Table of Contents
This article is, as it currently stands, a jumbled mess of notes taken from one or two lectures from the University of Stanford.
People use “schizophrenia” in their everyday vernacular for behaviour that has nothing to do in the slightest with it. A definition of schizophrenia is somewhat elusive to the layman because it disrupts the most abstract elements of human behavior and cognition, so it is rather simple to look for a reductionist definition—the problem is that these definitions mingle with rumor and popular belief to the point they become harmfully wrong.
Schizophrenia can be grossly summarized in a more technical fashion: it is a human disease where, when you begin to talk to a schizophrenic1), you realize something is fundamentally strange in their way of thinking, usually within two or three sentences (this is, also, the basis for praecox gefuhl). Schizophrenia manifests, thus, as abnormal2) thinking and abnormal communication. Let me warn you, the full definition isn't much more specific than this.
Schizophrenia = Thought Disorder = Inappropriate emotion = Inappropriate 「attribution of things」
It is not a generic, catch-all term for “being crazy”, because in schizophrenia you can find and identify [almost stereo]typical structures (i.e. models, “stereotypes”) of cognitive “failure” in schizophrenic behavior. Schizophrenia is also not a single disease; its wide variety of subtypes turns it, by definition, into a set of heterogeneous diseases and its clinical floridity turns it into a proper syndrome. Some subtypes that are usually around in the common clinical setting are paranoid schizophrenia (thought disorder built around a sense of persecution), catatonic schizophrenia (a “frozen”, immobile state for a long period of time), schizoaffective (schizophrenia + depression)… while some of the symptoms show up more commonly in certain subtypes over others, there’s still a sense of heterogeneity and overlap which eludes strict clinical classification. This heterogeneity, in fact, was the driving point behind the DSM-V doing away with “subtypes” of schizophrenia altogether in 2013: with such overlap, diagnostic precision diminishes.
Schizophrenia is, at its executive core, a disease about abnormal sequential thought, and is the base definition for the cognitive abrnormalities that, in turn, define it. This is manifested in the patient in what’s called loose association: normally, one would be able to narrate a story in a sequential order sufficiently strong for it to make sense and be coherent to the other listener; you do not see this in schizophrenics—what you see is an impairment of sequential thinking, where the narration bounces all over the place in endless tangential thinking. This tangential thinking may make some sense if you look at the thought chain hard enough. Exempli gratia3): schizophrenics that get confused in a sentence where boxers are involved, because they can’t isolate in a single sense the multiple meanings of the word boxer (the dog vs the brawler) and therefore slip back and forth between meanings within the same block of information they intend to transmit. Getting caught up in these tangents, these loose associations, occurs due to the inability to hold on to sequential logic.
Another consistent sign is the inability of abstraction, i.e. the “intuitiveness” about comprehending the degree of concreteness vs. abstraction about the information in a sequentially logical story. Schizophrenics always default into the hyper-concreteness of all possible interpretation, very aptly and unimaginatively called concreteness of thought. A rather quick test for schizophrenia is to perform an association task. “What do these three items (apple/orange/banana) have in common?” and the answers will be almost invariably hyper-concrete (maybe even meta) and convoluted, unable to step back and abstract the big picture, they'll jump through endless hoops before telling you that all three items are fruits. “Can you write a sentence for me?” and the guy gives you the piece of paper back saying “A sentence for me”. This also comes out a lot in what's called “proverb tests” where schizophrenics will not be able to get out of the most concrete interpretation out of a proverb (refranes). “Loose lips sink ships” is a proverb so abstract in the English language that it discriminates these “schizophrenic executive tendencies” very accurately and are likely to conjure images of giant lips biting into ships and sinking them before even a hint of an abstract understanding shows.
Some other psychopathological elements:
- Delusion: Believing in things that cannot be, participation in historical events that cannot be, conversation with people that do not exist or no longer exist.
- Paranoia: More florid in paranoid schizophrenia (but not exclusive to it, vide supra), it's self-explanatory, and understandable in the context of schizophrenia—if the world is making so little sense to you, it will naturally be threatening.
- Hallucinations: Because it's so commonplace, and almost always auditory for reasons not yet fully understood (it may be because of how “direction-less” auditory signals can be, therefore making humans more vulnerable to artificial input), that a patient with claims of “hearing voices” is almost pathognomonic. Counterintuitively to what the neurobiology says (!), these hallucinations have both structure and content—people overwhelmingly hear voices instead of the random noise of what one would expect from neurons' aberrant misfires, and are in fact so structured that studies corroborate a clear cultural tendency in the voice's content: the No. 1 voice heard in the United States by schizophrenics is Jesus, seconded by Satan, thirded by the current head of state, and so on. Clearly the most florid clinical feature of schizophrenia to the point that most of neuropharmacological research has been laser-focused there.
