Unlocking the potential of brexpiprazole

Hanna van den Munkhof (Stuber Lab, Department of Psychiatry University of North Carolina at Chapel Hill, USA) is a junior scientist who presented at the 29th ECNP Congress in 2016 on the novel antipsychotic brexpiprazole, which has recently been approved for the treatment of schizophrenia and as an adjunct in major depressive disorder (MDD). Van den Munkhof's findings showed that brexpiprazole reverses a disruption of thalamocortical function induced by phencyclidine, which is used as a pharmacological model of schizophrenia.^[1]

She carried out this work as part of the Innovative Medicines Initiative Novel Methods leading to New Medications in Depression and Schizophrenia (IMI-NEWMEDS) consortium, which is part of a Europe-wide initiative to address bottlenecks in drug development.^[2]
Van den Munkhof spoke to ECNP to describe her work and life as a junior scientist.

What are you working on at present?
I am currently working on two projects: firstly, the lateral hypothalamic circuitry of food reward in relation to obesity, using mostly optogenetics in behavioral set-ups; and secondly, developing new methods to automatically analyse mouse behaviour using a depth camera, which we can use to study animal behaviour in a more detailed manner.

Recent literature on brexpiprazole (which surrounds its FDA approval) amongst many things highlights its lesser D2-related side effects, such as restlessness and insomnia, compared to its precursor aripiprazole. Can you say anything else about its binding profile relative to other similar medications and common side effects of antipsychotics?
In fact, brexpiprazole – like aripiprazole – is a D2-receptor (D2R) partial agonist, which means that it stabilises the dopamine balance, rather than stimulating the D2R too much (leading to side effects) or not sufficiently (less efficacy). Apart from this, it has superior affinity for the 5-HT1AR (partial agonism too), which might be involved in its beneficial effects on cognitive symptoms of schizophrenia.

Considerable affinity for serotonin receptors in addition to D2R partial agonism are properties of the so-called third generation drugs, to which also aripripazole belongs. Yet what makes brexpiprazole really unique is that it also has very strong antagonist properties at the α1B-adrenergic receptor, a receptor that is abundantly expressed in all areas of the thalamus except the reticular nucleus. We are trying to find out how this mechanism is involved in the antipsychotic properties of brexpiprazole.

Do we know much at this stage how brexpiprazole affects different schizophrenia subtypes or indeed major depressive disorder (MDD)? It would also be interesting to hear your thoughts on the ADHD data – do you think anything could ever come of that?
Most trials so far only have been including patients with acute schizophrenia and acute or resistant MDD, so future studies should address that question.

It is likely that brexpiprazole affects individual patients in a different way, as the effects of antipsychotics in general depend a lot on the specific symptoms, which show especially high variability in schizophrenia. The same drug can be beneficial for one patient, while not improving symptoms in another patient.

As brexpiprazole seems to have procognitive qualities, it might be, for example, that patients with cognitive symptoms benefit most from this drug. The same for MDD patients: there might be specific groups of patients that benefit most from the drug, but this hasn't been investigated yet (of interesting could be manic depression, because of brexpiprazole’s partial agonist properties, which are stabilizing monoamine systems).

As for ADHD, although the results so far don't seem that promising, there is very little research done yet. It might be that a subgroup of patients that were not included in the studies benefits from brexpiprazole. Considering brexpiprazole's procognitive effects, it is not a strange idea that it could help in ADHD (e.g. concentration problems).

Brexpiprazole's approval came at a time when some of the key second generation antipsychotics became generic, and hence much cheaper. Given this, how can the use of newer, more expensive drugs be justified?
Its unique profile comes with strong advantages, such as higher effectiveness and fewer side effects, which indicates that it might be a drug that is superior to most second generation antipsychotics. Also, as I mentioned earlier, the effects of antipsychotics vary highly between patients and depend on the specific symptoms. A higher availability of the second generation drugs might benefit some, but not all patients, for whom a new class of medication might be necessary. Therefore, brexpiprazole could be especially beneficial for patients who experience no improvement with other cheaper antipsychotics, or who are about to discontinue treatment because of the side effects.

