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 Could probiotics be used to treat depression? The medical site Medscape reported on a very small preliminary study (only 10 people) that tested that idea, with findings that suggested that taking certain probiotics does help treat the symptoms of mild to moderate depression. The bacteria taken were Lactobacillus helveticus and Bifidobacterium longum (in the product Probio'Stick). Specifically, the symptoms of mood, anhedonia (inability to feel pleasure), and sleep disturbance were significantly reduced after probiotoc therapy.

Sounds great, yes? But ....just a few months ago a much larger study was published where people were randomly assigned to either a placebo group or the treatment group (the same 2 probiotics: Lactobacillus helveticus and Bifidobacterium longum). It was also "double-blind" - so no one knew who got the placebo or the treatment. And here the results were: the probiotics did NOT help the depression symptoms. This study found "no evidence that the probiotic formulation is effective in treating low mood, or in moderating the levels of inflammatory and other biomarkers".

Why the different results? Maybe the "placebo effect" was why the 10 person study had a positive effect. Wanting and thinking something works can definitely influence results. (This is why ideally studies are double-blind, randomized, and with a placebo.) Or was it because the study was done "in association" with the manufacturers of Probio'Stick? Yup, it's not surprising the manufacturer of a product finds a "positive effect" from its product. Bottom line: Be careful and critical when reading "study results".

However, after saying all that - there is a "gut-brain axis" in humans, and some researchers are examining whether probiotics can treat various symptoms such as anxiety (here and here). So perhaps some other probiotic bacteria might work to treat depression.

The problematic study from Medscape: Probiotics Promising for Mild to Moderate Depression

Probiotics may be effective in reducing core depressive symptoms in treatment-naive patients with a mild to moderate form of the disorder, results of a new pilot study suggest. Investigators led by Caroline Wallace, PhD candidate, Queen's University, Kingston, Ontario, Canada, found that symptoms of mood, anhedonia, and sleep disturbance were significantly reduced with probiotic therapy after just 4 weeks, with results maintained at 8 weeks..... The hypothesis is that the effects are mediated via the gut-brain axis by reducing inflammation and increasing serotonin levels.

To assess the efficacy of probiotics in treatment-naive patients with depression, the researchers carried out a pilot study using Probio'Stick, a probiotic supplement that combines two different strains known to act on the gut-brain axis ― Lactobacillus helveticus R0052 and Bifidobacterium longum R0175. The 8-week, single-arm, open-label intervention pilot study involved 10 treatment-naive patients with major depressive disorder who were experiencing a current episode of depression..... Next steps will be to confirm these findings in a double-blind, randomized, placebo-controlled trial of Probio'Stick. 

Same probiotic bacteria, but no effect from the treatment. From The Australian and New Zealand Journal of Psychiatry: A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression.

No significant difference was found between the probiotic and placebo groups on any psychological outcome measure or any blood-based biomarker.

This study found no evidence that the probiotic formulation is effective in treating low mood, or in moderating the levels of inflammatory and other biomarkers. The lack of observed effect on mood symptoms may be due to the severity, chronicity or treatment resistance of the sample; recruiting an antidepressant-naive sample experiencing mild, acute symptoms of low mood, may well yield a different result. Future studies taking a preventative approach or using probiotics as an adjuvant treatment may also be more effective. Vitamin D levels should be monitored in future studies in the area. The results of this trial are preliminary; future studies in the area should not be discouraged.

 Perhaps a nutrient deficit is associated with depression? This study found that eating a Mediterranean diet or a similar diet in which fruits, vegetables, legumes (beans), nuts, and low in processed meats is associated with lower rates of depression. From Medical Xpress:

Fruit and vegetables aren't only good for a healthy body—they protect your mind too

Eating a Mediterranean diet or other healthy dietary pattern, comprising of fruit, vegetables, legumes, and nuts and low in processed meats, is associated with preventing the onset of depression, according to research published in the open access journal BMC Medicine. A large study of 15,093 people suggests depression could be linked with nutrient deficits..

