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The Relationship Between Mood Disorders and Metabolic Syndrome

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.

  1. Alberti KG, Eckel RH, Grundy SM et al. 2009. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 120(16): 1640-1645.
  2. Stefan N, Kantartzis K, Machann J, et al. 2008. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 168: 1609-1616.
  3. Mottillo S, Filion KB, Genest J, et al. 2010. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol. 56: 1113-1132.
  4. Vancampfort D, Vansteelandt K, Correll CU, et al. 2013. Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators. Am J Psychiatry. 170(3): 265-274.
  5. Kupfer DJ. 2005. The increasing medical burden in bipolar disorder. JAMA. 293: 2528-2530.
  6. Solmi M, Murru A, Pacchiarotti I, et al. 2017. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Therapeutics and Clinical Risk Management. 13: 757-777.
  7. Janney CA, Fagiolini A, Swartz HA, et al. 2014. Are patients with bipolar disorder active? Objectively measured physical activity and sedentary behavior using accelerometry. J Affect Disord. 152-154: 498-504.
  8. Merikangas KR, Swendsen J, Hickie IB, et al. 2018. Real-time mobile monitoring of the dynamic associations among motor activity, energy, mood and sleep in adults with bipolar disorder. JAMA Psychiatry. Published online December 12, 2018. doi:10.1001/jamapsychiatry.2018.3546.
  9. Yamagata AS, Brietzke E, Rosenblat JD, et al. 2017. Medical comorbidity in bipolar disorder: the link with metabolic-inflammatory systems. J Affect Disord. 211: 99-106.
  10. Hu C, Torres IJ, Qian H, et al. 2017. Trajectories of body mass index change in first episode of mania: 3-year data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). J Affect Disord. 208: 291-297.
  11. Kemp DE, Gao K, Chan PK, et al. 2010. Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome. Bipolar Disord. 12(4): 404-413.
  12. McElroy SL & Keck PE. 2014. Metabolic syndrome in bipolar disorder: a review with focus on bipolar depression. J Clin Psychiatry. 75(1): 46-61.
  13. Yamagata AS, Mansur RB, Rizzo LB, et al. 2017. Selfish brain and selfish immune system interplay: a theoretical framework for metabolic comorbidities of mood disorders. Neuroscience and Biobehavioral Reviews. 72: 43-49.
  14. Forhan M, Salas XR. 2013. Inequities in healthcare: a review of bias and discrimination in obesity treatment. Can J Diabetes. 37(3): 205-209.
  15. Bartels SJ, Pratt SI, Aschbrenner KA, et al. 2015. Pragmatic replication trial of health promotion coaching for obesity in serious mental illness and maintenance of outcomes. Am J Psychiatry. 172(4): 344-352.
  16. Daumit GL, Dickerson FB, Wang N, et al. 2013. A behavioral weight-loss intervention in persons with serious mental illness. N Engl J Med. 368: 1594-1602.

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Ch-Ch-Ch-Ch Changes!  What Causes Depression and How Do Antidepressants Work, Part II

Five years ago, I reviewed some of the scientific literature on the neuroplasticity model of depression – a fascinating new way to think about mood disorders.  Departing from the earlier, monoamine-based ideas – too little serotonin or dopamine –  this model suggests that depressive states are associated with a reduction in the brain’s ability to change in response to experience.  In my earlier review of neuroplasticity, I described how our brains are not fixed organs but are instead constantly changing in response to novel information and new learning.  These changes involve strengthening or weakening of synaptic connections along with growth or shrinkage of neurons.  In health, there is a constant growth, sculpting and refinement of neural pathways. This plasticity becomes impaired in depression:  the brain becomes less malleable, there is reduced new learning and people become trapped in despair.  The neuroplasticity model is a radically different way of thinking about mood disorders.  What follows is an update on research on this area, which has focused on several major developments.  These include the following: 1) investigations of brain plasticity based on visual evoked potentials (VEPs); 2) the use of learning and memory tests to evaluate structural change in the CNS and; 3) emerging research on the impact of antidepressants on neuroplasticity.

While initial investigations of neuroplasticity involved animal research, more recent work has examined correlates of brain modifiability in living humans.   The issue was this: it’s hard to count and measure neurons in healthy adults. Technically near-impossible and ethically impermissible. If the theory holds that changes in the structure and function of neurons mediate mood, how can this be evaluated in human subjects?  Turns out, there are a couple of neat ways to get at this: electroencephalographically (EEG) and behaviorally. In the first case, Normann and colleagues in Freiburg, Germany used the standard brain changes in electrical activity that occur after visual stimulation to evaluate neuroplasticity [1].  The idea is simple: if you present an image of something to a person, neurons in the visual cortex will analyze and register the new stimulus and electrically fire at a certain strength and frequency. Repeat the process and the neuron will fire more strongly indicating that learning and structural change in the brain has taken place and the stimulus is now recognized.  Voila! Using this format, Normann found that these post-stimulation electrical discharges, termed visual evoked potentials (VEPs) are reduced in depressed as opposed to healthy controls.  Evidence entry number one.

