Can Treating Psychosis Reduce Motivation and Pleasure?
I am Martin Osugo, a psychiatrist and neuroscientist working to improve the lives of people with schizophrenia through both clinical practice and research. I first became deeply interested in schizophrenia in my first year of medical school. That interest eventually led me to a PhD at King’s College London’s Department of Psychosis Studies, two years after I qualified as a doctor.
I have cared for people with psychosis in my community and inpatient settings. Part of the responsibility I feel comes from seeing first-hand how psychosis disproportionately affects young Black men like me, and several people I’ve cared for have told me they felt more able to relate to me for this reason.
The Problem I Identified
Most people think that hallucinations and delusions define schizophrenia. Although that is partly true, even when these symptoms are successfully treated, many people with schizophrenia do not return to the lives they had before becoming unwell. Due to the disabling nature of schizophrenia, more than 90% of people affected are unemployed in the UK.
The difficulties that contribute most to this are called ‘negative symptoms.’ These include a reduced ability to enjoy activities, low motivation to socialise, work, and pursue hobbies, and a reduced range of emotional expression. They are called “negative” because they represent a reduction from previous function, rather than something added on to previous experience (as with “positive” symptoms like hallucinations). Personally, I think this clinical label obscures what is actually being talked about, which is disability in psychosis.
There are no effective treatments for negative symptoms, and our understanding of what causes them remains limited. My supervisor, Professor Howes, and I have spent the last seven years trying to improve the treatment of negative symptoms, including investigating the brain mechanisms that underlie disability in psychosis.
How Do Antipsychotics Work?
Dopamine is often described as the brain’s “pleasure chemical”. Although there is some truth to that, it is too simplistic. A better way to think about it is that dopamine helps the brain learn what matters and decide how much effort a reward is worth.
Excess dopamine in the brain’s reward system, particularly in a region called the striatum, is linked to psychosis. This is likely why antipsychotics, which work by blocking dopamine receptors, help to alleviate delusions and hallucinations (although the full picture is more complex, as dopamine alone doesn’t explain every aspect of psychosis).
Despite their beneficial effects, antipsychotics not only block dopamine in the pathways important for psychosis, but they also block it in the pathways associated with motivation and reward. In theory, this could cause or worsen negative symptoms.
In practice, this is difficult to test in people with schizophrenia, as they experience other important contributors to negative symptoms, including social isolation, stigma, lack of opportunity, and the illness itself. To untangle the effects of antipsychotic medication from these problems associated with having psychosis, we designed a study to isolate how antipsychotics affect reward and motivation.
What Did We Test?
We gave antipsychotics to healthy volunteers who had no psychiatric or medical diagnosis. Although this may sound odd, there was a very good reason for this.
The study was designed to test cause and effect directly. Combined with a rigorous study design, studying healthy volunteers meant we could be confident they caused any changes that appeared after taking antipsychotics. We gave two different antipsychotics to healthy volunteers for seven days each, and they also received placebo pills containing sugar for the same amount of time. Our study was a double-blind study, meaning that neither the volunteers nor the researchers knew which treatment each participant had been randomly chosen for.
As well as measuring symptoms, we also studied whether we could explain any changes in behaviour and emotion in terms of brain activity. We did this by conducting MRI scans of the brain while the volunteers played a game in which they could win money.
The two drugs we studied were amisulpride and aripiprazole. Amisulpride is a dopamine-blocking antipsychotic. Aripiprazole acts in a similar way to amisulpride when dopamine levels are high but can also have the opposite effect when dopamine levels are low. You could think of the difference as though amisulpride is like a standard light switch whilst aripiprazole is like a dimmer switch.
What Did We Find?
After taking amisulpride for seven days, healthy volunteers developed problems with motivation and emotional expression, like those seen in schizophrenia, although not as severe. The response of the striatum to winning monetary rewards in the scanner was also lower on amisulpride than it was with placebo pills.
Interestingly, the changes in behaviour and the changes in the brain’s reward response were related. People who developed more severe negative symptoms also showed a greater reduction in reward-related brain activity. The effects of aripiprazole were different: it did not cause negative symptoms and did not affect the brain’s response to reward.
What Does This Mean for People Taking Antipsychotics?
Our most important finding was the first direct evidence in humans of the key role of dopamine signalling in the striatum for reward and motivation. Our study shows that negative symptoms can be caused by dopamine-blocking antipsychotics, like amisulpride, by altering how the brain responds to rewards.
But this does not mean that all negative symptoms are caused by antipsychotics.
For one thing, aripiprazole is an antipsychotic, and we found that it did not cause negative symptoms or alter the brain’s reward system. Additionally, many people with schizophrenia experience negative symptoms before ever taking antipsychotics. Negative symptoms were, in fact, described as core features of schizophrenia 40 years before antipsychotics were even invented.
So, our study does not suggest that people should stop taking antipsychotic medication. It is important to stress that antipsychotics are very effective in reducing delusions and hallucinations. Antipsychotics are among the more effective treatments in the whole of medicine.
But what our study does confirm is what many people who take antipsychotics have reported for a long time: dopamine-blocking medications can worsen problems with motivation, reward, and emotional expression. I think our findings validate those experiences and should help people who experience negative symptoms following antipsychotics to be taken seriously.
What’s Next?
Blocking dopamine has complicated, interconnected effects on psychosis, reward, and motivation. That complexity is exactly why this research matters. It motivates us (pun intended!) to continue developing and testing treatments that can reduce psychosis without reducing motivation and expression.
Our findings with aripiprazole suggest it should be possible to treat psychosis without reducing motivation and reward. What’s needed now are well-designed studies that directly test whether switching antipsychotic medications or lowering doses can improve negative symptoms, as our findings suggest might be possible. However, I want to stress that this is a recommendation for research. We did not test any effects in medication changes, and treatment decisions should always be made jointly between people with psychosis and the clinicians directly responsible for their care.
Another possible treatment option could be to alter serotonin levels. Our findings from another study show that alterations in the brain’s serotonin system are related to negative symptoms in people with schizophrenia who were not medicated with antipsychotics.
Understanding these different biological pathways, alongside the social barriers people face, is central to my broader goal: helping people with schizophrenia rebuild their lives.
Martin Osugo is a recipient of the Psychiatry Research Trust’s Alfred Meyer Prize, which recognises outstanding research into the relationship between brain mechanisms and mental illness. If you would like to support the next generation of researchers working to advance our understanding of mental health, please consider supporting the Psychiatry Research Trust.
