Schizophrenia By Robert Sapolsky
Part I: The Genetics and Evolution of Language
A couple of days ago, we skirted the edge of the genetics of language. When looking at this, we start with the usual techniques from behavioral genetics. We look for covariance of language abnormalities in families. For example, Williams syndrome and selective language impairments show classical Mendelian inheritance—they run in families. Then we pull out the usual armamentarium: adopted individuals, twins separated at birth. What that shows is a fair degree of heritability for things like vocabulary complexity, ability to spell, and phonology.
But the modern version of this is looking at the actual genes, the molecular biology. And the first thing that comes up is a gene that has been at the center of the field for years: FOXP2.
It was originally identified when a mutation was found in a family that suffered from a very specific linguistic problem regarding language generation and speech. So, you find the genetic marker, narrow it down, and it turns out to be FOXP2, which is a transcription factor. Now, to make things confusing, it’s preferentially expressed in the basal ganglia—the part of the brain playing a role in the motoric aspects of language, like facial gesturing and prosody. Initially, people thought this family just had a mechanical, motor aspect problem with speech. But it’s messier than that; they have cognitive language impairments too.
Of course, the immediate question is: what is FOXP2 doing in other species? It turns out, it’s everywhere. You find it in birds, in mammals, in everything large and small. It is immensely conserved evolutionarily. But the human version is different. The differences in the human version emerged very recently—best estimates say the last couple of hundred thousand years. And each change was extremely positively selected for. Whatever this gene does, once it went down the hominid path, it changed fast under major selective advantage.
When you look at the genes this transcription factor regulates, they are distinct from other primates. One of the all-time coolest studies happened recently: scientists took mice, knocked out their FOXP2 gene, and inserted the human version. What happened when these animals matured? They spoke just like Mickey Mouse. No, I'm kidding—Disney is probably working on that. But what actually happened is they vocalized more, and their vocalizations were far more complex. Just a screaming imprint of major positive selection.
The Miracle of Creoles and the Tragedy of Extinction
Let's look at another indirect piece of evidence for the genetics of language. What happens when you throw a bunch of people together from different cultures who don't understand each other’s languages? This happened historically with slave populations in the Caribbean or plantation workers in Hawaii. Initially, what emerges is a fragmented communication system made of bits and pieces of the original languages. This is called a pidgin language. It has virtually no complex grammar; it's a limp-through communication system.
But here is the cool part. Within a generation or two, the children of these people evolve that pidgin into a real, fully-formed language, known as a Creole. These Creole languages have real grammar. And what is staggering is that Creole languages from all over the planet—built from completely different original languages—all tend to default to the exact same grammatical structures.
It’s not just because they are picking the simplest possible grammar. Out of 24 possible ways to organize subjects, objects, and verbs, the vast majority of all languages on Earth only use about four of them. It strongly implies that there is a hardwired, ancient, default pattern of grammar built into the human brain—a prepared learning structure that humans default to when pulling a language out of thin air.
Finally, touching on ecology and language—this is totally depressing stuff. Studies show that diverse ecosystems, like rainforests, produce not only high biological diversity but immense linguistic and cultural diversity. But linguistic diversity is currently going down the tubes faster than biodiversity. In this century, 90% of Earth’s languages will go extinct. The vast majority of humans today speak fewer than 10 different languages out of the 6,000 existing ones. Along with that comes a huge loss of cultural diversity. We are turning the whole world into a lowest-common-denominator McDonald's culture.
Part II: Schizophrenia — A Disease of Abnormal Thought
Now we jump to our next topic: our first psychiatric disease. (As a reminder, we won't have a formal lecture on depression; read the chapter in the Zebras book with the attention of a full lecture). Today, we focus on schizophrenia.
We start off making sense of the disease as a bunch of behaviors. Right off the bat, you have to challenge the colloquial use of the word. People say, "Oh my God, I’m having such a skitzy day! I missed class, but I got an A on a test, then I fought with my friend—what a schizoid day!" That has absolutely no resemblance to how the term is actually used.
On the most fundamental level, schizophrenia is a disease of disordered thought. When you talk to a schizophrenic, within two or three sentences, you realize their thinking is not normal.
