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The unintended negative consequences of the coronavirus disease 2019 (COVID-19) pandemic continues to be a problem. Reduced social interaction and closure of public places, along with increased home confinement, has led to a sharp decrease in physical activity, a steady increase in food intake, and a 

 Stress has similarly impacted sleep, unhealthy eating, and even increased consumption of alcohol.

Public health and economic crises have been associated with serious, long-lasting negative impact on individual and population-based mental health outcomes. Indeed, a recent meta-analysis found higher rates of 

, depression, posttraumatic stress disorder, psychological distress, and stress during the COVID-19 pandemic.

 To further complicate matters, individuals are less likely to seek non-emergent health care, including care for mental disorders, during the pandemic.

Related health consequences of obesity such as hypertension and diabetes mellitus are a major source of morbidity.

 Stress, fatigue, physical inactivity, and a sedentary lifestyle can advance obesity and, subsequently contribute to a number of mental health disorders.

 Depression and obesity share a bidirectional relationship, where the presence of one disease increases the risk for developing the other (

 Increased carbohydrate consumption, a risk factor for obesity, is common in patients with depression. The presence of obesity often has a chronic course of illness and can result in poor treatment response in depression.

 are predominantly treated with antidepressants as a first-line treatment option, with 79% of primary care physicians prescribing antidepressants to these patients.

 Recent studies have shown that antidepressant medications can contribute to weight gain through various mechanisms, including increased food consumption and abnormal metabolic processes.

 Reductions in depressive symptoms and antidepressant usage may coincide with weight loss (as seen with bariatric surgery patients), and this underscores the importance of monitoring the increasing rates of obesity.

For the last 2 decades, depressive disorders have consistently ranked amongst the top 5 illnesses for years of life lived with a disability.

 Cognitive deficits is a core symptom of depression, and it often persist between affective episodes and beyond the remission of mood symptoms.

 Executive functioning, attention, memory, and learning can be affected.

 Obesity also contributes to impairments in cognition; individuals with obesity exhibit significantly impaired cognitive functioning and structural changes in brain regions associated with executive functioning.

 Moreover, in individuals with obesity, cognitive impairments 

 lower weight loss success, poor treatment adherence, and decreased physical functioning.

Individuals with a longer duration of illness and a higher frequency of depressive episodes are more likely to experience cognitive impairments. Persistent cognitive impairment contributes to consequences in occupational and social domains.

 In particular, evidence from adults with mood disorders implicates cognitive impairment as a mediator of workplace function and attendance, as well as patient-reported outcomes (eg, quality of life).

 Approximately 15% of patients with major depressive disorder attribute their unemployment to cognitive symptoms. Unfortunately, few treatments, including psychotropic medications, have proven effective in improving cognitive function in adults with mood disorders, especially in cases of treatment resistance.

Patients with comorbid depression and obesity often demonstrate higher levels of baseline inflammation, which is characterized by a higher level of inflammatory cytokines (a type of signaling molecule that promotes inflammation). Likewise, obesity involves a pro-inflammatory state. Conversely, findings have shown improved cognition is linked to a reduction in inflammation.

 Indeed, in a meta-analysis evaluating inflammation and treatment response, researchers found increased levels of inflammatory cytokines in patients with depression. In cases that successfully responded to treatment, the levels of inflammatory cytokines were decreased.

There are several proposed mechanisms that may mediate the relationship between chronic stress, inflammation, and mood disorders. Stressful experiences have been shown to increase production of cortisol. Glucocorticoids increase activities of the sympathetic system, such as heart rate and blood pressure, to reduce the stress response. However, if this system is dysregulated, chronic stress and cortisol production can lead to the desensitization of the glucocorticoid receptors. It can be conjectured that the dysregulation of the inflammatory pathway is also worsened by the presence of insulin resistance and increase in adipocytes. The bidirectional relationship between the 2 illnesses and the co-occurrence of an inflammatory state underscores the involvement of inflammation in the pathophysiology of depression and obesity.

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects. For more severe cases of depression, 

 in conjunction with other treatments (ie, pharmacological).

 Exercise may also help improve cognition in individuals with depression. In a study investigating the dose-dependent effects of 

 on cognition in patients with depression, high-intensity exercise was associated with improvements in executive function and working memory tasks. Meanwhile, other cognitive domains, such as attention, visual memory, and spatial planning, improved regardless of dose.

 Therefore, it is importan that adequate social and physical activities are integrated into treatment plans to promote well-being.

is a researcher at the Canadian Rapid Treatment Center of Excellence and the Institute of Medical Science at the University of Toronto. 

is a professor of psychiatry and pharmacology at the University of Toronto, and Head of the Mood Disorders Psychopharmacology Unit for the University Health Network, Toronto, Canada.

Effect of obesity and body mass index on coronavirus disease 2019 severity: A systematic review and meta‐analysis

2 .Xiong J, Lipsitz O, Nasri F, et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review.

3. Alosco ML, Spitznagel MB, Strain G, et al. Improved serum leptin and ghrelin following bariatric surgery predict better postoperative cognitive function.

4. Sarris J, O’Neil A, Coulson, et al. Lifestyle medicine for depression.

5. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.

Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices.

