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Depression

Depression featured article

Depression is a neuropsychiatric disorder characterized by negative mood, loss of interest in doing things, and metabolic, hormonal, and immune disturbances that can degrade a person's quality of life and increase their risk of disease and death. The World Health Organization estimates that approximately 322 million people – more than 4 percent of the global population – currently live with depression, the most common mental health disorder worldwide. Between 2005 and 2015 (the most recent years for which robust meta-analyses are available), the number of people living with depression worldwide increased by more than 18 percent. It is estimated that only one-third of people struggling with depression receive treatment.

Clinicians diagnose depression as major depressive disorder based on a set of diagnostic criteria including one of two primary symptoms – depressed mood (e.g., sadness, irritability) and/or anhedonia (i.e., loss of interest or pleasure in...

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Episodes

intestinal permeability

Intestinal Permeability: the Bacterial link to Aging, Brain Barrier Dysfunction & Metabolic Disorder

Posted on May 30th 2022 (about 3 years)

Dr. Patrick's keynote: compromised intestinal barrier affects human health—cardiometabolic function, neurological health, behavior, and more.

sauna

Sauna Benefits Deep Dive and Optimal Use with Dr. Rhonda Patrick & MedCram

Posted on April 13th 2022 (about 3 years)

MedCram co-founder Kyle Allred discusses sauna's exercise mimetic, anti-inflammatory, mood-elevating, and detoxifying properties in this episode.

depression

Aerobic exercise alters tryptophan and kynurenine metabolism (beneficial for depression)

Posted on April 9th 2022 (about 3 years)

In this clip, Dr. Patrick explains how intense exercise beneficially alters tryptophan and kynurenine metabolism in a way that may benefit depression.

Topic Pages

  • Aerobic exercise

    Aerobic exercise mitigates depressive pathophysiology via hippocampal BDNF upregulation, monoaminergic enhancement, HPA-axis normalization, and anti-inflammatory cytokine shifts.

  • Berberine

    Preclinical studies indicate berberine alleviates depressive-like behaviors by inhibiting monoamine oxidase and upregulating BDNF/TrkB signaling.

  • Cold exposure

    Acute cold exposure elevates central norepinephrine and beta-endorphin, potentially ameliorating depressive states via augmented monoaminergic signalling.

  • Creatine

    Creatine augments brain phosphocreatine stores, enhancing ATP buffering and mitochondrial function, which can ameliorate bioenergetic deficits observed in depression.

  • Depression

    Major depressive disorder involves dysregulated monoaminergic neurotransmission, neuroinflammation, HPA-axis hyperactivity, and impaired neuroplasticity driving persistent low mood.

  • Omega-3 fatty acids

    Omega-3 EPA/DHA modulate neuronal membrane fluidity, monoaminergic receptor function, and inflammatory signaling, mechanisms hypothesized to alleviate depressive symptoms.

  • Red light therapy (photobiomodulation)

    Transcranial red-near-infrared photobiomodulation activates cortical cytochrome-c oxidase, boosting ATP and neurotrophic signaling, countering depressive pathology.

  • Sauna

    Sauna-induced whole-body hyperthermia may ameliorate depression by lowering pro-inflammatory cytokines and recalibrating hypothalamic-pituitary-adrenal stress responsiveness.

  • Whole-body hyperthermia

    Whole-body hyperthermia elevates core temperature, modulating peripheral cytokines and central serotonergic circuits, thereby attenuating depressive symptoms.

News & Publications

  • Chronic stress inhibits autophagy—the brain's recycling system—but restoring its functionality yields rapid antidepressant effects. pubmed.ncbi.nlm.nih.gov
    Brain Depression Stress Autophagy

    In small doses, stress can sharpen focus and improve resilience, but chronic stress gradually erodes emotional stability, increasing the risk of major depressive disorder. A recent study found that autophagy—the brain’s recycling and housekeeping system—helps maintain emotional stability by removing old or damaged proteins.

    Researchers explored how short-term and long-term stress influenced autophagy in mice and investigated whether antidepressant drugs could restore this process. Employing genetic techniques, the researchers selectively inhibited or enhanced autophagy in a region of the brain called the lateral habenula and then monitored how the animals reacted to stress.

    They found that acute stress activated autophagy, while chronic stress inhibited it. When autophagy ceased functioning properly, stress-related behaviors increased. However, restoring autophagy—even briefly—produced rapid antidepressant-like effects. Drugs commonly used to treat depression also reactivated autophagy in this brain region. Additional experiments indicated that autophagy helps regulate brain cell activity by breaking down excess glutamate receptors, which are often overactive in depression.

