Emily Dickinson described such a descent into psychosis with terrifying clarity:
I felt a Cleaving in my Mind—
As if my Brain had split—
I tried to match it—Seam by Seam—
But could not make it fit.
The thought behind, I strove to join
Unto the thought before—
But Sequence ravelled out of Sound
Like Balls—upon a Floor.
Though most people experience schizophrenia as just such a sudden cleaving, it appears in fact to be a developmental disorder that is inscribed in the brain even before birth. It is degenerative, unlike autism, which, albeit pervasive and persistent, does not generally become increasingly debilitating over time. There is a rare syndrome of schizophrenia in preadolescence and childhood. The usual course for the condition, however, is that it unfolds through five predictable stages. It is asymptomatic until puberty in the premorbid phase, though recent research points to delays in walking and talking, more isolated play, poor school performance, social anxiety, and poor verbal short-term memory. This is followed by a prodromal phase, which lasts for four years on average, in which positive symptoms begin gradually to appear. The adolescent or young adult in this phase experiences changes in cognition, perception, volition, and motor function; has strange thoughts flash across his mind; struggles to understand whether illogical beliefs are true; and becomes suspicious and wary. Some people who will develop schizophrenia seem curiously detached from the real world even in childhood and gradually slip into psychosis. Most appear to have a dramatic break, sometimes in reaction to trauma and sometimes with no obvious trigger, in which they are suddenly transformed beyond recognition. This marks entry into the psychotic phase, with the onset of hallucinations or bizarre delusions, including delusions of control, thought insertion, thought broadcasting, and thought withdrawal. This usually occurs between ages fifteen and thirty and lasts for about two years.
No one has yet been able to discover what maturational event triggers psychosis. There are three primary possibilities. One is that the teenage rush of hormones changes gene expression in the brain. The second is that myelination, the adolescent process in which the brain wraps neuronal cables in a sheath so that they become maximally functional, goes wrong. The third is that synaptic elimination, or pruning, malfunctions. During normal brain development in infancy, new cells migrate within the brain, position themselves, and establish synaptic connections. An excess of these connections is made; during adolescence, only those that have been strengthened through repetition—that appear useful in the particular person—become enduring neural structures. An unhealthy brain may prune too much, not enough, or in the wrong places.
After somebody becomes ill, further changes occur in the progressive phase, which leads to clinical deterioration except when effectively controlled with medication. As the patient has repeated psychotic episodes, the condition worsens, finding its level after five years or so and settling into the chronic and residual phase. By this time, there has been an irrecoverable loss of grey matter in the brain. Positive symptoms tend to fade somewhat, while negative ones become more pronounced. Patients remain disabled, and persistently symptomatic. While more than 80 percent of patients respond well to antipsychotics during a first episode, only half of those treated at this stage show a comparable response.
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When Janice Lieber was born, in 1953, her mother, Connie, had preeclampsia, a potentially fatal rise in maternal blood pressure, and the birth was rough. Janice seemed disengaged from the start. Connie thought she might be autistic; the pediatricians said she was mentally retarded. As it became clear that she was gifted at mathematics, the autism diagnosis stuck. At twenty-two, she had a psychotic break during her final year of college. Her father, Steve, brought her home; when she got there, she threw everything she loved out the window because a voice told her to do so. Connie called her doctor, who prescribed Mellaril, an early antipsychotic, for the weekend. Monday, Janice saw a psychiatrist and received a diagnosis.
Connie decided to learn all about schizophrenia, but not much information was out there. Then she and Steve went to Columbia for a meeting on schizophrenia and heard about NARSAD, the National Alliance for Research on Schizophrenia and Depression. NARSAD had at that time raised a total of $50,000 to support scientific investigation. Connie soon became president, a post she held for nearly twenty years; when she stepped down, Steve, who runs an investment fund, took over as chairman. The Liebers built NARSAD into the world’s largest private funder of psychiatric and brain research; by 2011, it had given more than three thousand grants totaling almost $300 million to scientists in thirty-one countries. The Liebers personally review over a thousand research applications every year. They focus on original proposals by young researchers who cannot secure other funds. Herbert Pardes, president of NewYork-Presbyterian Hospital, said, “Most Nobel Prize winners could learn science from the Liebers.”
Connie and Steve were messianically busy with NARSAD. One of Janice’s psychiatrists asked her if she minded her parents being so occupied, and Janice said, “I don’t see my mother as much as I’d like, but I know what she’s doing. She’s giving of herself for me and others. For mankind.” Steve felt that their dedication affirmed for Janice how central she was in their lives, while also relieving some of the pressure that goes along with being an ill child. “She was the emblem of the challenge, and that was healthier than being the entire challenge herself,” he said. When they began, the Liebers thought it would take ten years to reach a scientific breakthrough that could change their daughter’s life. As this did not occur, they wanted to help Janice directly, and in 2007 they opened the Lieber Clinic at Columbia, which provides rehabilitative services. Janice goes to a day program there that teaches interpersonal sensitivity and other practical skills to people with schizophrenia. She has done remarkably well given the ongoing psychosis she faces, and now lives independently.