Schizophrenia is not just one disease; it is a heterogeneous cluster. You have paranoid schizophrenia (thought disorder built around persecution), catatonic schizophrenia (frozen motor states), schizoaffective disorder, and others. But the defining feature across the board is a profound cognitive abnormality in sequential thought, known in the business as loose associations.
All of us can tell a story sequentially so it makes sense. Schizophrenics cannot. Their thoughts tangent all over the place. If you mention a boxer (the athlete), a schizophrenic might slip mid-sentence into talking about dogs (the breed) and then express an opinion on how a Saint Bernard would do in a boxing ring. They get derailed by the literal sounds of words and multiple meanings.
Next, there is a consistent trouble with abstraction, known as concreteness of thought. We intuitively know the difference between a literal story and a parable. Schizophrenics lack this intuition; they interpret things as concretely as possible. If you ask a schizophrenic, "What do an apple, an orange, and a banana have in common?" they won't say "They are fruit." They might say, "They are all multi-syllabic words," or "They all have letters with closed loops."
A therapist might ask, "What's on your mind today?" and they will say, "My hair."
One of the classic diagnostic tools is a proverb test. Proverbs are inherently abstract. If you ask a schizophrenic what "A rolling stone gathers no moss" means, they will give you an exhaustive geological and physical breakdown of how difficult it is for vegetation to attach to a smooth, rolling, angular object. My favorite example is from a psychiatrist friend who used a World War II poster slogan: "Loose lips sink ships." A beautifully abstract way to say "don't gossip about troop movements." Try asking a schizophrenic what that means, and they will immediately conjure images of giant, disembodied lips coming out of the ocean to capsize naval vessels.
Delusions, Hallucinations, and the Lack of Hidden Blessings
What else? Delusions. A schizophrenic might ask you, "Have you heard of the Great Wall of China? My idea. The generals came to me at night with the map." You see immense paranoia—fruit wired for sound, a world constantly threatening them.
Then, most famously, there are hallucinations. For reasons completely un-understood, the vast majority of hallucinations in schizophrenia are auditory. And they aren't just random noise; they are highly structured. Researchers have even studied the "Hit Parade" of schizophrenic voices. In Western cultures, number one is Jesus. Number two is Satan. Number three is typically whoever the current head of state is.
Everybody thinks of schizophrenia as this disease of florid, positive symptoms—the hallucinations and paranoia. But more and more, people realize it is profoundly a disease of negative symptoms: social withdrawal, apathy, flattened affect, and physiological dampening. These people are painfully isolated.
There is also a myth regarding schizophrenia and violence—the fear of the schizophrenic who goes postal. In reality, schizophrenics are far less dangerous to others than normal individuals. The danger they pose is overwhelmingly to themselves. Self-injury is a massive feature of the disease. Half of all schizophrenics attempt suicide. And the horrifying reality is that they are most likely to attempt suicide during periods of remission—when their heads clear just enough to realize what their lives are like the rest of the time.
I want to emphasize a horrific trend from the 1960s, driven by psychiatrists like R.D. Laing. There was this lunatic-fringe view that schizophrenia was a "hidden blessing." That it was the disease of being a sane person in an insane world. Movies romanticized it. Let me be clear: you only need to know one person with this disease to know there are no hidden blessings. It is an unmitigated nightmare that destroys lives.
Part III: A Cross-Cultural Perspective
When dealing with a disease defined by "thinking abnormally," you inevitably skate on thin ice. Who defines normal? Psychiatry has a dark history of weaponizing the diagnosis of schizophrenia against political dissidents. To truly understand what constitutes abnormal thought objectively, you have to look at the disease cross-culturally.
Let me tell you about the one case of cross-cultural schizophrenia I've ever personally encountered. I was in East Africa, living a few miles away from a Maasai village. The Maasai are nomadic pastoralists. Their men are warriors. They drink cow blood. They have a completely different worldview and set of norms from us.
