Photo:  Jeffrey Alan Lieberman, M.D., and Gabriella Dishy, M.A.

More than any other mental illness, schizophrenia is synonymous in the public’s mind with madness: The homeless person standing barefoot in the cold shouting at no one in particular, the person who suddenly believes a neighbor is sending poison gas through the walls, the delusional perpetrator of mass violence. Schizophrenia is neither new nor rare; it has likely existed for centuries, if not millennia. It affects approximately 1% percent of the world’s population—2.6 million people in the United States and 27 million worldwide affecting all segments of the population. Gender, race, ethnicity, affluence, education—none of these provide immunity. Once thought to be due to spiritual affliction or moral deviance, schizophrenia today is known to be a brain disorder arising from multiple avenues. This modern picture of schizophrenia is the accumulation of innumerable clinical descriptions and extensive scientific research stretching from ancient history to the present—from King Saul to John Nash, Joan of Arc to Elyn Saks.

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However, despite its longevity, virtually all of what we know about schizophrenia has been learned in the past 200 years and predominantly in the latter 20th and 21st centuries. This body of work has been documented in hundreds of thousands of books, clinical case descriptions, and scholarly reports in academic and scientific journals.

Scientific research is the pursuit of truth, which is then operationalized through clinical practice. It is a painstaking process that is rarely linear or predictable. It is the evidentiary distillate of this rigorous process of hypothesis testing, replication, and attempts at falsification that forms the empirical basis of our clinical practice.

Most research efforts fail to prove their hypotheses, find the correlation, achieve the intended outcome, or demonstrate effectiveness. And if they do, they don’t survive replication. Moreover, even if they do fulfill the study’s goal and the results are replicated they may not prove scientifically heuristic or prove clinically significant. In the final analysis, it is a small fraction of the universe of research that contributes to our knowledge and ability to treat schizophrenia and marks the milestones of progress.

This article provides a chronology of key milestones in the trajectory of scientific and clinical progress in schizophrenia derived from the collective historical efforts of the scientific and medical communities. These milestone advances have been replicated, stood the test of time, and proved scientifically heuristic or clinically meaningful. Not reflected in this timeline are the numerous disproven hypotheses, unreplicated results, and epiphenomenal or inconsequential findings (such as endotoxins or inborn errors of metabolism causing schizophrenia, hemodialysis being an effective treatment, or upregulated D-2 receptors being a biomarker of disease). There is no doubt that we have discovered much and learned a great deal, but of the vast sums spent, titanic efforts made, and voluminous number of papers published, the question can be asked, How much of this research has made a difference in the lives of people with or at risk for schizophrenia?

From Asylums to Progress in Treatments

The process of scientific illumination and clinical progress in schizophrenia has been slow, long, and arduous. From ancient times to the mid-20th century, only Phillipe Pinel’s belief in the moral treatment of the psychotically ill—which gave rise to asylums—and Emil Kraepelin’s definition of dementia praecox—the first evidence-based attempt of diagnostic criteria—can be considered truly seminal. The tipping point finally came in 1950 with the discovery of chlorpromazine and the so-called “neuroleptic” drugs that followed. This event transformed the field of psychiatry in a way that is comparable to the discovery of antibiotics for infectious diseases and insulin for diabetes. As their acute and prophylactic efficacy was proven, their prevalent array of neurologic side effects came to light, as well as their efficacy being limited to psychotic symptoms and not affecting negative or cognitive symptoms even despite claims to the contrary.

A flurry of studies on the pharmacology of antipsychotic drugs generated a torrent of data that crystallized into the “dopamine hypothesis.” For the next six decades, the D-2 receptor became the “holy grail” of antipsychotic drug development. Even as the second- and now third-generation “atypical antipsychotics,” with their lower D-2 and broader range of other neuroreceptor affinities, supplanted chlorpromazine and the original antipsychotics, no drug without a modicum of antagonism of DA at the D-2 receptor has yet been approved by the FDA as an antipsychotic (though two such drugs are currently wending their way toward approval). That includes clozapine, which remains unique for its superior efficacy in treatment-resistant patients, distinctively dangerous side-effect liabilities, and unusual pharmacology including its low affinity as an antagonist at the D-2 receptor.

