The landscape of pharmaceutical development for mental disorders has changed over recent years, with pharma companies abandoning traditional neuroscience drug discovery programs and turning instead to gene-based research.
Schizophrenia is one mental illness which, despite numerous attempts and lots of promise, has not seen a successful new drug emerge to the market with a novel mechanism of action in over 60 years, when researchers found that symptoms could be alleviated by targeting the brain’s dopamine system.
Let’s take a look at how this discovery was made and why it’s too soon to abandon the quest for new and better drugs.
What is schizophrenia?
Schizophrenia is a complex disorder made up of a number of signs and symptoms, which researchers classify into two major groups:
Positive symptoms are abnormal experiences, such as delusions, hallucinations and formal thought disorders, where the person’s reality is distorted. These symptoms are often accompanied by bizarre behaviours.
The positive symptom category is perhaps the most widely recognised, as the media often depicts people with paranoid-type delusions or threatening auditory hallucinations (think of Shine).
Negative symptoms are an absence of normal behaviours such as anhedonia (lack of pleasure), avolition (lack of motivation), alogia (lack of speech) and affective flattening (reduced emotional intensity). These are similar to symptoms and signs of depression.
Sometimes people with schizophrenia have cognitive impairments, affecting their working memory and attention. These symptoms are most prominent in a particular genetic subtype of schizophrenia.
None of these symptoms are unique to schizophrenia, but the combination of symptoms is relatively easily recognised. The symptoms often lead to significant social and occupational impairments, making schizophrenia one of the major social burdens in the world.
Discovery of antipsychotic drugs
Like most therapeutic classes of drugs in use today, antipsychotics were not first developed in attempt to treat schizophrenia.
Chlorpromazine was the first drug noted for its antipsychotic properties; but it was developed for its antihistamine properties, as an extension of anaesthesia research in the 1950s. Physicians found it could sedate patients without loss of consciousness and reduce patients’ interests in their surroundings.
From this came the first treated case of schizophrenia with chlorpromazine. But it wasn’t until after the discovery of its ability to treat psychosis that we began to understand chlorpromazine’s mechanism of action.
Most neurons in the brain communicate via the release of signalling molecules (neurotransmitters) into the small gaps (synapses) separating one neuron from the next. There are many neurotransmitters in the brain and each has specific receptors, a protein spanning the cell membrane of neurons. One such neurotransmitter, dopamine, is released by a very specific group of neurons in the brain.
It turned out that the antipsychotic effect of chlorpromazine is to prevent dopamine signalling by blocking the attachment of dopamine to dopamine receptors. In particular, chlorpromazine targeted a subtype of dopamine receptor, the D2 receptor.
Even today, 60 years after the discovery of the first antipsychotic, all currently used antipsychotic medications have one common feature of acting on dopamine D2 receptors.
Since then, we’ve found that people with schizophrenia create and release more dopamine than healthy people and that changes in dopamine activity in people with schizophrenia coincide with the more active periods of psychosis.
What dopamine does in the brain
Dopamine is one of the few neurotransmitters that has a relatively high public profile.
Some of the earlier research on dopamine noted its importance in basic behavioural concepts such as reward and reinforcement. Many recreational and habit-forming drugs also increase dopamine activity in some way. This led to ideas that dopamine was responsible for the hedonic or pleasurable aspects of drugs of abuse.
But stimulating dopamine does not necessarily give the experience of pleasure. Whether removing dopamine neurons or blocking dopamine receptors can result in an inability to experience pleasure is also controversial. Some argue that these kinds of manipulations make it more difficult to engage in activities leading to pleasurable outcomes, rather than reducing the pleasurable experience.
One of the more modern ideas is that dopamine codes the importance of a stimulus, or the “incentive value”. Dopamine is released in response to significant stimuli like natural rewards, drugs, and other important things that guide our behaviour (perhaps also aversive stimuli). The dopamine signal conveys a message about the importance of these stimuli and engages the necessary brain machinery to do something about it.
In people with schizophrenia, however, heightened dopamine activity may result in psychotic experiences. This may be due to a state called “aberrant incentive salience”. In other words, importance may become attributed to an inconsistent and irrelevant array of objects, experiences and people. This would have the effect that these objects have now been prioritised in the brain and require our attention.
Here’s one scenario: when enhanced levels of dopamine are sporadically released, the person may over-attribute the importance of the thing they were focusing on at the time, like a crack in the wall. The person then needs to explain why a seemingly innocuous feature is attracting so much of their attention. And the object takes on the unshakeable feeling of being somehow important.
From this, we can start to see the beginnings of the creation of a delusion. The delusion is an explanation of the strange sensation of importance attributed to the crack. Perhaps the person starts to think that there may have been a listening device implanted in the wall where the crack is and that’s why it is important.
This hypothesis can explain the preoccupation with insignificant details and behaviours associated with the delusion.
Future drug development
Antipsychotics have a range of unpleasant effects, which include mimicking some negative symptoms, disrupting the ability to perform smooth movements, metabolic disturbances and chronic use can result in brain atrophy.
The newer generation of antipsychotic medications appear to have a different adverse effect profile. But they may not actually be more effective than the older antipsychotics, with one possible exception — clozapine.
Excess dopamine activity is not the only neurological change seen in patients with schizophrenia. It is also not the only neurotransmitter model of schizophrenia – albeit the most well-established and the only one to withstand the test of time so far. Promising developments in other neurotransmitter systems may see the emergence of some more successful treatments or adjuncts.
It’s important for researchers to continue to search for medications that have improved efficacy and side-effect profiles compared to the current range of treatments.