One day, I’m sitting in my camp, and a group of Maasai women comes running up the mountain in a state of absolute agitation. Now, Maasai do not agitate easily; these are people who have to kill lions as a puberty rite. But they demanded I bring my Jeep to the village because a woman had done something horribly wrong. As we drive down, they explain that this woman, who lived completely isolated on the edge of the village, had killed a goat with her bare teeth.
I’m sitting there thinking, "Wow, a psychotic break! This is going to be fascinating to study."
We get to the village, and out comes this huge, naked woman covered in goat blood and feces, with the goat by the throat in her mouth. She gives a howling yell, charges the Jeep, knocks me over, and attempts to strangle me.
Never once in my wildest fantasies did this seem like a good way to die—throttled by a woman with a goat in her mouth. Fortunately, the Maasai pulled her off me, shoved her into the back of my Jeep, piled on top of her, and said, "Drive." We drove to a tiny, remote government clinic where they essentially shoved her inside, locked the door, and told me, "Let's get the hell out of here." It turns out, even in a culture as radically different as the Maasai, nobody has a whole lot of tolerance for the mentally ill.
On the drive back, I turned to my Maasai friend and asked, "So, what do you think is wrong with her?" She looked at me like I was an idiot and said, "She's crazy." "How do you know?" I asked. "She hears voices." I said, "Wait, you guys hear voices! You do trance dancing, you hear ancestral ghosts. What's the big deal?" She replied, "No, no, it's different with her." "Well, she killed a goat," I said. "You guys kill goats." "But women aren't allowed to kill goats, and certainly not with their bare hands in the middle of the village!" Finally, I asked, "So how do you fundamentally know she's crazy?" She looked at me and delivered the ultimate objective diagnostic criteria for schizophrenia across any culture on Earth: "She hears voices at the wrong time."
Part IV: The Neurobiology of Schizophrenia
What is going on in the brain chemistry? For decades, the dominant model has been the Dopamine Hypothesis—the notion that there is an excess of dopamine signaling in the brain, particularly in the frontal cortex.
The evidence?
The classic antipsychotic drugs (neuroleptics like Haldol and Thorazine) all work by blocking dopamine receptors.
If you look at the brains of schizophrenics post-mortem, they have elevated levels of dopamine receptors.
If you give a healthy person a drug that dumps massive amounts of dopamine into their synapses—like amphetamines—they will transiently look exactly like a paranoid schizophrenic.
But the most fascinating evidence comes from a completely different disease: Parkinson’s. Parkinson's is a disease where a part of the brain called the substantia nigra loses its dopamine neurons, causing motor freezing and tremors. In the 1960s, a drug called L-Dopa was introduced to replace that dopamine. It was miraculous. Oliver Sacks wrote about this in his book Awakenings. But there was a catch. You can't just squirt dopamine exactly where it's missing; you have to put it in the bloodstream. So, while L-Dopa fixed the motor issues, it flooded the rest of the normal brain with far too much dopamine. Give a Parkinsonian patient too much L-Dopa, and they become a floridly hallucinating schizophrenic.
Conversely, if you give a schizophrenic too much dopamine-blocking medication over decades, they develop a movement disorder called tardive dyskinesia—they begin to tremor and look exactly like a Parkinson's patient.
It’s an elegant, almost perfectly inverted mechanism. Though it's not the only neurotransmitter involved. Serotonin is highly implicated because every major hallucinogen (LSD, psilocybin, mescaline) fits almost perfectly into serotonin receptors. When you hallucinate, your primary sensory cortex is quiet, but the rest of your brain is wildly active, reacting to signals that never actually came from the outside world.
Structural Abnormalities
Beyond chemistry, there are physical structural abnormalities in the schizophrenic brain. Through brain imaging and rapid autopsies, we consistently see enlarged ventricles (the fluid-filled caverns in the brain). If the ventricles expand, the brain tissue must compress. That compression occurs heavily in the frontal cortex.
Furthermore, if you look at the hippocampus—the center of sequential memory—the pyramidal neurons are often disorganized, flipped upside down, and pointing in the wrong direction. You cannot have solid, sequential, logical thought if the neurons responsible for sequence are physically wired backward. Additionally, we see lower levels of a protein called reelin, which is essential for the final maturation of the frontal cortex.
