Robert Sapolsky explores our biological understanding of Schizophrenia in this 1h 40 minute video (except the first 23 minutes which concludes a discussion on language). These notes summarize just the material after the topic switches to schizophrenia.

Schizophrenia is a technical term that has nothing to do with ordinary everyday usage. Schizophrenia is a disease of disordered thought, inappropriate emotion, inappropriate attribution of things. Schizophrenia is heterogeneous: the disordered thoughts manifest differently in different individuals and the biology almost certainly has multiple causative pathways.

Some of the different forms of schizophrenia include paranoid schizophrenia, a thought disorder of persecution, catatonic schizophrenia where a person is immobile for long periods of time, and schizoaffective disorders which is a mixture of depression and schizophrenia.
Schizophrenia is a disease of cognitive abnormalities: abnormal sequential thought or loose associations (tangential thinking). In schizophrenia, sequential thinking is greatly impaired. For example, in a sentence about boxers they confusedly slip back and forth between thinking about the dog and the sport. Schizophrenics follow loose associations like these and lose the thread of a conversation.

Schizophrenia entails a consistent problem with abstraction: they cannot fathom which level of abstraction (concrete, second hand story, parable) is involved in a story. They always interpret things far more concretely than would be appropriate. So in the test "what is common among an apple, an orange, and a banana?" Schizophrenics might say they are all multisyllabic or that each has letters forming closed loops. They are not able to step back and see the abstraction "fruit". Other examples: if you ask "what's on your mind", they might answer "hair". Or if asked "can I take your picture?", they say "I have no picture to give you". They can't understand parables which involve metaphor ("birds of a feather flock together", "a rolling stone gathers no moss", "loose lips sink ships").

I often err on the side of being too concrete, don't we all? Do we all have at least a mild form of Schizophrenia? Sapolsky emphasizes that it is a complex and subtle diagnosis. Is schizophrenia characterized by being unable to get the thread of abstraction or metaphor even on the third or forth try? But Sapolsky suggests that they have clear-headed days and psychotic breaks. So their performance is probably uneven. As is mine!

Schizophrenia entails delusions and beliefs in things that cannot be, belief in having participated in historical events that cannot be. Also paranoia: what apples, oranges and bananas have in common is that they are all wired for sound. "If the world is making so little sense to you, it is a world that is very threatening."

Schizophrenia entails structured hallucinations "hearing voices". Most hallucinations are auditory, but they are structured as voices and not random sounds. The most common voice heard is of Jesus followed by Satan followed by the head of state.

Schizophrenia entails social withdrawal, abnormal social affiliation, ostracized, apathy (there is some damping of the autonomic nervous system; see these notes for more about the ANS:

I feel I too have a lack of social affiliation, but maybe mine isn't abnormal? I was ostracized in school. Some of these symptoms are almost universal. How can we understand the subtleties of this affliction? How do we integrate the whole of what Sapolsky says without erring by misinterpreting pieces of his description?

Schizophrenia has often been associated with violence, but their rates of committing violence are lower than in society in general except for self-mutilation, most often involving damaging their genitals. Wikipedia seems to disagree:

In the 60s some argued that schizophrenia was a blessing. Sapolsky pushes back hard: "All you need to do is be schizophrenic or know someone who is or have a family member and you will see there are no hidden blessings. This is not a disease of hidden compensations and more insight into the world. This is one of the most horrific ways that biology can go wrong. And one of the best demonstrations of it is that half of Schizophrenics attempt suicide."

During periods of remission, the chance of suicide increases suggesting that "the more often you have periods of where you are clear headed enough to see what your life is like the rest of the time, the more likely you are to try to kill yourself."

More and more people are thinking the core of the disease is disordered thinking.

Schizophrenia tends to manifest in late adolescence or early adulthood (it never(?) emerges after age 30). Schizophrenia is centered in the frontal cortex which is only just finishing development at this time. The first "psychotic break" tends to be associated with major stress. It seems that a fragile frontal cortex suffering stress can breakdown. With aging the positive symptoms (loose associations, hallucinations) lessen and the negative symptoms come to predominate (withdrawal, etc.).

Schizophrenia is not associated with gender or class, but once the affliction manifests there tends to be a downward economic spiral for those affected. "The majority of people living on streets in this country are individuals with schizophrenia."

Because schizophrenia is fundamentally a disease where everyone else thinks you're not thinking normally, there is a slippery slope to all sorts of hidden agendas and abuse. To "get rid of someone", the powerful can often simply ascribe a diagnosis of schizophrenia.

Can we avoid falling into the strangleholds of ideology?

