Good Reasons for Bad Feelings

by Randolph M. Nesse

  While depression rates tend to be stable across decades in a given culture, they vary widely by country. Lifetime rates range from 1.5 percent in Taiwan to 19 percent in Beirut.37 Another study found rates ranging from 3 percent in Japan to 17 percent in the United States.38 Why such huge differences? That is the most important unanswered question for mood disorders research.39 If we could get the rate in every culture down to the 1 to 3 percent rates in Taiwan and Japan, that would reduce depression more than all treatment efforts put together. Differences in family stability and support are likely important. Differences in values and expectations for success and competition influence mood. Differences in diet, drug use, social structure, and shared beliefs are all likely relevant. Some combination of factors must account for the huge differences in depression rates. Discovering what those are should be a research priority.

  Modern media make life more interesting, but they also encourage social comparisons that cause dissatisfaction.40,41 Vivid stories about other people’s fame and wealth spur ambitions that few can satisfy. Characters on television, whether Downton Abbey or Keeping Up with the Kardashians, are so extraordinarily attractive, successful, wealthy, and famous that the rest of us can’t help but feel inadequate (or superior or contemptuous). Even the actors and actresses can’t live up to the expectations aroused by the characters they play.

  Media exposure generates dissatisfaction, not only with ourselves but with our friends and partners, who rarely measure up to alternatives we see in the media. Dozens of studies show that mood plummets when people compare themselves to others who have more than they do.42,43,44 Even browsing Facebook posts of friends, inevitably biased toward the positive, tends to make people feel worse about themselves and their lives.45,46 Despite the documented ability of social media exposure to cause dissatisfaction, there is little evidence that the use of social media is increasing rates of pathological depression. However, the pursuit of grand goals may be relevant.

  The biggest rewards in mass societies go to those who pursue grand goals single-mindedly. This usually requires an unbalanced life. In many fields, the price of trying to get into the big leagues is neglect of self, health, partner, children, and friends. The predictable problems provide fodder for television shows that exploit the problems of the famous to provide schadenfreude for the masses. Magazines about celebrities are equal parts veneration of superachievers and consolation for the rest of us. Every issue offers advice for getting rich, thin, attractive, and famous, followed by advice about how to cope with feelings of inadequacy, anxiety, and low self-esteem.

  Physical aspects of modern life also increase vulnerability to mood disorders. Electricity provides light and entertainment that disrupt sleep. Increased inflammation due to obesity47 or high levels of omega-6 fatty acids48 may also increase depression. Lack of exercise may account for some depression in modern societies,49,50 and increased exercise can relieve symptoms a bit on average.51

  One week before I was scheduled to leave for an extended sabbatical, I saw a new patient who was desperate. She had experienced chronic severe suicidal depression for ten years and had gotten no relief from behavior therapy, cognitive therapy, psychoanalysis, and many medications. She said she would do anything. I said, “Anything?” She replied, “Yes, anything.” I told her to join a gym and spend at least one hour every day working out to the maximum of her endurance on a treadmill, followed by a long walk outdoors. I was not hopeful, but it was the only untried option. A few months into my sabbatical I got an email message saying that she had called the front desk at the clinic, asking them to let me know that she was symptom-free and immensely grateful.

  What Natural Selection Can’t Do

  Mood regulation mechanisms seem prone to failure even in natural environments. One possible explanation is that there are some things selection can’t do, such as prevent all genetic mutations. Perhaps mood disorders exist because mutations happen and they are only slowly purged from the gene pool. About a third of the variation in depression vulnerability is accounted for by genetic variations. The siblings and children of people with major depression are 2.8 times more likely to get the disease. Over a lifetime, that means the average risk of about 10 percent in the United States increases to about 30 percent for those whose close relatives have had depression. Nearly all of that increase is from shared genes; what family you are raised in has remarkably little influence.52

  This evidence for inheritance has spurred a huge search for the genetic culprits. Studies in the first years of the twenty-first century identified many suspects, but subsequent studies exonerated every one. The arrival of cheap DNA sequencing changed everything. Hopes for answers were raised by a mega-analysis that pooled data from nine studies. It analyzed more than 1.2 million genetic locations in 9,240 people with a history of major depression and 9,519 controls. However, the results, published in 2013, found that not one of those 1.2 million sites reliably predicted who would get depressed.53 The authors of the report pleaded for larger studies on more homogeneous populations.

  A subsequent study looked for genetic variations in a genetically homogeneous group of more than 10,000 women of Han Chinese descent, half of whom had major depressive disorder. It identified two locations on chromosome 10 that predicted rates of depression. However, together they explained less than 1 percent of the variation.54 A further analysis of the data provided a remarkable finding: larger chromosomes had more locations influencing depression; the correlation was 60 percent.55 This suggests that depression is caused not by a few alleles on a few chromosomes but by thousands spread relatively evenly over the entire genome.

