Authors: Lauren Pulling
As part of #NCMentalHealthMonth, we recently sat down with Expert Panel member Gabriel Vargas (Amgen, San Francisco, CA, USA) to discuss the current status of biomarker development and personalized treatment for psychiatric disorders. Gabriel has previously held posts at the University of California at San Francisco (UCSF; CA, USA) and Roche (CA, USA and Switzerland), and is now Executive Medical Director and Neuroscience Therapeutic Area Head, Early Development at Amgen in San Francisco. His research at UCSF centered around membrane trafficking of GPCRs, in particular dopamine receptors, as well as clinical work with the schizophrenia patient population and the creation of a prodromal schizophrenia research clinic. At Roche, Gabriel was Head of the Neuroscience biomarker group, working on biomarkers for a variety of psychiatric disorders.
Since joining Amgen, Gabriel has been working on the early development of neuroscience compounds, mainly focused on migraine, neurodegenerative and pain disorders. His group is also interested in mobile health approaches to drug development and clinical models.
You can view Part 1 of this interview here.
As we see research moving towards personalized medicine for a number of diseases, do you think this is something we could witness in the treatment of psychiatric disorders in the next decade or so?
Absolutely, we’re already observing this in the treatment of Alzheimer’s disease, which I view as a neuropsychiatric disorder. A number of clinical trials are aiming for participants with the specific genotype APOE4, a genotype that makes individuals susceptible to Alzheimer’s, putting them at higher risk, so I can imagine this to be true for a variety of psychiatric disorders. As we learn more about disorders in general and the genetic underpinning of these psychiatric disorders, you can envisage people with particular genotypes being followed more closely and being assessed more readily, and maybe being treated and seen as ultra-high risk.
“…I think genetics will play a stronger and stronger role in our treatment of psychiatric disorders.”
As with anything in psychiatry, there’s not just the genetics but also the environment: it’s a combination of a particular susceptibility gene plus the environmental stress – combining the two together will lead to a psychiatric disorder. So I think genetics will play a stronger and stronger role in our treatment of psychiatric disorders.
What do you envisage personalized treatment of, for example, schizophrenia could look like? How could this approach change treatment and prognosis for patients?
“Now that the sample sizes of these studies are beginning to get larger, we’re actually pulling out genes that we wouldn’t have otherwise identified in smaller samples in genome association studies…”
Well I think genetics is very powerful, and we are gradually indentifying more genes involved in schizophrenia. For example, a publication  that came out in 2014 identifiedadditional loci that are involved in schizophrenia. Now that the sample sizes of these studies are beginning to get larger, we’re actually pulling out genes that we wouldn’t have otherwise identified in smaller samples in genome association studies – those are giving out additional genes that are relevant to the development of schizophrenia.
As we develop a better understanding of how these genes are working together, one personalized approach to diagnosis would be to devise a genetic score; the idea being that each gene by itself may not give you a disorder – the environmental stress is still required on top of the genetics – but it’s a susceptibility gene. Therefore, you can envisage each one giving you a risk score, and then as you add them up, your score becomes greater – so you can imagine treatment in the future being dependent on your genetic load. We could give each individual patient a genetic load score that informs the physician that this individual is at ultra-high risk and we have to intervene early with psychotherapy or pharmacotherapy. So that would be one area in which you could personalize medicine.
The other, I think, would be utilizing our understanding of genetics and pathophysiology and targeting these specific medications that may be relevant to one subset of the population versus another. Schizophrenia, for example, is a very heterogeneous disorder – what we call schizophrenia is really multiple different diseases that all have a similar presentation. So as we come to understand the genetic underpinnings of the disorder, we could observe a variant of schizophrenia that is more glutamatergic-dependent as opposed to dopaminergic-dependent, for example, resulting in different treatments.
The other thing would be dosage, which may be different even within the samepatient population. For example, take a glutamatergic approach: treatment may involve different types of glutamatergic agent, or the same agent but at a different dose due to a particular sensitivity that the patient has. There has been plenty of interest over the last 10 years on phosphodiesterase 10A (PDE10A) inhibitors, which are thought to be very important in schizophrenia – the preclinical data are very robust, showing that there is an impact on positive symptoms, negative symptoms and perhaps even negative symptoms of schizophrenia in preclinical species. Pfizer conducted a Phase II trial on schizophrenia with PDE10A inhibitor – the control was risperidone, which came out positive, but PDE10A came out negative so it was very disappointing. This trial demonstrated some of the challenges of translating from preclinical work to clinical work, but perhaps one reason it failed is because this is an area where treatment should be personalized, for example dose should be adjusted dependent on the patient’s dopaminergic tone. Because ultimately, those PDE10A inhibitors modulate both D1 and D2 signaling in the striatum and if a patient’s dopaminergic tone is high, you may require a different dose to someone whose dopaminergic tone is low, so first of all you may have to determine the dopaminergic tone of the individual, and then set the dosage accordingly.
So, that is all speculation, but I think it is a useful example of how medication and its dosing may need to be tailored to the individual.
So finally, what are the main hurdles to be overcome before we could get to this stage?
“…we need to do more basic science research in psychiatric disorders, more genetic research and additional work in identifying susceptibility factors for psychiatric disorders.”
We have many hurdles; however, I think a lot of it depends on basic scientific research, because at the end of the day, the clinical work that we do is dependent on the basic science research that illuminates the basic mechanisms that are involved in psychiatric disorders. Therefore, we need to do more basic science research in psychiatric disorders, more genetic research and additional work in identifying susceptibility factors for psychiatric disorders. As I mentioned previously, optogenetics has been very useful for identifying pathways that are involved in psychiatric disorders, so that’s going to be very useful for all the ongoing work. The connectome is also very useful.
I think it just requires a lot of work, with plenty of fields collaborating. Once we acquire additional basic science, we need translational science, which takes preclinical and basic science findings and translates them to humans. This involves asking questions about how we can detect these mechanisms in individuals with psychiatric disorders through approaches utilizing imaging and other biomarker approaches to see if we can observe the same effects as in preclinical data, and then based on those, adapt them to clinical trials, which may enable us to identify relevant targets for specific pathways.
So altogether, it’s a lot of work, but the end game is to come up with medications that alleviate the suffering from psychiatric disorders. It’s a very noble aim and it takes a lot of work to get there, but there is certainly a lot of interest in doing that.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).