Using Danish health registries, Kety found that the rate of schizophrenia in the population was about 1 percent, while the rate among individuals with at least one family member with schizophrenia was 10 percent. His data also revealed that if both your parents had schizophrenia, then you had a 50 percent chance of developing schizophrenia yourself. Similarly, if you had an identical twin with schizophrenia, then you also had a 50 percent chance of being schizophrenic, but if your fraternal twin had schizophrenia then your chance of being schizophrenic was only 10 percent. Thus, it seemed that the more genes you shared with a schizophrenic, the more likely you were to develop the disorder—though this correlation was clearly not perfect. After all, identical twins share 100 percent of the same genes, so if there was a “schizophrenia gene” in one twin, it should presumably be found in the other.
Citing this fact, many critics took Kety’s finding as strong evidence that schizophrenia was primarily environmental, arguing that the greater incidence of schizophrenia within families with at least one schizophrenic member was due to an unhealthy domestic environment rather than anything genetic. To settle the question of schizophrenia’s genetic basis, Kety started a new study. He identified individuals with schizophrenia who had been adopted at birth and examined the rates of schizophrenia among both adoptive and biological relatives. He found higher rates of schizophrenia in the biological relatives, but not in the adoptive families. He also found that children born to a mother with schizophrenia but reared in an adoptive family developed schizophrenia at the same rate as those reared by the biological mother with schizophrenia. These findings demonstrated that schizophrenia was at least partially due to one’s genetic endowment, and not solely due to environmental factors like “double-binding mothers” or poverty.
Similar studies of other disorders quickly followed, showing that autism, schizophrenia, and bipolar disorder featured the highest heritability among mental disorders, while phobias, eating disorders, and personality disorders featured the lowest. Yet even though the epidemiologic studies carried out by Kety and other researchers seemed to demonstrate that a predisposition toward mental illnesses could be inherited, the findings posed a number of genetic puzzles. For one thing, even monozygotic twins—individuals with identical sets of genes—didn’t always develop the same mental illness. Further complicating the picture was the fact that sometimes schizophrenia skipped entire generations, only to reemerge later in the family tree. And sometimes, schizophrenia appeared in individuals with no family history of the disease at all. All of this also held true with depression and bipolar disorder.
Another riddle was presented by the fact that individuals with schizophrenia or autism were less likely to form romantic relationships, marry, and have children compared to people without mental illnesses, yet the frequency of both disorders in the population remained relatively constant or increased over time. As the role of genetics gained prominence in biomedical research in the 1980s, psychiatrists became convinced that these strange patterns of inheritance would be explained once scientists discovered the fabled pot of gold at the end of the genetic rainbow: a specific gene (or gene mutation) that caused a specific mental illness.
Psychiatrists began searching for mental illness genes in unique, geographically isolated or founder populations like the Old Order Amish and among aboriginal peoples in Scandinavia, Iceland, and South Africa with all the fervor of miners headed for the Klondike gold rush. The first report of a mental illness gene came in 1988 from a team of British scientists led by geneticist Hugh Gurling. Gurling’s team reported that they had “found the first concrete evidence for a genetic basis to schizophrenia” residing on chromosome 5. But Gurling’s gene proved to be fool’s gold: Other scientists could not replicate his finding with DNA from other schizophrenic patients. This reversal of fortune was to become a recurring and deeply frustrating pattern in psychiatric genetics.
By the 1990s, researchers had succeeded in identifying specific genes that caused illnesses like cystic fibrosis, Huntington’s disease, and Rett syndrome, but psychiatric researchers were unable to pinpoint any specific gene associated with any mental illness. Psychiatrists began to experience an unsettling sense of déjà vu: More than a century earlier, using the cutting-edge technology of the era (the microscope), biological psychiatrists had been unable to identify any gross anatomical basis for mental illness, even though they were certain it must exist somewhere. And now it seemed to be happening again with genetics.