    These findings suggest that disrupted autophagy in the lateral habenula plays a central role in how chronic stress contributes to depression. Learn more about autophagy in this episode featuring Dr. Guido Kroemer.

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  • Anti-inflammatory treatments, particularly omega-3 fatty acids and plant-based compounds, effectively reduce depression symptoms in older adults. www.nature.com
    Omega-3 Inflammation Depression Mental Health NSAID Polyphenol

    Inflammation and depression are often linked, particularly in older adults, who tend to experience chronic low-grade inflammation and elevated rates of depression. A recent study found that anti-inflammatory interventions may help reduce symptoms of depression and the risk of developing depression in older adults.

    Researchers conducted a systematic review and meta-analysis of 31 randomized, placebo-controlled trials that assessed the effects of anti-inflammatory therapies on depression in older adults. The various anti-inflammatory agents included omega-3 fatty acids, nonsteroidal anti-inflammatory drugs, and plant-based compounds. The researchers included only trials with at least 20 participants.

    The analysis revealed that anti-inflammatory treatments were more effective than placebos in reducing depression symptoms among older adults. On average, people receiving these treatments exhibited a moderate improvement in symptom severity compared to those taking a placebo. Omega-3 fatty acids and plant-based compounds, such as curcumin and soy protein, appeared particularly beneficial. There was also some evidence suggesting that these treatments might help prevent depression, although the results were not statistically conclusive.

    These findings suggest that targeting inflammation is a promising strategy for managing depression in older adults, especially those with chronic inflammation. Learn more about links between inflammation and depression in Aliquot #36: Inflammation and Depression, part 2

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  • Misaligned sleep patterns and natural sleep preferences increase mental health risk, hinting at the crucial role of sleep timing and chronotype consistency for healthy aging. www.sciencedirect.com
    Sleep Depression Mental Health Anxiety

    The timing of when a person sleeps—not just how long—plays a vital role in mental health, influencing mood, cognitive function, and overall well-being. A recent study found that misalignment between bedtime and natural sleep preferences can increase the risk of mental health disorders like depression and anxiety.

    Researchers identified the chronotype—whether they were morning or evening types—of nearly 74,000 middle-aged and older adults enrolled in the UK Biobank. They tracked sleep patterns using accelerometry and evaluated their sleep and chronotype alignment. They assessed mental health outcomes through standard diagnostic codes.

    They found that morning types who went to bed late had a greater risk of mental health disorders, including depression and anxiety, than those whose sleep timing matched their chronotype. Interestingly, evening types who went to bed early had a lower risk of depression and a trend toward reduced risks of other mental health issues.

    These findings suggest a mismatch between one’s biological preferences and sleep schedule can harm mental well-being. The investigators posited that people should aim to sleep before 1 a.m. for optimal mental health, even if their natural chronotype favors later sleep. Learn more about chronotypes in this clip featuring Dr. Matthew Walker.

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  • Running may be as effective as traditional antidepressant therapies for reducing symptoms of depression. www.sciencedirect.com
    Exercise Brain Depression

    Running may be as effective as traditional antidepressant therapies for reducing symptoms of depression.

    A new study found that running was as effective as traditional antidepressant drugs at reducing symptoms of depression. In addition, people who ran had better physical health than those who did not.

    The study involved 141 people with depression. Participants chose which 16-week therapy intervention they preferred: running at least twice a week with a group (96 participants) or taking traditional antidepressant medication (45 participants). They underwent mental and physical health assessments before and after the interventions.

    The two therapies were comparable in terms of reducing depressive symptoms. However, running therapy improved many aspects of the participants' health, including body weight, waist size, blood pressure, heart rate, and heart rate variability.

    Nearly 25 million adults living in the United States take some form of antidepressant medication. Most antidepressants work by altering the brain’s chemistry to affect mood. Side effects of the drugs include nausea, weight gain, decreased libido, and anxiety, among others. Evidence suggests that antidepressants are only about 20 to 30 percent more effective at reducing symptoms of depression than placebo treatments.

    Exercise boosts the production of molecules that enhance mood and promote mental health. Learn more about the mental health effects of exercise in this video featuring Dr. Rhonda Patrick.

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  • Breathing exercises reduce stress and improve mental health. www.news-medical.net
    Depression Stress Meditation Mental Health Anxiety

    Breathwork improves mental health, a new study shows. People who practiced breathwork reported less anxiety, depression, and mental stress, regardless of how frequently they engaged in the practice.

    Researchers reviewed the findings of 12 randomized controlled trials that investigated the effects of breathwork on stress. The breathwork techniques were presented in person, remotely, or via both.

