Antipsychotics block dopamine. So, problem solved. A straight line from molecule to medicine to human.

It’s a great theory. The dopamine hypothesis has been the core theory in academic psychiatry for the last 50 years. There is just one problem: currently, in 2026, we know more about it, and it just isn’t correct. Not entirely, not linear, and not like the leaflets claim.

And that’s interesting, because the dopamine hypothesis isn’t nonsense. It contains an element of truth. But it’s more poetic, more erratic, and more uncomfortable then we thought for a very long time. It’s time to speak the truth.

How it all started

In the sixties, someone noticed something. People who used amphetamines, which heightens dopamine levels in the brain, sometimes had psychotic experiences. And the first antibiotics, that were discovered by accident, seemed to block dopamine receptors. One and one is two. So: psychosis is caused by high levels of dopamine, the dopamine hypothesis was born.

In 2003 Shitij Kapur fine-tuned this to an elegant idea. Aberrant salience. Dopamine gives meaning to stimuli in your environment. Too much dopamine, and you will find meaning in everything you see. The newspaper on the table contains a message for you. The neighbour blinks his eyes because he knows something about you. It was a great theory, because it tried to connect the neurochemistry (chemical processes in the brain and nervous system) to the phenomenology (how people experience the world through their own perception).

Dopamine Hypothesis: What has become clear over 20 years?

Last year a review was published in the American Journal of Psychiatry: Twenty years Kapur, what has it brought us? The writers, Corlett and Fraser, looked closely at the specific predictions of the aberrant salience hypothesis. Their conclusion: they were lacking. The prediction about where in the brain, and how in the behaviour dopamine would derail, are not confirmed after two decades of animal testing and human research.

The simple dopamine derailment is not in the place we thought it was. The connection between dopamine and finding meaning is much more complicated. Dopamine doesn’t just do something to what feels important to you, it does something to your beliefs, to how you adjust your view of the world when you’re unsure about things, and to the question what explanation for what happens to you you come up with. It’s not just a button, but an entire network.

And even that network is not the whole psychosis. Oliver Howes, who tried to decipher the dopamine hypothesis for years, published a third version of the synaptic hypothesis. In there, the dopamine is not the main focus any more, but a result. According to him, the primary derailment lies in the way the brain cuts the synapses in adolescence. The dopamine only becomes a problem later on.

And then came KarXT

This is where it gets really surprising. In September 2024 the American FDA approved a new medicine for psychosis: xanomeline combines with trospium, KarXT for short. It affects the muscarinic receptors, and doesn’t work the same way as dopamine. It doesn’t even touch the D2-receptor.

And it ‘works’, in the biomedical way of looking that is. A meta-analysis from 2025 shows that KarXT lowers the PANSS-score (the standard measure for psychotic symptoms) by almost fourteen points compared to the placebo. That’s on the same scale as the old dopamine blockers, but without weight gain, heightened prolactin, and other side effects.

So let’s recap: A drug that helps with psychosis, without doing anything with dopamine. What does that tell us about the dopamine hypothesis? It says: guys, we may have missed something over the last 50 years.

What do those antipsychotics actually do?

This is the uncomfortable part. Imagine getting a hammer and bashing it on the dopamine system. What will happen? You become more indifferent. The world hits you less hard, stimuli lose their urgency. Food loses taste, sex doesn’t feel as good, you become less motivated, and you become jaded. And yes, your psychotic thoughts also lose intensity; not because they’re gone, but because you find them less important.

Joanna Moncrief has been writing about it for years. Antipsychotics aren’t antipsychotics because they do something about the psychosis. They are neuroleptic, literally: nerve holders. They slow down your entire system. A hammer, not a key.

That sounds cynical, but it isn’t. Sometimes a hammer is exactly what you need. When the world is so overwhelming you can’t sleep, eat, or think, numbing feelings can be life saving. Buy some time. Take a breath. Don’t feel everything at once.

But let’s be honest about what we do. We’re not fine-tuning medication for a specific illness. We just turn off the amplifier. That has consequences, long term and short term ones. The longer you do that, the more your system resists it. The lower the dose can be, the better. With proper guidance and preferably reduce with tapering strips if that’s appropriate.

So what is it really about?

Psychosis is an experience of finding the meaning of things. Something that we use in our system that we use to make sense of the world, gets disrupted. Associations run away with us. Random occurrences seem more significant. Connections become visible to you, but nobody else can see them. Some people manage to live with this, but for others it becomes a cage.

We really wanted to understand how that works. That’s why we studied dopamine for fifty years. It wasn’t for nothing. We now know more about how meaning and purpose can be created through the brain, how beliefs are adjusted, how are default brain network works. The research we did was fascinating.

But it is not a linear connection. High dopamine levels don’t cause psychosis, and low levels don’t cure psychosis. It’s like an ecosystem in our head that gets disrupted, closely connected to what is going on in your life: trauma, lack of sleep, loneliness, drug use, migration and isolation. The biology and biography are actually linked.

What can we do with this information? Three things:

Be careful with the dopamine hypothesis: explaining psychosis by saying it’s an illness caused by dopamine. It isn’t a lie, but it isn’t the truth either. It’s a metaphor that suited us once upon a time, but is kind of blocking our view now, because it gives people the idea that there’s a biological switch we can just pull.

1. Be honest about what antipsychotics do. They slow down, they break off, they make us more indifferent. And sometimes that’s just what we need, but often it’s too much or too long. Take the lowest possible dose, that’s the standard recommendation. And if there’s a possibility of reducing the medication, do it slowly, with proper guidance, and tapering-strips for the final steps.
2. Try and see psychosis for what it really is. A disruption of the most human system we have, the system we use to make sense of the world. The vulnerabilities people have to such a disruption, often go hand in hand with their talents: intuition, creativity, a big imagination. Nobody becomes psychotic out of nowhere – something happened to them, there is always context around it, and there is always a story to tell.

Dopamine is a tiny part of it. Noting more than that. Conclusion: we have work to do.