The Mind Thief: Why Schizophrenia Remains an Unsolved Medical Mystery

In recent years, scientists have learned to quickly and affordably sequence the human genome, have curbed the AIDS epidemic and come close to creating an HIV vaccine, synthesized several promising cancer drugs, and developed precision oncology therapies. Yet one stronghold remains unconquered—we still do not know what truly causes schizophrenia or how to treat it effectively.

Scary Cats: The Story of Louis Wain

Louis Wain loved drawing cats. After graduating from the West London School of Art, he began supporting his mother and five sisters through his art at age 20, following his father’s death. At 23, Wain married Emily Richardson, a 33-year-old governess, but their marriage was short-lived. Emily was diagnosed with breast cancer, and to cheer her up, Louis gave her a kitten. The adorable pet inspired a series of paintings. Emily soon passed away, but the “cat” theme remained central to Wain’s work.

Wain’s skill grew, and his cats became increasingly anthropomorphic, often depicted in witty, satirical scenes. His works sold briskly, and he was invited to illustrate children’s books, magazines, and newspapers. He was even elected president of the English National Cat Club. Those around him considered Wain eccentric; his youngest sister was institutionalized at 30, but Wain himself adapted well to social life until age 57—when his cat paintings began to change. The once cheerful cats became sad or sinister, with abstract, puzzling backgrounds and strange flowers for eyes.

Wain’s behavior changed too. He wandered the streets at night, preferred solitude, endlessly rearranged furniture, and wrote meaningless texts. He grew increasingly paranoid, suspecting his sisters of stealing from him. At 64, his obsession peaked—he attacked his sister and pushed her down the stairs, leading to his hospitalization in Springfield Psychiatric Hospital. His cat paintings transformed into abstract silhouettes, barely resembling living creatures. Madness escalated until his death at 78.

Modern psychiatrists consider Wain’s case a classic example of schizophrenia, with both positive symptoms (disturbed perception and thinking, hallucinations, delusions) and negative symptoms (autism and social withdrawal). Typically, schizophrenia manifests earlier, but Wain’s late onset is thought to be linked to the cat parasite Toxoplasma gondii. The theory that this protozoan triggers schizophrenia has existed since 1953, but remains unproven.

Wain is not alone. Each year, two out of every 10,000 people worldwide are diagnosed with schizophrenia. Epidemiologists estimate that 0.3 to 1 percent of the global population suffers from this psychiatric disorder. The World Health Organization lists schizophrenia among the top 10 most economically devastating diseases. Yet, until 1908, scientists weren’t even sure the disease existed, and its true mechanism remains unknown.

For a long time, medications for schizophrenia mainly targeted positive symptoms—delusions, hallucinations, and other disturbances of consciousness. Negative symptoms, such as psychophysical indifference, anhedonia, and cognitive impairment, often remained untreated. In 2015, a drug was registered in the U.S. that could reduce both positive and negative symptoms; in 2019, a similar drug became available to Russian patients.

The Psychiatrist in the “Orient Express”

In 19th-century psychiatry, “dementia” or “insanity” was a key concept, encompassing everything from intellectual decline to odd thinking. In 1860, French psychiatrist Bénédict-Augustin Morel described a mental disorder affecting young men at puberty, which always led to dementia. He called it Dementia praecox—early or premature dementia.

A decade later, German psychiatrists Ludwig Kahlbaum and Ewald Hecker detailed the disease’s progression, naming it hebephrenia (from Greek for “youth” and “mind”). Hecker wrote: “Young patients show clear deviations from logical sentence construction, cannot connect thoughts, and express themselves poorly. Then come episodes of mania and melancholy, followed by indifference, interrupted by brief excitement or hallucinations, mostly auditory. It ends in exhaustion and death.”

Kahlbaum also identified catatonia (spontaneous, purposeless motor activity or stupor) and paranoia (unhealthy suspicion, fears, and overvalued ideas, such as erotomania). By the late 19th century, so many symptom complexes had been identified that diagnosis became more art than science, with no unified classification.