The researchers compared three diets; the Mediterranean diet, the Pro-vegetarian Dietary Pattern and Alternative Healthy Eating Index-2010. Participants used a scoring system to measure their adherence to the selected diet, i.e. the higher the dietary score indicated that the participant was eating a healthier diet. Food items such as meat and sweets (sources of animal fats: saturated and trans fatty acids) were negatively scored, while nuts, fruits and vegetables (sources of omega-3 fatty acids, vitamins and minerals respectively) were positively scored.

The study included 15,093 participants free of depression at the beginning of the study. They are former students of the University of Navarra, Spain, registered professionals from some Spanish provinces and other university graduates....Questionnaires to assess dietary intake were completed at the start of the project and again after 10 years. A total of 1,550 participants reported a clinical diagnosis of depression or had used antidepressant drugs after a median follow-up of 8.5 years.

The Alternative Healthy Eating Index-2010 was associated with the greatest reduction of risk of depression but most of the effect could be explained by its similarity with the Mediterranean Diet. Thus, common nutrients and food items such as omega-3 fatty acids, vegetables, fruits, legumes, nuts and moderate alcohol intake present in both patterns (Alternative Healthy Eating Index-2010 and Mediterranean diet) could be responsible for the observed reduced risk in depression associated with a good adherence to the Alternative Healthy Eating Index-2010.

Almudena Sanchez-Villegas says, "A threshold effect may exist. The noticeable difference occurs when participants start to follow a healthier diet. Even a moderate adherence to these healthy dietary patterns was associated with an important reduction in the risk of developing depression. However, we saw no extra benefit when participants showed high or very high adherence to the diets....This dose-response pattern is compatible with the hypothesis that suboptimal intake of some nutrients (mainly located in low adherence levels) may represent a risk factor for future depression."

Two recent meta-analyses of studies looked at depression. The first found that in 12 out of 26 studies eating fish (but NOT fish-oil supplements) was linked to lower rates of depression. The researchers hypothesize that "Fish is rich in multiple beneficial nutrients, including n-3 polyunsaturated fatty acids, high-quality protein, vitamins, and minerals." Another meta-analysis looked at dietary patterns and depression and found that a high intake of fruit, vegetables, fish, and whole grains may be associated with a reduced depression risk. From Medscape:  Fish-Rich Diet May Significantly Reduce Depression Risk

A nice summary article about the benefits and risks of coffee consumption. Summary of effects of drinking coffee1) May potentially increase blood pressure, but also may lower the risk for coronary disease, and protect against heart disease. 2) May cut stroke risk by as much as 25%, 3) Linked to  improved glucose metabolism, reduced risk for type 2 diabetes, and promotion of weight loss in overweight patients. 4) May reduce the risk for several cancers. 5) Appears to slow the progression of dementia and Parkinson's disease. 6) A significantly decreased risk of developing depression. 7) Slows progression in alcoholic cirrhosis, hepatitis C, and NAFLD (non-alcoholic fatty liver disease). 8) May be beneficial in dry-eye syndrome, gout, and in preventing MRSA infection. 9) May increase blood pressure, anxiety, insomnia, tremor, withdrawal symptoms, and potential increased risk of glaucoma. From Medscape:

How Healthy Is Coffee? The Latest Evidence

Earlier this year, the Dietary Guidelines Advisory Committee (DGAC) released a report[1] stating that up to five cups of coffee per day, or up to 400 mg of caffeine, is not associated with long-term health risks. Not only that, they highlighted observational evidence that coffee consumption is associated with reduced risk for several diseases, including type 2 diabetes, cardiovascular disease (CVD), and neurodegenerative disorders. The body of data suggesting that moderate coffee—and, in all likelihood, tea—consumption is not only safe but beneficial in a variety of mental and medical conditions is growing fast.

