16Chapter 13. Biological Theories: In Search of the Key to the Brain

In 1952, an event took place in France that would later be recognized as one of the most significant milestones in the history of medicine. It was an event that transformed the lives of millions of patients. But, as is often the case in psychiatry, it happened entirely by chance.

French anesthesiologist Henri Laborit (1914–1995) was desperately searching for a drug. His goal was singular: to alleviate postoperative shock in surgical patients. He tested compound after compound until he stumbled upon something unusual—a synthetic substance from the phenothiazine group. In laboratory records, it bore the nondescript code RP-4560. And it worked. But not in the way Laborit had expected. The drug didn’t just sedate patients; it induced what Laborit described as “euphoric indifference” (désintéressement euphorique). Patients stopped worrying. They stopped fearing surgery. Their chests relaxed, their breathing steadied, their shoulders dropped. They became strangely calm—yet remained conscious.

Laborit wondered: Could this be useful in psychiatry?

He shared his findings with colleagues. Two Parisian psychiatrists, Jean Delay (1907–1987) and Pierre Deniker (1917–1998), working at the Saint Anne Hospital, took notice. They obtained several vials of the drug, now marketed under the name chlorpromazine, and began administering it to their patients with psychotic disorders.

The outcome was staggering.

Patients with acute schizophrenia, who had previously been thrashing against walls, screaming for hours, and enduring tormenting hallucinations, began to calm down. Not merely sedated into sleep, but returning—at least partially—to a state of connection with reality. Delusions receded, hallucinations lost their intensity, and emotional tension eased.

Delay and Deniker published their findings in 1952 in Annales Medico-Psychologiques. By 1954, chlorpromazine hit the U.S. market under the brand name Thorazine. In 1955, it reached Britain. By the end of the decade, it was in use across all developed nations.

It was the first antipsychotic. The first medicine in history that genuinely—not illusorily, not as a placebo, not ritualistically—alleviated the symptoms of schizophrenia.

With the advent of chlorpromazine, a new era dawned in psychiatry. An era in which the hospital ceased to be solely a place of confinement. But how did a tiny molecule manage to breach such towering walls? In the 1950s, American and European psychiatric hospitals housed hundreds of thousands of chronic patients. Frozen bodies. Empty stares. Many had lain there for decades, immobilized on cold cots. Then came antipsychotics. And everything changed. The number of hospitalized patients began to decline. This process became known as deinstitutionalization. Thirty years later, most of these “snake pits” had vanished. Care shifted to outpatient settings.

But chlorpromazine did more than just produce clinical results. It also raised a scientific question: why did it work?

Pharmacologists began to study the mechanism of action. Gradually, throughout the 1960s and 1970s, they reached a crucial conclusion: chlorpromazine blocks dopamine receptors in the brain. Dopamine is a neurotransmitter involved in numerous functions, including motor control, emotional regulation, and the reward system. Chlorpromazine particularly targeted D2 receptors in the brain’s subcortical structures.

From this emerged the first major biological theory of schizophrenia—the dopamine hypothesis. In its classic formulation, proposed in the 1960s and 1970s, it posited that schizophrenia arises from excessive dopaminergic activity in specific brain regions. By reducing dopamine activity through receptor blockade, symptoms could be alleviated.

Two observations shored up this hypothesis. First, drugs that ramp up dopaminergic transmission — amphetamines, cocaine, L-DOPA (used for Parkinson’s disease) — can, in large doses, trigger psychotic states resembling schizophrenia. Second, every antipsychotic that worked in those years, from chlorpromazine to haloperidol, blocked D2 receptors. The correlation between a drug’s effectiveness and the strength of its D2 blockade was remarkably high.

For several decades, the dopamine hypothesis dominated biological psychiatry. It seemed elegant. It seemed promising. It held the promise that one day, with a more precise understanding of the brain’s dopaminergic systems, we would learn to treat schizophrenia rationally, rather than empirically.

But half a century has passed. And the picture turned out to be far more complicated.

