy they feel? How can we assume that these reported set points reflect anything more than our natural tendency to say we are fine, when asked? Braun does not let us squirm away. He points to several reasons for trusting the results. First, the answers people give about their own happiness tend to match assessments from their families and friends. Identical twins, too, whether raised together or apart, generally report the same degree of well being. Although there is no universal happiness set point, the average seems to fall slightly above the midpoint between euphoria and despair—a finding that makes good evolutionary sense, Braun argues. 

Braun goes on to explain that having a slightly positive emotional baseline—in other words, a built-in pair of rose-tinted glasses—makes negative feelings, such as anxiety and fear, stand out more, just as black text stands out best on white paper.

Braun goes on to explain that having a slightly positive emotional baseline—in other words, a built-in pair of rose-tinted glasses—makes negative feelings, such as anxiety and fear, stand out more, just as black text stands out best on white paper. This contrast, in turn, makes most people more aware of the impending dangers that fear and anxiety normally signal, and so more likely to survive to reproduce, bequeathing their rosy world view to the next lot in life. This much makes a certain sense. Certainly if your baseline falls nearer to negative emotions, as in Generalized Anxiety Disorder, it becomes more difficult to distinguish real danger such as a heart attack from the imagined danger that a panic attack may seem to signal. 

But our built-in, rose-tinted glasses have another interesting effect, Braun suggests. Most people are a little overly positive when it comes to judging themselves. He quotes a study published in 1983 by C. Layne that concluded: 

Normals appear to be less in touch with reality than are depressives. Normals are even less in touch than are depressed outpatients and even hospitalized inpatients! The major implication of the empirical literature is that depressives’ thoughts are painfully truthful, whereas non-depressives’ thoughts are unrealistically positive.

This assertion seems oversimplified. Isn’t the study demoting happiness to little more than an “ignorance is bliss” feedback loop? In other words, being happy makes you less able to see your faults, which makes you feel better about yourself, and so on? At the other end of the emotional spectrum, the same reasoning implies, depression typically grants sharper insight. But that is certainly not true; delusional thoughts are the calling card of many a black mood. Perhaps it is most reasonable to suggest that depression can sometimes shed a more realistic light on the world, just as mania can sometimes enhance creativity. In both cases, “sometimes” is the key word.

“Sometimes” is also the key to Braun’s central thesis: Depression itself is adaptive. It can hone our self-perception, making us more aware of potential threats to our emotional well being. As a consequence, depression is not always abnormal and should not always be eliminated—just as pain, under most circumstances outside of the operating room, is a healthy and appropriate warning signal. (Braun recalls the 1950s case of Miss C., who was unable to feel any pain and as a result died prematurely at age 29.) “Listening to depression,” as Braun titles his fourth chapter, can be as important as listening to Prozac.

As for what depression is actually saying, Braun cites Swedish psychotherapist Emmy Gut. In her book Productive and Unproductive Depression, Gut suggests that depression speaks of an internal, unconscious crisis. Depressive symptoms, including decreased energy and social withdrawal, can prevent an animal (or person) from pursuing hopeless goals or activities that reinforce the root conflict. They can also enforce a period of keen introspection that is useful when major life changes are overdue. Maybe.

In giving this perspective, Braun is not siding with the pharmacological Calvinists, who view taking medication to enhance happiness as a weakness or shortcut. Braun is not anti-drug. In fact, he calls again on Darwin, as interpreted by Randolph Nesse, to argue for the use of antidepressants, sometimes. According to Nesse, natural selection has seen to it that many of our “warning signals”—including pain and depression—are too easily tripped, like dashboard lights connected to faulty fuses. If these warnings are more intense and last longer than need be, it may make an animal more likely to survive, and so Mother Nature has erred on the side of caution, making the lights flash when there is nothing wrong. These are the cases when antidepressants prove useful, Braun says. But rarely are these medications sufficient without “talk” therapy, he adds, because depression most often has multiple causes.

Thus the developmental perspective reduces depression to the result of abnormal maturation; the cognitive-psychological perspective blames it chiefly on dysfunctional thought patterns; the sociocultural view gives added weight to the effects of poverty, injustice, and excessive stress; and the biomedical model, touted by the drug companies, equates depression with faulty brain chemistry. Probably some combination of these factors holds sway in most instances, says Braun. He cites several cases to illustrate the disease’s complexity and quotes Christian Fibiger, a vice president in charge of research at Eli Lilly Company:

The current approach to the diagnosis of depression is what somebody called the Chinese menu approach. If you have one symptom from column A and one more from column B and one more from column C, then you end up with a diagnosis of depression. It is quite possible, given the current way of doing psychiatric diagnosis, for two depressed patients to not share a single symptom.