A 2012 study of over 400,000 people, published in the New England Journal of Medicine, reported that coffee consumption is associated with a 10% reduction in all-cause mortality at 13-year follow-up.... It's important to note that much of the evidence on the potential health effects of coffee, caffeine, and other foods and nutrients is associational and doesn't prove causality—observational investigations come with limitations and often rely on error-prone methods such as patient questionnaires. However, the sheer volume of existing observational data linking coffee and/or caffeine with various health benefits—as well as, in many cases, evidence of a dose response—suggests that the most widely consumed stimulant in the world has positive influences on our health. 

Cardiovascular Disease:...However, when caffeine is ingested via coffee, enduring blood pressure elevations are small and cardiovascular risks may be balanced by protective properties. Coffee beans contain antioxidant compounds that reduce oxidation of low-density lipoprotein (LDL) cholesterol, and coffee consumption has been associated with reduced concentrations of inflammatory markers. Moderate coffee intake is associated with a lower risk for coronary heart disease as far out as 10 years, and data suggest that an average of two cups per day protects against heart failure.

Cerebrovascular Disease and Stroke: The vascular benefits of coffee are not lost on the brain. According to a 2011 meta-analysis, consuming between one and six cups per day reportedly cut stroke risk by 17%. A 22%-25% risk reduction was seen in a large sample of Swedish women followed for an average of 10 years.

Diabetes:...Numerous studies have linked regular coffee drinking with improved glucose metabolism, insulin secretion, and a significantly reduced risk for diabetes. Most recently, findings from a long-term study published this year suggest that coffee drinkers are roughly half as likely to develop type 2 diabetes as are nonconsumers, even after accounting for smoking, high blood pressure, and family history of diabetes.

Cancer: ...Evidence suggests that moderate to heavy coffee consumption can reduce the risk for numerous cancers, including endometrial (> 4 cups/day), prostate (6 cups/day), head and neck (4 cups/day), basal cell carcinoma (> 3 cups/day), melanoma,and breast cancer (> 5 cups/day). The benefits are thought to be at least partially due to coffee's antioxidant and antimutagenic properties.

Neurodegeneration: Beyond the short-term mental boost it provides, coffee also appears to benefit longer-term cognitive well-being. A 2012 study reported that patients with mild cognitive impairment and plasma caffeine levels of > 1200 ng/mL—courtesy of approximately three to five cups of coffee per day—avoided progression to dementia over the following 2-4 years. On a related note, a study from last year reported that caffeine consumption appears to enhance memory consolidation....Caffeinated coffee has long been thought to be neuroprotective in Parkinson disease (PD)....—as well as in multiple sclerosis

Depression: A 2011 study suggests that a boost in coffee consumption might also benefit our mental health: Women who drank two to three cups of coffee per day had a 15% decreased risk for depression compared with those who drank less than one cup per week. A 20% decreased risk was seen in those who drank four cups or more per day. Newer work also suggests that regular coffee drinking may be protective against depression.

Liver Disease: The liver might help break down coffee, but coffee might protect the liver (in some cases). Evidence suggests that coffee consumption slows disease progression in patients with alcoholic cirrhosis and hepatitis C, and reduces the risk of developing hepatocellular carcinoma. A 2012 study reported that coffee intake is associated with a lower risk for nonalcoholic fatty liver disease (NAFLD), while work published in 2014 found that coffee protects against liver fibrosis in those with already established NAFLD.

And That's Not All…: An assortment of other research suggests that coffee intake might also relieve dry-eye syndrome by increasing tear production, reduce the risk for gout, and potentially fight infection. Coffee and hot tea consumption were found to be protective against one of the medical community's most concerning bugs, methicillin-resistant Staphylococcus aureus (MRSA). While it remains unclear whether the beverages have systemic antimicrobial activity, study participants who reported any consumption of either were approximately half as likely to have MRSA in their nasal passages.