- Social Withdrawal: Schizophrenia is also a disease of abnormal social affiliation, so observations of ostracism and social disconnection are common. Also very present is apathy (our first “Negative symptom”, vide infra), absence of affect (a “flat” style of personal expression), and a clinically-verifiable “damping” of the autonomic nervous system.
- Violence: only seen mostly towards themselves in self-injury. Rate of violence towards others is incredibly low, perhaps lower than average population. Usually seen during moments of lucidity within the chronopathological timeline. First on the list is genitals, breasts, thighs, and so on.
- Schizophrenic suicide: technically the ultimate act of self-violence, also most seen during moments of lucidity. Let's stop on that last part for a single second. There's been a tendency of not merely depathologizing schizophrenia, but also of idealizing it. “Schizophrenia as a hidden blessing”, “schizophrenia is just being healthy in a crazy world”, etc.4) Sapolski brings up an interesting reply: this attitude undermines the palpable horrors of schizophrenia, a disease that can be so terrible that, where the more often you begin to have periods of lucidity, you are more likely to kill yourself.
Epidemiology and gerontologic findings: Schizophrenia is found in “1-2% of the population”, according to Sapolski, though in reality I think it's more like ~0.5%. It makes no socioeconomic (other than the downward spiral brought on by the disease, such being the case e.g. in the vast majority of US homeless) or even cultural or historical distinction, as schizophrenia can be found from the biggest city to the smallest tribe, and historical descriptions of maladies matching schizophrenia have existed for millennia. As one gets older, the clinic configuration shifts as the positive symptoms fall back and the negative ones take the center stage. It's worth pointing out the chronological onset: late teens/early adulthood, timeframe compatible with the “stressor trigger” hypothesis—taking advantage of the lack of maturity of the frontal cortex, schizophrenia rears its head around or shortly before the quarter-life crisis. A thirty-year old who has been clinically appraised to affirm he has no schizophrenia will have virtually zero chance of having it.
The word schizophrenia is too strong for what it ultimately is: “the disease where everyone else thinks you're not thinking normally”. Psychiatry has historically wielded the power this word has in its social context in order to get rid of whoever the “social undesirables” were at the time, on the basis that some of the time schizophrenia is a psychiatric illness that mutilates your life, ignoring all the other benign cases. The objective study schizophrenia is thus inevitably marred by pseudo-ideology; however, a good way to attain self-reconciliation with objectivity is looking at how the disease appears in completely different cultures and noticing the surprising amount of elements in common between cases, fortifying the idea that there is always a “core set of dysfunctions”. As a consequence of this, if you need to define a thought as abnormal, you first have the challenge of understanding all the different ways that “normal thought” manifests itself. This is not to say that one should go down the other end and underplay its severity for the sake of destigmatizing—the “very accomplished artists” who later turned out to be schizophrenic didn't become creative because of their schizophrenia, but despite it, evidenced by the fact that many of these artists have had their careers destroyed as a result of their psychiatric condition.
As it stands, the most prevalent paradigm for the neurochemical foundations of schizophrenia is the dopamine hypothesis, which has worked for decades as a mostly solid model for schizophrenia: the cause for the disease is, the theory says, because of an excess of dopaminergic activity. This is backed up prima facie by findings showing an increase of dopamine breakdown products in fluid samples from patients with schizophrenia, and the fact that all classical neuroleptic medication, used for the acute management of schizophrenic symptoms such as psychosis, work by blocking dopamine receptors and thus decreasing dopamine's exacerbated effect; administering dopaminergic medication to a schizophrenic (or just giving them dopamine outright) worsens the symptomatology5).
Post-mortem analyses have shown that schizophrenic patients have a higher concentration of dopamine receptors at the frontal cortex. An excess of pretty much any neurotransmitter activity can be due to either too much of the neurotransmitter being produced, too many neurotransmitter receptors causing an increase in sensitivity (In dopamine's case, D1 and D2), or an impairment at the breakdown (i.e. metabolization) of the neurotransmitter (which, for dopamine, is via the COMT enzyme). I’m generally on the fence about commitment to a decades-old theory about any psychiatric ailment but the fact that the substantia nigra, a “mesencephalon basal ganglia” —in short, a clump of neurons located within the brainstem— which runs on dopamine6), becomes affected in patients with schizophrenia. The substantia nigra also becomes affected in the Parkinsonism of the old age, and virtually destroyed outright in Parkinson’s disease—which explains Parkinson’s pathophysiology, as the lack of dopaminergic activity in the area in and around the substantia nigra and the miraculous (albeit temporary) recovery patients with Parkinson’s have when administered Dopamine as part of treatment. Incidentally, if you give too much Dopamine to a patient with Parkinson’s you’re increasing the overall levels of dopamine in all the regions of the brain instead of just where it’s lacking… which causes psychosis, essentially indistinguishable from schizophrenic psychosis.