7. Gill H, Gill B, El-Halabi S, et al. Antidepressant Medications and Weight Change: A Narrative Review. (Silver Spring)

8. Collaborators G 2016 ORF, GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of disease and injury in 2016 arising from occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016.

9. McIntyre RS, Lee Y. Cognition in major depressive disorder: a “Systemically Important Functional Index” (SIFI).

10. Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR. Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

11. Spitznagel MB, Garcia S, Miller LA, et al. Cognitive function predicts weight loss after bariatric surgery.

12. Rasmussen LJH, Caspi A, Ambler A, et al. 

Association of Neurocognitive and Physical Function With Gait Speed in Midlife

13. Baune BT, Air T. Clinical, Functional, and Biological Correlates of Cognitive Dimensions in Major Depressive Disorder – Rationale, Design, and Characteristics of the Cognitive Function and Mood Study (CoFaM-Study).

14. McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: response to remission to functional recovery.

15. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. 

16. Schuch FB, Vancampfort D, Richards J, et al. 

Exercise as a treatment for depression: A meta-analysis adjusting for publication bias

17. Greer TL, Grannemann BD, Chansard M, et al. Dose-dependent changes in cognitive function with exercise augmentation for major depression : results from the TREAD study. 

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects.

A Recipe for Homemade Obesity: The Association Between Depression, Obesity, and Cognitive Deficits

Aaron Burstein, PharmD, senior vice president of 

, shares the history and current status of development of 

for the treatment of dementia and diabetes, including results recently presented at the 2020 Alzheimer's Association International Conference.

Aaron Burstein, PharmD, shares details from a scientific presentation at the Alzheimer's Association International Conference.

Investigational Treatment Shows Potential to Supress Memory Loss

Longstanding evidence suggests that schizophrenia is associated with type 2 diabetes mellitus (DM2). The research includes maternal and birth studies that identify common risk factors for both conditions, including nulliparity, gestational diabetes, preeclampsia, birth weight, and season of birth.

 Studies before the advent of antipsychotics showed an increased prevalence of abnormal glucose metabolism in patients with schizophrenia, albeit with methodological limitations.2 There is also evidence for impaired glucose tolerance and insulin resistance in patients with first-episode psychosis who are either antipsychotic-naÃ¯ve or have minimal antipsychotic exposure.

These findings suggest that some of the increased risk of DM2 in schizophrenia may be independent of antipsychotic medications and involve host-agent-environment interactions. However, this hypothesis has largely been overshadowed by known metabolic adverse effects of second-generation antipsychotic medications, which increase the risk of DM2.

Schizophrenia is associated with an increased risk of the metabolic syndrome, a constellation of metabolic risk factors-including abnormal glucose tolerance-associated with cardiovascular disease morbidity and mortality.

In an earlier study, patients with schizophrenia and other nonaffective psychoses (NAP) and a parental history of DM2 were found to have a 3.7-fold increased odds of comorbid DM2 compared with patients without this parental history.

to understand the association between a family history of DM2 and DM2 comorbidity in patients with NAP.

Studies were identified by systematically searching Medline, PsycInfo, Web of Science, and Science Direct. Nonaffective psychosis was defined to include schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, schizoaffective disorder, and psychotic disorder not otherwise specified. One hundred thirty-six potential studies were identified; however, most were excluded because of missing family history data about DM2, or because the diagnoses were primarily affective psychosis. Case reports were also excluded. After a detailed review, 10 studies met the inclusion criteria.

Data used included number of subjects with and without a family history of DM2 based on comorbid DM2 status, as well as other clinical and demographic variables. Effect size estimates (odds ratios [ORs] and 95% confidence intervals [95% CIs]) were calculated using the random effects method. Given significant between-study heterogeneity, a sensitivity analysis and a series of meta-regressions to explore possible moderating variables we used to account for heterogeneity (eg, age, sex, geographic region, body mass index, year of publication, study quality).

The total sample consisted of 3780 patients with nonaffective psychoses, including 804 subjects with a family history of DM2 and 2976 without a family history of DM2. A family history of DM2 was associated with more than a four-fold increased odds of comorbid DM2 (OR = 4.3, 95% CI 2.9-6.4, P < .001), with significant between-study heterogeneity. In sensitivity analyses, after removing two outlying studies with the highest OR, the association remained significant (OR = 3.3, 95% CI 2.6-4.3, P < .001), but between-study heterogeneity was no longer significant. A funnel plot and Egger’s test were not significant for publication bias, although findings should be interpreted with some caution given the small number of studies. In meta-regression, there was a significant, positive association with age, but all other potential moderating factors were unrelated to the association between comorbid DM2 and family history of DM2.

The findings showed a family history of DM2 is associated with more than a four-fold increased odds (OR=4.3) of comorbid DM2 in patients with nonaffective psychoses. Sex, geography, BMI, study quality, or year of publication did not moderate this association. However, the association was moderated by older age, which is a known risk factor for DM2. The results are broadly consistent with those in general population studies, which have reported a 2- to 4-fold increase risk of DM2 with a parental history of DM2.

 Therefore, the results do not suggest that a family history of DM2 is associated with differentially increased odds of DM2 in patients with schizophrenia compared with individuals in the general population.

