In a 3-part series, Adrian Dutkiewicz introduces us to a brief history of schizophrenia and the interesting road pharmacology has taken in the course of treating psychosis. Adrian writes:
Pharmacological treatments are sometimes perceived as being discovered from the top-down; health concerns are investigated, mechanisms identified, and then drugs designed. Usually, however, it’s the reverse sequence of events that happens. Typically doctors notice that a drug prescribed for one disease ends up dramatically improving symptoms of another, unrelated disease. Scientists must then work from the bottom-up to identify the drug’s target so that they can study the role that target plays in the disease. Building a better understanding of the disease allows us to design better treatments. The example I explore in this post is how antipsychotic drugs (neuroleptics) have directed our understanding of schizophrenia. While I think the guidance of medicine has mostly been a boon to science, the treatments have also made health problems deceptively simple.
Before discussing the pharmacology of schizophrenia, I should first describe the symptoms and progression of schizophrenia. Symptoms of schizophrenia are divided into two categories: positive and negative. Positive symptoms of schizophrenia are abnormalities present in people with schizophrenia but absent in people without schizophrenia. Two profound positive symptoms are hallucinations and severe delusions (e.g. delusions of persecution, or paranoia). Hallucinations and delusions are frequently referred to as psychosis, but these psychotic traits are not necessarily synonymous with schizophrenia. Negative symptoms are deficits of normal functions. For example, people with schizophrenia often display flat affect (lack of demonstrated emotions) and an inability to experience pleasure – known as anhedonia. Cognitive deficits in one’s working memory (ability to remember and update mental lists) are also commonly seen in schizophrenia and generally considered to be component of the negative symptoms. The first positive symptoms tend to emerge in early adulthood, coinciding with rapid expansion of the brain’s prefrontal cortex.1,2 As you might expect, given the wide range of symptoms, various brain structures are believed to be involved.
One of these affected structures is the pre-frontal cortex (PFC), a large section of the brain at the foremost position in the skull. Among the many functions of this region is controlling working memory as well as inhibiting impulsive behavior. Both of these cognitive functions are classified more broadly as being part of “executive function.” These features are mediated, in part, by dopamine-secreting neurons originating from other parts of the brain. However this region is most likely not the origin of psychotic hallucinations.3 The brain area related to hallucinations will be discussed towards the end of this series of posts.
Although dopamine is more popularly known as the “pleasure neurotransmitter,” it is simply just a versatile chemical that is used in a variety of different brain circuits. Dopamine acts as a neurotransmitter, or chemical messenger that is secreted from neurons and onto other neurons, which have receptors that bind dopamine. These post-synaptic (“synapse” refers to the space between neurons that neurotransmitters need to traverse) cells can then regulate themselves based on the activity of the receptors. When enough receptors are activated for a sufficient duration, these changes may manifest as altered behaviors or thought patterns. For instance, inadequate dopamine signaling in the PFC may cause one to have chronically poor working memory and forget things that were just said to them. This is a feature seen in people with schizophrenia.
The first antipsychotics
People with hallucinations and delusions were frequently locked up out of concern for public safety but by the middle of the 20th century, things began to change. The practice of torturing their psychiatric patients until they got better was apparently ineffective, and medical practitioners were looking towards more humane treatments.4 Talk therapies were effective for some psychiatric ailments but generally failed for people with psychotic illnesses. Pharmacological methods and scientific means of testing them were gradually becoming more popular, despite drawing contempt from Freud’s disciples because drugs had no place in their mythical realm.
Chlorpromazine (Thorazine™) was the first drug to be manufactured and promoted as an antipsychotic. But the road from its invention to discovery of its unique properties is a long and convoluted one. To start this story, chlorpromazine had been developed by the chemist Paul Charpentier in 1950, and known to cause lab animals to display indifference to painful stimuli.5 This made the drug useful for surgery anesthesia, where indifference to pain is a very welcome attribute.
The French physician and anesthesiologist Henri Laborit was among the first to notice that chlorpromazine seemed to have calming effects beyond what one might expect from a sedative. He even believed that it could stabilize psychotic patients – though he had little evidence for this at the time. His enthusiasm for the drug persuaded the French doctors Jean Delay and Pierre Deniker to put together the first sample to investigate chlorpromazine’s predicted antipsychotic effects. They revealed their successful results to the world in 1952. Soon, other researchers were replicating their exciting findings.5-7 The term “neuroleptic” (literally meaning “seizing neurons”) originates from Jean Delay’s observations about the new class of drug. Doctors were prescribing chlorpromazine as an antipsychotic within just a few years of its invention. This discovery enabled doctors to deinstitutionalize vast numbers of people. Cruel “treatments” such as lobotomies fell out of fashion in favor of more humane pharmacological therapies. While many researchers sought to understand how the drug worked, some chemists modified existing drugs to try to refine their qualities.
Chemists had become exceedingly good at performing modifications of certain substances to derive analogues with slightly different properties. These analogues were then screened on large scales to probe for any kind of physiological effect. Their talent for modifying chemicals arose mostly from the need to quench an insatiable consumer appetite for new dyes in the late 1800s.5 In many respects, the modern fields of pharmacology and organic chemistry owe their legacy to the dye industry of the Victorian Era. Modifications of existing drugs produced even more antipsychotics.
