As people enter early adulthood, some unexpectedly experience episodes of psychosis.¹ These episodes, which involve persistent hallucinations, delusions, and unusual thoughts or behaviors, can seem to come out of nowhere and affect people from many different backgrounds. They can last weeks, months, or years. When these episodes persist or recur, they can lead to diagnoses such as schizophrenia or bipolar disorder.²

Schizophrenia, for example, involves months of hallucinations, changes in cognition and behavior, muted emotions, social withdrawal, and unusual jerky movements.

This transformation can be very disorienting, altering lives, straining relationships, and affecting people’s ability to live and work as they would want.

In the past, we had little understanding of these conditions or how to manage them, and without rigorous clinical trials, it was difficult to distinguish effective treatments from hype.

With better scientific practices and technology, we can now treat these conditions more effectively and safely.

But the story of psychosis treatment is incomplete. By understanding its history, we’ll see how much progress has been made and how much potential remains.

The development of antipsychotic medications

When people think about psychiatric treatment in the past, confinement and psychoanalysis — an approach once commonly used to explore unconscious thoughts — are often the first examples that come to mind.

But fad medical cures were also common. Doctors experimented with many risky treatments as there was very little medical regulation.

One example was “insulin coma therapy,” which was popular in the early twentieth century. It involved injecting high doses of insulin into the bloodstream, causing people to go into hypoglycemic shock. Some doctors claimed this would reactivate their nervous system and metabolism and cure them.³

Lobotomies were another example, where a pick was inserted through the eye sockets and used to detach connections in the brain's frontal lobe.⁴

Both procedures were ineffective at treating symptoms and frequently caused intellectual disability, permanent brain damage, or death.⁵

Other scientists had explored potential drug treatments by extracting organic compounds from coal tar, testing their effects, and modifying the structures of chemical compounds that appeared effective.⁶

This procedure involved a lot of trial and error. Still, it also helped discover many effective medications in the twentieth century, including antipsychotic, antidepressant, antiparasitic, antibacterial, and chemotherapy drugs.⁷

To understand the development of antipsychotic medications over time, I have compiled a dataset showing when each antipsychotic medication was in general use in the United States and visualized it in the timeline below.

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The timeline shows two broad groups of antipsychotic drugs: “conventional” and “atypical”, which are distinguished by their side effects. Many conventional drugs cause movement-related side effects, such as spasms and tremors, while atypical antipsychotics are less likely to cause these side effects.

As you can see on the timeline, chlorpromazine was the first antipsychotic drug to be introduced in 1954. Many more “conventional” antipsychotic drugs followed until a slowdown in the 1960s and 70s.

Clozapine, developed in 1958 but introduced in 1990, inspired further innovation. Its unique mechanism, with lower action on dopamine receptors and fewer motor side effects, showed there were new ways to treat psychosis.

The drug xanomeline-trospium (KarXT) was approved in 2024. It's a new kind of antipsychotic that works by targeting “muscarinic receptors”, which are involved in regulating various brain functions. More innovations are likely to follow, and the timeline is incomplete.

The development of antipsychotic drugs ran alongside the development of randomized controlled trials, as well as medicinal chemistry, drug regulation, and theories of schizophrenia and bipolar disorder.

Our ability to treat and understand these conditions has grown through trial and error, scientific research, and regulation.

Newer antipsychotic drugs tend to have similar levels of efficacy as older drugs but are safer.⁸ As drug regulation has expanded and new, safer options have become available, some older antipsychotics are no longer in use.⁹

Modern antipsychotic treatments need broader efficacy and safety

Antipsychotic drugs have changed the lives of many people with schizophrenia and bipolar disorder and provide doctors with safer and more effective options for treatment.

They are effective in reducing some symptoms of schizophrenia, especially hallucinations, delusions, and unusual thoughts, and reducing the chances of a subsequent episode of psychosis.¹⁰

But there are remaining challenges. Most antipsychotic drugs are less effective in treating other symptoms that can also develop in people with schizophrenia. This includes “negative symptoms”, such as emotional blunting and social withdrawal, and “cognitive symptoms”, such as disorganized thoughts, memories, and attention.¹¹

Although modern antipsychotic drugs are safer and less likely to cause movement-related side effects, many still carry risks of other long-term complications — such as weight gain, diabetes, metabolic problems, and cardiovascular disease.¹²

Given these gaps, more progress is needed to develop drugs that are more effective against a broader range of symptoms and safer, with fewer significant long-term side effects.

In recent clinical trials, xanomeline-trospium was demonstrated to be effective against the broader symptoms (including negative symptoms) of schizophrenia, while lacking the movement, metabolic, and weight-gain side effects. Research continues into its potential use in treating other conditions, such as bipolar disorder, and to monitor potential long-term side effects. It demonstrates the potential for further innovations in the field.

In the Appendix below, I review some of the major developments in the history of antipsychotic drug development in more detail.

Appendix

Conventional antipsychotic medications (1954 – 1990)

The first antipsychotic medication, chlorpromazine, is shown in the timeline. It was developed by Paul Charpentier and Simone Courvoisier, who modified organic chemical compounds previously used to treat allergies or prevent surgical shock; it was first introduced in the United States in 1954.

Early studies found that it had calming effects on patients with psychosis but also commonly led to side effects such as spasms and tremors.¹³

It was followed by the development of many more antipsychotic drugs, which are now called “conventional antipsychotics”. They are known for their action on dopamine (D₂) receptors in parts of the brain and for the movement-related side effects they cause, which include spasms, stiffness, and tremors.¹⁴

However, this first set of antipsychotic drugs was introduced mainly at a time when many “miracle cures” were being hyped up, and randomized controlled trials were still emerging.

Why randomized controlled trials matter and the procedures that strengthen them

Randomized controlled trials are a key tool to study cause and effect. Why do they matter and how do they work?