An important strength of the study was the relatively large cumulative sample size of patients with and without comorbid DM2. A limitation was the heterogeneity in the definition (eg, parents versus any first-degree relative) of what constitutes family history of DM2. For most studies, a family history of DM2 was based on subject self-report. Thus, there is potential for selective recall bias. Data on family psychiatric history were not available for the vast majority of studies, limiting inferences on what proportion of cases of a family history of DM2 might be attributed to psychotropic medication-induced diabetes. However, it is reassuring that the odds of a family history of DM2 in patients with nonaffective psychosis was broadly consistent with findings in the general population. The study did not permit inferences regarding the mechanism(s) of this association, which may be due to shared environmental or genetic risk factors, or gene-environment interactions.

Given the high risk for metabolic syndrome, the association in the study suggests that screening for a family history of DM2 is germane to the clinical care of patients with schizophrenia and other nonaffective psychoses, as it can inform on risk of incident diabetes with antipsychotic treatment. However, it is important to emphasize that patients without a family history of DM2 are also vulnerable to the diabetogenicity of some antipsychotics. Nevertheless, stratifying patients based on DM2 family history status may increase the signal-to-noise ratio of future trials of adjunctive agents for antipsychotic-induced metabolic dysfunction.

This article was originally posted on December 5, 2019, and has since been updated. -Ed.

is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is the Schizophrenia Section

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Kandhal P, Miller BJ. Shared early life risk factors for schizophrenia and diabetes. 

2. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. 

3. Greenhalgh AM, Gonzalez-Blanco, L, Garcia-Rizo C. et al. Meta-analysis of glucose tolerance, insulin, and insulin resistance in antipsychotic-naÃ¯ve patients with nonaffective psychosis. 

4. Perry BI, McIntosh G, Weich S, et al. 

The association between first-episode psychosis and abnormal glycaemic control: systematic review and meta-analysis

5. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. 

6. Miller BJ, Goldsmith DR, Paletta N, et al. 

Parental type 2 diabetes in patients with non-affective psychosis

Meta-analysis of comorbid diabetes and family history of diabetes in nonaffective psychosis. 

8. Papazafiropoulou AK, Papanas N, Melidonis A, Maltezos E. 

Family history of type 2 diabetes: does having a diabetic parent Increase the risk? 

New insights on the association between family history of type 2 diabetes and comorbid diabetes in patients with schizophrenia and other nonaffective psychoses.

Family History of Diabetes: Is There an Association With Nonaffective Psychosis?

A. Comorbid anxiety and diabetes mellitus is known to occur more than would be predicted by chance alone

B. The American Diabetes Association recommends screening patients for symptoms of diabetes-related anxiety and distress

C. GAD-7 is not an appropriate instrument for screening of anxiety disorders in individuals with diabetes mellitus

D. Hypoglycemic episodes can be a cause of anxiety and panic symptoms in diabetes mellitus

What do we know about psychiatric symptoms that may present in patients who also have diabetes? Take the quiz and learn more.

Mini Quiz: Diabetes Distress and Anxiety

The neuroprotective role of resilience in patients with schizophrenia who experienced early childhood trauma is evaluated in this brief update.

Silver Linings After Abuse and Neglect


with David Carreon, MD and Jessica A. Gold, MD, MS

Here: Part 3 of 3 with Emeran Mayer, MD, PhD on the mind-gut connection. Dr Mayer talks about the role of the gut in psychiatric illnesses and mood-from a history of forced colectomy in psychiatric patients to an inflammatory diet influencing mood. He answers the question: are we happier when we don’t eat sugar or gluten and should we all be gluten-free? Dr. Mayer is a pioneer of medical research into brain-gut interactions and author of 

The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health.

David Carreon: Let's also talk about nutrition and diet and microbiology of psychiatric conditions. I know there's been some discussion and some work that you've ended up with around depression and probiotics or depression in the microbiome. How good is this evidence, or what is the relationship between something that we would consider a psychiatric illness and the gut?

Emeran Mayer: As you know, some 100, 150 years ago, there were psychiatrists who are actually obsessed with the role of the colon and fermentation and it led to this unfortunate situation that many psychiatric inpatients in hospitals had to forcefully undergo colectomy and many died because ... There was a phase where psychiatry was actually very much interested in the microbes playing a major role in the psychiatric disease. That obviously has completely disappeared. Today, there's something new that's sort of come up, and that's the role of diet in influencing the nervous system. Felice Jacka in Australia has recently published the SMILE Study. She and her colleagues found that in a randomized study, if they compared the outcomes of patients, I think it was with major depressive disorder, who underwent conventional therapy and their regular diet vs with conventional therapy with a Mediterranean-type diet, there was a significant difference. She has written about this topic.

One explanation of that is related to this concept of an inflammatory diet. We know that high fat, high sugar diets change the microbiota in a way that there's a whole series of events. Increased permeability of the gut is the result of that, increased access of micropolysaccharides or other pro-inflammatory molecules, the gut-associated immune system, which then creates a ... It's not full-blown inflammation, like in inflammatory bowel disease, but a low-grade inflammatory state which then often becomes systemic, so you have circulating LPS levels. My opinion, that's most plausible explanation. As you know, neuroinflammation has been so implicated for depression and other psychiatric diseases as well, so it could well be that diet plays a role in exacerbating it. Certainly not diet is the cause of psychiatric disease, but it's a significant modifier.