And Finally, the Risks: As is often the case, with benefits come risks, and coffee consumption certainly has negative medical and psychiatric effects to consider. Besides the aforementioned potential increase in blood pressure, coffee can incite or worsen anxiety, insomnia, and tremor and potentially elevate glaucoma risk. Also, given the potential severity of symptoms, caffeine withdrawal syndrome is included as a diagnosis in the DSM-5.

The wonders of nature! A small study found that taking a 90 minute walk in "natural" (wild) environments boost mental well-being by reducing rumination  (obsessive, negative thoughts focused on yourself). It is thought that rumination is associated with increased risk for depression and other mental illnesses. Rumination actually shows up in MRIs scans as increased activity in a brain region called the subgenual prefrontal cortex, an area of the brain that regulates negative emotions. The researchers suggest that these findings support the need for natural areas (parks) in urban areas.There have been a number of other studies finding that nature reduces stress and improves well being. Bottom line: take a walk in nature to feel better. From Medical Xpress:

Walking in nature found to reduce rumination

A team of researchers working at Stanford University has found that people walking in a "natural" environment tend to engage in less rumination...Biomedical researchers believe that some instances of both anxiety and/or depression come about due to what they call rumination—constantly flogging oneself with criticism of past mistakes and some studies have suggested that living in an urban environment might contribute to an increase in rumination. In this new effort, the researchers sought to learn if it might be possible for people to lessen the degree of rumination they engage in by simply going for a walk in a natural setting.

To find out, the team enlisted the assistance of 38 reasonably healthy adult male and female individuals—they were asked to participate in a study that consisted of taking questionnaires and undergoing fMRI scans before and after going for an hour and a half walk. The volunteers were split into two groups, one got to walk in a grassy area near the Stanford campus that was lined with lots of trees—the other group found themselves marching around in a strictly urban setting. The questionnaires were designed to illuminate rumination, while the fMRI scans focused on the subgenual prefrontal cortex—prior research showed it tended to light up during periods of rumination.

Afterwards, the researchers analyzed and crunched the data from the questionnaires and brain scans and came up with a rumination score which they then used to compare people in the two groups. They found that rumination remained level for the urban walkers but fell on average from 35.4 to 33.1 for the nature walkers. This the team claims, shows that taking a walk in a natural environment setting can reduce rumination, and possibly reduce symptoms of anxiety and depression, though they acknowledge that their sample size was small and suggest more research will need to be done to confirm their findings.

This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world.

 Views from the nature (A and B) and urban (C and D) walks the participants took (PNAS)

The possibilities are exciting. See my earlier posts on psychobiotics for more information. From Medical Xpress:

How gut bacteria ensures a healthy brain – and could play a role in treating depression

But medicine in the 21st century is rethinking its relationship with bacteria and concluding that, far from being uniformly bad for us, many of these organisms are actually essential for our health. Nowhere is this more apparent than in the human gut, where the microbiome  – the collection of bacteria living in the gastrointestinal tract - plays a complex and critical role in the health of its host.

The microbiome interacts with and influences organ systems throughout the body, including, as research is revealing, the brain. This discovery has led to a surge of interest in potential gut-based treatments for neuropsychiatric disorders and a new class of studies investigating how the gut and its microbiome affect both healthy and diseased brains.

The lives of the bacteria in our gut are intimately entwined with our immune, endocrine and nervous systems. The relationship goes both ways: the microbiome influences the function of these systems, which in turn alter the activity and composition of the bacterial community. We are starting to unravel this complexity and gain insight into how gut bacteria interface with the rest of the body and, in particular, how they affect the brain.

The microbiome-immune system link is established early on. Over the first year of life, bacteria populate the gut, which is largely sterile at birth, and the developing immune system learns which bacteria to consider normal residents of the body and which to attack as invaders. This early learning sets the stage for later immune responses to fluctuations in the microbiome's composition.

When a normally scarce strain becomes too abundant or a pathogenic species joins the community of gut bacteria, the resulting response by the immune system can have wide-reaching effects. Depression has been linked with elevated levels of such molecules in some individuals, suggesting that treatments that alter the composition of the microbiome could alleviate symptoms of this disorder.

