The brain is the seat of the mind – this fundamental governing principle has driven the study of the biological causes of mental illness for the past century and beyond. For years, scientists have studied the inner workings of our brains in order to better understand mental illness, its causes, and potential treatments. Initial efforts in this area focused on the gross anatomy of the brain and the study of large brain regions. With the discovery of effective psychotropic medications, this gave way to investigation of neurotransmitters such as serotonin and dopamine, and their role in mental illness. In recent history, the focus of scientific investigation has shifted towards the study of brain networks, and the expression of the genes they contain.
In addition to these developments, neuroscience is also moving from a ‘brain-in-isolation’ perspective to a more integrated and connected view of mental and bodily processes. Not only does the brain influence the body, through the release of hormones and neurotransmitters, but the brain is, in turn, influenced by hormones, inflammatory compounds, and other chemicals that are produced by the rest of the body. So, one way to better understand mental illness is to understand how conditions affecting our bodies might be influencing our brains. One such condition that has received recent attention is “metabolic syndrome.”
The concept of “metabolic syndrome” requires some explanation. Metabolic syndrome is a term used by scientists to denote people who have a particularly high-risk form of obesity. People with metabolic syndrome demonstrate signs and symptoms that suggest their body may be more “stressed” by being obese than the average obese person. These signs and symptoms can include increases in blood pressure and blood sugar, changes in blood lipids, and prominent abdominal fat accumulation (1). Why make this distinction? First, there remains debate among medical experts as to whether people can have a “healthy” obese state – meaning that they are obese but not at higher risk of other medical problems due to their weight (2). People with metabolic syndrome are, by definition, already having problems that are due in part to their weight, so it is difficult to argue they are a part of this latter group. Secondly, people with metabolic syndrome are known to be at particularly high risk for cardiovascular diseases such as heart attack and stroke, as compared to the general population and people who are merely overweight or obese (3). Estimates suggest that between 20-50% of people with mood disorders also suffer from metabolic syndrome (4). Recent research has attempted to investigate why metabolic syndrome is so common in people with mood disorders, what effect it might have on the mood disorder itself, and what can be done to prevent and treat this condition.
For a long time, researchers have thought that the connection between mood disorders and metabolic syndrome followed from the behavioral symptoms of the mood disorder (5). Depressive episodes are common in all forms of mood disorder, and the symptoms of depression (such as low motivation, low energy, hopelessness, sleep problems, and changes in appetite) can contribute to changes in the amount of exercise and diet, potentially leading to metabolic syndrome. Additionally, many of the medications used to treat mood disorders (especially certain atypical antipsychotics) are known to lead to weight gain and metabolic syndrome (6).
Recent research has suggested the true picture of the relationship between mood disorders and metabolic syndrome is more complicated. For example, Janney et al. used objective data on daily amounts of physical activity (not just intentional periods of exercise) to demonstrate that, on average, people with mood disorders engaged in only half as much daily physical activity as people without a mental illness (7). This was true even when the people with mood disorders were not currently depressed. It is unclear why this is happening, but it does suggest that the daily number of calories burned due to movement is likely different in people with mood disorders, and not just because of depression. This is a stunning finding that also dovetails with other areas of current research that suggest that “mood disorders” are as much disorders of activity level as they are disorders of mood (8). There is something essential about having a mood disorder that makes a person move less vigorously, less often. Might this mean that a core component of treatment for mood disorders involves increasing daily levels of activity?
Current research has also suggested that the link between mood disorders and metabolic syndrome may be due in part to a shared cause, such as underlying hormonal and biochemical dysregulation. For example, both mood disorders and metabolic syndrome are thought to be caused by elevated levels of inflammation, and by changes in stress hormones such as cortisol (9). If this is the case, then we might hope that treating the underlying shared causes (such as general levels of inflammation) would lead to improvement or prevention of both conditions. Unfortunately, it isn’t clear how that can be done effectively, but research is ongoing.
