From stigmatisation to brain investigation: The evolving understanding of schizophrenia

Two hands holding up two puzzle pieces side by side in front of a backdrop of the sky and some trees.

How far have we come in our understanding of schizophrenia? Image credits: Vardan Papikyan via Unsplash

Schizophrenia is a severe psychiatric disorder that has long been a subject of fascination and mystery in the field of psychiatry. Characterised by a kaleidoscope of symptoms, schizophrenia has often been misunderstood, shrouded in stigma, and even feared. Historically, the mere mention of the word “schizophrenia” has evoked images of madness and unpredictability; the barefoot homeless person shouting at no one in particular, the person who hears voices whispering commands, the person who believes their neighbour is an alien. 

Instead of saying that a hallucination is a false exterior percept, one should say that the external percept is a true hallucination.

H. Taine

Schizophrenia most commonly presents during late adolescence and today the condition affects approximately 24 million people worldwide. Symptoms are generally divided into three categories: (i) positive (reflecting an excess of normal function), including hallucinations and delusions, (ii) negative (reflecting the absence of normal behaviours), including social withdrawal and lack of motivation and (iii) cognitive, including impaired attention and memory. Treatment options mainly include antipsychotics and forms of talking therapy, however, the vast majority of people with schizophrenia are not currently receiving mental health care. To add to this, there has been a half-century-long stagnation in revolutionising novel psychiatric treatments, which largely reflects our limited understanding of schizophrenia’s etiology. The slow progress of scientific developments in the field of schizophrenia can in part be ascribed to the delayed acknowledgment that psychiatric disorders are, at their core, manifestations of brain function abnormalities, rather than phenomena solely linked to madness or eccentricity. Tracing the historical milestones that have shaped our understanding of schizophrenia can allow us to more profoundly challenge the persistent stigma that has obscured the path to empathy and effective care.  

Ancient times and evil spirits 

Descriptions of conditions resembling schizophrenia are rare prior to the 19th century although the ancient Greeks and Romans are found to have a general understanding of psychiatric illnesses. People experiencing psychotic symptoms were frequently considered possessed, cursed, or believed to have incurred the wrath of gods. Treatment approaches ranged from dietary changes and exorcism to purging and trepanation, a surgical procedure that involved drilling holes into the skull to release evil spirits or alleviate brain pressure. Advancements in medical knowledge eventually led to the discontinuation of trepanation, however, the idea that psychiatric illnesses, including schizophrenia, were manifestations of spiritual or supernatural causes remained prominent for centuries. 

People experiencing psychotic symptoms were frequently considered possessed, cursed, or believed to have incurred the wrath of gods.

The birth of the schizophrenia concept 

Emil Kraepelin, a German psychiatrist, was the first to provide a formal description of schizophrenia as a distinct psychiatric illness in the late 19th century. Kraepelin used the term ‘dementia praecox’ (early dementia) to describe a biological illness caused by anatomical or toxic processes that typically emerged in early adulthood. Falsely, this denomination as ‘dementia’ was used because Kraepelin considered dementia praecox a progressive neurodegenerative disease and by calling it ‘early’ Kraepelin meant to differentiate dementia praecox from conditions with later onset such as Alzheimer’s disease. Nevertheless, Kraepelin correctly identified that dementia praecox was primarily a condition affecting the brain. Importantly, Kraepelin distinguished dementia praecox from other mental illnesses like depression and bipolar disorder, which had a fundamental role in advancing the field of psychiatry and reshaping society’s views on psychiatric illnesses during the 20th century. 

Lessons from Bleuler on schizophrenia

In 1908, Swiss psychiatrist Eugen Bleuler made a profound departure from prevailing psychiatric thought by coining the term ‘schizophrenia’. Bleuler believed that this new term more accurately encapsulated the essence of the condition, as the word schizophrenia comes from the Greek roots schizein (σχίζειν, ‘to split’) and phren (φρεν, ‘mind’) and translates to ‘split mind’. He believed that schizophrenia was characterised by a disconnection of core cognitive processes: thinking, memory, personality, and perception. 