But in 2003, two game-changing events occurred. First, the Human Genome Project was completed, mapping the entire set of genes encoded in human DNA. This was soon followed by the invention of a stunning new genetic technique known as representational oligonucleotide microarray analysis (ROMA). Prior to ROMA, molecular geneticists analyzed genes by determining the sequence of nucleotides in a given gene to see if any nucleotide was missing or out of place (called single nucleotide polymorphisms, or SNPs). ROMA, in contrast, scanned a person’s entire genome at once and tabulated the number of copies of a specified gene, revealing whether a person had too many copies of the gene or too few.
Michael Wigler, a biologist working at Cold Spring Harbor Laboratory, invented ROMA as a method to study cancer. But he quickly realized its implications for understanding mental illness, and with the help of geneticist Jonathan Sebat, Wigler began applying ROMA to the DNA of patients with autism, schizophrenia, and bipolar disorder. Before ROMA, the question that psychiatric geneticists asked was, “Which specific genes cause mental illness?” But ROMA reframed the question as: “Can too many (or too few) copies of a healthy gene cause mental illness?”
Using ROMA, Wigler and Sebat were able to examine a wide array of genes in mentally ill patients’ DNA and compare them to the genes in healthy persons. They targeted genes that produced proteins essential to healthy brain functions, such as a gene that produced a protein forming part of a neurotransmitter receptor or guided the formation of neural connections. Their research paid off almost immediately. They found that mentally ill patients possessed the same brain-related genes in their DNA as their mentally healthy counterparts, but the patients possessed either more copies or fewer copies of these genes than healthy people. Wigler had discovered the genome’s Goldilocks phenomenon: To have a healthy brain, not only did you need the right kind of genes, but you needed a “just right” number of these genes—neither too numerous nor too scarce.
Wigler’s new methodology divulged other unexpected insights. While most genetic mutations in the DNA of patients with autism, schizophrenia, and bipolar disorder were specific to each illness, some genetic mutations were shared by two or more disorders, meaning that some manifestly different mental disorders shared common genetic factors. ROMA research also revealed a possible explanation for the sporadic nature of mental illness within families, such as how it skipped entire generations and sometimes appeared in only one identical twin: While a particular brain-related gene might get passed on to one’s offspring (or appear in both twins), the number of copies of that gene could vary. Sometimes, copies of a gene were spontaneously created or deleted within the DNA of the sperm or egg cells. Even though twins shared 100 percent of the same type of genes, they didn’t share 100 percent of the same number of copies of these genes.
Wigler’s findings also provided a possible explanation for why older men and women are more likely to have children with mental conditions like autism or Down syndrome. Their egg and sperm cells have been genetically dividing and replicating for a longer period of time than in young parents, so they are more likely to introduce extra or fewer copies of genes into their children’s DNA, since genetic replication errors accumulate over time and are more likely to occur than a mutation creating an entirely new gene.
As psychiatry progressed through the first decade of the twenty-first century, buoyed by the emergent technologies of brain imaging, neuroscience, and genetics as well as the proliferation of new pharmacological advances and psychotherapy, the
once-stagnant field of psychiatry showed all the signs of a profession undergoing intellectual rejuvenation.
A New Kind of Psychiatry
When I first saw Jenn in 2005, the doctors couldn’t figure out exactly what was wrong with her. A twenty-six-year-old woman born to an affluent family who had enjoyed a privileged upbringing, Jenn had attended private school in Manhattan and then a liberal arts college in Massachusetts, which is where her behavior first became problematic.
