by D. F. Swaab
Genetic factors can cause the stress axis to be put into a higher gear during development. This is why certain tight-knit groups, like the Amish in the United States, have a higher than average rate of depression. Depression has been seen to run in certain famous families, like that of Virginia Woolf. Studies of families with this condition helped to locate the first variations in genes (polymorphisms) that increase the risk of depression. Many tiny variations in genes for chemical messengers in the brain also predispose individuals to this condition. People whose mothers were pregnant during the Hunger Winter of 1944–1945 (fig. 9), when famine struck Dutch cities, have a higher incidence of depression. Food shortages are a thing of the past now, but the stress axis can also be permanently activated by a malfunctioning placenta, causing a child to be malnourished and underweight at birth. Exposure to nicotine or certain medicines (like DES) in the womb also increases the risk of depression. After birth, the stress axis of a child who is seriously neglected or abused can be permanently set on red alert. Lasting changes of this type caused by external factors affecting gene expression—in this case of the stress axis genes—are known as epigenetic programming.
We have also found that female hormones (estrogens) stimulate the stress axis, while the male hormone (testosterone) inhibits the stress axis, which would explain why women are twice as likely as men to suffer from depression.
So depression is basically a developmental disorder of the hypothalamus. If a person’s genetic background and development cause their stress axis to be switched to a high setting, it overreacts to stressful life events, which can lead to depression. In adulthood, depression can also be caused by other factors, for instance certain types of medication. Prednisone, a much-prescribed synthetic corticosteroid drug, frequently causes mood disorders when taken in high doses. Brain infarcts or damage from MS lesions, particularly on the left half of the brain, also increase the risk of depression, due to the stress axis becoming hyperactive when it’s no longer controlled by the cerebral cortex.
Different Types of Depression
We all have a greater sense of well-being in summer than in winter. Some people suffer from extreme seasonal mood swings, though. In summer they can develop hypomania (a state approaching mania) or even become truly manic, while suffering severe depression in winter. This is known as seasonal affective disorder, appropriately shortened to SAD. The former West German chancellor Willy Brandt would tend to become depressed as autumn progressed and the days grew shorter. During these bleak periods, he couldn’t bear to see anyone, not even his wife. Seasonal depression is triggered by a lack of sunlight in winter; exposure to sunlight alleviates the symptoms. In the United States there are even insurance companies that send SAD patients from the north of the country to a southern state in order to speed up their recovery. Information on the amount of light in our surroundings is relayed directly to the biological clock, which isn’t just a day-night clock but also a seasonal clock, which plays an important role in SAD. Tiny variations in the genes that make the biological clock function pose a risk factor for depressions of this type.
A bipolar disorder with periods of mania and depression can also occur without any clear seasonal link. When Mrs. De Vries came back from walking the dog in the nearby dunes, she found her husband, who had just retired, slumped over the breakfast table, apparently lifeless. She immediately called the emergency services, and the medics tried to revive him, but without success. In the days that followed, her husband’s body lay on a bier in the living room. His widow was full of energy, quite tireless in fact, and after the cremation this became even more pronounced. She developed hypomania and then became truly manic a few days later. She went around to all her acquaintances with mementos of her husband, laughing excitedly. In the middle of the night she would call the police, only to menace them with a hockey stick when they arrived at her house. When she threatened her adult daughter with a knife because she didn’t want to be incarcerated in a psychiatric institution and be given electroshock treatment, as had happened to her father, the situation became untenable. At length she was persuaded to enter a clinic. There her mania became even worse, despite the medication. She told everyone excitedly that she’d always wanted to stay in this fabulous hotel, and after each hospital meal she would leave a one-guilder tip for the excellent waiters. She would skip through the clinic, singing, arm in arm with a friend who visited her every day, time and again introducing her to a “former classmate,” an unfortunate man who had never seen her before and was being driven mad by her constantly harking back to their mythical school days. Her condition improved briefly, and then she fell prey to a terrible depression. The story ended happily, however: She made a full recovery and is enjoying life to the fullest with her eight grandchildren.
The Dutch cabinet minister Ger Klein also suffered from a bipolar disorder (see chapter 15). Hypomanic periods can be very productive. The composer Robert Schumann composed over twenty works in his hypomanic phases, in 1840 and in 1849, while he was unable to compose at all during his periods of depression, in 1844 and 1854. In the winter of 1854 he tried to commit suicide by jumping into the icy Rhine river. He was rescued and spent the last two years of his life in a mental institution. Johannes Brahms, deeply shocked by the illness and death of his friend, started work on Ein Deutsches Requiem, which he dedicated to Robert Schumann, his mother, and humanity.