Such an intervention could potentially be achieved using either prebiotics – substances that promote the growth of beneficial bacteria – or probiotics – live cultures of these bacteria. It is even possible that the microbiome could be manipulated by dietary changes.

In one experiment, researchers transplanted the human microbiome into germ-free mice (animals that have no gut bacteria) in order to study it in a controlled setting. They found that, simply by changing the carbohydrate and fat content of the mice's food, they could alter basic cellular functions and gene expression in the microbiome.

Depression is not the only psychiatric disorder in which the microbiome may play a role.Research in rodents, as well as a few preliminary studies in humans, indicate that the state of our resident microbes is tied to our anxiety levels.

This research also reveals the complexity of the relationship between the microbiome and psychological state. ...Researchers have shown that the presence or absence of microbes in young mice affects the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis – a key pathway in the body's stress response system. The activity of the microbiome during development thus sways how we respond to future stressors and how much anxiety they cause us.

How do the bacteria in our gut wield such influence over our brains and bodies? The mechanisms of microbiome-host interactions appear to be as numerous and varied as the interactions themselves.

Two articles which together point out that there are alternative approaches to the treatment of depression. From Medscape:

Patient Expectations Largely Dictate Antidepressant Response

People's expectations about how effective their antidepressant medication is going to be almost entirely predicts their response to it, such that giving patients a placebo pill as active therapy during an 8-week period results in very similar reductions in symptoms, new research shows.

Investigators at the David Geffen School of Medicine at the University of California, Los Angeles, found that patients assigned to either active antidepressant therapy or placebo pills had better clinical outcomes than supportive care alone and that there was little difference between outcomes for the medication and placebo groups.

"Supportive interaction with the subject helped them get better, and antidepressant therapy helped them get better, but I think our key finding was that patients' belief in the effectiveness of medication was a unique factor that contributed to them getting well. So belief in the power or effectiveness of the medication may be a contributor to placebo responses in the treatment of depression."

From Science Daily:

Sport, physical activity help against depression

Depression is the most frequently diagnosed mental illness. In the western industrial nations, at least every tenth person suffers from depression once in the course of their life. Depression influences physical health more than diabetes or arthritis, clinicians say. Treatment of depression traditionally occurs with antidepressants and psychotherapy. But as research has shown, sport and physical activity partially encounters the same neurophysiological changes as antidepressants. That is why a large number of meta-analyses showed a positive effect of sport and physical activity on depression.

Sport and physical activity bring about various changes in the brain which are otherwise achieved only through drugs. Similar to sport and physical activity, drugs for treatment of depressions act on the brain's capacity to absorb serotonin. They strengthen the epinephrine activity and ensure the release of various factors for nerve growth. These factors promote cell growth in the brain and prevent the death of cells in the hippocampus which is otherwise caused by depression. Together with these changes, sport and physical activity also lead to a reduced activity of the stress hormone cortisol and therefore have an effect similar to psychotropic drugs.

More research on the benefits of exercise. From Medical Xpress:

An hour of moderate exercise a day may decrease heart failure risk

In a new study reported in the American Heart Association journal Circulation: Heart Failure, researchers say more than an hour of moderate or half an hour of vigorous exercise per day may lower your risk of heart failure by 46 percent. Heart failure is a common, disabling disease that accounts for about 2 percent of total healthcare costs in industrialized countries. Risk of death within five years of diagnosis is 30 percent to 50 percent, researchers said.

Swedish researchers studied 39,805 people 20-90 years old who didn't have heart failure when the study began in 1997. Researchers assessed their total- and leisure time activity at the beginning of the study and followed them to see how this was related to their subsequent risk of developing heart failure. They found that the more active a person, the lower their risk for heart failure. 

From Medical Xpress:

Workers who exercise lower health risks, cost less

Get moving: just 20 minutes of exercise a day dramatically lowers the risk of diabetes and heart disease, even for employees with a high risk of developing those conditions.