What have been for you the most exciting developments in our understanding of drug action on thalamocortical circuits, and what we hence or otherwise have learned about specific illness mechanisms?
I think it was exciting to learn that drugs that act on the glutamatergic system, such as NMDA-R antagonists (e.g., ketamine), can mimic schizophrenia, and can alleviate depression at the same time. Apparently there is an opposing mechanism involved in these two disorders.

Also, it made us realise that other mechanisms than dopamine and serotonin system alterations, which we believed were the cause of these disorders, are involved in schizophrenia and depression, and thus changed our way of thinking.

NMDA-R antagonists such as ketamine and PCP seem to act on the thalamocortical circuit, which makes sense as this circuit is considered a sensory gateway. This opens up exciting possibilities for novel drug development! It proves again that psychiatric disorders have a very complex cause and that a balance of multiple interacting circuits is important to maintain a healthy state (we should focus on interactions rather than singling out one circuit).

You have recently moved to the US – what are you doing there?
I moved to the US temporarily to work on an extra project, because I was very interested in the research of this lab and I wanted to learn new techniques such as optogenetics. I have finished the brexpiprazole project.

Do you see yourself remaining squarely within your discipline, and why?
I am flexible and open to move into new directions. Working on the boundaries of different fields and therefore combining approaches and ideas (being creative) seems the best way to discover new things, so I'm definitely supporting that. Collaboration with people outside of your own field in general helps with outside-of-the-box thinking.

Neuroscience specifically benefits a lot from interdisciplinary collaboration! Especially computer science and maths are necessary to completely understand neuronal function via the development of models. Neuronal networks are so complex that computation and modelling are very helpful.

Also, the size of the data we collect is ever increasing, so we need new methods to deal with all that data (the 'Big Data' issue), and those methods need to come from informatics. The other way around, computer science also benefits from neuroscience knowledge and computers/programmes are created by mimicking neuronal networks.

In addition, collaboration with clinical psychiatrists is necessary to not lose sight of what the patient needs, as ultimately we are trying to cure diseases. Last, the brain is connected to the rest of the body and therefore other processes, such as the immune system or endocrine factors, influence neuronal function. For example, lately there has been more and more attention to the role of inflammation in neurological disorders, and changes in the brain associated with obesity are greatly intertwined with metabolic signals.

It seems that, having studied and lived in Belgium, Spain, and now the US, your feet are prone to wandering. Would you name any stand-out destination so far?
The Canary Islands – which were for me very different from everything I have seen so far. In Lanzarote you can feel like you're on the moon or in a desert, and the area around the volcano Teide in Tenerife was simply amazing nature. Also this island has a few hundred microclimates, despite its small size. The people were very hospitable as well – I stayed with the mother of someone I had met only for a few days in Madrid – so it was a unique experience! Apart from this, living in Barcelona was great, as it has simply everything.

What advice do you have for students and junior scientists attending their first congress or perhaps presenting for the first (nerve-racking) time? How can they prepare, and what should they be doing while there?
Have a look at the programme beforehand to decide where to go, as there are usually various parallel sessions. The organised dinners or events are a good opportunity to talk to other scientists, which might give you new perspectives on your work or new connections.

Presenting for the first time can be scary, but remember it is for most people. And don't forget to enjoy!

In 2016 Hanna van den Munkhof gave a lecture in a Junior Scientist symposium (S.12.04). You can view the webcasts.

In this video Hanna talks about her experience at the ECNP Congress, and her interests related to the field.

More information about benefits and special activities for Junior Scientists at the 30th ECNP Congress in Paris, 2-5 September 2017.

References:
1. Van den Munkhof HE et al. The novel antipsychotic brexpiprazole reverses a disruption of thalamocortical function induced by phencyclidine: exploring the involvement of 5-HT1A and ɑ1B-adrenergic receptors. In Kazakova O and Millan MJ (Chairs) Junior Scientist symposium ─ Emerging targets for improved control of psychiatric disorders. Symposium conducted at 29th ECNP Congress, Vienna Austria, 2016.
2. Artigas F et al. Defining the brain circuits involved in psychiatric disorders: IMI-NEWMEDS. Nat Rev Drug Discov. 2017 Jan;16(1):1-2.

This work was carried out at the Department of Neurochemistry and Neuropharmacology of the IIBB (CSIC-IDIBAPS), Barcelona, under a research contract with Lundbeck.