One approach is to look at schizophrenics in different cultures. Sapolsky tells a story of Maasai woman with schizophrenia 25 years ago. In their culture men spend 10 years around puberty in warrior clans "pillaging the neighbors and getting killed in return". They settle down around age 25 taking their first wife ("typically a 13 year old"). Until recently their life expectancy was 30. "This is a culture where people believe in all sorts of things that we would view as being paranormal." So, poignantly, Sapolsky reports the real problem with the Maasai schizophrenic: "She hears voices at the wrong time."

Can we accept and try to understand individuals whose alternative thinking is just different from ours let alone those whose thinking is clinically disordered?

The Maasai are no more tolerant of mental illness than we are.

Can we learn to tolerate others with mental illness and various forms of disordered thinking? How could we even try to do that?

There are a large variety of ways to be "normal" in any culture, it takes a lot of understanding of the diversity of "normal" before one can competently make a diagnosis that someone's thinking is not normal or schizophrenic. There have been many creative artists with schizophrenia, but Sapolsky argues that it wasn't schizophrenia that made their creativity it is what destroyed their careers.

How could I prove to a psychologist that my brain works normally? There doesn't appear to be a definitive test for schizophrenia. How do we deal with such a fuzzy ailment, with its difficult diagnosis, and imperfect treatments with significant side effects?

The dopamine hypothesis: the dominant model for explaining schizophrenia: an excess of dopamine in the synapses in the frontal cortex to help manage executive function. Dopamine breakdown products (in bloodstream and cerebospinal fluid) are elevated in schizophrenics. All of the classic drugs (neuroleptics or antipsychotics such as Haldol, Thorazine, etc.) that help with schizophrenia block dopamine receptors. When schizophrenics receive dopamine or drugs that activate dopamine receptors, their symptoms get worse. Postmortem, there are elevated numbers of dopamine receptors in the frontal cortex.

Dopamine is also involved in fine motor control in the substantia nigra (involved with the basal ganglia). These dopaminergic neurons degrade in old age giving the characteristic hand tremors of the elderly and they die in Parkinson's disease. L-DOPA is a precursor to dopamine and can treat Parkinson's and Encephalitis lethargica. Since L-DOPA is delivered via the bloodstream, it doesn't just go to the substantia nigra where it is needed. The elevated L-DOPA leads to elevated dopamine in the rest of the brain which can cause psychotic breaks. Amphetamines cause a rapid dumping of dopamine resulting in a transient schizophrenic episode. Overmedicated schizophrenics develop the symptoms of Parkinson's. Tardive dyskinesia refers to individuals who look like they have Parkinson's. But there is at least one antipsychotic drug that increases dopamine and helps schizophrenics.

Seratonin is chemically structured almost identically to many hallucinogens such as LSD & mescaline, & psilocybin. Each fits into and activates seratonin receptors. The hallucinogens cause signaling in the post-synaptic neurons that typically receive a signal from the pre-synaptic neuron but in this case they are "hearing voices". So seratonin has been implicated in schizophrenic hallucinations.

Glutamate which is the chief excitatory neurotransmitter in the vertebrate nervous system has been implicated in schizophrenia: activation of some glutamate receptors from PCP (Phencyclidine or angel dust) resembles symptoms of schizophrenia. This has led many to argue for a glutamate role in schizophrenia. One study suggested PCP leads to increased receptors for seratonin.

Brain metabolism during hallucination is widespread except for the primary sensory cortexes (the visual and auditory cortexes) --- which is similar to the brain activity during dreaming. When schizophrenics are given memory tasks and metabolism in the hippocampus (involved in learning & memory and turning off the stress response) does not increase as much as in other individuals.

Structural abnormalities in the brains of schizophrenics. First he explains the challenges of identifying these: even rapid autopsy teams take 30 minutes to extract a brain for analysis after death, the brains of elderly schizophrenics may manifest symptoms of malnutrition and other effects of the disease and its treatment instead of evidence of schizophrenia itself. Brain imaging helps solve some of these problems.

In schizophrenics there is enlargement of the ventricles in the brain where cerebospinal fluid (CSF) is produced which in turn results in compression of the cortex, particularly the frontal cortex. Schizophrenics have fewer hippocampal neurons and some of them are misaligned. Sapolsky says "this is not going to make for a whole lot of solid sequential thought if you have neurons pointing the wrong direction." In the frontal cortex, some studies have counted fewer neurons and fewer glial cells (non-neural cells in the brain). Reelin, a protein involved in cortical maturation, is deficient in schizophrenics (another clue that it is a disease of the maturation of the frontal cortex between late adolescence and age 25). There is atrophy of the thalamus.

What about the genetics?

