Authors Note: If you are interested in taking part in the CODA study, please visit our CODA study page or email coda@kcl.ac.uk.
For millions of people worldwide, obesity and depression are a one-two punch, with each exacerbating the severity of the other in a vicious feedback loop. In England alone, recent reports suggest that around two-thirds of adults are living with overweight or obesity, meanwhile, one in five adults report experiencing depressive symptoms. With how widespread and interlinked the two disorders are, the need for better, more holistic treatments has never been more urgent.
The classic “one-size-fits-all” treatment approach is far from helpful for many conditions; research over the years has continually emphasised the importance of tailoring treatment to each individual. This push towards personalised medicine has inspired exploration into how we look at disorders – not as discrete events but rather as overlapping and interlinked with other disorders.
A Promising Alternative
The frustrating but expected reality is that developing new drugs from scratch is an extremely lengthy and expensive process. In 2023 alone, global pharmaceutical research and development spending surpassed $300 billion, an almost 17% increase from the previous year’s total. The trade association PhRMA estimates that it can take up to 15 years for a novel drug to ultimately receive approval for medical use.
So, what’s the alternative?
One promising option: repurposing existing medications.
Utilising medications that we know are safe for use in humans saves years of time, millions in research funding, and countless failures. In turn, this can grant an expedited approval process, ultimately allowing patients to access necessary treatments more quickly. This can be a particularly attractive route for scientists researching treatments for rare and under-funded conditions.
Furthermore, using an already vetted medication means that we already have information regarding how it works, safe dosing, and potential side effects. This provides researchers, participants, and clinicians greater insight into how the drug will be administered and reduces the risk of unexpected adverse effects. Of course, just because a drug works in one condition doesn’t guarantee it will in another, so vigorous testing must still be conducted.
The Story So Far
In comorbid obesity and depression, one often-suggested link between the two disorders is a dysregulated immune response. The immune system is our body’s built-in first response against infection and other threats in the body. When we are sick, the immune system is activated as a protective response. Though this is a normal and necessary reaction in the short term, when the immune system continually perceives harmful stimuli in the body despite no infection, it can lead to chronically elevated levels of inflammation. This is something that researchers have been noticing in people with obesity and depression and why our lab, The PIXIE Lab, decided to investigate further.
The BARIDEP study (BARiatric surgery and DEPression) was an observational study following patients undergoing weight loss surgery before, 6 months, and 3 years after the procedure. We looked at inflammation in the blood and depressive symptoms over time. In short, we found that those living with both depression and obesity had more chronically elevated CRP levels (C-Reactive Protein: a biological marker of inflammation) than their obesity-only peers.
Running in parallel was the MINDEP study (MINocycline and DEPression): a clinical trial investigating the effects of minocycline in people with depression. Over the years, minocycline has garnered great interest in the field of psychiatry for a myriad of reasons. First and foremost, though the drug is well-known as an antibiotic, its benefits go far beyond fighting infections and, in the context of treatment-resistant depression, its anti-inflammatory properties are particularly noteworthy.
Studies have shown promise for minocycline as an add-on treatment for depression, especially in individuals with elevated C-reactive protein (CRP) levels – a biological marker of inflammation in the blood. If you’re a long-time Inspire the Mind reader, you may remember an article from a few years ago by Dr Etta Nettis about the MINDEP study. Our findings were compelling: while four weeks of minocycline treatment alleviated depressive symptoms compared to a placebo (a sugar pill with no active drug), these effects were only seen in individuals with CRP levels above 3mg/L.
Minocycline’s anti-inflammatory impact isn’t limited to the blood and body though. In fact, thanks to its ability to cross the blood-brain barrier, the drug is able to act directly on the brain's immune cells, called microglia. In individuals with depression, these cells often become overactive, disrupting mood regulation and cognitive functions. Research suggests that minocycline may help “calm” this overactivity, potentially alleviating depressive symptoms.
So, what’s next in the obesity meets depression meets inflammation story?
Introducing: The CODA Study
Taking what we learned from BARIDEP and MINDEP, we designed the CODA study (Comorbid Obesity & Depression with Adjunctive treatment): a feasibility study testing whether individuals with both obesity and treatment-resistant depression can complete an 8-week course of daily minocycline alongside their regular antidepressant treatment, as well as a series of biological sample collections, questionnaires, and brain scans. The study will also aim to provide insight into how minocycline functions in this population, and how helpful using biomarkers of inflammation, like elevated CRP, are to identify patients most likely to benefit from anti-inflammatory treatments.
And after many many months of admin, planning, writing, and rewriting, we finally received our ethics approval and official go-ahead to begin recruitment.
Taking what we learned from MINDEP, we’re only recruiting people with depression, a body mass index (BMI) above 30kg/m2, and a CRP above 3mg/L, since research suggests they are most likely to see improvement with minocycline treatment.
What could this all mean for the future?
As a feasibility study, CODA will help pave the way for a future randomised clinical trial where we can explore the efficacy of this medication in a much larger sample. Likewise, our findings could highlight new targeted approaches to ameliorating depression in people with obesity. Instead of a “one-size-fits-all” approach, we could use criteria like BMI and CRP levels to identify who with TRD is most likely to benefit from anti-inflammatory treatments like minocycline.
Depression and obesity are complex conditions, and finding effective treatments isn’t easy. However, by looking beyond traditional approaches and exploring the role of inflammation, we hope to provide new options for those who need them most.
Research like this is a collaboration between scientists and participants, so now that the study is ready to go, we need your help! You can read more about what participation entails on our website. If all this has you interested, and you think you might be eligible to take part, please don’t hesitate to reach out to us at coda@kcl.ac.uk for more information.