Order was brought by Emil Kraepelin, who, in his “Textbook of Psychiatry” (1893–1927), proposed that all psychoses fall into two groups: those affecting mainly mood (manic-depressive disorder) and those leading to cognitive breakdown. Kraepelin concluded that Dementia praecox, hebephrenia, catatonia, and paranoia were not separate diseases but different syndromes or stages of one illness—much like Hercule Poirot accusing all suspects of the same crime in the “Orient Express.”

Not Weak, but Split

Kraepelin believed Dementia praecox was caused by an unknown brain pathology, leading to a poor prognosis. Once the pathology was found, he thought, effective treatments would follow. Eugen Bleuler, a contemporary of Kraepelin and Carl Jung’s first teacher, disagreed. He theorized that the disease involved a splitting of mental functions, not just early dementia, and coined the term “schizophrenia” (from Greek for “split mind”).

Bleuler developed a systematic model of schizophrenia symptoms, dividing them into “core” and “secondary.” He considered classic symptoms like hallucinations and delusions as secondary—reactions to the illness. The core symptoms, known as the “5 As” (sometimes 4 or 6), included autism, apathy, abulia, ambivalence, associative disturbances, and abnormal affectivity—many seen in Wain’s behavior.

Based on this model, Bleuler identified the main forms of schizophrenia: hebephrenic, catatonic, paranoid, latent, and simple. Thus, in 1908, the medicalization and construction of the disease was complete, but its causes remained unknown. Was it triggered by life experience and trauma, or by a primary brain pathology with hereditary and degenerative roots? Genetics and neurophysiology still haven’t answered this question.

Schizophrenia as an Atavism

What we now see as strange and pathological—visions, voices, odd behavior—was once considered divine. American psychologist Julian Jaynes suggested that modern consciousness arose only at the end of the Bronze Age (around the 12th century BCE). Analyzing texts like Homer’s “Iliad” and “Odyssey” and the Old Testament, Jaynes noted that heroes never made decisions themselves; instead, a god’s vision or voice told them what to do—what we’d now call hallucinations.

Jaynes believed ancient consciousness was “bicameral”—mental functions split between brain hemispheres, so decisions felt external, as voices or visions. Modern consciousness emerged when people realized these voices were internal. Jaynes’s ideas influenced science fiction more than science (e.g., “Westworld” features bicameral consciousness). Today, “commanding voices” are a common schizophrenia symptom, and Jaynes saw schizophrenia as a regression to a pre-conscious state. However, his theory can’t be falsified and offers no treatment guidance.

Reaction to Stress

In 1939, Norwegian psychiatrist Gabriel Langfeldt found that, besides progressive schizophrenia, some previously healthy people suddenly developed psychotic symptoms, often after severe stress. He called these “schizophreniform psychoses.” These patients responded well to treatments like insulin shock and convulsive therapy, unlike typical schizophrenia patients. The diagnosis became popular, as it identified a subgroup responsive to treatment and even full remission. Langfeldt’s discovery supported Bleuler’s view that many symptoms are secondary and nonspecific, highlighting the need to focus on core symptoms and their causes.

It’s in the Brain

Kraepelin’s brain pathology hypothesis has long attracted psychiatrists. The logic is simple: organ dysfunction causes disease. But for years, there were no adequate methods to prove it. In 1972, neurologist Fred Plum joked that schizophrenia was a “graveyard for neuropathologists.”

Early theories focused on observed brain changes. Autopsies showed enlarged ventricles (fluid-filled brain cavities) in schizophrenia patients, indicating loss of gray matter. This was later confirmed by CT and MRI scans. By the late 20th century, it was clear that schizophrenia patients have smaller frontal lobes than healthy people. But is this degeneration a cause or a result of the disease?

Another theory focused on brain metabolism. In 1974, Swedish neurophysiologists found that schizophrenia patients’ frontal lobes received less blood, especially with age, indicating reduced metabolism in the prefrontal cortex. Daniel Weinberger expanded on this, showing that healthy subjects increased blood flow to the dorsolateral prefrontal cortex during cognitive tests, but schizophrenia patients did not—pointing to a problem with neuron activity in this region.