Seymour Kety's adoption studies are discussed in these notes

Heritability is discussed in these notes

If someone has schizophrenia, their identical twin has a 50% chance of also being afflicted; a full sibling will have a 25% chance; a half sibling 12%; a random person 1-2%. So there is a large genetic component for schizophrenia. Other relatives of schizophrenics also experience a higher rate of "mild versions of thought disorder".

In the 1980s the first genetic markers for schizophrenia were identified. But each study identified a different marker and none have been replicated.

The modern approach of studying actual genes has identified some correlates. Some variants of the enzyme that degrades dopamine have a small statistical correlation to schizophrenia. Sapolsky reports that three recent studies have identified genes affecting the MHC or major histocompatibility complex (which is involved in pheromones and cell signaling and the immune system). The DISC1 (Disrupted in schizophrenia 1) is a gene that has been implicated, but there hasn't been much progress in understanding how and why.

Many studies suggest that although some genes may not be different in schizophrenics, copy number variations (different numbers of copies of a gene) is frequently different in schizophrenics. But again there is little consistency in the findings. Sapolsky summarizes: "It's not a disease it's a whole bunch of heterogeneous ones and there's going to be all sorts of different genetic components to it."

"People who were fetuses during the Dutch hunger winter have a higher than expected rate of schizophrenia." Same with the Chinese famine of 1959-1961. Birth trauma, a brief hypoxia (reduced oxygen), are all associated with an increased incidence of schizophrenia. Rats exposed prenatally to high levels of glucocorticoids have elevated dopamine levels in their frontal cortex. Monochorionic twins (identical twins that share the same placenta) are more correlated with schizophrenia than dichorionic twins. Because of the complex of correlates to stress, Sapolsky opines that more stress leads to more schizophrenia.

In the 1950s, the learned opinion of psychologists was that abnormal parenting (or mothering: those were sexist times) was considered to be the cause of schizophrenia. This was called schizophrenic mothering. Generally they identified "conflicting emotional messages" or "conflicting double bind" or "raising kids with distorted contradictory fragmented emotional demands" as leading to schizophrenia. In the early 1950s the first neuroleptics were used in treating schizophrenia and the view that it was caused by parenting not only waned but resulted in an outpouring of regret from many of those psychologists realizing "my god, what have we done" as biochemistry demonstrated that pathological psychology isn't necessarily caused by bad people.

In families of schizophrenics there is a somewhat higher correlation for "communication deviance" meaning a fragmented, telescoped, broken phrase style of communication. When schizophrenics explain a Rorschach blot to their close family, there family members can often can pick out the correct pattern (control families cannot; family members can only pick out patterns correctly within the family). One possible explanation is that these families have compensated for the thought disorder.

Schizophrenics have on average been exposed to certain viruses in the third trimester of pregnancy (perinatal stress). They have more retroviral DNA in their genome than the average person. They have an elevated history of neonatal infections.

Toxoplasma gondii reproduces in cats. Infected rodents infected with toxoplasma gondii like the smell of cats increasing their chance of predation. A protozoan that changes behavior of a species in support of its life cycle. 30-50% of the global human population has been infected. Humans infected have a higher rate of mild neuropsychological disinhibition, that is, some impact on frontal cortex function. Infected humans have a higher than expected rate of car accidents, higher rates of suicide, higher rates of a certain degree of impusivity. "Toxoplasma exposure increases the risk of schizophrenia." There is evidence of increased infection of mothers during pregnancy, increased levels of antibodies to Toxoplasma, increased association between cats and schizophrenia. Many of the findings have been replicated.

Perhaps the MHC genetic effects relate to these kinds of infections, but no one knows.

How do you put together adolescent stress with prenatal infections with enlarged ventricles with some genetic abnormalities? There is no integrated model of schizophrenia yet.

The evolution of schizophrenia. In the animal world you see depression and meloncholia, but if they had the kind of disordered thinking of schizophrenia they'd probably become prey pretty quickly. So there are no animal precedents for schizophrenia.

Schizophrenics have much less reproductive success than their unaffected siblings, yet it persists at the 1-2% rate in every culture. Historical records suggest schizophrenia has been extant for a long time.

Are there circumstances in which schizophrenia is adaptive, or advantageous and increase reproductive success? Schizophrenics tend to have lower rates of lung and esophageal cancers. There are some suggestions that mild forms of schizophrenia could have adaptive qualities. But he omits the details.

Did Sapolsky convince you that schizophrenia is a disease? What are the implications of treating it as a disease? Is it just to get more funding for research? Can the disease status help us help schizophrenics? Can it help us understand how to help homeless schizophrenics? Does a disease status help us remove the stigma of schizophrenia? As non-psychologists, can we help them be the best they can be? Do you have more compassion for the schizophrenic after watching the video? What can we do with what we learned from Sapolsky?