Without going too far into convoluted pharmacological interactions, you can find another good example in drugs that modulate the release velocity of dopamine: metamphetamines, for example, cause a rapid release of dopamine into the synaptic cleft and can cause symptoms very similar to an acute schizophrenic crisis.
Dopamine’s role in the frontal cortex is ultimately kind of an enigma. Dopamine coordinates movement at the substantia nigra, and it's linked to the pleasure and reward mechanisms in the mesolymbic system, but nothing as clear-cut around the frontal cortex. The best bet out there is that dopamine at the cortex level has something to do with the modulation of executive function: an excess of dopamine gives the patient a frontal cortex that isn’t making much sense, i.e. loose associations, etc.
So far, the predictions involving this model are rather rational. In fact, the reader can probably aim for one right now: we already know what happens if we globally increase dopamine to people with locally decreased dopamine (Parkinsonians becoming psychotic), what can we expect from excessive neuroleptic medication on schizophrenics, which globally decreases dopamine (or rather, dopamine signaling) in people with locally increased dopamine? The result shouldn’t surprise you: it’s called “tardive diskinesia” which, granted, isn’t the stereotypical motor abnormality you find in Parkinson’s, but it comes very very close. Of course, as it’s usually the case with you can ignore all I just said because the drug aripiprazole is as good an antipsychotic as it can get and it works by… increasing dopamine levels, only antagonizing a subtype of serotonin receptors. The dopamine hypothesis model for schizophrenia, then, only makes partial sense at best. No need to throw the whole thing out just yet, dopamine is clearly doing something important and the dopamine hypothesis remains the most solid model to date, but there’s obviously still the shadow of something else lurking around. What is that something else, exactly?
Serotonin also plays a big role, as shown with aripiprazole affecting it more than it affects dopamine. It should come as no surprise that all major hallucinogenic drugs (LSD, mescaline, etc) are very serotonin-shaped and thus fit into serotonin receptors quite adequately, causing serotonin signaling without serotonin being involved at all; incidentally, this has an interesting consequence: if a neuron gets its serotonin receptor activated not from serotonin but from a drug going around in the body, the neuron will behave just like if the neuron before it in the synaptic chain has communicated with it through serotonin; in short, the activated neuron is hearing voices. Once researchers figured out this is the etiological basis for drug-induced hallucinations, the question can quickly extend to attempt to answer whether all hallucinations are the cause of abnormal serotonin activity.
Glutamate has also been implicated: to go with another associative example, if you administer a strong glutamatergic agent the patient will act a bit schizophrenic. Or, in this case, let the patient administer the glutamatergic agent on himself, the agent in question being PCP… on glutamate, it’s all mostly circumstantial, but there’s a well known association between glutamate stimulation and an increase of receptor synthesis for serotonin and dopamine. There’s also a bunch of other neurotransmitters with lesser roles.
Brain metabolism studies during a hallucination paints a picture of a cerebral cortex activated en-masse, except for partial regions in the visual or auditory cortex—these areas are “seeing things” (or, perhaps for the latter, “hearing voices”), as they were, without initial stimulation of the primary sensory cortex through external stimuli (the hippocampus’ activation also dampens in patients that suffer hallucinations).
Most of the analysis of this aspect was performed on post-mortem studies which yield incredible variability and artifacts as you’re dealing with different brains with different mechanisms of death, handling, management, time spent without preservation and in preservation. Neuropsychiatrists at the time valued the idea of “fast autopsies” where the brain could be removed from the subject ASAP, maximizing freshness and minimizing post-mortem damage.
It’s rather difficult to properly analyze schizophrenic brains because there's an overlap with poor dietary habits (schizophrenics eat like shit—who would’ve thought?) or the long-term effects of antipsychotic medication, which eventually cause quantifiable physical change from the molecular level to gross anatomy modifications; neuropsychiatrists now not only value rapid autopsies, but also working on unmedicated schizophrenics for this very reason. Bioimaging techniques have culled a bit the urge for autopsies and is crucial for rather elementary things, such as measuring structures without having to scoop out the whole thing. This has all yielded some very interesting findings:
- Enlargement of the ventricles, at the expense of the cortex which is compressed against the brain with resulting loss of grey matter. This is seen particularly at the level of the frontal cortex!
- Fewer neurons in the hippocampus, with some of them even “pointing” (i.e. sending their axons) the wrong way. Not much room for sequential thought when you've got neurons pointing at the wrong direction!
- Less of pretty much everything (neurons, glia, etc) in the frontal cortex; in particular, some proteins in charge of frontal lobe maturation are conspicuously missing—something worth pointing out given that, once again, the average age of schizophrenia matches the average age for the final stages of frontal lobe maturation: late adolescence/early adulthood.