Jessi Gold: I've heard people say that when they went on sugar-free diets, or when they went on gluten-free diets that their mood improved. Do you think that's true with what you're seeing in research? Is it totally subjective and they just believe in the diet?

Emeran Mayer: There's certainly, with anything diet, a huge psychological dimension. I think there's few things that have such a placebo effect as diet has. The high-sugar phenomenon, I do believe, because we know a lot about this. High sugar, high fat, it's sort of like opiates. It makes you feel better right away. That's why people almost self-medicate when they're stressed out you crave for something like that. In the long-term, it has these detrimental effects and leads to this low-grade inflammatory state. I think when people say that when they switch their diet to a healthy diet that they feel better, I certainly believe that. In terms of the gluten, that's a whole other story.

As a gastroenterologist, I'm obviously fully aware of the seriousness of celiac disease. It does appear now probably also related to the microbes and the early interaction with the immune system that people develop more and more hypersensitivities and even allergies to food items that 20 years ago nobody ... Like the peanuts and wheat ... If you have that condition, if you eliminate any agent, most likely you will feel better as well, but then you have, it's like 40% of the US population now, who thinks gluten is toxic for them. That's really unsubstantiated. There's nothing that's been found, sort of like IBS, you can take biopsies, you don't find any possible pathological or pathophysiological mechanism.

There was an interesting phenomenon. This really started with a book that came out by a person, an author, won't mention the name, that before was really on the candida connections. This was an early phase that people say all your symptoms, including IBS and fibromyalgia and everything was related to candida and it was due to the high sugar. The same group of people that promoted that like some 20 years ago, are now promoting this gluten-free diet. All the things before there was sugar across all these orders, now it's gluten. That single book, called

 I personally think is responsible for most of that worldwide, I like to call it hysteria, really, which is centered in the US, which is interesting. You go to any other part of the world, people love bread, couldn't live without bread. Whenever I go to France, I ask people, "Have you heard of a gluten sensitivity?" They just laugh at you.

Like many things in science, there may be a certain truth to it. Give you this example about the candida connection, so now that we not just measure the microbiomes, as people have started to look at the virome and the fungi, there is now scientific evidence that people have increased levels of certain fungi, including candida. It would be sort of an amazing thing that 25 years after this non-scientific theories came out that we would support this. That could happen with gluten as well. I have a personal opinion, but as a scientist, I like to say nothing is impossible.

Jessi Gold: Yeah, it's crazy to think one person could write a book and then everyone stops eating bread.

Emeran Mayer: Yeah, it's amazing. An amazing phenomenon.

David Carreon: Yeah. We are running low on time, so we'll have a few more rapid-fire questions and if you can answer in one or two sentences max, we'll go through these questions. Before we do, I also wanted to ask you to say a little bit about the book that you just published. What's it about and who should read it?

. It's written for the lay public and I would say it's not just for the lay public, it's also the lay public, but also for a lot of professionals who are not microbiome experts and have not been aware of the science that has involved brain-gut connections and brain-gut microbiome connections. It has a lot of different things in it, different topics in it, from neurobiology of gut feelings, emotional regulation, early life events and influence to diet and optimal health, which is the final conclusion. I think everybody should read it. Even for experts in the area, there's parts in it, including patient anecdotes. Interesting thing to me, now a lot of patients come to me that have heard about the book or read the book and they say, "I am so-and-so in your book. I don't have to tell you much about my symptoms. I'm so-and-so in your book." I think it must have resonated a lot with patients.

Jessi Gold: As a psychiatrist, which sort of patient in my clinic should I recommend would read your book? Is it any illness, anything?

Emeran Mayer: I would certainly say patients with depression, anxiety, particularly if they also have experienced GI symptoms. Autism spectrum disorders, those would be the three main that ... There's also a lot of evidence, Parkinson's disease playing a role. I would say you could probably recommend it to every patient.

David Carreon: Good. I think that sounds like a fascinating book and I'm looking forward to reading it myself.

David Carreon: First rapid-fire question is, in a sentence or two, what does the field of psychiatry and mental health, where is it that we go most wrong? What is the biggest oversight or mistake that we make?

Emeran Mayer: I don't see patients in a psychiatric clinic. I would say to kind of stop at the neck or not go into the body is, in my opinion, a big flaw. I'm sure there's some psychiatrists who do that. I see the same patients from the opposite end. Most of them have anxiety and depression and compulsive disorders, but I start at the body. I always see the symptoms at the body. They're clearly both there, and I think with psychiatrists, that would be an important lesson.

Emeran Mayer: My favorite book, I would say 

by Taleb. Realizing the complexity of the world and the more complexity, the more interconnectedness and the more unpredictable it becomes. I think our brain functions, also discusses in the book, is a prediction machine that tries constantly to make predictions and if that's done in a linear way, they will almost certainly go wrong. In a complex world as today, it's no longer possible to do that.

David Carreon: What advice would you give to a young doctor, a trainee?