A University of Michigan study looked at the impact of exercise on 4,345 employees in a financial services company that had just started a workplace wellness program. Roughly 30 percent of employees were high risk and suffering from metabolic syndrome, a dangerous cluster of risk factors associated with diabetes and heart disease. Overall, about 34 percent of U.S. adults have metabolic syndrome.

The study found that when the high-risk employees accumulated the government-recommended 150 minutes of moderate-intensity exercise a week, their health care costs and productivity equaled that of healthy employees who didn't exercise enough, said Alyssa Schultz, a researcher at the Health Management Research Center in the U-M School of Kinesiology.

"It was a real surprise, the level of protection physical activity gave to people with metabolic syndrome," Schultz said. 

Research done in mice, but may apply to humans. From Science Daily:

How physical exercise protects the brain from stress-induced depression

Physical exercise has many beneficial effects on human health, including the protection from stress-induced depression. However, until now the mechanisms that mediate this protective effect have been unknown. In a new study in mice, researchers show that exercise training induces changes in skeletal muscle that can purge the blood of a substance that accumulates during stress, and is harmful to the brain.

"In neurobiological terms, we actually still don't know what depression is. Our study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress," says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet.

 

Article about the growing body of research supporting exercise in the treatment of depression. From The Atlantic:

For Depression, Prescribing Exercise Before Medication

Depression is the most common mental illness—affecting a staggering 25 percent of Americans—but a growing body of research suggests that one of its best cures is cheap and ubiquitous. In 1999, a randomized controlled trial showed that depressed adults who took part in aerobic exercise improved as much as those treated with Zoloft. A 2006 meta-analysis of 11 studies bolstered those findings and recommended that physicians counsel their depressed patients to try it. A 2011 study took this conclusion even further: It looked at 127 depressed people who hadn’t experienced relief from SSRIs, a common type of antidepressant, and found that exercise led 30 percent of them into remission—a result that was as good as, or better than, drugs alone.

Though we don’t know exactly how any antidepressant works, we think exercise combats depression by enhancing endorphins: natural chemicals that act like morphine and other painkillers. There’s also a theory that aerobic activity boosts norepinephrine, a neurotransmitter that plays a role in mood. And like antidepressants, exercise helps the brain grow new neurons.

But this powerful, non-drug treatment hasn’t yet become a mainstream remedy. In a 2009 study, only 40 percent of patients reported being counseled to try exercise at their last physician visit.

Instead, Americans are awash in pills. The use of antidepressants has increased 400 percent between 1988 and 2008. They’re now one of the three most-prescribed categories of drugs, coming in right after painkillers and cholesterol medications.

After 15 years of research on the depression-relieving effects of exercise, why are there still so many people on pills? The answer speaks volumes about our mental-health infrastructure and physician reimbursement system, as well as about how difficult it remains to decipher the nature of depression and what patients want from their doctors.

When it comes to non-drug remedies for depression, exercise is actually just one of several promising options. Over the past few months, research has shown that other common lifestyle adjustments, like meditating or getting more sleep, might also relieve symptoms. Therapy has been shown to work just as well as SSRIs and other medications. In fact, a major JAMA study a few years ago cast doubt on the effectiveness of antidepressants in general, finding that the drugs don't function any better than placebo pills for people with mild or moderate depression.

The half-dozen psychiatrists I interviewed said they’ve started to incorporate non-drug treatments into their plans for depressed patients. But they said they’re only able to do that because they don’t accept insurance. (One of the doctors works for a college system and only sees students.)

That’s because insurers still largely reimburse psychiatrists, like all other doctors, for each appointment—whatever that appointment may entail—rather than for curing a given patient. It takes less time to write a prescription for Zoloft than it does to tease out a patient’s options for sleeping better and breaking a sweat. Fewer moments spent mapping out jogging routes or sleep schedules means being able to squeeze in more patients for medications each day.