The second method uses what is thought to be the prime behavioral marker of neuroplasticity:  learning as indexed by memory. Here too, the logic is straightforward: if new learning is thought to be mediated by microscopic changes in synaptic strength, neuron size and branching, then we should see reduced assimilation of new information and memory integrity in depressed compared to healthy individuals.  Using this experimental design, Nissen and colleagues documented exactly these predictions [2]. In the first case, subjects were instructed to associate one word to another and then remember the pairing. This type of declarative memory is supported by the hippocampus. Depressed patients were significantly impaired compared to their non-depressed brethren.  In the second case, subjects were given mild electrical shocks paired to certain neutral stimuli. Here, depressed patients demonstrated a heightened, amygdala-based, fear conditioning compared to healthy subjects; this suggested abnormally increased neuroplasticity in brain fear pathways in depression.  Human evidence entry number two.

But what’s this got to do with antidepressants?  This brings us to the third and final area of this review.  If structural remodeling and strength tuning cycles are necessary for mental health, what bearing does this have on past and future antidepressant medications?  First, in a 2017 article, Segi-Neshida and colleagues, examined the neuroplastic effects of standard serotonergic antidepressants [6]. Even though these drugs were thought to act through standard monoamine pathways, they outlined previously under-appreciated serotonergic effects on neurogenesis in the hippocampus.  In addition, these drugs also are capable of rolling back or dematuring cells in the hippocampus to a less defined, more pluripotent state. This reversion also supports increased neuroplasticity as the cells can evolve to serve different functions. It appears then that some of the effectiveness of our current crop of antidepressants may be due to their change-inducing properties on neurons.  A group in Italy has taken this idea to the extreme, proposing that depression medications act primarily by enhancing neuroplastic potential and that the actual source of improvement itself, is caused by our life circumstances.  Based on a reanalysis of the STAR-D clinical depression trials and new animal research, they advance the idea that antidepressants serve to loosen things up, so to speak, in our brains and that once we return to a state of optimal responsiveness and reactivity, that the (hopefully) beneficial effects of our psychosocial environments can kick in and lift our spirits [7, 8].  Wow!

In addition to this re-examination of the mechanism of action of existing antidepressants, current research is exploring the design of new antidepressants that specifically target hippocampal neurogenesis.  This is huge! For the past fifty years, antidepressant drug development has largely been a process of repetition and minor-tinkering; these drugs have been designed to inhibit the reuptake of various monoamines and alleviate depression in the process.  While confined to animal research, Mohammed and colleagues recently reported that inhibition of a particular kinase protein in the hippocampus stimulated new cell production and alleviated anxiety [9]. They close their paper by advocating the targeting of this molecule as an avenue for novel therapies against affective disorders.  Hence, neuroplasticity appears to have been a hidden component of past depression treatments and is now an overt target for new antidepressant drug development.

For those of you that have found this area of interest and want to learn about additional new research pertaining to the role of sleep in regulating neuroplasticity, click here.

To summarize, the major developments in the past five years in the field of neuroplasticity and mood include the following headlines:

Using clever new methods, research on neuroplasticity is moving from predominantly animal-based to clinical studies with human subjects.

Sleep and the sleep-wake cycle is a major driver of daily cycles of growth, breakdown, sculpting and refinement of our neural architecture.  Our brains expand and contract on a nightly basis by 20%!

Existing antidepressant medications appear to have previously unappreciated effects on neurogenesis that may contribute to their mood-lifting effects.

New antidepressant medications are being designed to specifically target hippocampal neuroplasticity.

Stay tuned!

John Gottlieb, M.D.

1. Normann, C., et al., Long-Term Plasticity of Visually Evoked Potentials in Humans is Altered in Major Depression. Biological Psychiatry, 2007. 62(5): p. 373-380.
2. Nissen, C., et al., Learning as a Model for Neural Plasticity in Major Depression. Biological Psychiatry, 2010. 68(6): p. 544-552.
3. Tononi, G. and C. Cirelli, Sleep and synaptic homeostasis: a hypothesis. Brain Research Bulletin, 2003. 62(2): p. 143-150.
4. de Vivo, L., et al., Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science, 2017. 355(6324): p. 507-510.
5. Diering, G.H., et al., Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science, 2017. 355(6324): p. 511-515.
6. Segi-Nishida, E., The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors. Frontiers in Cellular Neuroscience, 2017. 11: p. 142.
7. Alboni, S., et al., Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Molecular Psychiatry, 2015. 22: p. 552.
8. Chiarotti, F., et al., Citalopram amplifies the influence of living conditions on mood in depressed patients enrolled in the STAR*D study. Translational Psychiatry, 2017. 7: p. e1066.
9. Mohammad, H., et al., JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche. Mol Psychiatry, 2016.