- Thalamus atrophy. Nobody is entirely sure why this one happens.
Genetic and Environmental Causes (and Consequences)
Schizophrenia is perhaps the first psychiatric ailment that's been confirmed to have a genetic component, via the Seymour S. Kety adoption studies on identical twins yielding an end-result of ~50% of heritability for schizophrenia7) vs. the general population of ~0.5%. Also worth mentioning that close relatives of schizophrenics have higher rates of thought disorder (but not full-blown schizophrenia) than the general population.
Some genetic markers for schizophrenia were found in the 80s-90s but they could never be replicated; instead, the genes themselves were eventually found and researches identified in schizophrenic variations on a bunch of genes. Some of these genes were obvious (such as the ones coding for COMT, the enzyme that breaks down dopamine—if there’s not enough COMT around, dopamine will linger around for longer. Not a lot of work has been done on this mutation in particular) yet the most promising genes involved, found in common with incredibly large populations of schizophrenic test subjects… are the so-called major histocompatibility genes, thought to be involved essentially just in immune responses.
Genetic studies on schizophrenia are all met by walls of some type or another: for example, there’s a gene called DISC1 that seems to become disrupted in schizophrenia (and depression, bipolar disorder, and so on…). What does it normally do? Something about brain maturation and neuron proliferation, as long as it works in harmony with a whole bunch of other genes in the pathway. Other than that nobody has much of an idea, and researches had zero idea what it even did when discovered—it was even called DISC because it means “Disrupted In SChizophrenia”. Some other findings include the fact that a whole bunch of genes in schizophrenia show up with an abnormal amount of copies instead of abnormalities in the genes themselves; the problem with these findings is that, again, there’s very few (if any) attempts of replicating the studies and still nobody really knows what many of the abnormally-expressing genes even do. If anything, this cements the whole thing as a heterogeneous group of diseases, all clumped up in a conjunction of genetic and neurological mixups.
We’ve already seen that the stress model for schizophrenic onset makes sense, i.e. the adolescent/quarter-life crisis stressor. It can be successfully extrapolated to childhood stress and even prenatal and perinatal stress (e.g. people who were being gestated during huge famines, at-birth trauma, fetal virus infection, toxoplasmosis, monochorionic identical twins, etc have a higher incidence rate of schizophrenia). The second the concept of “early parenting” was added into the mix many early psychiatrists began to use the term “schizophrenogenic mothering”, in which the mother gave conflicting emotional messages and raised a kid with contradictory and fragmented emotional demands. A bridge was raised in order to meet the people who said this could be stigmatizing to mothers of schizophrenics halfway: the theory was revised to… also include fathers in the mix. When chlorpromazine, a dopamine antagonist, came out and started having incredibly fantastical results on schizophrenia and thus cementing its biochemical basis, psychiatrists began to realize they, by placing the blame on mothering for half a century, may have caused irreparable harm.
Communication within families of schizophrenics does look rather skewed sometimes, though. On first-degree relatives, communication appears rather fragmented, broken, terse, with emphasis in the intensity in private communication and understanding between the patient and these first-degree relatives—they “know” what their child is talking about and viceversa. Luckily, there's no need to jump through many hoops for this one, as it's likely just the result of overcompensation for a thought disorder.
Some microbiological agents such as viruses have been found to be correlated to schizophrenia when caught by the mother and/or the fetus in-utero. The most remarkable one is the correlation between the protozoa Toxoplasma gondii and schizophrenia: people exposed to T. gondii have an almost 50% higher chance of developing schizophrenia. Not too surprising given what T. gondii does when infecting rodents: because the parasitic cycle involves cats and rodents' consumption of cat droppings, T. gondii has somehow found a way to make rodents lose their innate fear of cat urine and overall fear of cats in general, an adaptive strategy to increase the likelihood of the parasite's cycle to complete. It's believed that T. gondii has found a way to permanently alter and rewire, perhaps through the stimulus of dopaminergic circuits, certain aspects of the human brain and particularly within areas of fear control an decision making. It's a very compelling mechanism when extrapolated to humans, but good luck trying to figure out a good study for it.
No equivalent to schizophrenia has been found in the animal kingdom. You can check primates out and see veritable cases of even fatal depression, but nothing remotely resembling schizophrenia. Perhaps for the better, given that an animal becoming schizophrenic wouldn’t survive for long in the wild at all. This, however, makes schizophrenia in humans rather contradictory: it’s been around pretty much since recorded history, and it’s by all intents a negative trait for the main objective of natural selection: schizophrenics have a lower reproductive rate and a lower life expectancy, the two things a biological trait is usually challenged for. It begs the question: can schizophrenia be adaptive? Has it ever been? Does it increase your chances of survival or reproduction under the right circumstances? In which case, are the traits and symptoms of schizophrenia useful for living in society?