The first problem: antipsychotics block dopamine almost instantly, yet the clinical effect takes weeks to appear. If schizophrenia were nothing but an excess of dopamine, symptoms should ease the moment the receptors are blocked. They don’t. So dopamine isn’t the whole picture.

The second problem: antipsychotics handle the “positive” symptoms well — hallucinations, delusions, disorganized behavior. But they fare poorly against the “negative” symptoms — apathy, emotional flattening, social withdrawal, loss of interests. They’re also not effective enough against cognitive impairments — deficits in attention, working memory, and executive function, which today are considered one of the defining features of schizophrenia.

This means that dopamine blockade removes the “tip” of the clinical picture but leaves its foundation untouched.

The third problem. Researchers turned to PET — positron emission tomography — and looked straight into the living brain. The 2000s. The 2010s. Years of painstaking scans. And then — a blow. In patients with schizophrenia, the striatum really is awash in dopamine: its synthesis and release are desperately elevated. Hypothesis confirmed? Victory? Not so fast. The same brain, the same patients — but now the gaze shifts to the prefrontal cortex. And there everything is reversed. Dopaminergic activity drops relentlessly. How is that possible? One neurotransmitter — and two utterly opposite realities in a single head. This shatters the usual logic. No simple “too much dopamine everywhere.” What we have is breakdown, chaos, an imbalance between different brain regions. And the mystery only grows darker.

The modern formulation of the dopamine hypothesis (the so-called “third version,” proposed by Howes and Kapur in 2009) accounts for this complexity. It speaks of region-specific dysregulation of the dopaminergic system as one of many mechanisms underlying schizophrenia — but not the only one, and perhaps not the most important.

The second major candidate in biological theories is glutamate.

Glutamate is the brain’s main excitatory neurotransmitter. The observation that made scientists shudder was simple and dramatic. Ketamine and phencyclidine (PCP) — dissociative anesthetics that completely block glutamate’s NMDA receptors — can induce states in healthy people that are terrifyingly indistinguishable from schizophrenia. But how? Why does blocking a receptor breed madness? Amphetamine psychosis reproduced only the positive symptoms — delusions, hallucinations. Ketamine psychosis, by contrast, brought down everything: negative and cognitive components alike. Patients on ketamine froze in icy depersonalization. They felt emotionally detached, as if their souls had left their bodies. Disordered thinking swept over them. Almost like real schizophrenics. A breach in the glutamate system — and the mind falls apart from within.

Hence the glutamate hypothesis of schizophrenia: the core problem is not an excess of dopamine but rather NMDA receptor hypofunction. On this hypothesis, dopaminergic disturbances are secondary — they arise as a consequence of glutamatergic dysfunction.

This hypothesis has an ironclad foundation. It explains what the dopamine theory cannot. Neuroimaging. Genetics. Biochemistry. The data all point in one direction: glutamate plays its part. But here is the riddle. Where is the drug? There isn’t one. No medication yet exists that can reliably tame a dysregulated glutamatergic transmission and break the chain of schizophrenia. A scientific dead end? Salvation seemed close at hand. One after another, promising compounds entered clinical trials: glycine, D-serine, metabotropic glutamate receptor agonists. Scientists waited for a breakthrough. Patients waited for a miracle. But the ending proved deceptive. The results landed with a crushing disappointment. Moderate at best. No cure. The mystery of glutamate remains locked away.

An interesting contemporary drug is lumateperone (marketed as Caplyta), approved by the FDA in 2019. It simultaneously modulates the dopaminergic, serotonergic, and glutamatergic systems. But even this isn’t a revolution—just one of several next-generation treatments.

The third front of biological research: genetics.

Schizophrenia is a highly heritable disorder. If one identical twin has it, the probability that the other will develop it is around 40–50 percent. For fraternal twins, it is about 15 percent. That is far higher than in the general population (roughly 1 percent). Such high heritability (around 80% according to twin studies) points directly to the fact that genetics plays an important role.