The Russian leader Nikita Khrushchev suffered from alternating depressive and hypomanic phases. After he was deposed in 1964, he fell into a deep depression. In the case of government leaders, especially, there’s a strong tendency to deny the existence of a bipolar disorder, because of doubts about the ability of individuals with this condition to make well-informed decisions. Winston Churchill suffered from terrible bouts of depression, which he called his “black dog.” According to his private secretary, he could also become madly excited and experienced extreme mood swings with bursts of energy. The terms hypomania and mania weren’t used at the time, but it seems from eyewitness accounts that he must have been bipolar. Lyndon Johnson, who became president after John F. Kennedy was assassinated in 1963, was afflicted by such severe depression after surgery to have his gallbladder and a kidney stone removed that he considered resignation. He, too, had a bipolar disorder, characterized by episodes of profanity and temper. Whether he received medication for it isn’t known.
When depression doesn’t involve hypomanic or manic interludes, it’s classified as unipolar depression or “major depression,” of which melancholic depression is a subtype, involving severe disruption of the day-night rhythm and loss of appetite. The type of depression induced by prednisone or similar substances, called atypical depression, is marked by an increased appetite and need for sleep.
The Various Brain Systems and Areas Involved in Depression
Various cell groups become hyperactive in the hypothalamus of depressive patients. In many cases, the stress axis (the hypothalamus-pituitary-adrenal axis) is strongly activated. In postmortem brain material from donors with lifelong periods of serious depression we found a considerable increase in the number of cells in the hypothalamus producing CRH, even if the patient hadn’t died during a depressive episode. This ties in with the theory that the stress axis has been set in a higher gear during the development of such individuals. We know that the activation of CRH neurons contributes to the symptoms of depression, because if CRH is injected in the brains of laboratory animals they develop the same symptoms: diminished appetite, changes to the motor system, sleep disorders, fearfulness, and loss of sexual interest. An increase is also found in other stress hormones, like the hormones vasopressin (produced in the hypothalamus) and cortisol (produced in the adrenal gland), which contribute to such symptoms.
Located in the brain stem are three more stress systems that produce the chemical messengers noradrenaline, serotonin, and dopamine and regulate many brain areas, including the hypothalamus. Their possible link with depression was discovered by chance as
the result of a side effect of reserpine, a common medication for high blood pressure. The drug was shown to reduce the amount of noradrenaline and serotonin in the brain stem, and depression was a not uncommon side effect. Conversely, the first antidepressants, MAO inhibitors, increased noradrenaline and serotonin levels. The most commonly used antidepressants nowadays are selective serotonin reuptake inhibitors (SSRIs), compounds that increase the level of serotonin by preventing its reabsorption into the body. This gave rise to the theory—now immensely popular—that depression may be caused by abnormally low concentrations of noradrenaline or serotonin. However, patients whose depression can definitely be ascribed to low serotonin levels are in the minority. The mere fact that it takes a few weeks for SSRIs to become effective, even though they raise the serotonin level almost instantly, shows that the link between serotonin and depression isn’t that clear-cut. In the case of depressive patients who are very fearful, however, serotonin systems can be disrupted. Low serotonin and noradrenaline levels have also been found in the cerebral fluid of patients who had ended their lives violently, for instance by jumping in front of a train. This group was also found to have high levels of the stress hormone cortisol. Dopamine, the chemical messenger of the reward system, is also involved in the symptoms of depression. When depressive patients are unable to enjoy life anymore, it is probably because of a dip in dopamine.
Our examination of postmortem tissue from the brains of depression sufferers also revealed that the circadian clock, the suprachiasmatic nucleus, is less active in people who suffer from depression. This explains not only their disturbed day-night rhythms but also the effectiveness of light therapy.
Functional scanning studies of depressive patients showed changes in the activity of the temporal and prefrontal cortex as well as the amygdala. The latter may explain the increase in fearfulness. The reduced activity in these brain areas may partly result from raised cortisol levels.
To sum up, an entire network of brain systems and various chemical messengers are involved in the onset of depression. The systems that are the prime cause of depression vary from individual to individual, but in all cases the stress axis is central to the pathological process.
Therapies
Many therapies are used to treat depression that would appear to have nothing in common with one another, but ultimately they all normalize stress axis activity.
SSRIs are very commonly prescribed for depression. In the Netherlands, around nine hundred thousand people take antidepressants. In around 75 percent of these cases, the patient is indeed very down but not suffering from severe depression, so they won’t help very much. Indeed, SSRIs aren’t very effective at all. They start to work only after a couple of weeks, during which period there’s a real risk of suicide. (And that’s not a negligible problem. Around fifteen hundred people kill themselves every year in the Netherlands, and ten times as many attempt to do so). Moreover, these drugs have a placebo effect of 50 percent. Indeed, it’s not so strange that the placebo effect is so marked in the case of depression. The expectation that a placebo will alleviate one’s pain is linked to increased activity in the prefrontal cortex (see chapter 16). This inhibits the hypothalamus, thus normalizing the activity of the stress axis. Stimulating the inhibitory effect of the cerebral cortex on the stress axis explains why transcranial magnetic stimulation of the cortex is effective. Cognitive therapy and online treatment for depression are successful for the same reason; they produce the same inhibitory effect on the stress axis as transcranial magnetic stimulation, but by different means. We don’t know why electroshock therapy is so effective in the case of very severe depression. Perhaps it’s a bit like when your computer seizes up: You switch the power off, switch it back on again, and hey presto, it works again. A disadvantage of this therapy is that it can impair memory.