Meanwhile, British psychiatrist Timothy Crow proposed two types of schizophrenia: one with positive symptoms (hallucinations, delusions) linked to dopamine activity in the mesolimbic pathway, and another with negative symptoms (flat affect, apathy, poverty of speech) linked to dopamine in the mesocortical tract. Dopaminergic neurons in these pathways regulate motivation, pleasure (anhedonia is a key symptom), and the significance of objects (e.g., erotomania, delusions of jealousy or grandeur). They’re also found in the striatum, which controls muscle tone and movement—excess dopamine here may cause catatonia.

By the early 21st century, three main neurophysiological theories existed: structural brain changes (gray matter loss), altered neuron activity in the dorsolateral prefrontal cortex, and neurotransmitter imbalances (mainly dopamine, sometimes glutamate).

The Case of the Dendritic Spines

Three different pathologies underlying one disease suggest either multiple diseases with similar symptoms or a single, yet-undiscovered mechanism. Recent research suggests all neurophysiological theories may be connected. Neurons have special protrusions called dendritic spines, which form synaptic connections and neural ensembles for processing information and behavior. The Arp2/3 protein complex, discovered in 1989 and described in 1994, is crucial for forming these spines.

Between 2015 and 2017, studies showed that mice with “schizophrenia” had fewer dendritic spines in the dorsolateral prefrontal cortex than normal mice. This reduction may decrease neural connections, lower nutrient needs, reduce blood flow, and trigger apoptosis (cell death) in this brain area. The dorsolateral prefrontal cortex also connects to the striatum and can modulate dopamine production. Thus, reduced neuron activity here can cause excess dopamine in the striatum, linking all known schizophrenia-related brain pathologies in one theory.

Innate or Acquired?

Understanding the neurophysiology of schizophrenia still doesn’t answer what causes these brain changes. Several possibilities exist:

• Genetic predisposition: Unlike many other diseases, no consistent genetic markers have been found for schizophrenia. In 2002, it was classified as a polygenic disorder. Genome-wide association studies have found over a hundred single-nucleotide polymorphisms linked to schizophrenia, scattered throughout the genome.
• Prenatal and postnatal factors: Parental age, especially paternal age, is a strong risk factor. Children of fathers over 50 are 1.46 to 3.37 times more likely to develop autism or schizophrenia than those of fathers aged 20–25, likely due to accumulated genetic mutations and epigenetic changes in sperm.
• Other factors: Maternal stress, infections during pregnancy, and deficiencies in iron, folic acid, and especially vitamin D (particularly in winter or early spring births), as well as fetal hypoxia, may play a role.
• Toxoplasma infection: As possibly seen in Louis Wain’s case, the cat parasite Toxoplasma gondii can alter mouse behavior and may affect human psychology, sometimes causing psychotic symptoms indistinguishable from schizophrenia. Haloperidol, a common antipsychotic, inhibits toxoplasma in cell cultures. Recent research suggests toxoplasma may be responsible for 21.4% of schizophrenia cases.
• Neuroimmune theory: The most radical and advanced theory links schizophrenia to immune system dysfunction. The connection between the nervous and immune systems is a hot topic in biomedical research. For example, Harvard biologists found that Staphylococcus aureus can manipulate lung sensory neurons to suppress immune responses. A sensational case involved a 24-year-old Japanese man with paranoid schizophrenia who experienced remission after a bone marrow transplant for cancer. His psychotic symptoms decreased, and social adaptation improved, suggesting a possible immune link.

A Century with Schizophrenia

More than 110 years after its “official” recognition, schizophrenia’s symptoms and syndromes are well described, but its true causes remain as hidden as they were in the early 20th century. Many concepts have fallen by the wayside: psychological theories, the “schizophrenogenic mother,” and the “double bind” in dysfunctional families. The bicameral mind theory persists only because it can’t be disproven. Hopes for genetics have not been fulfilled, and neurophysiology raises more questions than answers.

Schizophrenia remains an unconquered peak, challenging new generations of doctors and biologists. The main goal is to achieve lasting remission, especially in severe catatonic cases, and to find truly effective treatments. Some argue that perhaps we shouldn’t try—after all, “Great wits are sure to madness near allied, and thin partitions do their bounds divide.” Without schizophrenia, we might not have game theory (John Nash), Philip K. Dick’s novels, Scriabin’s color music, Louis Wain’s paintings, and other pinnacles of human creativity. But are the breakthroughs of a few worth the suffering of hundreds of thousands?