For a long time, researchers hunted for “the schizophrenia gene” — one or a few mutations that could explain the illness. Expectations ran high. The results proved disappointing. No “schizophrenia gene” was ever found. Instead, with the rise of genome-wide association studies (GWAS) beginning in the 2000s, an entirely different picture emerged.

Schizophrenia is a polygenic disorder. Hundreds, perhaps thousands, of different genes contribute to its risk. And each one adds only a tiny, almost imperceptible contribution. Who are they — these molecular conspirators? As of 2022, more than 250 loci in the genome have been identified as statistically associated with schizophrenia risk. More than 250 secret hideouts. But what do they do? They are involved in the most varied processes: neurotransmission, immune function, regulation of gene expression, synaptic plasticity, myelination of nerve fibers. They strike everywhere. The signal collapses. Defenses weaken. The code is corrupted. Connections break. Insulation frays. The disease assembles this puzzle piece by piece.

This means that schizophrenia is not a “breakdown of a single gene” but a complex disruption involving numerous genetic factors and their interaction with the environment. Much the same pattern is seen in type 2 diabetes or cardiovascular disease. It is the biology of “many small contributions,” not the biology of “a single cause.”

This is crucial for understanding the current situation. The search for a “biological marker for schizophrenia,” which could be identified through a blood test, remains out of reach for now. A genetic risk profile—yes, that can be assessed, but it doesn’t provide a diagnosis. It merely indicates an increased predisposition.

The fourth front — neurodevelopment.

One of the most influential contemporary theories is the neurodevelopmental hypothesis of schizophrenia, most fully articulated by the American psychiatrist Daniel Weinberger in 1987.

The crux is this. Schizophrenia is not a “brain breakdown” that arises in adolescence or young adulthood when the first clinical symptoms appear. It is the result of disruptions in brain development that occurred much earlier, in the prenatal period or in early childhood. These disruptions remain “silent” for many years. They manifest when the brain passes through critical periods of development — especially during the synaptic “pruning” that occurs in adolescence and young adulthood, when the brain actively eliminates excess neural connections. If the structure of connections was impaired from the start, this pruning process can exacerbate the disruptions and lead to the clinical onset of schizophrenia.

This hypothesis is supported by multiple lines of evidence. Epidemiological studies reveal that schizophrenia patients exhibit more prenatal and early developmental risk factors than the general population: maternal infections during pregnancy, birth complications, hypoxia, low birth weight. Neuroimaging detects specific structural brain abnormalities in patients—enlarged ventricles, reduced gray matter volume—which appear present at illness onset rather than resulting from it. Cognitive studies show many patients display subtle childhood impairments years before their first psychotic episode—mild academic struggles, motor coordination issues, and social behavior deviations.

This shatters conventional assumptions. Schizophrenia isn’t an acute catastrophe? Not a thunderbolt shattering rationality? Apparently not. It’s the culmination of a prolonged, covert process. A smoldering. And this insight has immediate clinical implications: early intervention. Now the gold standard in European healthcare systems, its premise is brutally simple—identify those showing prodromal symptoms. Detect at-risk individuals before the first full psychotic episode strikes. Intercept rationality at the cliff’s edge. Then deliver specialized care.

The fifth front is the immunological and infectious hypothesis.

This is a newer and still less established line of research. Its key observations include:

Maternal infections during pregnancy—particularly in first and second trimesters—increase offspring schizophrenia risk. This holds for influenza, toxoplasmosis, and other infections. The likely mechanism involves maternal immune activation, where cytokines disrupt fetal brain development.

In the brains of patients with schizophrenia, researchers have found signs of chronic neuroinflammation: heightened activation of microglia (the brain’s immune cells) and elevated levels of pro-inflammatory cytokines in both the blood and cerebrospinal fluid.

Some schizophrenia risk genes—such as those found in the major histocompatibility complex (MHC) region on chromosome 6—are linked to immune function.

This data gave rise to the immune (immuno-inflammatory) hypothesis of schizophrenia. There have even been small studies attempting to use anti-inflammatory drugs as adjuvant treatment — aspirin, celecoxib, minocycline — with mixed but encouraging results.