Initial studies of psychiatric treatment were therefore fairly limited in how informative they were. Many studies were small, lacked proper control groups, and lacked oversight. Because of this, many doctors remained skeptical of their benefits.¹⁵

There were efforts to test some psychiatric treatments more rigorously. The first randomized controlled trial (RCT) in psychiatry involved testing chlorpromazine: 28 patients in 1954 were given either chlorpromazine or a placebo and then switched over to the alternative, with each person acting as their own control.¹⁶

In addition, the first “double-blinded” RCT in history¹⁷ involved testing reserpine as a treatment for depression in London in 1955.¹⁸

Reserpine, shown in the timeline, is an organic compound extracted from the Indian snakeroot plant. It was soon used as an antihypertension and antipsychotic drug and was fully chemically synthesized in 1958.¹⁵

Despite these early efforts, it was not the norm to use RCTs to test medical treatments, and drug manufacturers in Europe and North America did not need evidence from them to market drugs at the time.¹⁹

This changed in the United States in 1962 with the Drug Efficacy Amendment²⁰, which required drug manufacturers to submit evidence of efficacy, not just safety before they could promote and sell products as medical treatments.

This regulation slowed the development of new drugs but raised the rigor of clinical testing, helping doctors and patients understand which treatments were effective.²¹

When more extensive clinical trials were conducted later on, they confirmed the efficacy of chlorpromazine¹⁶, but led the FDA to limit other drugs or drug developers to withdraw them, such as reserpine and triflupromazine.⁹

Theories on the causes of schizophrenia also shaped the development of antipsychotic drugs.

Although there was evidence that antipsychotic drugs were effective, how they worked had been unclear. With new techniques in medical imaging and chemistry, scientists discovered that many antipsychotic drugs blocked dopamine receptors in parts of the brain.

This led to belief in the “dopamine theory” of schizophrenia — that the condition was caused by excess dopamine in parts of the brain.

In addition, since many antipsychotics led to movement-related side effects, another belief solidified: that the side effects of these drugs were related to their efficacy, and they were inevitable from proper treatment.²²

Some previous research had already challenged this belief²³, but it began being seriously questioned after the introduction of clozapine.¹⁴

“Atypical” antipsychotic medications (1990 – current)

Clozapine, shown as the first “atypical antipsychotic drug” on the timeline, was developed as early as 1958 in Europe. However, it was only introduced in the United States 32 years later, in 1990.

It was developed by Swiss scientists who modified the chemical structure of antidepressants. They noticed that it appeared to be effective against both psychosis and the “negative symptoms” seen in schizophrenia — but with a lower risk of the movement side effects that had been seen before. In addition, it had much lower action on dopamine receptors in the brain.²⁴

Counterintuitively, these led to delays in its acceptance. Clinical researchers and drug developers believed that the lack of movement-related side effects was a sign that clozapine’s benefits wouldn’t hold up and that the drug wasnʼt worth pursuing.²⁴

Another challenge was that it was linked to a fatal side effect. In Finland, some clusters of patients who took it died from a condition called “agranulocytosis”, in which patients’ white blood cells are depleted, and they become very vulnerable to infections.²⁵ Further research revealed that this condition was rare and could be easily managed if detected early.

Years later, drug developers ran clinical trials to test its effect on patients who did not respond to other treatments. These trials showed a large benefit of clozapine on both psychosis and the “negative” blunting symptoms of schizophrenia. In 1990, it was finally introduced in the US, using a close monitoring system that would withdraw the drug from any patients who showed signs of developing agranulocytosis.²⁴

Inspired by the success of clozapine, research and development in the field grew once again¹⁵, as the timeline shows.

The drugs that followed clozapine are also called “atypical antipsychotic drugs”, as they generally also lack movement-related side effects.

Despite this, antipsychotic drugs have actions on multiple neurotransmitters in the brain, not just dopamine receptors, and drugs within each group also vary in their mechanism, other side effects, and efficacy.¹⁴

Today, atypical antipsychotic drugs are more often used because they are less likely to cause movement-related side effects. However, some carry other long-term side effects, such as weight gain, diabetes, and metabolic and cardiovascular complications, which require management.²⁶

A new generation of antipsychotic medications?

In 2024, a new antipsychotic medication was approved: xanomeline-trospium. Unlike previous drugs targeting dopamine receptors, xanomeline-trospium focuses on muscarinic receptors in the brain.

Xanomeline was initially tested as a potential drug for Alzheimer’s disease in the 1990s, and surprisingly reduced symptoms such as hallucinations, delusions, and agitation.²⁷ It was then tested for schizophrenia, but caused side effects like vomiting and stomach pain, and the drug was shelved.

Researchers found these side effects occurred because xanomeline also affected muscarinic receptors outside the brain, such as in the digestive tract.²⁸ They therefore combined xanomeline with trospium, which blocks muscarinic receptors outside the brain, to reduce these side effects.

Large clinical trials have found the combination effective against a broad range of schizophrenia symptoms, while lacking movement, metabolic, and weight-gain side effects,²⁹ and the drug was recently approved in the United States.³⁰ This represents a new, hopeful approach to treating psychosis, and paves the way for more innovation.

Saloni Dattani (2024) - “Antipsychotic medications: a timeline of innovations and remaining challenges” Published online at OurWorldinData.org. Retrieved from: 'https://ourworldindata.org/antipsychotic-medications-timeline' [Online Resource]

@article{owid-antipsychotic-medications-timeline,
    author = {Saloni Dattani},
    title = {Antipsychotic medications: a timeline of innovations and remaining challenges},
    journal = {Our World in Data},
    year = {2024},
    note = {https://ourworldindata.org/antipsychotic-medications-timeline}
}

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