Emeran Mayer: I would say listen to your patient. Most things that the patient will tell you can be explained in a holistic model of brain and body. I would say listen to the patient and don't reject things that don't fit your textbook description. Most textbooks will become obsolete in 10, 15 years. What the patients say, I've experienced this in ideas, research, has stayed the same, and now we're finding so many answers.

Jessi Gold: What is your favorite food and what is your favorite food to recommend to patients to feel better?

Emeran Mayer: While writing my book, I've become a big fan of the Mediterranean diet for various reasons. Since then, since I pay a lot more attention now to dietary factors, it seems there's almost universal agreement that a Mediterranean-style diet, it doesn't have to come from Italy or Spain, many traditional Asian diets have the same composition of 75% plant-based foods and small amount of meat, protein. I would recommend, even in psychiatry now I think it's the same that's in the study showing the slowing of Alzheimer's progression, depression seems to be universal truth to that. It's tasty, you don't have to eat strange things or elimination diets. It's a tasty diet and it's probably one of the best documented health benefits of anything.

David Carreon: What is your favorite species of bacteria?

Emeran Mayer: That's a tough one. There's one, one out of several, that's called Akkermansia muciniphila, funny name. The second name, you can hear the recent connections. They are a bacteria that stimulate especially the cells in intestines that put mucin, mucous, and that's a very healthy thing because the thicker the mucous layer is, the more we're protected from a leaky gut and Akkermansia goes up with a high plant-based diet. It's the food that nourishes these organisms.

Jessi Gold: The last question is, is there a person that you would consider a hero, either living or dead or fiction, somebody that you would consider a hero?

Emeran Mayer: That's a tough one. I would say, let's limit it to the microbiome field, Martin Blaser from NYU, who has sort of been the main driving force behind revealing the detrimental effect of antibiotic use, inappropriate antibiotic use on microbial diversity. He's written a phenomenal book, Missing Microbes, which I would recommend to anybody because you will change your antibiotic prescribing behavior dramatically once you've read this book.

David Carreon: Excellent. Thank you for joining us on the show.

Are we happier when we don’t eat sugar or gluten and should we all be gluten-free?

Is There a Relationship Between Mood and Diet?

Here: part 2 of a 3 part interview, with Emeran Mayer, MD, PhD on the mind-gut connection. Dr Mayer talks about irritable bowel syndrome (IBS) as an example of a known brain-gut disorder, focusing on the research on dysbiosis-alteration of the gut microbe from healthy individuals-and what it means for the 15% of world population suffering from IBS. He answers the question: is it all in patients' heads? He also discusses the development of the gut microbiome in infants and the influence of prenatal events, breastfeeding, and antibiotics on gut content.

 This is the fascinating idea that neural hacking, that the bacteria are hacking into our nervous system to get what they want. That's such a cool idea and I’m certainly excited to see what the science shows as this field develops. Would you talk a little bit about maybe an area where the communication relationship is more well established. You mentioned IBS a little bit earlier. Could you explain what is IBS and what is the gut microbiome have to do with it?

 IBS is the acronym for Irritable Bowel Syndrome, a very common disorder, about 15% of the world population are affected. It's a syndrome defined by symptoms because we don't really have a biomarker for it. It's a combination of chronic, recurrent abdominal pain and discomfort and altered bowel habits. It seems like a very loose definition, but it's pretty accurate, with a pretty high sensitivity and specificity, if you can rule out other causes for these symptoms.

 I think just to pause and emphasize there's something that I don't think everybody is aware of, but 15% of population and you put an endoscope in, do a colonoscopy and there's nothing there, there's nothing that you can see or take tissue. It's not something that you can diagnose with objective, at least thus far, signs. That's a huge burden. I think the emphasizing the importance of figuring out what it is, what's going on, trying to better characterize this thing that's rather common and underdiagnosed.

 What has happened this area, because it's recognized as a 

, so when the microbiome science started, immediately people jumped on it, including ourselves. There's a series of studies that they all can be criticized based on small sample size, mixing males and females, not controlling for diet. Then, not unexpected, several labs found different abnormalities. These abnormalities are called dysbiosis; that means an alteration of the gut microbial composition from a healthy control population. Most of the studies have found evidence for dysbiosis even though the type of dysbiosis, what taxa are altered, if there's increased or decreased diversity and abundance has varied from study to study. The latest evolving concept is that there are several subtypes of IBS based on their microbial signature, as many want to call it. One that's indistinguishable from healthy controls and one that has significant dysbiosis. Interestingly, these two do not correlate with the typical clinical parameters that we use, like bowel habits, subtype, or pain versus discomfort. Seems to have a different function.

You may ask yourself, if half of the patients have a normal microbial composition, the others have an abnormal, but they have the same symptoms, do these microbes really have a causative role, or is this something that's a consequence of something else? My personal feeling about this is that, and that's often forgotten now in this fascination that the microbes can talk to us, that our brain can really effect the microbes, both their environment in which they live, meaning the transit rate through the intestine and the stomach, which is regionally regulated, slow versus fast transit, the secretion.