The DA hypothesis went through various iterations that paved the way for additional pathophysiologic models of the illness, chief among them being the glutamate hypothesis. This posited that hypoactivity of the N-methyl D-aspartate (NMDA) receptor leads to a dysregulation in the trafficking of presynaptic glutamate, which triggers the symptoms of the illness. Subsequent research further revealed that GABA expressing interneurons acting on specific receptor subtypes mediated inhibition of pyramidal cells disinhibiting glutamatergic signaling. The potential influence of the glutamate system was a welcome discovery as it offered a potential connection to the negative and cognitive symptoms in addition to the DA-driven psychotic symptoms of schizophrenia. While glutamate remains the prioritized target for treatment development, no glutamate-targeted drug has crossed the goal line of FDA approval by proving its efficacy.

Importance of Early Identification, Treatment Recognized

While the neurotransmitter-based hypotheses were heuristic and clinically informative, they did not explain the origins of schizophrenia or its pathogenesis. The longstanding observation that schizophrenia runs in families gave rise to the first etiologic hypothesis of schizophrenia. This genetic hypothesis has evolved and expanded, and its complexity has been described in ever greater detail with increasingly sophisticated and powerful molecular genetic technology. This enabled epidemiologic studies and pedigrees to be probed at the molecular level by a series of innovative techniques. While findings have emerged that are informative and will eventually lead to clinical uses beyond polygenic risk scores, precision medicine has yet to be translated into clinical practice.

An outgrowth of the genetic hypothesis was the conceptualization of schizophrenia as a neurodevelopmental disorder, which begins at conception and expresses its phenotype in the course of the individual’s maturation much like fragile X, Down’s syndrome, and autism—though later in life. Additional support for the neurodevelopmental hypothesis came from postmortem studies of neuropathology, which found no evidence of neurodegeneration (such as fewer number of neurons, increased glial cells, protein aggregation, and so on) in the brains of patients with schizophrenia. Further support came from the seminal proposal by Irwin Feinberg that the maturational process of eliminating extraneous synapses that had been shown by Peter Huttenlocher to occur during adolescence normatively, might occur excessively in people who were vulnerable to develop schizophrenia. The most recent contribution to this theory was the finding of genetic abnormalities in the compliment system genes on chromosome 6 and specifically a gain of function mutation in the C4 gene. Compliment gene products had previously been shown to play a key role in shaping neural circuits by Carla Shatz. Thus, the genetic evidence of the C4 gene’s overexpression provided an important link to synaptic pruning and, by extension, the neurodevelopmental hypothesis.

Although clearly heuristic, the neurodevelopmental hypothesis has neither provided any validated approaches to prevent or delay the onset of clinical symptoms nor guided optimal treatment selection. In fact, the neurodevelopmental hypothesis, however inadvertently, has fostered a therapeutic pessimism, in which people with schizophrenia were considered “doomed from the womb.”

Shortly after its ascendence, the neurodevelopmental hypothesis was augmented by a complimentary neurodegenerative hypothesis corresponding to the onset and course of schizophrenia. While this conception harkened back to Kraepelin’s emphasis on clinical deterioration, it was reviews by Thomas McGlashan and Richard Wyatt that rekindled the research community’s interest in this aspect of the illness. Prospective studies followed that showed good treatment response, symptom remission, and outcomes with patients with first-episode psychosis and that delays in their treatment had deleterious effects on response and outcome. Moreover, subsequent psychotic relapses were often followed by progressive declines in treatment response, levels of recovery, and reductions of brain volumes in patients followed longitudinally over the early years of their illness.

These findings suggested that schizophrenia could be modified by treatment and spurred the early detection and intervention strategy and what ultimately became the “coordinated specialty care” model of service delivery for early psychosis. Clinicians and patients alike saw hope in early intervention research, and within two decades coordinated care programs for people experiencing first-episode psychosis have become the aspirational standard of care across the globe. This model of care has gained support from the U.S. government as the Substance Abuse and Mental Health Services Administration has sanctioned it (provisionally named OnTrack-US), and the Centers for Medicare and Medicaid Services has approved funding for services offered in this care model.