I call dementia praecox “schizophrenia” because, as I hope to show, the splitting of the different psychic functions is one of its most important features. In each case there is a more or less clear splitting of the psychological functions: as the disease becomes distinct, the personality loses its unity.’ 

He believed that schizophrenia was characterised by a disconnection of core cognitive processes: thinking, memory, personality, and perception.

Indeed, through meticulous clinical observations, Bleuler recognised that individuals affected by schizophrenia presented with a breakdown in their thought patterns, leading to disorganised speech and an altered perception of reality alongside hallucinations and delusions. Bleuler placed a great emphasis on the cognitive aspects of schizophrenia and sought to distinguish it from dementia since his patients did not always suffer from memory loss. To this day, Bleuler remains a pivotal figure in the history of psychiatry since he challenged the accepted wisdom of the time and set the stage for a more nuanced understanding of schizophrenia. 

The freudian influence

Sigmund Freud, the founding father of psychoanalysis, exerted a profound influence on the field of psychiatry throughout the 20th century. His revolutionary ideas about the unconscious mind and the significance of early childhood experience brought about a paradigm shift in psychiatry. Freud described schizophrenia as the result of disordered family patterns and explained that it develops when a child has not successfully formed an attachment with the parent of the opposite sex. Indeed, throughout the late 1940s to the early 1970s, the concept of the “schizophrenogenic mother” gained widespread acceptance. Freud’s singular focus on early life experiences contributed to a prevailing notion that schizophrenia is a condition primarily rooted in psychological rather than biological factors. This perspective, while influential, has been debunked and should be viewed in the context of the evolving and multifaceted understanding of psychiatric illnesses. 

Schizophrenia in the shadow of eugenics

Advancements in the understanding of schizophrenia were overshadowed by persistent stigma and misunderstanding of psychiatric illnesses throughout the 20th century. Eugenics refers to the belief in improving the human population by selective breeding to enhance desirable traits while eliminating those deemed undesirable. Tragically, this ideology found its most infamous and horrifying manifestation during the Nazi regime, when individuals with mental illnesses were considered as ‘having a life unworthy of life’. Under the banner of eugenics, the Nazis implemented a ruthless program that targeted individuals with various mental illnesses, including schizophrenia, for forced sterilisation and ultimately, mass extermination. It is estimated that 80,000-100,000 mentally ill people, including 5000 children, were killed between 1939 and 1941. At the same time, Denmark, Sweden, Norway, and Switzerland implemented forced sterilisation programmes and eugenics laws, while up to 25,000 forced sterilisations of mentally ill people were performed in the USA. This chilling chapter in history underscores the perilous consequences that can arise when the understanding of psychiatric illnesses is clouded by ignorance and serves as a stark reminder for society to continue dismantling the barriers of misconception and prejudice surrounding mental health. 

This chilling chapter in history underscores the perilous consequences that can arise when the understanding of psychiatric illnesses is clouded by ignorance and serves as a stark reminder for society to continue dismantling the barriers of misconception and prejudice surrounding mental health. 

The biological revolution

The mid-20th century marked a pivotal turning point in the understanding of schizophrenia, as psychiatry underwent a remarkable transition towards a more biologically-grounded perspective. This transformative shift was profoundly influenced by a series of significant advancements in neuropharmacology during the 1950s that yielded a game-changer: antipsychotic medications. Drugs like clozapine and chlorpromazine emerged as powerful tools in the management of schizophrenia, offering relief from the positive symptoms of schizophrenia. This biological revolution not only led to improved symptom control but also played a key role in reducing the stigmatising consequences of the disorder, allowing the deinstitutionalisation of large numbers of individuals with schizophrenia, and marking a significant step forward in the history of schizophrenia understanding and care. Nevertheless, it is essential to recognise that antipsychotics, while transformative, are not a panacea. These medications are often accompanied by a range of side effects including dizziness, sedation, blurred vision, weight gain and the occurrence of involuntary movements. Additionally, antipsychotics fail to improve most of the debilitating negative and cognitive symptoms of schizophrenia, while in a significant proportion of patients, they fail to improve even the positive symptoms. 