This perfectly mirrors the epidemiology of the disease. Schizophrenia almost universally strikes in late adolescence and early adulthood (age 18 to 25). If you make it to age 30 without it, you almost certainly will never get it. What finishes maturing exactly at age 25? The frontal cortex. Schizophrenia is the devastating unmasking of a vulnerable frontal cortex that fails its final maturation phase.
Part V: Genetics and the Environment
Schizophrenia has a huge genetic load. Identical twin studies show a 50% heritability rate. (Remember, random strangers on the street have a 1-2% rate).
In the 1980s, people thought they would easily find "the" schizophrenia gene using genetic markers in isolated populations like the Amish. The problem? Every study found a completely different marker. The field stalled for a decade. Today, we know the genetics are wildly complex. Recent massive studies unexpectedly found abnormalities in the Major Histocompatibility Complex (MHC)—the immune system genes that handle cell signatures. What does the immune system have to do with thought disorder? Nobody knows.
We also see "copy number variants"—schizophrenics often have wildly abnormal numbers of copies of various genes. It’s highly heterogeneous.
The Tragedy of Schizophrenogenic Mothering
Where does the environment fit in? If there is one thing I want you to remember from this, it is the horrific failure of psychiatry in the 1950s.
Before neuroleptics, the greatest minds in psychiatry believed schizophrenia was purely psychological, caused by a parenting style. Specifically, they blamed mothers. They coined the term "Schizophrenogenic Mothering." The theory was that mothers sent contradictory, "double-bind" emotional messages to their children (e.g., demanding love but rejecting it when offered), which structurally fragmented the child's mind.
Then the 1950s hit, Thorazine was invented, and 90% of the psychiatric hospital beds emptied out. It was a biochemical disease all along! The entire field had to look in the mirror and realize what they had done. For half a century, mothers brought their terrified, hallucinating teenagers into clinics, completely shattered by the diagnosis, only for the leading medical authorities to look at them and say, "You did this to him. You caused this with your mothering."
It was a staggering, deeply shameful chapter in psychiatric history.
Viral and Parasitic Stressors
While mothers don't cause it, the early environment does matter. The genetics are a vulnerability, but stressors pull the trigger. Fetal malnutrition (like during the Dutch Hunger Winter) increases the rate of schizophrenia. Birth trauma and hypoxia increase the rate.
Most fascinating is the infectious environment. Mothers exposed to certain viruses in their third trimester have a higher rate of schizophrenic offspring. And then there is a bizarre protozoan parasite called Toxoplasma gondii.
Toxo's life cycle requires it to reproduce in the gut of a cat. It gets excreted in feces, which are eaten by rodents. To get back into a cat, toxo rewires the rat's brain so that the rat is actively attracted to the smell of cat urine. The rat walks right up to the cat, gets eaten, and the parasite completes its cycle.
What happens when toxo gets into humans? People with toxo antibodies show mild frontal disinhibition, higher impulsivity, more car accidents, and a statistically highly replicated increased risk of developing schizophrenia. There is a bizarre, deeply rooted connection between feline parasites, immune responses, and the unraveling of the human mind.
Part VI: The Evolutionary Paradox
We end with a Darwinian puzzle. By all evolutionary logic, schizophrenia is maladaptive. Schizophrenics have profoundly lower reproductive rates than their healthy siblings. A trait that lowers reproductive success should be selected out of the gene pool within a few generations. Yet, schizophrenia stubbornly persists at a stable 1-2% across every single human culture on Earth.
There are no animal models for schizophrenia. Animals don't have loose associations or literal interpretations of parables. If an animal starts hallucinating, it gets eaten by nightfall.
So why does it persist in humans? Is there an adaptive advantage? Some weak data suggests schizophrenics have a slightly lower incidence of certain cancers, but that hardly explains its persistence.
The real answer likely lies not in the full-blown, devastating disease, but in the milder, sub-clinical versions of the genetic traits found in the healthy relatives of schizophrenics. These mild versions—schizotypal traits, magical thinking, loose but highly creative associations—might not just be tolerated by society, but actively revered and selected for under the right circumstances.
