by Lauren LeBano
At the American Psychiatric Association Meeting in Toronto, Canada, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, took part in a Presidential Symposium on the relationship between the body and mind. After his talk, he answered some questions about the immune inflammatory metabolic model for mood disorders.
Psych Congress Network: In your presentation, you mentioned that diabetes and mental illness are related. How do diabetes and mental illness converge from a clinical and circuitry standpoint?
Dr. McIntyre: We’ve known for a long time that diabetes and mood disorders co-occur in the clinical space. We’ve learned that in the brain, there are disturbances in circuits in individuals who have mood disorders and that in diabetics there are disturbances in exactly the same circuits.
So there is not only a convergence from the clinical perspective, but also from the underlying biology perspective as the brain circuits implicated as subserving the disturbance in mood, cognition, and behavior in mood disorders are broadly identical to what we see in diabetes. That convergence implies a common, underlying pathogenesis, which has led to the notion that perhaps we should try to target these circuits with intervention.
That idea is not confined to pharmacology. For example there are interventions that target inflammation and target metabolism and presumably have relevant effects on those very circuits e.g meditation,psychotherapy, diet, exercise.
I often tell my students to remember the CNN, the Circuits, Nodes, and Networks. Imagine the motherboard of your computer and all the little nodes and how a circuit connects them all. And then the circuits connect by networks. And that’s how the brain works. And these circuits, nodes, and networks are what is abnormal in depression and diabetes.
Psych Congress Network: Does this mean that the paradigm that stresses the importance of serotonin is outdated?
Dr. McIntyre: I think there’s been inertia in the field insofar as we had a paradigm based on serotonin. We’ve had 6 or 7 decades with this paradigm, what I call the “high school crush” on serotonin, and we’ve had treatments that fit into that paradigm, such as the Prozac-type drugs, the serotonin agents, etc.
Although that paradigm/treatment applies to a subset of around 10-20% of patients remarkably well, we need to think of ways to reach other subpopulations of patients—the vast majority of patients—and expand our overall success rate from 20% to 100%.
Psych Congress Network: Would a new paradigm replace the old paradigm that focuses on serotonin?
Dr. McIntyre: No, to discard the old model would be throwing out the baby with the bath water. Instead, we need to see if there are other models that can coexist with the old model. And it just so happens that the way the brain is wired means that the two models are not entirely in isolation because of crosstalk. For example, inflammation reduces serotonin.
Psych Congress Network: In your talk, you mentioned glucagon-like peptide I as potentially playing a part in a new approach. Can you expand on that?
Dr. McIntyre: Glucagon-like peptide (GLP-1) is a BDNF mimetic. In addition, it’s a BDNF mimetic that has very high occupancy in the brain. It crosses the blood-brain barrier and has been shown to increase connectivity in the human brain in real people.
So, if we have a hypothesis that what’s really wrong in the circuits, nodes, and networks of the brain is a problem with the synchronization and the calibration of the circuits, then here we have an intervention that is capable of facilitating calibration and connectivity. I say, let’s go with it.
My research group has actually just started studying one of the compounds called liraglutide (Victoza), which is quite common in the diabetes world and is a very popular drug with primary care physicians. That category of agents looks extremely promising because the GLP-1 receptors are in the brain. There’s not a clinical application at the moment, but it’s on the horizon.
Psych Congress Network: Can you comment on why patients with anhedonia still might be active and vigilant? How does this phenomenon relate to new paradigms in approaching mental illness?
Dr. McIntyre: People often ask the question, “If depression is so bad, then how come it’s survived for thousands of years? Wouldn’t it be eliminated through evolutionary selection, ie, people who were very depressed wouldn’t reproduce?”
Well, we know that if you make somebody inflamed by injecting an endotoxin you do 2 things in their brain: cause anhedonia and reduce locomotor activity.
The inflammation also increases the activity in the vigilance region known as the anterior cingulate cortex. That means that the person withdraws emotionally and motorically yet is hypervigilant.
Evolutionarily, this makes sense because what killed us hundreds of years ago was infection and predation, not excess caloric consumption,habitual inactivity and other traditional risk factors for cardiovascular disease. We were being killed by bugs up until 100 years ago at a pretty high rate, until the advent of sanitation, plumbing, vaccination, and other advances.
If our ancestors were foraging for food and became infected, then they needed more energy to fight the wound. However, as they withdrew and reduced locomotor activity to fight the wound, they became susceptible to predators. That’s why it makes sense to be hypervigilant, because we are evolutionarily wired from an immune perspective to fight infection and to heal our wounds.
This is not just a theory. MRI scans have shown that if you make someone immune activated, the hypervigilance center is activated, activity in the motoric region is reduced, and the person becomes withdrawn and hypervigilant. And that’s what depression is. What’s the classic presentation of depression? People are anxious, agitated, and experience a lack of spontaneous activity and increased emotional withdrawal.
In modern times, we’re not going to typically be eaten by a tiger, but we have still evolved to be hypervigilant. We are wired to preserve our energy, to fight infections, and to pass our genes on to the next generation. It’s not very romantic, but that’s why we’re here.
I’ve long passed the days where I would ever believe that one model is going to fit everything, but the immune inflammatory metabolic model has great applicability at the level of connecting the dots between different disorders, because we are wired to fight infection and preserve energy. Energy homeostasis in fighting infections was our day job for the last 50,000 years.
Of course, it’s important to remember that immune inflammation is not going to explain everything for everybody. It will apply to be a subgroup.
Psych Congress Network: Can we identify which patients are in the subgroup that might benefit from the immune inflammation approach?
Dr. McIntyre: It’s important for clinicians to realize that this is not meant to be the only explanation for everyone with a brain illness. It is the explanation for a subgroup, and our task is to become more precise at identifying these individuals. They might have a mood disorder and another disorder, such as diabetes or an autoimmune condition. Maybe they have elevated CRP or IL-1. We don’t know for sure yet.
Psych Congress Network: Without knowing more about who comprises these subgroups, what can clinicians do now?
Dr. McIntyre: Some of the things that have emerged may seem basic—sleep, hygiene, weight management, diet, reducing sugar intake—but many patients aren’t following best practices regarding those habits. Even though these things are admittedly basic, they are potent. Patients who make those changes are helping their immune system and metabolic system.