Neuroplasticity: What’s Sleep Got to Do with It?

Neuroplasticity: What’s Sleep Got to Do with It?

We start with a powerhouse team of neuroscience researchers at the University of Wisconsin:  Giulio Tononi and Chiara Cirelli. These two have been wrestling to understand the basic function of mammalian sleep:  why do we do it? What critical functions does it serve?   In 2003, using a collection of EEG, fMRI and some behavioral memory data, they formulated a new theory on the role of sleep:  The Synaptic Homeostasis Theory, or SHY, for short [3].   This theory asserts four main points:

.   Waking life is characterized by a strengthening of synaptic connections (synaptic potentiation) and a growth of neurons and their component parts.

.   In order to prevent a runaway process of strengthening and growth, which would be taxing on energy supplies and the bony limits of our skull size, sleep selectively reverses these wake-based increases in structure and function through a downscaling, which removes the weaker, newer connections and preserves the more established and important ones.  The growth and revision actions are ultimately balanced resulting in a regulated and constant neuronal weight and size, a homeostasis of synapses., or SHY.

.   The downscaling of synaptic size and function is accomplished by a nightly component of our sleep assemblage, slow wave brain activity (SWA or slow wave sleep, SWS).  Tononi and Chiarelli review the electrochemical magic of how SWS accomplishes this downscaling in depth.

.   Last, they posit that this turnover process of neuronal growth and selective pruning allows for optimal human learning and memory.  It is the basis for taking in and remembering new information.

This theory has received a great deal of attention since its original publication in 2003.

It extends and magnifies the idea of neuroplasticity, suggesting that it occurs not only in adult mammals but that it occurs every night!  Day in and day out.  Again, nearly mind-blowing.

While Tononi and Cirelli marshalled lots of circumstantial evidence to support their original claim, their ideas remained untested until last year.  At that time, two research teams, using different and new technical methods, conducted a pair of studies that were able to evaluate this proposition in decisive fashion.

Published in Science, last year, De Vivo et al used electron microscopy to measure the size of a particular part of the synapse, the axon-spine interface, in over 7000 neurons from two different areas of mouse brain, that were obtained during sleep, on awakening, and after 8 hours of being awake [4].  The results were astonishing. Synaptic area was reduced by approximately 20% after each sleep period. Our brains selectively expand and contract on a nightly basis by 20%!   In further support of their theory, they found that the downscaling preferentially culled the weaker, newer synapses. That last point is relevant in the following way:  each day, we’re each exposed to thousands of new words, sounds, images, sensations, ideas, and interactions. If we remembered everything, our minds would become cluttered and inefficient. To improve the signal to noise ratio, we engage in ‘smart forgetting’ at night that allows us to dispense with the unimportant noisy inputs we all receive and hang on to only the most important new bits.  Though it used mice and not human brains, there is every reason to think that these cycles of daily growth and nightly reduction measured by this study captured a universal micro-architectural turnover process that occurs throughout the central nervous systems of all mammals.

The second examination of SHY was led by Graham Diering at John Hopkins, using another novel method [5].  Instead of counting and examining synapse size, this group measured the cellular signatures and molecular breadcrumbs left behind whenever neurons shift size, change their strength, or form new wiring attachments.  Just like any other building project, when the brain undertakes construction and rehab work on neuronal assemblies, it requires energy, materials and chemical support, the latter termed, trophic support. Trophic support comes in the form of special molecules like BDNF (Brain Derived Neurotrophic Factor) and NGF (Nerve Growth Factor) that encourage growth and neuronal sprouting.  Once construction is started, evidence of the renovation work can be found in several areas. One of the main ways, which brain cells enlarge, is through the incorporation of specialized glutamatergic receptors on their outer membranous layer. Another bulk-adding sign occurs when these receptors become activated through a chemical process of phosphorylation. Employing sophisticated protein fractionation techniques; the team isolated and measured the number of glutamate receptors, their activation level, and density in mice brains comparing the results between the waking and sleep states.  This molecular detective work produced complementary findings to the Di Vivo paper: the number and activation levels, thus the overall weight, of these major synaptic ingredients were reduced by approximately 20% after sleep compared to after wake. Together, these companion publications in one of the world’s most rigorous scientific journals, moves the synaptic homeostasis theory from proposition towards established fact. In so doing, it highlights, like nothing before, the reality and magnitude of neuroplasticity and its indispensability for emotional and cognitive health. Sleep downscales our brain on a nightly basis in the service of memory, and learning.

John Gottlieb, M.D.