Lithium, the classic medication for bipolar disorder, affects the circadian clock, inhibiting the overactive stress axis and stabilizing mood.
Light improves mood among depressive patients, through its effect on the circadian clock. The latter becomes more active, inhibiting the CRH cells of the stress axis. In the northern United States, seasonal depression is more common than in the sunny southern states. Physical activity can also stimulate the clock, so walking the dog is doubly effective because of the extra light and the extra activity. We found that increasing the amount of light in the living areas of patients with dementia also improved their mood (see chapter 18). Antidepression lamps work just like sunlight, although they’re not as efficient. Even on a cloudy day, you’re exposed to more light outside than you can obtain from a lamp of this type. (Incidentally, using a light box can get out of hand, and it can very occasionally induce mania or psychosis, so light therapy needs to be carried out under the supervision of a doctor.) In older people, lack of vitamin D can also increase the risk of depression. Vitamin D is made in the skin in response to sunlight. That’s why people who live in towns are more likely to have this deficiency than people in rural areas. So sunlight protects you in two different ways. Disrupting the day-night rhythm (for example by going without sleep for a night) has also been found to improve mood, but the effect is unfortunately brief.
When considering all these therapeutic options, we must however bear in mind that depression is essentially an early developmental disorder and that the cause, disrupted brain development, can’t be remedied by these therapies. That’s why depression frequently recurs.
PRADER-WILLI SYNDROME
“I’m a social worker at an institution in western Iowa. There I met a man who has been diagnosed with Prader-Willi syndrome. He is forty-two years old, and over the last few years we have seen him deteriorate rapidly, both mentally and physically. My question is, do you know a doctor or psychiatrist in or near Omaha, Nebraska, whom we could contact, so that he could help the man in question? He is an exceptionally pleasant person and it is sad to see him struggling with his mental problems. I appreciate your help.”
A wealthy Japanese businessman, the CEO of a car parts factory, married a biologist, and they had two sweet little daughters. But it was unthinkable in Japan for a daughter to inherit his business, so they decided to have a third child. During the pregnancy, the wife felt far fewer signs of life than on the previous occasions. The child was born three weeks prematurely, and the birth was much more prolonged and difficult than before—but it was a boy! However, the baby was so floppy that he couldn’t suck, so he was given tube feeding. When he was eighteen months old he started to eat—and seemed to be making up for lost time. However much he ate, he was never satiated; he invariably cried for more and became grossly overweight. When he was four years old he was diagnosed with Prader-Willi syndrome. The parents were also told that the child would always be mentally disabled and that they would face a lifelong struggle to prevent him from becoming obese and getting diabetes, with all its attendant dangers. The mother put electronic locks on the kitchen food cupboards and devoted all of her time to teaching him, stimulating him, and giving him new experiences to take his mind off food. As a result, the child had a strikingly normal build for a young Prader-Willi patient. Yet all of the mother’s efforts couldn’t prevent the boy from occasionally falling prey to terrible bouts of rage. She joined the Japanese Prader-Willi Association and took him with her to a biennial international conference at which scientists and parents meet to learn from each other. Parents often take their Prader-Willi children to these gatherings, and you can spot them on the flight on the way there: lots of obese children from Europe, Japan, India, and North Africa overflowing their seats, with their disproportionately small hands and feet and their typical almond-shaped eyes. You need only follow them to find the conference.
It was at that conference that the mother of the Japanese boy heard about a new growth hormone therapy that normalized the metabolism of Prader-Willi children, allowing even the fattest children to regain a normal build and ending the incessant battle against hunger. She was fortunate in being able
to afford the expensive new therapy, because her Japanese insurance company wasn’t yet prepared to foot the bill.
In the United States, Prader-Willi syndrome is known as H3O syndrome (hypomentia, hypotonia, hypogonadism, and obesity). The symptoms are largely due to a disturbance of the hypothalamus. The abnormal birth is actually the first sign of the child’s defective hypothalamus, because that brain system plays an active role in timing the start of the birth and in speeding up its various stages (see chapter 1).
Most Prader-Willi patients lack a small piece of chromosome 15; in others, that section of the chromosome doesn’t function at all. It’s located in the section that they inherited from their father. The opposite strand—the one inherited from their mother—was chemically silenced at the very earliest stage of development and so can’t compensate for the absence or malfunctioning of the paternal part. This process whereby the expression of genes is determined by the parent who passed them on is known as imprinting. When we examined the hypothalamus of Prader-Willi patients, we found that the paraventricular nucleus, the center of autonomic and hormonal regulation, was a third smaller than normal and contained only half the normal number of oxytocin neurons. The latter act as your “satiation neurons,” signaling to your brain when you have eaten enough. Disabling these neurons in laboratory animals has been shown to cause increased appetite and obesity, and the fact that Prader-Willi patients have fewer oxytocin neurons may account for their inability to feel satiated no matter how much they eat. We’re still searching for a link between the Prader-Willi genes at chromosome 15 and the malfunction of the hypothalamus.