THE MACHINERY OF A MOOD

What all cases of depression do share is their origin in the brain—the organ targeted by medications and psychotherapy alike. Obviously, understanding the neural “machinery of mood,” as Braun puts it, is essential if we ever hope to adjust our happiness set point with ease and sensitivity. Indeed, although antidepressants seem to raise some people’s set points, this happens for a minority of users; nor is not clear why it happens when it does. Braun reminds us that most antidepressants were discovered entirely by accident. The very first, Iproniazid, introduced in the 1950s, was developed to treat tuberculosis.

Even so, Braun reports that researchers have recently uncovered new clues to how the structure and function of the brain might be involved in depression. Some of this insight has come from understanding the actions of selective serotonin re-uptake inhibitors (SSRIs), the newest class of antidepressants that includes Prozac, Zoloft, Paxil, and the like. These drugs cork up receptors on neurons in the brain that otherwise would bind to the neurotransmitter serotonin; as a result, less serotonin gets sopped up and more is freely available. About a third of people who take SSRIs respond well to this increase in serotonin, and so the idea has taken hold that a dearth of serotonin causes depression.

But evidence now suggests that the converse may be true; the depression accounts for the deficiency in serotonin. If serotonin is not in fact the problem, notes Braun, that also explains why SSRIs do not kick in immediately. Although serotonin levels rise within minutes of taking one of these drugs, the symptoms of depression do not normally lift for another two to four weeks. Eliminating serotonin as depression’s lead player also helps explain why the SSRIs as a whole do not work better than older antidepressants, which boost the levels of other neurotransmitters, dopamine and norepinephrine. Nevertheless, the fact that all of these antidepressants have a relatively uniform response implies that they must have some common effect.

As it turns out, Braun says, antidepressants across the board increase levels of growth factors that make neurons sprout new dendrites, branches by which they communicate with other neurons. Could this new growth bring about the changes in mood and personality that are seen after antidepressant therapy? Well, the reverse is certainly true, says Braun. When dendrites die, our memories fade, coordination fails, hormone levels plummet, and moods takes a downward turn. Another piece of positive evidence is that genes regulating dendritic growth factors are found in those very same neurons affected by serotonin, dopamine, and norepinephrine. Would drugs that stimulated these genes more directly be more effective and have fewer side effects than current antidepressants?

If these considerations do not thoroughly dissuade you of the “biogenic amine” model of depression, Braun reports an additional discovery. In the September 11, 1998, issue of Science, Merck researchers described a drug molecule that appeared to lift mood by blocking substance-P, a chemical messenger that carries pain impulses through the body. This reported result has since met with some skepticism, and Merck later wrote that Phase II studies for this initial drug, MK-869, used in depression were inconclusive. Still, Braun’s point that depression involves compounds other than amine neurotransmitters stands up.

Leaving neurochemistry behind, Braun turns to key discoveries about where in the brain mood circuits that regulate the happiness set point might actually be. He cites primarily the work of Richard Davidson of the University of Wisconsin at Madison, who has focused his search on the prefrontal cortex. This region behind the forehead links areas involved with higher cognitive functions such as reasoning to emotional centers buried deep within the brain. Consider one interesting reason to look in the prefrontal cortex for happiness: There are more fibers sending messages to the prefrontal cortex from the emotional centers than there are fibers for signaling in the other direction. That might explain why emotions can be so hard for reason to control.

Consider one interesting reason to look in the prefrontal cortex for happiness: There are more fibers sending messages to the prefrontal cortex from the emotional centers than there are fibers for signaling in the other direction. That might explain why emotions can be so hard for reason to control.

Also, Davidson has found that the left prefrontal cortex prompts us to initiate actions that increase our chances of survival, whereas the right orchestrates reactions to threats. He reports that electrical activity in the left and right prefrontal cortices varies widely among individuals. People with greater activity on the left side tend to be more upbeat; those with greater activity on the right tend to be down. Damage to the left often manifests as symptoms of depression and direct stimulation to the left can generate feelings of euphoria. Most compelling of all perhaps, in people who respond well to SSRIs, the drugs appear to increase activity in the left prefrontal cortex and inhibit it in the right.

In the end, Braun’s blueprint for the machinery of mood seems a bit sketchy: 

The set point—and happiness itself—is an emergent property of a brain in which activity in the left prefrontal cortex predominates and in which neurotransmissions between the prefrontal cortex and other discrete mood-related areas are balanced, robust and unimpeded...The machinery of these networks depends critically on the number and strength of the dendrites. These dendrites, and the functioning of each individual neuron, depend, in turn, on the proper functioning of millions of even smaller machines —the neurotransmitter receptors, reuptake pumps, storage and release mechanisms, and the long chains of chemical reactions required to relay messages to genes.

