Why do we persist in our dopamine-centric approach to drug development in schizophrenia?
These were the concluding remarks from a thought-provoking presentation given by Celso Arango, Spain, during the educational session entitled ‘First episode psychosis: beyond the dopamine paradigm’. This sentiment conveyed his frustration at the lack of new therapies for the better management of schizophrenia becoming available. Being deliberately skeptical and provocative, he cited Einstein’s definition of insanity: doing the same thing over and over again and expecting different results. Why, he asked, do we persist in our dopamine-centric approach to drug development in schizophrenia? As 87% of the voting audience agreed with Einstein’s definition, he cheekily suggested that there must be lots of insane people conducting schizophrenia research!
However, joking aside, the statistics tend to support his disappointment in the lack of recent progress in this field. Indeed, of 219 drugs trialed in schizophrenia, just 9 are licensed, all of which have dopaminergic effects. Maybe, he suggested, it is time to stop this ‘one size fits all’ approach and seek drugs that actually treat the symptoms of schizophrenia?
Currently 30% of patients fail to respond to any second generation dopamine antagonist
Interactive voting allowed Dr Arango to ask the audience which antipsychotic agent improved primary negative symptoms. Unlike most of the voting audience, Dr Arango believes that any D2 blockade worsens negative symptoms and cognition in schizophrenia. And, as, according to the audience, currently 30% of their patients fail to respond to any second generation dopamine antagonist, he suggested this implies targets other than dopaminergic ones are implicated in the underlying pathophysiology of schizophrenia.
He examined in some depth the wealth of potential non-dopaminergic candidate targets that could be explored. In may be that such targets, including possibly ‘failed’ dopamine antagonists, may also need to be better targeted to subgroups of patients with the same underlying pathology in order to achieve positive outcomes in all aspects of schizophrenia management.
Timing of intervention is also likely to be very important and he suggested ultimately the focus will shift towards the development of drugs and interventions for the primary and secondary prevention of neurodevelopmental anomalies that contribute to schizophrenia.
Whatever we do, Dr Arango concluded, we need to be more ambitious and do more for our patients in the future.
As the second speaker, Dr Oliver Howes, UK, stated in his presentation, there is still a lot to learn about the regulation of dopamine synthesis. Therefore, targeting the dopaminergic system - but more appropriately - might have more to offer.
He presented evidence that in some patients with schizophrenia, the synthesis and release of excessive amounts of dopamine is occurring. This means, theoretically, that blockade of D2 receptors, should be helpful for these patients. However, for any D2 blocker to be used effectively, it must be used appropriately: block fewer than 50% of receptors and you do not obtain optimal benefits but greater than 87% site occupancy, and you have side-effects.
Antipsychotics, therefore, appear to be homing in on the right symptoms but they do not normalize D2 dysregulation. So, how to move forward?
One approach is to target molecules upstream of dopamine production in the presynaptic neuron. Several candidate molecules were described. However, Dr Howes acknowledges, there are some patients in whom dopamine blockade will never work. The identification of such patients will permit newer candidate drugs possibly to be more appropriately tested in a population for whom nothing else is, as yet, available.
Thus, just as Dr Anango concluded, so did Dr Howes - a one size approach does not fit all.