Connie has advised thousands of parents. “My name was on a lot of materials,” she said. “And we never had an unlisted phone number; I don’t believe in that. Anyone could find us, and if I could help them, I would.” She smiled. “Some people take advantage, but I listen to them.”
• • •
Schizophrenia, like autism, is a blanket term. Eugen Bleuler, who coined the word in 1908, actually referred to schizophrenias. In 1972, the eminent neurologist Frederick Plum famously said, “Schizophrenia is the graveyard of neuropathologists,” meaning that no one had understood or would understand its etiology. We now understand more of schizophrenia than we do of autism. It is unclear whether schizophrenia should be subtyped according to biology (genotype) or behavior (phenotype). Despite the variety of genotypes and phenotypes for schizophrenia, no particular form or course of the disease has been linked to a particular set of genetic markers. Some people without the gene defects have the illness, and some people with these mutations do not; they are markers for vulnerability rather than guarantees of disease. One member of a family with a defective gene can be schizophrenic, but another member with the same gene defect might be bipolar or severely depressed.
Schizophrenia clearly runs in families; the most reliable predictor of developing the condition is having a first-degree relative who has it. But most who develop schizophrenia don’t have such a relative. “Fact one: most schizophrenics do not have a schizophrenic parent,” Deborah Levy, a practicing psychologist and a professor at Harvard, said. “Fact two: the incidence of schizophrenia is not decreasing, and in some places it is actually increasing. Fact three: schizophrenics have a very low reproductive rate. So how do we account for the persistence of the genes that give rise to it? One possible explanation is that most carriers and transmitters of schizophrenia genes are not schizophrenic.” Identical twins show only a slightly higher than 50 percent concordance rate—the shared vulnerability is enormous, but the consequences of that vulnerability are by no means predestined. The
children of the well twin and those of the ill twin are at the same escalated risk for the disease. So a person can have the susceptibility genes, not express them as schizophrenia, then transmit them to his or her children, who may develop schizophrenia. Nobody knows what protects some gene carriers from the condition. One mechanism of psychosis is an imbalance in neurotransmitters, particularly dopamine. Schizophrenic brains show reduced volume in the frontal cortex and hippocampus, and dysregulation of the striatum. Genetics most likely mix with environment to cause a shift in biochemistry, which then has a degenerative effect on brain structures. New work suggests that a genetic vulnerability may be activated by a parasite.
Everyone has a blueprint of thirty thousand or so genes, but the way those are expressed depends on the way the chromosomes are configured and on how external processes suppress or enable gene expression. A great deal of biochemistry determines when, how, whether, and to what extent a gene will be activated, and schizophrenia genes may go unexpressed, while protective genes may be overexpressed. As in autism, instead of a single genetic anomaly accounting for a large proportion of cases, a multiplicity of so-called private mutations—many, copy-number variations—may each be sufficient to cause the illness. These occur more often in offspring of older parents, especially older fathers. Another mechanism is spontaneous genetic mutation, the same process responsible for most occurrences of Down syndrome. It is now emerging that some spontaneous genetic defects, be they changes in copy number or single gene mutations, are found in schizophrenia, autism, and bipolar disorder. Is mental illness on a single spectrum, rather than a set of discrete disease entities? “I’d say it’s more like a grid,” said John Krystal, chairman of Yale’s Department of Psychiatry and editor of the preeminent journal Biological Psychiatry.
The best way to determine what the gene defects are actually doing is to insert them artificially into the genomes of lab mice. The animals are observed to see if they mimic aspects of the illness in humans; then researchers try to understand how the gene is affecting brain development. Of course we have no way to tell if mice are hallucinating. Some such transgenic mice, however, become reclusive, hyperaggressive, or asocial; some refuse to affiliate with animals of the opposite gender or recoil from strangers. Many refuse to do work rewarded with food, giving up on tasks that normal mice will gamely pursue—a startlingly good approximation of the demotivation of schizophrenic people. Eric Kandel, who conceived and is designing some of these vast research protocols, has come to what he terms a “paradigm shift for schizophrenia.” Many illnesses arise from the way a gene expresses itself ongoing; turn off the gene, and the symptoms vanish. Schizophrenia may originate in genes, but turning them off will not mitigate the illness; once it’s in play, it must play itself out.
In 2011, I was privy to a conversation between a biotech executive and James Watson, the Nobel Laureate who, with Francis Crick, discovered the structure of DNA, and who has a son with schizophrenia. The executive opined that schizophrenia research was diffuse and chaotic; he had a grand scheme for getting everyone to collaborate, so people could each benefit from the knowledge of others. He had hoped he could inspire a breakthrough if he raised $400 million to address the problem. Watson said, “We’re nowhere near the stage where collaboration is useful. We don’t know enough; there’s nothing anyone has figured out for anyone else to build on. We need an insight, not a refinement. If I had your four hundred million dollars, I’d find a hundred bright young scientists and give each of them four million. If I chose right, one of them would come up with something.”