To be honest, we must admit that the immune hypothesis hasn’t yet been proven therapeutically significant. It’s a promising avenue of research, but not an established truth.

So, after seventy years of intensive biological research, where do we stand?

We possess multiple fragmentary models: dopamine, glutamate, neurodevelopmental, genetic, immune, oxidative stress, myelin dysfunction. Each explains part of the picture. None explains all. No current synthesis integrates these findings into a unified biological model of schizophrenia.

Our antipsychotics effectively relieve positive symptoms in most patients but poorly address negative and cognitive symptoms. Second- and third-generation drugs (clozapine, risperidone, olanzapine, quetiapine, aripiprazole, lumateperone) offer varying efficacy and side-effect profiles—yet none surpass chlorpromazine’s original breakthrough. Psychosocial interventions complement pharmacotherapy, improving long-term outcomes.

This is an honest scientific conclusion. Schizophrenia remains one of the most challenging issues in modern medicine. It’s difficult to comprehend, difficult to predict, and difficult to fully cure. But it can be managed. With proper treatment and support, most patients can lead reasonably functional lives.

And here I want to say something important—something that runs like a thread through this entire book.

No credible biological hypothesis of schizophrenia promises miracles. Remember this. Not dopamine, not glutamate, not genetics, not neurodevelopment. They whisper the same truth—because truth never sounds sensational. This illness is complex. Multifactorial. We grasp its biological underpinnings only partially. Here’s what real scientists do: They publish in peer-reviewed journals. They preemptively state their models’ limitations—before critics can. They track the literature. They continuously revise their positions. Ask yourself: Why? Why would someone who’s found “the truth” voluntarily admit its incompleteness? The answer is simple: Because they seek truth—not dominion over it.

Now compare that with any purveyor of a “unique method” who promises to resolve, in a single session, a problem rooted in genetics, prenatal development, neurochemistry, and psychosocial factors.

The difference is astronomical. On one side, you have people who’ve dedicated decades to studying an extraordinarily complex biological system, painstakingly piecing together knowledge bit by bit. On the other, people who got “certified” as “masters of the method” over a single weekend and are ready to sell their services.

When someone tells you that “modern psychiatry knows nothing about the causes of schizophrenia, but my method has cracked the problem,” know this: the second claim is a lie. Not because the speaker is malicious, but because they simply have no idea how complex the biology of the brain really is, and how long and honestly real science has been studying it.

Psychiatry as a science knows a great deal about schizophrenia—far more than we often assume. And it recognizes the limits of its knowledge, which is a hallmark of a mature scientific discipline, not a sign of its weakness.

Biological psychiatry is poised on the brink. Now. Today. A breakthrough lies ahead. Four technologies are tearing down the wall of ignorance. Single-cell genomics. Connectome research. Optogenetics. CRISPR. They offer what only yesterday seemed like science fiction: the brain lays bare its secrets at the finest, most elusive levels. What awaits us in the coming decades? Drugs fundamentally superior to today’s antipsychotics — outdated, crude, blind. But that’s only the beginning. Will we be able to predict the risk of developing schizophrenia? Yes. With enough accuracy to intervene in the prodromal phase — to intercept the disease before it takes root in the mind. And the final blow: we will find biomarkers. They will allow us to carve schizophrenia into subtypes. To differentiate. To see each patient individually. And to prescribe individualized therapy — not blindly, but with precision on target.

This is science in motion. It is unfinished. Yet it moves forward—honestly, methodically, with mistakes and corrections.

The next chapter throws open a door into a different dimension of schizophrenia. Systemic approaches. They don’t scan the brain of an isolated patient — they find the virus in the very fabric of connections. The family. The social context. The labyrinth of interactions where the psyche stumbles and collapses. Gregory Bateson’s double-bind theory. Family therapy. Communication models. These schools won’t offer you a pill. They have no chemical scalpel. But they offer something else — a way of seeing that strikes precisely at the blind spot. A way of seeing that, in a crisis, can become a therapeutic rescue.