Many things are being secreted, which the brain sort of modulates, like the defensins from Paneth cells, there are many endocrine cells, serotonin cells in the gut, enterochromaffin cells, which are under autonomic control, so that we now know that serotonin, as well as norepinephrine, can, under stress for example, increase in the lumen of the gut. Since these microbes have receptor or analogs for those substances, can influence their behavior. What I think, and I've had sort of this bias for a long time and seen a lot of those patients, that this is something that really starts at the brain level, possibly, most likely early in life. Could be stress, hyper-responsiveness, or increased emotionality, which sends chronic signals to the 

 and changes their development. The first three years of life, the microbes, the community is actually shaped, so if during that time there's an imbalance of the autonomic influence on these microbes, they will assemble in a different way. That may happen in some patients and not in others. That's why I personally think you now find a subgroup of IBS patients that have a normal gut microbiota. There's other people that disagree with that, but I think, we'll see.

IBS has been an interesting research area, interesting in quotation marks. So many hypothesis, just during my career, have been proposed to explain it, and most of them have come and gone. Right now it's the microbiome. We'll see if this is the final answer.

 I've heard people say that IBS is all in people's heads and it's all anxiety and there's nothing else besides anxiety and the idea that it's a separate disease entity is wrong.

 That's the thing. When people say it's all in the head, this got a bad name and a very bad impression for patients because what the physicians meant, it's not a neurobiological process, but it's a neuroticism. I still am, in my early parts of my career I sort of taped these talks of the leaders in the field that would say it's a disease of neurotic housewives, middle-aged neurotic housewives. I think now, when we know so much more about the brain and how intricately it is connected and wired with the gut and back to the brain, I think this has a different connotation. I would never use that term to a patient, "It's all in your heard," but surprisingly, if you explain to them with the concept of the brain-gut axis, they all agree, they'll all tell you, "Oh, yeah, I've always known that it's connected to my emotional state or to the stress." It's very few patients, if you give them the right model, that would not accept that.

One of the things you said just a few minutes ago was that the gut microbiome is established around the ages of zero to three, which, as a psychiatrist, is very interesting. We talk about how critically important the first few years of life are for the psychological development, but you're saying that those years are especially important for the microbiological development as well.

 Yeah. The microbiome has added another dimension to the importance of developmental diseases. We also know that it predates delivery as well, so prenatal influences. Very interesting studies that, for example, nutrition of the mother, the pregnant mother, stress of the pregnant mother have an influence on the development of the microbial composition and abundance and diversity, and there's even an animal experiment that shows some very intriguing mechanism that stress of pregnant mother changes the microbial composition of the vaginal microbiome and when the baby goes through the birth canal, one initial seeding of the infant's gut microbiome comes from the vagina. In these animal experiments, it's been shown that stressed mother, different vaginal microbiome, the gut microbiome of the newborn is different because of that different priming. Again, in animals, that was associated with a change in brain development in the first few months of life. If that happens also in humans, it just illustrates the importance of prenatal events on the development and the architecture of the gut microbiome of the infant.

After three months, it seems to be fairly stable. It's also very important concept. Regardless what you do later, if you become a vegetarian or become gluten-free or whatever, your microbes will change and the metabolites that they produce will change, but if you go back to the default diet, you'll go back to that same architecture that you had after three years. You don't change that basic ... You can modify it in a certain bandwidth, but you can not really reverse it. There's very few exceptions.

Treatment with antibiotics could do that and also there's this one infection, this C. difficile colitis, which can basically knock out most of your microbes and lead to this overgrowth of the C. difficile organism. Antibiotics, I should mention that they also now have gotten a very new meaning because an extensive amount of antibiotics given to babies, the mother during pregnancy, treatment of the vaginal area with antiseptics, prophylactic antibiotics to the mother to prevent sepsis, this is a huge field. The amount, I forgot the number, that infants by the age of three have received an antibiotic dose is just phenomenal. That clearly interferes with that establishment of the gut microbiome.

 You're saying that before age three, there's stress, there's antibiotics, there's whatever else the mother went through, there's just natural stress to the infant, how does then from three on can you regain that, are you just now at a disadvantage as a kid because you have this altered microbiome for life?

 As I said before, it doesn't stay exactly the same, but I think the current thinking, and you always have to realize that we're just at the very beginning of this microbiome science. This is like, let's say the first decade of neuroscience 150 years ago. I think a lot of things we're talking about today will be thrown out. Yes, pretty much the basic structure, it's like the operating system is established. You don't change during life the operating system of your gut microbiome. You can add new software to modulate it, but the operating system stays the same.

 Interesting. That's an interesting analogy. What is the heritability of it? Where do the microbes that are in my gut, where do they come from? You mentioned the birth canal is one source.

 Yeah, there are a lot of influences. I should have also mentioned breast feeding during the first three years of life. One very interesting mechanism of how they're programmed. One is clearly the genetic make-up of the infant's GI tract that attracts certain parts of the gut, different communities of microbes. The microbes are not, the microbiomes are not a homogeneous population from the stomach to the end of the colon. In each of those areas, we have to assume there's different communities that are attracted to these regions by genetic influences of the person.

In addition, during programming, in the breast milk of the mother there are these so-called human milk oligosaccharides, or HMOs. These are large molecular substances that cannot be absorbed by the infant's GI tract, so they evolved to the evolution exclusively as food for the microbes of the infants. They play a major role in establishing this community early on. Does a large number of these HMOs that are contained in mother's milk, they're influenced by the genetics of the mother and they're also influenced by the diet of the mother. Two major genetic influences. One is through this early nutrition of the microbes comes exclusively from the mother, then the GI tract of the infant it comes only from genes of the father and mother. There are examples. Genetics don't dominate the population. They play an part. I think there is some mouse models, where  genetics play a much bigger role, but in humans, I think influences other than genetics have a major influence, including early nutrition.

