by Artemis Christoforatos
art by Sydney Siew
Once upon a time, very few people took medication for explicitly psychiatric reasons; mental health concerns were relegated to the outskirts of society, and the study of mental illness belonged to the fringes of science in psychoanalysis and the general study of the human condition.
In the mid-20th century, neuroscience “discovered” mental illness. The biomedical model, which claimed that mental illness was a biological issue, took root in medical circles and popular culture. Logic dictated that if abnormal human behavior was caused by faulty neurotransmitters, recessive genes, or irregular brain structures, then science could treat and eventually eliminate these problems. To the pharmaceutical industry, this shift from a psychoanalytic, mind-centered perspective to a biomedical one opened a lucrative new market [1].
Today, psychiatric medication–defined as any medication that causes changes in emotions, behavior, and general cognition –is prescribed readily by both psychiatrists and primary care physicians [2]. According to the CDC, in 2018, 13.2% of the United States’ population took antidepressants. This number is rising, indicating a growing culture of reliance on psychiatric medication, a tradition of scientists creating—and pharmaceutical companies attempting to market—drugs meant to “cure” supposed flaws in mental function [3]. Antidepressants claim to prevent depression, and antipsychotics claim to prevent a broad range of symptoms that represent “psychosis,” namely, hallucinations, delusions, and disorganized thought [4].
While antipsychotics are prescribed much less frequently than antidepressants, they are overwhelmingly considered a first-line treatment for psychosis [5]. Even with extensive discussion surrounding antidepressant use, the practice of antipsychotic prescription remains far more covert, hidden largely by the stigma surrounding psychosis and severe mental illness. Taken into perspective, the widespread use of antidepressants reflects general trends in our increasing faith in psychiatric drugs. Similarly, doctors’ unwavering use of antipsychotics reveals the extreme impact of the biomedical model on patients with severe mental illnesses, which are considered essentially untreatable except through prescription medication. In many ways, these patients have been on the frontlines of the battle between psychiatry’s biomedical and psychoanalytic models.
The practice of medicating patients with severe mental illness in the West has a troubled history. From the 19th century until around 1950, no one particularly cared to actually improve patients’ lives. In Europe and North America, patients were often isolated from wider communities in asylums and hospitals and were primarily treated with sedatives and hypnotics aimed at making them easier to control [6]. These medications were not created to target any supposed flaws in the function of the brain at their inception, but only to generally “quiet” it to the point where hallucinations and delusions (along with cognition at a functional level) did not occur [6]. Moreover, their precise neurochemical functions were still obscure.
And then there came chlorpromazine. In many ways, chlorpromazine was the true beginning of psychopharmacology, the study of the effect of drugs on the mind and brain, as it manifests today: a way to rectify abnormal cognitive pathologies. Created in 1950 by French chemist Paul Charpentier, it offered a previously unfathomable possibility for the treatment of psychosis: a cure [6].
Chlorpromazine was not meant to be groundbreaking. Charpentier had been working for decades on a drug with strong antihistamine (anti-nausea, calming, and anti-allergy) effects. Early 20th-century pharmacology focused heavily on sedatives, so he was especially interested in creating a pharmaceutical aid for general anesthesia [7]. When the company he worked for distributed chlorpromazine to various hospitals, doctors reported substantial efficacy in calming anxious patients compared to other methods [8]. But, more surprisingly, psychotic patients treated with chlorpromazine had such reduced symptoms that many were discharged after mere weeks. Reports across Europe between 1952 and 1955 subsequently lauded chlorpromazine as a “miracle drug” [7]. By 1954, it was FDA-approved and marketed as Thorazine in the United States [6]. Thus, from what was essentially going to be another anti-allergen, or at best a minor sedative, chlorpromazine became the first antipsychotic.
Despite raving early reports, chlorpromazine had major issues. Firstly, there were mixed results observed related to the reduction of psychotic symptoms upon its administration over the next few years: not all patients improved, and several doctors were reluctant to use it as a general treatment [9]. Furthermore, psychiatrists began to notice debilitating side effects, including Parkinson's-like tremors and rigid movement [10]. These were called extrapyramidal symptoms, after the extrapyramidal system in the brain that regulates involuntary motor processes [11]. They were known among patients as the “Thorazine shuffle,” and were so impairing that many refused to take the medication when prescribed it [6]. Finally, there was no end date to this treatment: chlorpromazine was meant to be an indefinite, long-term drug, which meant its side effects were also lifelong [6]. Still, chlorpromazine continued to be prescribed; at a time when harsh treatments like lifelong hospitalization and lobotomies (surgical procedures that involved severing frontal lobe connections to deeper brain structures) were still practiced, it was an overwhelmingly more humane alternative [12].
