Title: The Relationship between Cardiometabolic Disorders and Schizophrenia: From Early-Life Origins to the Development of a Cardiometabolic Risk Prediction Algorithm for Young People with Psychosis
Research group: Peter Jones
Supervisor: Golam Khandaker
Advisor: Peter Jones and Nick Wareham
Can you give us a short background into what your PhD/MPhil was about?
People with schizophrenia die on average 10-15 years sooner than the general population, mostly as a result of a substantially higher prevalence of physical comorbidity, for example, cardiometabolic disorders. Traditionally this excess physical comorbidity has been solely attributed to chronic lifestyle factors that are commonly associated with schizophrenia. For example, a poor diet, smoking and low levels of physical activity, or iatrogenic factors such as certain antipsychotic medications. Essentially, the received wisdom has been that cardiometabolic disorders occur after/as a result of a diagnosis of schizophrenia. However, more recent research suggests that subtle forms of developing cardiometabolic disorders, particularly insulin resistance, may be detectable from the onset of psychosis in young adults with no prior exposure to antipsychotic medication. This suggests the possibility that disruption to cardiometabolic function could precede the onset of psychosis, and/or may share pathophysiological mechanisms with it.
My PhD was divided into six studies over three sections. First, I used birth cohort data to explore the direction of association between cardiometabolic dysfunction from childhood and the risk of psychosis in adulthood, addressing key limitations of existing research. Second, I used a range of observational and genetic epidemiological techniques to explore whether inflammation and/or shared genetic liability may help to explain the comorbidity between schizophrenia and cardiometabolic disorders. Finally, I used patient data from three psychosis early intervention services to develop and externally validate a cardiometabolic risk prediction algorithm specifically tailored for young people with psychosis.
How would you sum up your main findings?
In some individuals who may go on to develop schizophrenia, subtle forms of developing cardiometabolic disorders (particularly disrupted glucose-insulin homeostasis, i.e. insulin resistance) may be detectable before the first onset of psychosis, and so are unlikely to be fully explained by the common attributions for the comorbidity. However, I also found that it is unlikely that insulin resistance could be a putative cause of schizophrenia. Rather, abnormal inflammation may be a common cause for comorbid insulin resistance and schizophrenia, and this may be related, in part, to shared genetic variation. These findings could at least partly explain why the conditions commonly co-occur. Finally, with the development and testing of the risk prediction algorithm, I showed that it is possible to identify the young people with psychosis who are at the greatest risk of developing future cardiometabolic disorders. In future, such a tool could help clinicians to direct the most intensive interventions in a more informed way to reduce the risk of, or even prevent the cardiometabolic disorders from developing in those individuals.
Five of the six studies in my PhD have now been published in peer-reviewed journals including JAMA Psychiatry, The Lancet Psychiatry and PLOS Medicine.
What made you want to do a PhD?
As a psychiatry trainee by background, I have long been interested in the links between cardiometabolic and psychotic disorders, partly as a result of my observations in clinical practice, beginning with my psychiatry placements in medical school. I found the commonality of schizophrenia and cardiometabolic disorders so stark, and found it such a crucial problem that needs tackling. This was around the time some influential papers were published on the links between inflammation and schizophrenia, which coincided with medical school lectures where we learned of the importance of inflammation in cardiometabolic disorders. I began to wonder if there might be a link! After medical school I joined the clinical-academic training pathway, first in South Wales on the “Academic Foundation Program” and then in the West Midlands as an “Academic Clinical Fellow”. The more I learned about research and research methodology, the more I recognized some important gaps in the literature examining associations of cardiometabolic disorders and schizophrenia. So, with the help of some fantastic supervisors and mentors, I put together some proposals for clinical PhD fellowships to address those gaps with the major funders (MRC, Wellcome Trust and NIHR). I was knocked back by MRC and Wellcome Trust, but this did nothing but drive fire into my belly and then I was extremely fortunate to be awarded a Doctoral Research Fellowship from NIHR which allowed me to come to Cambridge to do my PhD. Hooray!
What was your best day during your PhD?
There were lots, and they can be divided into PhD-related and non-PhD related! One PhD-related day that sticks to mind was the matriculation back in 2018. It was pre-pandemic (remember those days!) and all in-person. It felt such an honour to be joining the University, and the fancy dinner in the beautiful Clare College Great Hall was stunning. It was also a terrific opportunity to meet other matriculating PhD students across all disciplines. I had lots of really inspiring conversations with people who are as passionate about their own subject as I am about mine! Non-PhD-related – I had some huge life events during my PhD – I got married, and we had a baby daughter!
What was your worst day during your PhD?
Obviously, the pandemic made everyone’s lives harder, and the prolonged periods of lone homeworking were tough at times. Also, my parents both became really unwell at separate times during my PhD. Thankfully, the flexibility of the PhD gave me the freedom to travel for hospital visits and to help out at home where needed. In fact, during those times – engrossing myself in work, when possible, became really therapeutic. I’ll also never forget the support and kindness of my supervisors during those times, which really helped me get through.
Do you have any words of advice for future PhD/MPhil students in Psychiatry?
There will be days where it feels like nothing is going right and progress is so slow, or you get completely stuck on something. This happened to me many times during my PhD. At first, I’d glue myself to my laptop and obsess over the problem for hours – and I’d get nowhere. I soon realized that forcing myself away from work for a break to do something I enjoy (exercise always works for me), or even just to write off the day and come back to it the next, were always the best option! You’ll be amazed at what a fresh mind can do to help get past obstacles!
What do you hope to do next?
Now that my PhD is finished, I’ve returned to clinical training and was lucky enough to be appointed a Clinical Lecturer in the Department of Psychiatry. This means I spend half my week in clinical practice (currently in Liaison Psychiatry in Peterborough), and half my week at the University, where I am building on the research I did during my PhD. I’m passionate about one day seeing a version of the risk prediction algorithm I developed in my PhD being used routinely in clinical practice. There’s an awful lot of work to do between now and that passion coming to fruition – but I’m raring to go!