In this exclusive interview, Psyched! podcast hosts continue the conversation with a leading researcher on mind-gut connections.

IBS and the Developing Microbiome

The mind-gut connection: What is it and how did it evolve? That is the question posed for this short podcast (the first in a series of three on the topic) to gastroenterologist Emeran Mayer, MD, PhD, a pioneer of medical research into brain-gut interactions and author of 

In this 3-part podcast, Dr. Mayer talks about his interest in the mind’s relationship to the GI tract, some basics of what bacterial gut/brain communication is, and the evolutionary biology theories behind it. He even discusses the hypothesis that bacteria actually tells our bodies what to eat-like to crave sugary foods in obesity. Dr. Mayer's website is 

And this is Psyched, a psychiatry podcast. Today we have Emeran Mayer on with us. He was born in a small town in Bavaria, where his family ran a confectionary business since 1873. After deciding against taking over the family business he finished medical school at Ludwig Maximilian’s University in Munich, completed his residency training at Vancouver General Hospital in Vancouver, before moving to Los Angeles. Dr. Mayer is a professor in the department of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA, and Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience. And Co-director of the CURE: Digestive Diseases Research Center at UCLA. Dr. Mayer, thank you for joining us.

 So, you've done a fascinatingly broad set of work over your career, looking at your research interests from traditional healing, to hypnosis, to gut microbiology. How did you get such diverse research interests?

 Well, there was one common thread that goes through all of this from the very beginning and that is really I've always been interested in the interaction between the mind, the brain, and the body. And just have pursued this from really from college on, and so there's certainly a red line going, a straight line going through all of my visits to different topics in this area. I think right now ... so I was looking at the mind, brain, gut, micro environment interaction so that integrating all of these elements into one, and that's in some ways really been my interest from the very beginning.

Say more about that with the mind-gut connection. How do you conceive of the gut and how is there a connection?

 Well, I mean I've been interested in brain, gut interaction for the better part of my career. That topic was in some ways relegated to studying a disease called Irritable Bowl Syndrome, because that was sort of a classic entity where you had psychological commodity, GI symptoms, psychological interventions were beneficial. And then only about I would say seven years ago I developed this interest in including the gut microbes in this communication, so I think right now people are getting so excited about the microbes themselves. I mean there's always been this very intricate by directional communication between the brain and the gut. There's many interesting cells in the gut, but the microbes now play a role in using these various communication channels from the gut to the brain to be included in this dialogue.

Interestingly, and it was never been really great interest of people outside very narrow area of Neurogastroenterologists, until the microbiome arrived. Now, it's almost like everybody has become a gut microbiome expert of brain, gut microbiome expert. As you know there's many books written on this topic, the lay media loves it. And for me it's nice because at this stage in my career I get invited to all kinds of meetings outside of gastroenterology, including the APA meeting.

 So, you said something that was rather astonishing I think to most people, that there's a dialogue between the microbes and the person, or the brain. Are there really like signals sent back and forth? How do you justify saying that this is communication?

 If you go back in evolution you'll find that microbes were obviously the dominant life form on planet Earth for billions of years, four and a half billion, a billion years, and then at some point there was a decision made by some algae in the ocean to settle inside the digestive system of a primitive marine animal, the Hydra. That animal itself was a floating digestive tube with a nerve net around it. Very similar actually to our GI tract, so our GI tract started ... like the earliest forms of life were GI tracts with an attached nervous system around it.

The microbes started living inside that system, and used their own communication signals that they had developed over four and a half billion years in the oceans to start communicating with the nerve cells of these floating digestive tubes. That actually explains a lot why the gut and the brain are so closely connected. And it also explains why the microbes have developed this ability, not just to communicate with the host but also to most likely exchange genes with this process lateral gene transfer, to the host. You can almost assume that the similarity of some neuro active substances that the microbes can produce, that we know today like GABA and tryptophan metabolites, where actually transferred then to the entire nervous system of these marine animals, and were really the origin of our own neurotransmitters ultimately. So, it's a very interesting story, which I think is quite convincing in terms of why that is happening.

Wait, so the thought is that there was the bacteria are sending their own genes into the host organism, and the host organism is incorporating those and then producing those things that the bacteria want?

 Yes. So, that's the assumption and that probably explains why the host has common language, it's common biological language, which goes from the microbes to various cells and receptors in the gut, including nerve cells. And also, since a lot of microbes live on plants, many plants have again, very homologous structures that sort of resemble some of our neurotransmitters. So, this clearly is a certain universality in terms of these signals, and the origin of all this is most likely the microbes that four and a half billion years to develop that language, had 400 times more genes than we humans have. And they have the ability, this ongoing evolution, I mean this is not a static system, so there's constant selection and that may be one of the advantages of having these microbes inside of us, because you can adapt to many things much better than our human system could adapt.

So, what you're saying is, there's things that the microbes signal for in us? Like, what kind of things would a microbe want our brain to be thinking, or doing, or can you explain that a little bit more?