Chlorpromazine inspired an explosion in drugs that aimed to treat psychosis. As the decade progressed, other medications based on phenothiazine, the core molecule of
chlorpromazine, were released. Concurrently, researchers tried tackling the problem of extrapyramidal symptoms by searching for options outside phenothiazine chemistry. Reserpine, the first, was introduced in 1954 during research on an Indian medicinal herb but had particularly severe side effects [6]. Another acclaimed drug was haloperidol, which was synthesized in 1958 after research on analgesics (medicine used in pain management) [13]. Haloperidol and subsequent related drugs, together called butyrophenones, proved to be more effective in reducing psychotic symptoms in preliminary clinical trials than phenothiazines [14].
By the beginning of the 1960s, all these drugs, known then as major tranquilizers (and now as first-generation antipsychotics), were widely accepted in clinical practice. This shift towards managing symptoms using medication led to significant research on their actual biochemical mechanism in the (futile) hope that they could be perfected. But neuroscience was also getting ambitious: research on how the drugs impacted the psychotic brain could determine the root biology behind psychosis (and therefore justify the medication). This research was and still is, based on neurotransmitter systems, through which neurons communicate [15].
At the time, lysergic acid diethylamide (LSD) was very popular in both psychiatric research and popular culture. Research in 1953 had concluded that, because LSD caused psychotic symptoms and depleted serotonin (a neurotransmitter generally involved in mood) in the brain, by the flawed logic of reverse inference, psychosis must be caused by low serotonin levels. (Another example of reverse inference would be arguing that, because Advil relieves headaches, headaches are caused by an Advil deficiency.)
Scientists therefore set out to prove that their antipsychotics impacted the serotonin system. First, reserpine, previously known to decrease serotonin stores in neurons, was discovered to deplete other monoamine neurotransmitters, which regulate wide cognitive processes, namely, epinephrine, norepinephrine, and dopamine. Later, by treating mice with L-DOPA, a precursor to dopamine, which is implicated in motivation and mood, researcher Arvid Carlsson reversed the motor side effects of reserpine and therefore identified dopamine as the main target [6]. In 1963, Carlsson and Margit Lindqvist again proposed that chlorpromazine and haloperidol blocked the other monoamine receptors along with dopamine. Several further studies reported contradictory evidence that the dopamine system was primarily impacted. Thus, dopamine was established as the neurotransmitter to focus on [14].
Specifically, neuroscientists took these findings on dopamine and again used reverse inference to produce the dopamine hypothesis of schizophrenia, which at its core argues that psychosis is caused by excess dopamine [16]. Although this theory has undergone several iterations since the 1970s due to substantial scrutiny, it has been convenient in justifying the use of medications like chlorpromazine. If psychosis is a biological issue rooted in excess dopamine, then drugs that amend this problem could be profitable to pharmaceutical companies. Thus, major tranquilizers became “antipsychotics,” and, along with concurrent research and drug development surrounding depression, mental illness became a biological matter much more than a psychoanalytic one.
Medication at this point was thought to be the path forward, but there was considerable incentive to find drugs with a different mechanism of action due to the still present extrapyramidal symptoms, which were now attributed to dopamine manipulation [17]. Psychiatry decided that psychosis could be solved if only the right drug was found; there was no stopping the search now.
The next major medication was clozapine, synthesized in 1958 but relatively ignored until the mid-1960s [6]. It had a greater effect on the serotonin system than previous antipsychotics, targeting multiple neurotransmitter receptors in addition to dopaminergic ones, meaning it was better able to treat negative symptoms of schizophrenia and other psychotic spectrum disorders such as depression, apathy, and social withdrawal [18]. Moreover, although its wider impact on neurotransmitter systems did result in various metabolic and cardiovascular side effects, clozapine caused far fewer extrapyramidal symptoms [17].
So, while clozapine exhibited mixed results in reducing psychotic symptoms in early clinical trials, it entered the US market in 1974. It was recalled in 1976 due to concerns
surrounding potentially fatal complications but re-entered the market in 1990 for good once further studies demonstrated it had greater efficacy than chlorpromazine and was deemed safe for consumption. Despite having concerning side effects, such as excessive salivation and increased seizure likelihood, it was seen as the next best option. Thus, clozapine rapidly replaced the phenothiazines in the clinical world [17]. Many more drugs were developed on its basis, known as second-generation antipsychotics, including olanzapine and risperidone, which are still used today.
Psychiatry has not stopped looking for this elusive cure. Antipsychotics continue to be introduced with some progress in refining the medications’ mechanism of action. Aripiprazole (brand name Abilify), which received FDA market approval in 2002, and brexpiprazole (Rexulti), which received approval in 2015, are especially applauded, even sometimes considered atypical or “third-generation” antipsychotics.