The emphasis on providing a coordinated care package of services, including medical management, psycho-education, and psychosocial services, stems from another milestone in the field, the recognition that schizophrenia entails multiple symptom dimensions and pathologies. This was first described by the International Pilot Study of Schizophrenia as reported by John Strauss and William Carpenter. Their findings were later reified by research on the nature of negative symptoms and cognitive impairment and their relationships to functional disability. Since medications were largely ineffective against these components of schizophrenia, psychosocial rehabilitative treatments were developed to address cognitive, social, educational, and vocational deficits. The nagging problem of nonadherence and attrition from treatment was targeted by highly effective strategies such as Assertive Community Treatment and Assisted Outpatient Treatment. (The pity is that they are not widely available and utilized because of limited capacity to provide these services and the cumbersome process to invoke AOT.)

New Tools Show Promise for Greater Understanding, Treatment of Schizophrenia

Twenty years elapsed from McGlashan’s and Wyatt’s reviews to the translation of first-episode studies’ results to clinical practice. However, 30 years have elapsed since efforts to extend this model of care to people in the prodromal stage of illness began, yet current approaches for identifying “clinical high risk” patients who are in their prodromal stage of schizophrenia remain aspirational.

Of the enormous efforts applying diagnostic technology to identify biomarkers that inform diagnosis, prognosis, and treatment selection, none has yet proved ready for clinical prime time. While there are differences between groups of schizophrenia patients and healthy people on various imaging and electrophysiologic measures of brain structure and function, the magnitude of these differences cannot be applied to individual patients without risk of prohibitive false positive and negative rates. Similarly, neurocognitive testing has revealed the types of cognitive impairments characteristic of schizophrenia patients, but none has proved sufficiently relevant to diagnosis or pharmacologic treatment selection. On the other hand, such information has guided indications for psychosocial treatments such as cognitive remediation and social skills training.

In revisiting our history and recalling the successes and failures of schizophrenia research, we must remember Sir Karl Popper’s axiom that a scientific hypothesis can be proven only by failing to disprove it. Many early “advances” were never rigorously challenged, allowing unproven practices like psychoanalysis or psychosurgery to continue for too long. In contrast, by tackling the more pessimistic implications of the neurodevelopmental hypothesis, investigators found the path to early intervention, which has already benefited many people.

After centuries of wandering in the scientific wilderness, psychiatry has become a bona fide and clinically capable discipline of medicine. Scientifically and clinically, we are still playing catch up to other medical specialties, but our field is on track and the wind is at our back in our effort to reduce the burden of mental illness and eventually find cause and cure for schizophrenia.

Modern sophisticated technologies such as genomics, neuroimaging, and computational methodologies using artificial intelligence promise a bright future. But the rate-limiting factor in determining when we reach our goal is how wisely we invest our financial and intellectual resources so that the milestones of progress are more numerous and frequent and the evidentiary distillate resulting from our research enterprise becomes ever larger, thereby enhancing our clinical capability to care for people with schizophrenia. ■

For a timeline of the major milestones in the understanding and treatment of schizophrenia, click here.

Jeffrey Alan Lieberman, M.D., a former president of APA, is the Lawrence C. Kolb Professor and Chair of the Department of Psychiatry at Columbia University Vagelos College of Physicians and Surgeons; director of the New York State Psychiatric Institute; and psychiatrist-in-chief at the Columbia University Medical Center of the NewYork-Presbyterian Hospital.

Gabriella Dishy, M.A., is a research assistant for Dr. Lieberman at the New York State Psychiatric Institute.

Dr. Lieberman neither accepts nor receives any personal financial remuneration for consulting, speaking or research activities from any pharmaceutical, biotechnology, or medical device companies. He receives support administered through Columbia University and the Research Foundation for Mental Hygiene in the form of funding and medication supplies for investigator initiated research from Denovo, Taisho, Sunovion, and Genentech, and for company sponsored phase II, III and IV studies from Alkermes, Allergan, and Boehringer Ingelheim. However, none of this research support contributes to his institutional compensation. He is a consultant to or member of the advisory board of Intracellular Therapies, Lilly, Pierre Fabre, Pear Therapeutics, and Gilgamesh Therapeutics for which he receives no remuneration. He is a paid consultant for Signant, a clinical research services organization, and holds a patent from Repligen that neither has nor currently yields any royalties.

Milestones in the History of Schizophrenia. A Comprehensive Chronology of Schizophrenia Research: What Do We Know and When Did We Know It | Psychiatric News

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