Still, this model may include enough moving parts to account for the many factors, from economics to biology, that can contribute to depression. It is detailed enough, Braun thinks, to virtually guarantee that one day soon there will be new drugs on the market capable of “sculpting” our moods more effectively and subtly than current SSRIs. 

PERILS OF PSYCHOPHARMACOLOGY

Braun does not leave the reader on that seeming high note. One major complication, he says, is that drug companies are liable to disseminate half-truths about new medications for the sake of profit. In their advertising campaigns, many drug companies say that antidepressants “cure” depression because they change neurotransmitter levels in the brain—a clear error of emphasis. These campaigns are altering our very notion of sadness, says Braun, depicting it as an illness instead of an emotion. That some 34.5 million people use SSRIs speaks to this shift in perception. 

Narrowing the accepted definition of “normal” is a tactic that drug companies have used before. Among the case studies that Braun presents in Chapter 5 (“not to demonize drug companies,” but as a warning), is Genentech’s marketing of Protropin, a therapy developed to treat pituitary dwarfism. Children with this condition have an underactive pituitary gland and as a result have stunted growth. Genentech scientists found a way to produce human growth factor in mass quantities by inserting the requisite genes into bacteria. Their problem was that only 7,000 children are born each year with the disorder—hardly enough to cover the drug’s start-up costs. So the company funded a campaign to screen the heights of children and educate doctors and parents about the “problem” of children falling in the bottom 5 percentile of height. Selling Protropin to even a portion of this bottom 5 percent—some 90,000 short, but otherwise healthy, children—ensured Genentech a healthy profit. 

The “next Prozac” will mean even bigger profits. Drug companies are working at top speed to create (or stumbling upon) it. Some motivation surely arises from the fact that SSRIs work for only about a third of the people who take them, and that there are still significant side effects, including sexual problems, anxiety, and stomach upset. But potential profits are likewise fueling the race. Prozac is the most prescribed anti-depressant ever, and was the second highest selling drug in America in 1997. It accounts for 30 percent of Eli Lilly’s profits, Braun tells us—and their 20year patent on Prozac ends on December 2, 2003. At that point, generic variations on Prozac, which is fluoxetine hydrochloride, will join it on pharmacy shelves.

Lilly already has an interim solution: Through a licensing agreement with Sepracor, the company is developing a version of Prozac containing only right-handed isomers of the fluoxetine molecule. Just as the right-handed molecules of amphetamine are a more potent stimulant than the mirror-image left-handed forms, Lilly hopes that R-fluoxetine will have fewer side effects and quell anxiety more effectively than Prozac’s left-right isomer mix. Phase III clinical trials are underway. As Braun puts it, “Lilly desperately needs a short-term Prozac ‘upgrade.’”

QUICK FIXES FOR BAD MOODS

Braun is unequivocal that medication that could fine tune the machinery of mood would be a boon to sufferers from debilitating depressions. It is unclear, however, what they would mean for everybody else, he says. If depression, anxiety, and fear— like pain—are useful some of the time, it will be important not to use drugs to blot them out completely. As with any new technology (as atomic energy, computer science, or genetic engineering once were new), there are unforeseeable dangers, and these dangers may be peculiarly perilous when the technology is one that affects the very faculty that we use to judge it.

Braun is unequivocal that medication that could fine tune the machinery of mood would be a boon to sufferers from debilitating depressions. It is unclear, however, what they would mean for everybody else, he says. If depression, anxiety, and fear—like pain—are useful some of the time, it will be important not to use drugs to blot them out completely.

Drug company marketing isn’t the only possible impediment to using new antidepressants wisely, says Braun. Most people are all too ready to take pills. For one thing, it is a lot easier to pop a pill than to change your life; talk therapy for depression, like exercise for heart disease, takes time and discipline. Meanwhile, the biochemical explanation of mental illness— the one that makes medication look like the best option—is what we most often hear about in the media. Not only do pharmaceutical companies sponsor this view for obvious reasons, but managed care companies, too, prefer that patients use drug therapy, which costs less than years of psychotherapy. And on the individual level attributing mental illness to nothing more than a chemical imbalance is far more palatable to patients and their families who would prefer to dodge blame for life’s problems. 

Braun suggests that, just as we should view depression as a warning, we should view the drug industry’s need to turn a quick buck, and our own need for a quick fix, as warnings. Future antidepressants may not be what they seem. We should not be too ready to take them. Again, though, Braun is not being anti-drug. His note of caution is primarily for the “normal” people among his readers who will be presented with a new opportunity for attaining happiness. Others, for whom depression is truly an illness, do not have the luxury of judging mood-boosting drugs as critically as may the rest of us. For them, whatever is available—often a last resort—has to be good enough.