Instead of acting as a dopamine D2 receptor antagonist like previous antipsychotics, aripiprazole is thought to be a dopamine D2 receptor partial agonist: by binding to the dopamine receptor, it reduces but does not eliminate the downstream effects of regular dopamine binding, thus stabilizing dopamine neurotransmission. The newer brexpiprazole has a more potent effect on the serotonin system, therefore causing fewer side effects than aripiprazole and more broadly treating negative symptoms. It is categorized as a serotonin-dopamine activity modulator. As well as being a D2 partial agonist, like aripiprazole, it is an agonist on the serotonin 5-HT1A receptor and an antagonist on the 5-HT2A receptor. So far, there seems to be a much lower risk of extrapyramidal symptoms with both these medications, and clinical use demonstrates that negative symptoms of schizophrenia are often addressed, although other markedly less drastic side effects do exist [19].
Beyond dopamine, there has been significant discussion recently on glutamate, a neurotransmitter involved in learning and memory [20]. The FDA has just approved xanomeline in combination with trospium chloride as of September 2024 [20]. This is mainly an agonist, producing a response on acetylcholine receptors implicated in learning, memory, and cognition [21]. Shifting the target of antipsychotics from D2 receptors represents sizable progress from the not entirely sound dopamine theory of psychosis that has until now monopolized psychopharmacological interventions.
Since the introduction of chlorpromazine, which arguably marked the paradigm shift in psychiatry to the biomedical model, the definition of an “antipsychotic” itself has shifted. When chlorpromazine was created in the 1950s, the concept of such a drug broadly referred to medication that decreased psychotic behaviors, ways in which patients outwardly demonstrated symptoms. The broad definition of an “antipsychotic” today is a medication that can sufficiently reduce symptoms of both psychosis and the negative symptoms that tend to come with it to non-disabling levels in even treatment-resistant patients, while acting for long enough to protect against relapse [22]. We are still hunting for this miracle cure.
Throughout the history of this search, there has been a dominating view that antipsychotic medications are both necessary to treat psychosis and can do so perfectly, but every step of the way there have been changes, improvements, and a shifting and often cyclic understanding of how psychosis and antipsychotics are supposed to work. Every time a new medication has been introduced, it has been celebrated as the best option and largely forced onto patients even when what it does exactly is unclear, and even when it comes withs awful side effects. The truth is, we don’t know how psychosis works, especially when our understanding of antipsychotics and psychosis are so intertwined, particularly due to capitalist company interests that push a biomedical understanding of mental illness to reduce criticism and increase prescription of the medications they distribute.
The advent of antipsychotics is undeniably momentous; it is evident that antipsychotics have created optimism in psychosis treatment, and have offered countless people the opportunity to live much better lives. On the other hand, promoting the biomedical model as the only solution has complicated undertones: a “cure-all” is still largely driven by the urge to reduce patients being disruptive to society. As philosopher Justin Garson notes, there are therapeutic, non-medical interventions to psychosis, such as learning to accept and live alongside hallucinations, and the overwhelming rejection of this option in medical circles in many ways points to broader concerns that psychology and psychiatry problematize behavior that falls outside of a “normal” that society perpetuates. As antipsychotics attempt to normalize “broken brains,” he wonders: is psychiatry attempting to normalize the human experience as a whole? [23]. To what extent might this normalization close us to the possibility that psychosis might actually have some sort of psychobiological purpose, perhaps as a warning sign that society as it currently functions is harmful [24]?
Another significant development surrounding antipsychotics is in clinical practice. Aripiprazole has recently been approved as a medication to treat irritability in autism and has been used, like other antipsychotics, for some years as an add-on to increase the efficacy of antidepressants prescribed for conditions like OCD when maximum doses have been exhausted [25]. These expanding treatment applications may certainly be an indication of progress beyond the biomedical model; if psychiatry accepts that aripiprazole can treat more than psychosis, it is implicitly suggesting that medications can have chemical effects that reduce various symptoms without being expected to target specific disorders. This undermines the idea of mental disorders being a biological reality, rather than clusters of symptoms we have outlined roughly. On the contrary, as antipsychotics are expanding in use, they may very well overpower non-pharmaceutical treatments that have also proven essential, such as therapy and community care.
Psychiatry’s path into the present has been paved by research and investment into the prescription of antipsychotics, but we must tread cautiously; side effects exist, and there are substantial issues with “treatment-resistant” schizophrenia and similar phenomena where the drugs just do not live up to their assumed effect of preventing psychosis [17]. These problems persisting decades after chlorpromazine underscore that medication, at least right now, is not a cure. Rather, antipsychotics are tools that exist in a broader social context, in which forces such as the pharmaceutical industry exacerbate ideas of deviance and mental illness. In the end, this story has no happily ever after. Neuroscience, for all it has done for us,
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