Yeah, so that's a very good question. I think right now it's more speculative, the answers, so somebody has suggested that the microbes may actually be able to hack into our reward system, and get us to do things, particularly to eat things that is beneficial for their own growth. And that is not been proven yet, I mean there's a recent study in fruit flies where it's been shown that microbes are able to change the behavior of these fruit flies. I mean obviously in humans and even in rodents we don't have this yet, but there's an interesting possibility for example in obesity where people develop this craving for high fat, high sugary foods. The normal composition of our microbes changes in a way that certain strains start dominating that then send signals to our brain, into the reward system, that makes us crave for these particular food items. Almost then it becomes like a parasitic relationship. It's no longer the symbiosis that exists normally, that everything is beneficial for both players. In this case the microbes then would take over in terms. It's really speculation. You know.

 But it's intriguing because we don't have the clear answer as what they would like to tell our nervous system, so I guess that's still really a mystery.

An expert talks about his interest in the mind’s relationship to the GI tract, some basics of what bacterial gut/brain communication is, and the evolutionary biology theories behind it.

The Mind-Gut Connection: What Is It and How Did It Evolve?

Three new studies on genetic risk factors and lifestyle; the transition from cognitive health to Alzheimer disease; and metabolic syndrome in depressed older adults.

Lifestyle, Personality, and Metabolic Changes in the Elderly

Dr Citrome is Clinical Professor of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY.

Editor’s Note: We are pleased to present this Q&A with Leslie Citrome, MD, MPH, based on his presentation at the 2017 Psychiatric Congress, “Weight Gain and Metabolic Abnormalities in Patients with Schizophrenia.”

Patients with schizophrenia are at high risk for weight gain and metabolic abnormalities. There are many factors that contribute to this, including genetic predisposition to metabolic abnormalities, environmental factors such as poor diet, lack of exercise, cigarette smoking, and iatrogenic considerations such as exposure to medications that can lead to further disruption of metabolic health.

A: Metabolic syndrome (MetS) is a public health concept also referred to as “Syndrome X” or “Insulin Resistance Syndrome.” MetS describes a cluster of cardiovascular disease risk factors and metabolic alterations associated with excess fat weight. MetS has been compared to cigarette smoking as an equal risk partner to premature coronary heart disease. The concept of MetS serves as a starting point for clinical interventions known to reduce risk for obesity-related type 2 diabetes, cardiovascular disease, and perhaps even cancer.

A: The most commonly used US criteria are from the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III (ATP III). The ATP III criteria include meeting at least 3 of the following:

1. Abdominal obesity: waist circumference: men > 40 in; women > 88 cm 35 in;

2. High triglycerides blood levels: ≥ 150 mg/dL;

3. Low HDL-cholesterol blood levels: men < 40 mg/dL; women < 50 mg/dL;

4. High blood pressure: ≥ 130/85 mm Hg);

5. High fasting blood glucose (≥ 100 mg/dL.

Note that microalbuminuria is not included in ATP III criteria although it is in others.

A: Abdominal obesity is measured with a tape measure; we usually measure body weight as a proxy, but keep in mind that muscle weighs more than fat. A body mass index greater than 30 kg/m

 defines obesity. Getting blood work done (especially fasting) can be challenging, but one of the important clinical benefits of doing it early is that elevation of triglycerides can occur before substantial weight gain has accumulated. HbA

 can also be used for screening and does not require fasting. Blood pressure is now easier to obtain than ever before, given the availability of inexpensive automated blood pressure measuring devices.

Q: How common is MetS in people with schizophrenia?

Schizophrenia confers a high endogenous risk for diabetes, and this risk is further increased by both first-generation and second-generation antipsychotics.

A: In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia, MetS was present in 30% of all participants. This is higher than in the general population. It has been estimated that patients with schizophrenia have a 3-fold greater risk for MetS than the general population.

A: MetS is associated with a 4-fold relative risk for diabetes (in the general population); and with an approximate 2-fold risk for coronary heart disease, stroke, and premature mortality (in the general population).

Of additional interest is that MetS is significantly associated with cognitive impairment in schizophrenia and can potentially contribute to the functional decline observed in some patients with schizophrenia throughout the course of illness.

Q: What is the prevalence of type 2 diabetes mellitus in people with schizophrenia?

A: The prevalence of diabetes in persons with severe mental disorders is 2- to 3-fold higher than in the general population. The incidence of diabetes is also higher and the onset of diabetes appears to be 10 to 20 years earlier than in the general population.

The number of persons with diabetes mellitus has increased over the years. In a study of New York State hospitals, prevalence increased from 6.9% of 10,091 patients in 1997 to 14.5% of 7420 patients in 2004; incidence of newly treated diabetes increased from 0.9% in 1997 to 1.8% in 2004.

Diabetes is uncommon in young healthy adults, so it is important to note that the increased relative risk of diabetes is greatest in adolescents and young adults with severe mental disorders.

Q: Are genetic factors important in the development of diabetes mellitus?

Schizophrenia and T2 DM risk; short-term weight gain with specific antipsychotics; interventions to reduce weight and/or metabolic abnormalities. . .answers here.

Metabolic Disorders