During her junior year, she became suspicious and guarded and stopped socializing with her friends. She began to exhibit severe mood swings. She was friendly and pleasant one day but volatile and nasty the next, often hurling caustic insults over minor provocations. Eventually her hostility and volatility became so disruptive that the college implored her parents to have her seen by a psychiatrist. They obeyed, taking her to a leading psychiatric facility in the Northeast, where she was promptly admitted. But when she was discharged she did not follow through with her aftercare appointments or take her prescribed medication. She relapsed repeatedly, leading to multiple hospitalizations, and with every relapse she got worse. What made her situation even more daunting was that each time she was admitted, the doctors seemed to give her a different diagnosis, including schizophrenia, schizoaffective disorder, and bipolar disorder.
I was asked to consult on Jenn when she was brought to New York Presbyterian Hospital–Columbia University Medical Center after a violent incident with her mother, prompted by Jenn’s belief that her mother was trying to keep her from seeing her boyfriend. When I evaluated Jenn, her appearance was disheveled and her thinking seemed disorganized. She had been out of school for five years and was unemployed and living at home. She repeatedly voiced the conviction that a friend was trying to steal her boyfriend, and she explained to me that she and her boyfriend needed to immediately escape to New Mexico if they wanted to stay together.
After talking with Jenn’s family, I learned that in reality the object of her affections had no interest in her. In fact, the young man had actually called Jenn’s mother to complain that she was harassing him and threatening his real girlfriend. When Jenn’s mother attempted to explain these facts to her daughter she became enraged and knocked her to the floor, prompting her current hospitalization.
During our conversation, Jenn seemed disengaged and distracted, behaviors commonly associated with schizophrenia—but they are associated with other conditions, too. Her false beliefs were not systematic delusions; they simply reflected unrealistic appraisals of her relationships with others. She exhibited a full range of emotions, and while her feelings were often intense and erratic, schizophrenics more typically exhibit emotions that are constricted and flat.
Although the diagnosis assigned to her upon admission was schizophrenia, my clinical intuition was telling me that something else was going on. But intuition must be supported by evidence, so I started gathering additional data. When I asked Jenn’s parents about her early medical history, nothing much turned up—except for one fact. Her mother reported that Jenn was born prematurely and had a breech birth. That alone wouldn’t account for her bizarre behaviors, but breech births and other forms of trauma during pregnancy and delivery are associated with a higher incidence of neurodevelopmental problems. A traumatic delivery can produce complications in the infant’s brain, including a lack of oxygen, compression, or bleeding. In addition, due to an (Rh) incompatibility of blood types between her and her mother, she was born with anemia and required an immediate blood transfusion. As a consequence she had low Apgar scores (the ratings given by pediatricians to newborn babies to summarize their general physical status), indicating some birth distress, and she was kept in the neonatal intensive care unit for one week prior to going home.
I asked Jenn additional questions about her life and activities. She answered automatically with brief responses and seemed to be confused by the questions. She also exhibited limited concentration and poor memory. These marked cognitive impairments did not match the ones that usually occur in schizophrenia patients, who do not seem confused or forgetful as much as preoccupied and distracted, or engaged with imaginary stimuli. I began to wonder if Jenn’s volatility and bizarre behavior may have been provoked by her environment rather than her genes.
I asked about her drinking and drug use. Eventually, she admitted she had used marijuana since the age of fourteen and cocaine since age sixteen, and while in college she smoked pot and snorted coke almost every day. A hypothesis began to take shape in my mind. I suspected she had sustained some mild form of brain injury from her birth trauma that caused a neurocognitive deficit, which was then exacerbated in adolescence by her heavy drug use, producing these quasi-psychotic behaviors. One piece of evidence supporting this diagnostic hypothesis was the fact that the antipsychotic drugs, which had previously been prescribed for her, did not have much of an effect on her condition.