  A yet larger study of more than 300,000 people used self-report data on depression and genetic data from the consumer genome-scanning company 23andMe. Published in 2016, it identified seventeen locations that are associated with tiny increases in the risk for depression. However, the two locations found in the study of Chinese women were not among them.

  It is harder to measure depression than blood pressure or diabetes. Could that account for why these studies have not found specific alleles with large effects? Probably not. Type 2 diabetes and high blood pressure are also highly heritable, but they also have no common alleles with substantial effects.56 The same is true for something easy to measure, height. Ninety percent of height variation is caused by genetic variation, but there are no “height genes” with large effects. A 2008 study of 13,665 individuals found twenty genetic variants that each influence height by two to six millimeters, but taken together they explained only 3 percent of the genetic variation.57 All the genetic information from about 25,000 people explained about 4 percent of height variation. A sample of 130,000 people explained only 10 percent. To explain half of the genetic variation in height required combining seventy-nine studies with a quarter of a million people.58 Variations in thousands of genes influence height, diabetes, blood pressure, and depression, but their individual effects are minuscule. It makes no sense to call them abnormal. The hope that most cases of major depression are a disease that results from abnormal genes is misplaced. A new approach is needed.

  Cybernetics

  Everything is cyber this or cyber that these days, but cybernetics is a specific scientific approach described by Norbert Wiener in his brilliant 1948 book, Cybernetics; or Control and Communication in the Animal and the Machine.59 It describes how feedback mechanisms stabilize things such as blood pressure and mood and the dire results when stabilization fails. It includes a profound chapter on mental disorders caused by feedback dysregulation.

  Positive feedback is nice from your boss, but in cybernetics it refers to something different: vicious cycles, things like snowballs rolling downhill and runaway trucks. The founder of cognitive therapy, Aaron Beck, and a few other depression experts have noted that positive feedback loops can make depression worse,60 but much work remains to investigate the actual mechanisms. Positive feedback cycles worsen depression. People respon
d to low mood by going home, closing the door, getting in bed, and not answering the telephone and email. Out of contact, they soon conclude that no one cares about them. Poor nutrition and lack of exercise cause more depression and more isolation, creating a downward spiral.

  It is intriguing to consider whether this spiral is more likely in modern societies. Way back when, people got hungry and had to go out to find food. That meant seeing friends and getting exercise. Today, therapy that encourages active involvement in life despite lack of interest can initiate a virtuous cycle in which activity improves mood, which initiates more activity in an upward spiral to recovery.61,62

  Having one depressive episode may make future ones more likely. This is called “kindling,” because it is similar to how small pieces of wood can ignite a larger blaze.63 It is related to the observation that epileptic seizures are set off more easily after previous seizures. For depression, life events precipitate most first episodes, but the role of events declines with each subsequent episode, until they seem to come on for no reason.64,65 This observation is sometimes explained by suggesting that depression damages the brain in ways that make more episodes likely.

  Kindling could also be explained by a mechanism that adapts organisms to unfavorable environments. Just as multiple episodes of intense anxiety indicate a dangerous environment in which anxiety is especially useful, multiple failures may reflect an unpropitious social environment in which low mood is more useful. The mechanism that adjusts depression so it becomes more likely after bad times may be a feature, not a flaw.66,67 However, other explanations are possible. Depression episodes damage a person’s social network. Obstacles to major life goals that cause depression may persist after the symptoms lift, making more episodes likely. Such persisting problems may not show up on a checklist of life events, making some depression episodes appear to come out of the blue, when in fact they arise from continuing problems. The person’s spouse is still abusing alcohol. The mother-in-law remains in the house, as critical as ever. A beloved child still won’t return phone calls.

  Bipolar Disorder

  Bipolar depression is different from regular depression, and mania is very different from happiness.68 Bipolar disorder results from a fundamental failure of the mood regulation system. The normal system shifts mood higher and lower as situations change, then returns mood to the individual’s set point. We strive mightily to get a new job or house or spouse in the belief that it will finally bring enduring happiness. It works temporarily, and then mood reverts to its previous level. Like a thermostat, the moodostat keeps mood close to a set point.

  People with bipolar disorder have a broken moodostat. When they encounter a new opportunity, their mood goes up, but it does not come back down. Instead, increasing energy, ambition, risk taking, and optimism create imagined future successes that fuel still greater energy toward still more grandiose goals, in a process of runaway positive feedback that peaks in manic excitement that can be fatal, just from physiological exhaustion. Usually just before that point, some kind of overload switch turns motivation off suddenly and completely, sending elation plunging into depression that also feeds on itself, stabilizing mood at a negative extreme for weeks or months. It is as if the thermostat is missing, replaced by a switch with only two positions: full-bore high mood or motivation completely turned off.