In 1958, the eminent chemist Paul Janssen was attempting to modify a sedative called R1187. Janssen’s hope was to develop a sedative without analgesia – a property similar to the sedation exhibited by chlorpromazine even though he had no intention of inventing an antipsychotic. He knew modifying benzene rings on certain drugs could lead to new drugs with slightly different properties, and after testing hundreds of chemically modified R1187s, Janssen finally developed the drug haloperidol (Haldol™) in 1958.8 His drug was introduced as a tranquilizer, but was quickly found to have potent antipsychotic properties; scientists and doctors had developed a keen sense for detecting sedatives with antipsychotic properties by then.9 These drugs set the stage for research in schizophrenia but most of the tools necessary to determine how the drugs worked were not available until later. By the 1970s, more than a dozen antipsychotics had been found – most through chemical modifications with little progress towards discovering how they actually worked.
The dopamine hypothesis
Radiolabelling techniques had been refined by the late 1970s. The principle was to label synthesized drugs or proteins with a built-in radioactive isotope (a basically harmless but radioactive atom) and incubate the drugs with mashed-up material from different sections of the brain – or even various neurotransmitter receptors. Then they simply detect radioactivity and deduce that radiolabeled drug must be binding there. This assay enabled researchers to determine which section of the brain drugs were binding to, and even which receptor they would occupy – though the work is laborious and painstaking. Around this time Philip Seeman – one of the world’s foremost researchers on dopamine receptors – and other scientists had begun to show that therapeutic doses of antipsychotics often coincided with their efficacy of dopamine blocking (or preventing dopamine release).10 These researchers found that all effective antipsychotics had at least a moderate affinity for dopamine’s D2 receptor in clinically effective doses.11-13 But there was little idea at the time about what dopamine really was doing in the brain.
When ligands such as dopamine or antipsychotic drugs bind to receptors, they can either increase or decrease activity of the receptor depending on the more technical aspects of how they bind together. Antipsychotics were found to, effectively, deactivate the D2 receptor and silence its activity – whereas dopamine itself activates all of its receptors. Since antipsychotics seemed to be blocking dopamine receptors, and apparently relieved psychosis, researchers believed that schizophrenia was a disease hallmarked by hyperactive dopamine signaling. With present-day knowledge, we know that there is some truth to this, but the explanation was far too simple. The modern understanding of schizophrenia will be discussed towards the end of this post. There were much wider gaps in scientific knowledge back then, and people in the 1970s still only had a vague conception of what dopamine was, and what is did in the brain despite radioligand studies; we still needed to determine the functions of these neurons carrying the receptors.
The realization that the therapeutic effects of the first-generation antipsychotics were mediated through D2 receptors led to a stubborn and misled belief among chemists developing the drugs; they thought that all effective antipsychotics must be D2-acting, and that the more specific to that receptor, the better. Thus most chemists and pharmaceutical companies pursued the development of more specific D2 blockers.
- Brickman, A. M. et al. Neuropsychological Functioning in First-Break, Never-Medicated Adolescents With Psychosis. The Journal of Nervous and Mental Disease 192, 615-622 (2004).
2. Weinberger, D. R. Implications of normal brain development for the pathogenesis of schizophrenia. Archives of general psychiatry 44, 660-669 (1987).
3. Hawkins, S. A. & Hastie, R. HINDSIGHT – BIASED JUDGMENTS OF PAST EVENTS AFTER THE OUTCOMES ARE KNOWN. Psychol. Bull. 107, 311-327, doi:10.1037//0033-2909.107.3.311 (1990).
4. Gosden, R. Punishing the Patient: How Psychiatrists Misunderstand and Mistreat Schizophrenia. Scribe Publications (2001).
5. Owens, D. C. The origins of psychopharma. (Cambridge University Press, 2014).
6. Bonafede, V. I. CHlorpromazine (thorazine) treatment of disturbed epileptic patients. A.M.A. Archives of Neurology & Psychiatry 77, 243-246, doi:10.1001/archneurpsyc.1957.02330330029003 (1957).
7. Feldman, P. E., Lacy, B. S., Walker, A. E. & Garrez, N. J. A controlled blind study of effects of Thorazine on psychotic behavior. Bulletin of the Menninger Clinic 20, 25-47 (1956).
8. Sneader, W. Drug Discovery: A History. (Wiley, 2005).
9. Brandrup, E. & Kristjansen, P. A Controlled Clinical Test of a New Psycholeptic Drug (Haloperidol). The British Journal of Psychiatry 107, 778-782 (1961).
10. Seeman, P. & Lee, T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217-1219, doi:10.1126/science.1145194 (1975).
11. Seeman, P., Chau-Wong, M., Tedesco, J. & Wong, K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proceedings of the National Academy of Sciences of the United States of America 72, 4376-4380 (1975).
12. Seeman, P., Lee, T., Chau-Wong, M. & Wong, K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261, 717-719 (1976).
13. Seeman, P., Chau-Wong, M., Tedesco, J. & Wong, K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proceedings of the National Academy of Sciences 72, 4376-4380 (1975).