Every family member of a person with schizophrenia whom I met was scared by these genetic vagaries. One man told me that his girlfriend had refused to marry him because his schizophrenic brother represented a risk to his future children. “The history of schizophrenia is the history of blame,” Maryellen Walsh has written in her guidebook for families and friends of people with the condition. Mothers have borne the brunt of such blame. Freud never suggested that early trauma engenders schizophrenia and did not advocate psychoanalysis for psychotic disorders. The poisonous term schizophrenogenic mother was put forward by the Freudian analyst Frieda Fromm-Reichmann in 1948. In her wake came theories of schizophrenia in which the entire family was to blame. One author wrote, “The patient’s function is similar to that of an unsuccessful mediator of the emotional differences between the parents.” Another, Gregory Bateson, said that schizophrenia is likely to occur for “a child whose mother becomes anxious and withdraws if the child responds to her as a loving mother.” Such thinking was an antecedent to systems-oriented family therapy, based on the idea that the psychopathology of an entire family was manifested in a single individual as psychosis.
Thomas Insel, director of the National Institute of Mental Health, said that the most notable progress since the 1950s has been the end of the “blame and shame” game, but in my experience of people dealing with schizophrenia, both blame and shame remain highly operative. In 1996, two decades after the family systems theory had slipped out of vogue in professional circles, a national survey found that 57 percent of respondents still believed that schizophrenia was caused by parental behavior. An epidemic of self-help books such as the runaway bestseller The Secret argue that mental health is simply a matter of positive thinking. William James called earlier versions of this philosophy, written into Christian Science and other American metaphysical movements of the nineteenth century, “the religion of the healthy minded,” celebrating “the conquering efficacy of courage, hope, and trust, and a correlative contempt for doubt, fear, worry.” This concept is popular for its suggestion that healthy people have earned their health through personal courage. For those who are unwell, however, the suggestion that flawed discipline and weak character are the source of their psychosis is torture.
When mothers internalize blame, it interferes with the very support that people with schizophrenia most need. “I sometimes felt as though I wore a scarlet letter ‘S’ emblazoned upon my chest,” wrote the bioethicist Patricia Backlar, who has a schizophrenic son. “That ‘S’ might stand for schizophrenogenic, but is as likely to impute personal shame.” Another mother wrote, “An entire generation of mental health professionals was educated to believe that families cause schizophrenia. Some are still treating our sons and daughters. And still mistreating us.” The psychiatrist E. Fuller Torrey, founder of the Treatment Advocacy Center, finds the blame problem absurd. “Any parent who has raised a child knows that parents are not powerful enough to cause a disease like schizophrenia simply by favoring one child over another or giving the child inconsistent messages,” he wrote.
• • •
When the doctors at Long Island Jewish Hospital wanted to recruit Philip and Bobby Smithers for a genetic study of schizophrenia in the 1990s, their mother fought to keep them out of it. “What’s in it for us?” she asked. In the first decade of the new millennium, Philip, Bobby, and their unaffected older brother, Paul, were in their thirties, and Paul’s wife, Freda, wanted to know how vulnerable her children might be. As Freda began investigating the extended family, she found illness everywhere: Paul’s aunt had been institutionalized her entire adult life with “postpartum depression,” an uncle was “sick in the head,” and many “quirky” cousins could barely function. Although Paul and Freda were high school sweethearts, Freda had met Paul’s father only once before their marriage, because Paul kept everyone away from him. “You’d think that when Paul’s brothers both started acting strange,” Freda said, “their mother would have told the doctor that there’s a family history of schizophrenia. But that’s not the way they do it, so it took years for them to be diagnosed.”
Secrecy is a difficult habit to break. “Every year we have a Thanksgiving for Freda’s family, and then we have one for mine,” Paul said. “If we mix the two, I’m defensive, my mom is defensive of my brothers, and it’s upsetting to Freda’s family to see these sick people. I don’t discuss this with even my closest friends. I�
�m not in denial, like the rest of my family. I just don’t like talking about it. I have an emotional connection with my brothers. I think about them every day. But do I have a relationship with them? Not really. They’re very highly medicated.”
Paul and Freda, who now have two sons, live in terror of seeing them develop schizophrenia. They considered using a sperm donor, but couldn’t bring themselves to do so. “We’re making genetic rolls of the dice,” Paul said. Freda described her fear as a constant mental drain. She added, “We torture them in some ways. I read an article saying that people who develop schizophrenia have particular traits. We strip them naked; we’re going through their whole bodies looking for webbed toes. Someone said more schizophrenics are born in the winter, so we timed it to have summer babies. Nutty, I know. In some ways, it’s very liberating. Everyone wants their kid to be the smartest and the most athletic. We really don’t care. As long as they’re healthy.” In 2008, Paul and Freda agreed to participate in a survey on schizophrenia genetics. “We sit by the phone,” Freda said, “waiting to find out what the gene is, so we can test the kids.”
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