“Normal” folk, though, will have a lot to think about when, with relative impunity, they can swallow a new and improved Prozac to tweak their moods. What is the goal of “cosmetic” drug use? What is an optimal mood, anyway? Braun turns to the work of Robert Thayer at California State University at Long Beach who has studied so-called optimal mood. Thayer has concluded that two variables—energy and tension— affect our moods, and that different combinations of the two make for the best mood in different situations. Tense energy may be optimal for meeting a deadline; calm tiredness may be right afterwards. The bottom line is that we need a range of moods for enduring happiness. 

Thayer’s view, Braun says, echoes not only Darwinian psychiatry, but Zen Buddhism: We should not conquer our moods, but learn to dampen their damaging extremes. He quotes Lao Tzu: “Under heaven all can see beauty as beauty only because there is ugliness. All can know good as good only because there is evil. Therefore having and not having arise together.” So, as Braun describes it, true happiness is not being happy all the time. In the end, it is this conclusion that probably best explains why The Science of Happiness is a book more about sadness and depression than about happiness. 

EXCERPT

Excerpted with permission of the publisher John Wiley & Sons, Inc., from The Science of Happiness: Unlocking the Mysteries of Mind. Copyright © 2000 by Steven Braun. 

As we've seen, nature has apparently favored the natural selection among humans of a slightly-higher-than-neutral happiness set point. It is apparently in our genes’ best interests that we experience a range of moods that oscillate around a set point that leaves us, on the whole, somewhat more optimistic, somewhat more cheerful and outgoing, and somewhat more happy than might be expected of mortal animals cavorting on a tiny planet lost in the vastness of the cosmos. If, on average, nature has designed people to be happy, then it would make a great deal of sense to arrange one’s lifestyle to make it easy for nature to take its course. Thayer’s prescriptions for getting enough sleep, maintaining a healthy diet, reducing stress, doing regular exercise, and planning work to coincide with one’s natural energy cycles thus make eminent sense. 

Unfortunately, there are also many reasons to suggest that some individuals may, through bad genes or bad luck, have “natures” that are not ideal, not optimal, and not particularly enjoyable or satisfying. It is simply not true that “nature” really cares whether an individual is happy. We are not designed to be happy, except to the extent that our happiness increases our chances for survival and reproduction. And, in this regard, nature has apparently found it perfectly suitable to design creatures who are minimally happy— just happy enough to keep motivated, but not necessarily happy enough to really satisfy an aware, intelligent being pondering his or her finite life span. 

In addition to that general aspect of human nature, there is the incontrovertible fact of human variation—of people who are born with or have acquired the mood equivalent of poor eyesight or deafness. Drug intervention for such people may provide the buoyancy of outlook, the vim and vigor, the laughter and lightness that other people take for granted. 

The prospect of millions of people using drugs to correct their mood “astigmatism” strikes some people as outlandish or even immoral. But people already use drugs this way—and have for thousands of years. It’s just that the drugs in question—alcohol, caffeine, and nicotine—are not generally recognized as the drugs they are. And despite the serious issues raised in the previous chapter about drug industry tactics, the risks of unknown long-term side effects, the potential for abuse by ill-informed users, and the dangers of subtle changes to human consciousness, the potential benefits of more perfect mood-altering drugs are undeniable. 

Just as hearing aids and eyeglasses allow millions of people to experience richer, more meaningful, and more satisfying lives, just as insulin frees diabetics from painful or lethal complications, and just as analgesics provide enormous relief from unnecessary pain, so better drugs for manipulating moods could lead to a healthier, happier society if they are used wisely and with an appreciation for the holistic nature of human moods and with a respect for the essential utility of negative mood states in general. 

If Lou Anne’s father had taken medication to stabilize his moods, reduce his vulnerability to alcohol abuse, and provide him with a much higher degree of emotional resiliency, what scars might Lou Anne have been spared? How much child abuse, spouse abuse, and other crimes arising from mental dysfunction might be avoided with an enlightened use of appropriate drugs and counseling? Estimates for the direct and indirect costs of depression to society range up to $43 billion every year—but, of course, the cost in terms of pain, suffering, and lost opportunities for full and vibrant lives cannot be calculated. 

Whether more perfect drugs now in development in drug company laboratories around the world will, indeed, be used wisely, with appropriate respect for the nonbiological dimensions of mental illness, is an open question. Clearly, many forces are arrayed against such use: the human desire for quick and easy fixes; the profits to be made from drugs as opposed to nondrug treatments; the comfort provided to patients and their families by disease models of mental illness; and the cost-saving preferences of health organizations and insurance companies. 

Standing against these formidable forces is a fact of human nature that, if it does not provide utter comfort, at least provides a ray of hope that, in the end, mood-altering drugs will be used in a reasonable, appropriate and human way: human beings, and nature itself, are utterly and fundamentally pragmatic. If something works to achieve a desired end, it will be used. If it does not work, it will be dropped.



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Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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