Metabolic syndrome can be problematic in itself – in particular, it confers a greater risk of developing cardiovascular disease. However, evidence is accumulating that metabolic syndrome may also affect the course and nature of mood disorders as well. For example, Hu et al. in 2017 found that greater weight gain after a first manic episode was associated with subsequent greater risk of relapse, either depressive or manic (10). Kemp et al. in 2010 found that, among persons with rapid-cycling bipolar disorder, metabolic syndrome was associated with a decreased likelihood of response to treatment for bipolar disorder (11). On the whole, it seems that metabolic syndrome may worsen the course of mood disorders. Interested readers can review McElroy & Keck 2014 for a relatively recent, comprehensive review of such evidence (12). The suggestion is that part of the effective management of mood disorder means attempting to prevent the onset of metabolic syndrome, by managing weight, diet, and exercise, and preventing metabolic complications of treatment.
Why might metabolic syndrome make mood disorders worse? How can metabolic syndrome affect the processes in the brain relevant to mood disorders? Yamagata et al, in 2017, have advanced a novel hypothesis that attempts to synthesize what is currently known (13). Dubbed the “selfish brain / selfish immune system” theory, this group suggests that our brains are in constant competition with our immune systems for a precious resource – fuel, in the form of sugar (glucose). These two vitals organs may each require varying levels of fuel depending on their current status. For example, under the stress of a job interview, the brain needs more fuel in order to enhance performance, alertness, and cognition. In the case of a mood disorder, being depressed or highly anxious also causes the brain to demand more fuel. Similarly, under a stress (such as an infection), the immune system also demands more fuel in order to fight the infection. Metabolic syndrome is associated with elevated levels of inflammation; this inflammation also acts as a stress on the immune system, causing it to demand more fuel. So, in the case of having both a mood disorder and metabolic syndrome, there is chronic heightened competition between the brain and immune system for fuel. Under conditions in which this competition is too great, or there is not enough fuel, the brain may be damaged at the cellular level by the absence of adequate fuel. It is hypothesized that the accumulation of this cellular damage in the brain may account for the worsening of mood disorders associated with metabolic syndrome.
We thus have reason to pay special attention to metabolic status and weight in the management of mood disorders. But what can we do to address this concern? First, careful prescribing on the part of the psychiatrist, taking into consideration the likely metabolic consequences of medications and avoiding those with greater metabolic risk when possible. Second, the effective utilization of treatments for mood disorders that involve little to no metabolic risk – these include psychological interventions, chronotherapies, neuromodulation, behavioral therapies, and (some) medications. Third, the development of a shared understanding between doctor and patient as to the importance of managing weight and metabolic status as a component of the treatment of a mood disorder. This needs to be done in a sensitive and nuanced manner, that avoids stigmatizing or shaming persons with obesity – a problem found to be rampant in society at large, as well as pervasive in the medical community (14). Such an approach incorporates feedback from the patient as to how weight and potential struggles with diet and exercise have been experienced, and what has and has not worked for the patient in the past. Fourth, the application of evidence-based practices for weight management when possible, particularly incorporating evidence as to what practices work best for persons with mental illness. This latter area remains under further study, and indeed demands much further study. One clear finding from this body of research is that the most effective and sustained exercise programs for persons with mental illness are those that involve social contact and a regular, expected pattern of attendance (15, 16). Medications to treat and prevent metabolic syndrome may also be considered, however this must also be done carefully, as many such medications interact with psychotropic medications or can affect the patient’s underlying mental health conditions.
To review: metabolic syndrome is a complication of obesity associated with a multitude of biochemical changes in the body. Metabolic syndrome is common in patients with mood disorders, for a variety of reasons, including low levels of physical activity and iatrogenic effects. The presence of metabolic syndrome appears to worsen the course of mood disorders, potentially by depriving the brain of adequate fuel to sustain normal cellular functioning. Prevention and management of metabolic syndrome are therefore an integral part of the effective treatment of mood disorders.
Kurt Kastenholz, M.D.