I ordered tests that would help to assess my hypothesis. Neuropsychological test results revealed a significant discrepancy between her verbal and performance scores. With schizophrenia, verbal and performance scores tend to be similar even if lower overall than the population average. Performance scores are believed to be more sensitive to brain dysfunction than verbal scores, and the fact that Jenn’s performance score was markedly lower than her verbal score suggested that she had some kind of acquired cognitive impairment. An MRI revealed markedly asymmetric enlargement of the lateral ventricles and subarachnoid space, an asymmetry more often associated with trauma or a vascular event (like a stroke) than mental illness (in schizophrenia the ventricular enlargement is more symmetrical). The social worker assisting me developed an extensive pedigree of Jenn’s family using information provided by her parents that revealed a complete absence of mental illness in the family history. The only related condition in her biological relatives was substance abuse in some siblings and cousins.
I now felt confident about my diagnosis that her pathology was due to developmental injury and substance-induced toxicity. Her prior diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder had been reasonable guesses since in reality she suffered from a “phenocopy” of mental illness, meaning that she was exhibiting symptoms that mimicked a DSM-defined illness without suffering from the actual illness.
If Jenn had been admitted to a psychiatry ward thirty years ago when I started my training, she would have likely been committed to a long-term stay in a mental institution and almost certainly been given very powerful antipsychotic drugs that would have all but immobilized her. Or, she may have been subjected to months or years of psychoanalytic therapy exploring her childhood and especially her fraught relationship with her mother.
But in today’s world of psychiatry, Jenn was swiftly discharged from the hospital and given intensive substance abuse treatment and rehabilitative cognitive and social therapies, along with a low dose of medication to help stabilize her during her course of treatment. The quality of her life gradually improved and today she is focused and engaged and expresses gratitude for the help she received in turning her life around. And while not living independently or professionally successful or married with children, she works part-time, lives peacefully with her mother, and has developed stable social relationships.
Jenn’s modest recovery—one of a growing number of success stories—illustrates how clinical psychiatry has changed as a result of the brain revolution and the myriad scientific advances over the past decades. But there was one final breakthrough in the annals of psychiatry that helped shape the modern face of my profession—a breakthrough that may be the most overlooked and underappreciated discovery of them all.
Chapter 8
Soldier’s Heart: The Mystery of Trauma
We don’t want any damned psychiatrists making our boys sick.
—GENERAL JOHN SMITH, 1944
Military psychiatry is to psychiatry as military music is to music.
—CHAIM SHATAN, MD
Air Conditi
oner Anxiety
In 1972 I was living in a shabby brownstone near Dupont Circle in Washington, DC, a sketchy neighborhood back then. One morning as I was about to leave for my physiology class at George Washington University, I heard a hard knock on my apartment door. I opened it to find two young men staring straight at me with intense black eyes. I immediately recognized them as neighborhood toughs who often hung out on the street.
Without a word, they pushed me back into my apartment. The taller man pointed a large black pistol at me and growled, “Give us all your money!” My brain froze, like a computer encountering a file too large to open.
“Hey! I said where is your goddamn money?” he shouted, pressing the muzzle of the gun to my forehead.
“I don’t have anything,” I stammered. Wrong answer. The shorter man punched me in the face. The taller one smacked me on the side of my head with the gun. They shoved me into a chair. The shorter man began rummaging through my pockets while the taller man went into my bedroom and began yanking out drawers and ransacking closets. After a few minutes of searching, they cursed with frustration; apart from the television, a stereo, and thirty dollars in my wallet, they weren’t finding anything of value… but they hadn’t checked my dresser.
Tucked away in the top drawer beneath a stack of underwear was a jewelry box containing my grandfather’s Patek Philippe watch. I couldn’t imagine losing it. He had given it to me before he died as a gift to his firstborn grandchild, and it was my most treasured possession.
“What else do you got? We know you got more!” the taller man shouted as he waved the gun in front of my face.
Then, a peculiar thing happened. My churning fear abruptly dissipated. My mind became calm and alert, even hyperalert. Time seemed to slow down. Clear thoughts formed in my mind, like orderly commands from air traffic control: “Obey and comply. Do what you need to do to avoid getting shot.” Somehow, I believed that if I just kept my cool, I would escape with my life—and possibly the jewelry box, too.
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