Schizophrenia’s puzzle

In the decades that followed the biological revolution, the field of neuroscience saw a surge in research efforts aimed at unravelling the intricate neurobiological mechanisms underlying schizophrenia. Extensive scientific research resulted in the emergence of two prominent theories to explain the etiopathogenesis of schizophrenia.  

Firstly, the dopamine hypothesis of schizophrenia was introduced in 1966. Dopamine is a neurotransmitter which plays a crucial role in regulating various cognitive, motor, and emotional brain functions. At its core, the dopamine hypothesis posits that a dysregulation of neurotransmission in the dopaminergic system, leading to excessive dopamine signalling within specific brain regions, contributes to the development of schizophrenia. This hypothesis gained prominence due to its alignment with the observed effects of antipsychotic medications which block D2 dopamine receptors and alleviate the excessive dopamine activity associated with hallucinations and delusions. Indeed, the hypothesis is additionally supported by animal studies, post-mortem research and the exacerbation of psychotic symptoms by drugs that accentuate dopaminergic neurotransmission.  

In the 1990s the glutamate hypothesis of schizophrenia was introduced. Glutamate is a neurotransmitter involved in key brain functions including memory and learning. According to the glutamate hypothesis, abnormalities in glutamate neurotransmission, and specifically hypofunction of the N-methyl-D-aspartate (NMDA) receptor, are associated with the pathophysiology of schizophrenia. This hypothesis was formed on the observation that antagonists of NMDA receptors, including ketamine and phencyclidine, induce positive and negative symptoms in healthy individuals and exacerbate symptoms in people with schizophrenia. Evidence from pre-clinical and post-mortem studies have further solidified the link between glutamate dysregulation in the cognitive and negative aspects of schizophrenia. 

It is important to acknowledge that while both the dopamine and glutamate hypotheses have greatly advanced our comprehension of schizophrenia, this condition remains multifaceted, and neither theory provides a comprehensive explanation on its own. Ongoing research continues to refine these theories and explore the intricate interplay of neurotransmitters and genetics, in the manifestation of schizophrenia. 

Evidence from pre-clinical and post-mortem studies have further solidified the link between glutamate dysregulation in the cognitive and negative aspects of schizophrenia.

Decoding schizophrenia

Genetic analysis is an irreplaceable asset when searching for causal mechanisms underlying a disease since DNA sequence alterations that have been significantly associated with a disease indicate an unambiguous route towards causation. Genome-wide association studies (GWAS) involve investigation of the genomes of many individuals, surveying for genetic variants that occur more frequently in those with schizophrenia compared to those without the condition. Indeed, these studies have unveiled hundreds of common single nucleotide polymorphisms (SNPs, genetic variants at a single base position in the DNA) that make only minor contributions to the overall risk of developing schizophrenia. Most recently, the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) study investigated the protein-coding regions (exons) of the genome of more than 20,000 people with schizophrenia and 95,000 healthy controls. The largest schizophrenia exome sequencing study to this day, SCHEMA identified ultra-rare coding variants in ten genes as conferring substantial risk for schizophrenia. Interestingly, two of these genes, GRIN2A and GRIA3, encode subunits of the NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, respectively, providing further support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. Further research will allow the field to transition towards a more functional understanding of how and when these ultra-rare variants affect brain function and eventually lead to the manifestation of schizophrenia. 

A glimpse into tomorrow 

In tracing the evolving understanding of schizophrenia, the journey has taken us from ancient misconceptions to the ongoing research efforts to gain insight into the mechanistic underpinnings of this complex condition. The convergence of neuroscience, psychiatry and genetics has illuminated new avenues for exploration, forging the path towards more targeted treatments and improved support for individuals living with schizophrenia. As we stand at the crossroads of these multidisciplinary advancements, the future of the field holds the promise of deeper insights, innovating interventions, and greater compassion, ushering in a new era in the battle against schizophrenia.