  Modern thermostats do not turn on the furnace when the temperature gets below a certain point and turn it off again once the temperature again reaches the set point. That would result in wide swings of temperature because the temperature continues to go down while the furnace is getting going and heat keeps pouring out for a time after the temperature gets back up to the set point. To avoid these swings, thermostats have an “anticipator” that turns the furnace on or off a few minutes before the set point is reached. If the anticipator breaks, temperature swings are extreme. Could a broken anticipator mechanism explain why some people have wide mood swings? That could explain wider-than-usual oscillations, called cyclothymia, but not why the system gets stuck in high or low mood.

  Engineers who design control systems recognize what they call “bistable systems” that switch fast between two extreme states, never stopping in the middle.69,70 The best example is a light switch. It’s either on or it’s off, never in between. Many biological systems are bistable. For example, once the mechanism that initiates bacterial spore formation turns on, it goes all the way; stopping partway through the process would be fatal. The evolution of two sexes is another example. The advantages go to individuals who make either large eggs that last quite a while or millions of tiny sperm that can swim fast. Medium-size gametes that can swim at a medium speed are less likely to succeed, so most species have two sexes.71 The interesting thing about bistable systems is that they require positive feedback to work. Once the system deviates a bit from the middle, positive feedback pushes it all the way to the extreme, just like a light switch. This is a lot like bipolar disorder.72

  Why would natural selection have left mood regulation mechanisms especially vulnerable to dysregulation? To expand a speculation mentioned previously, I wonder if vulnerability to mood disorders is related to the fitness benefits of pursuing big goals. Mechanisms that motivate ambitious striving may be selected because they offer occasional big payoffs to a few people. This hypothesis predicts that many people will make big efforts to reach big goals despite experiencing many failures. The ability to disengage from a failing enterprise seems to be missing in many people with bipolar disorder. When ordinary low mood is not available to disengage failing efforts, positive mood escalates into ever-more-intense efforts that eventually collapse into serious depression.

  The fitness advantages of ambition may help to explain vulnerability to depression and mood swings. Ambition is not just for recognition and money; the craving to be appreciated can be equally strong. Accomplishments generate satisfaction that often seems to inflate ambitions that are already magnified by modern mass media and well-meaning encouragement from parents and mentors. William James captured the problem in a succinct formula: Self-esteem = Success/pretentions.73

  In the midst of an episode, bipolar patients think their extreme moods are rational. I have seen many examples.

  A sculptor was certain that hundreds of students would flock to her studio to learn her new methods. She had already sunk her life savings into a lease and was furious that the bank wouldn’t give her the loan she needed to furnish the studio.

  An entrepreneur woke in the night with the revelation that an empty storefront could be transformed into the first of a new chain of fine restaurants. He bought a Mercedes to take celebrities from the airport to the restaurant, but as a series of chef candidates turned him down, he became increasingly agitated and frustrated.

  A professor was certain that his brilliant new method could predict the stock market. Despite his wife’s objections, he remortgaged the house to get cash. He blamed the ensuing big losses on competitors, who he said had stolen his formula and manipulated the market.

  Obstacles and slowed progress toward a goal normally shift mood lower to conserve effort and reconsider options. In mania, this system does not kick in; instead, impending failure sets off yet more intense efforts to reach yet grander goals. Persistence in the face of adversity is widely praised, but it can lead to spectacular failures. Such failures convince many patients that they are worthless and have no possible future. The sculptor went to bed and would not get out, saying she was a fraud, she had no talent, and she would become a bag lady. The entrepreneur lost his car to the bank and ruminated about his inability to get any job. The professor was admitted to the hospital and crashed into depression a few days later. People who have bipolar disorder have broken mood regulation mechanisms, and losses sustained during episodes can make the objective situation bleak.

  It would be nice if bipolar disorder were one specific disease, but it has blurry edges and many subtypes. Type I, with serio
us episodes of both depression and mania, occurs in about 1 percent of populations worldwide. However, expanding the spectrum of bipolar disorders to include more mild versions of mania brings the rate up to 5 percent.74 Of patients with a diagnosis of major depressive disorder, 31 percent have had mild symptoms of mania as well.75

  Bipolar episodes come at unpredictable times, last for durations of weeks to months, and then depart. Patients experience mania about 10 percent of the time, depression about 40 percent, and neutral moods about 50 percent of the time.76 The most problematic cases experience both depression and mania at the same time, in what is called a “mixed state,” making it clear that high and low mood are not just opposites on a single dimension; both can be present simultaneously.

  Bad Genes?

  Who gets bipolar disorder is explained almost entirely by genetic variations; they account for more than 80 percent of the variation in vulnerability. If your identical twin has bipolar disorder, your risk is 43 times higher than that of other people.77 This strong effect suggests that it should be possible to find the responsible alleles. However, as is the case for so many other genetic diseases, no common alleles have a substantial influence on bipolar disorder.

  That is so disappointing! However, the situation is not as bleak as the search for depression alleles. In some families plagued by bipolar disease, specific large chunks of DNA are missing or duplicated only in affected individuals.78 Those chunks are all over the genome; however, tracking their functions gives hope of finding gene or brain networks crucial to causing the disorder.