    They found that slow-breathing exercises improved participants' mental health, regardless of how the techniques were presented. Participants who practiced breathwork reported having less anxiety, depression, and mental stress, compared to those who did not practice breathwork. Surprisingly, the researchers didn’t identify a dose-response effect with breathwork, aligning with other findings in which just a single breathwork session reduced anxiety.

    Breathwork is an umbrella term that refers to various breathing exercises and techniques. Evidence suggests that breathwork improves heart rate variability and promotes resilience to stress. People often engage in breathwork as part of general relaxation practices, yoga, or meditation. Learn more about the benefits of meditation in this audio episode featuring Dr. Rhonda Patrick.

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  • Mouse study suggests that interleukin-6-releasing immune cells outside the brain influence the propensity to develop depression. (2013) www.sciencedaily.com
    Brain Inflammation Depression IL-6

    Psychosocial stress promotes the release of IL-6, potentially driving the development of depression.

    Psychosocial stress, such as that experienced with divorce, discrimination, trauma, or the death of a child, can have profound effects on the human body. For example, evidence indicates that stress alters the immune system, driving inflammatory processes and impairing antiviral responses. Findings from a 2013 study suggest that psychosocial stress promotes the release of interleukin 6 (IL-6), potentially driving the development of depression.

    IL-6 is a pro-inflammatory cytokine that plays an important role as a mediator of fever and the body’s immune response. It is produced by almost all immune cells and is induced in the context of infection, autoimmunity, or cancer. Many physiological processes are influenced by IL-6, including glucose metabolism, blood cell production, neuroendocrine regulation, and fatigue, among others. IL-6 levels are often elevated in people who have depression.

    The investigators conducted their study using mice that had undergone radiation to destroy their bone marrow, compromising their immune function. Then they transplanted bone marrow from mice that exhibited either high or low levels of IL-6 levels in response to stress into the immune-compromised animals. Then they exposed the animals to a social stressor.

    They found that mice that received transplants from those that exhibited high IL-6 levels in response to stress demonstrated more depression-like behaviors than the mice that received transplants from those that exhibited low IL-6 levels. These findings suggest that IL-6 promotes a pro-inflammatory state that promotes depression-like symptoms in response to psychosocial stress. Identifying therapeutic strategies that inhibit IL-6 may benefit people who are vulnerable to the effects of psychosocial stress.

    Interestingly, hyperthermia, such as that experienced with sauna use or hot baths, has been shown to reduce IL-6 levels. Learn more about the beneficial effects of sauna use in our overview article.

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  • Microglial interleukin-6 signaling and prostaglandin synthesis may regulate depressive symptoms in neurological disorders. (2021) www.sciencedaily.com
    Brain Inflammation Depression Mental Health IL-6

    Microglia and IL-6 drive the negative mood often associated with inflammation.

    People who have certain neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, or stroke, often exhibit low mood. Evidence suggests that inflammation plays a role in the pathogenesis of these neurological disorders and likely influences mood, as well. Findings from a 2021 study suggest that microglia activation drives the low mood often associated with neurological disorders.

    Microglia are the brain’s resident immune cells. They serve an essential role in maintaining brain microenvironment homeostasis. Acute activation of microglia modulates inflammation and neurotoxicity, but chronic activation promotes brain inflammation and damage. Evidence suggests that microglia activation influences mood.

    The investigators used chemogenetics, a research technique that uses drugs or other chemicals to modulate neural activity, to stimulate microglia activation in the brains of mice. They noted that levels of interleukin-6 (IL-6, a pro-inflammatory cytokine) and prostaglandins (hormone-like molecules that are involved in inflammation) increased in the animals' brains. In addition, the animals exhibited a low mood. Blocking microglia activity restored the animals' positive mood, however.

    These findings suggest that microglia drive the low mood often associated with inflammation and that IL-6 is a prominent player in this process. Learn more about the role of inflammation and mood in this episode featuring Dr. Charles Raison.

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  • Pharmaceutical maker reports benefits of psilocybin on severe depression. www.forbes.com
    Depression

    Scientific interest in the therapeutic potential of psilocybin – the active ingredient of “magic mushrooms” (which remain illegal in much of the United States, with some exceptions) has increased in recent years. Now, findings presented in a press release from a pharmaceutical maker indicate the compound might be a promising therapy for treatment-resistant depression – albeit with some serious side effects.

    The findings add to a growing, though uncertain, body of research surrounding psilocybin’s effectiveness. While previous work indicates that it might offer a safe and effective alternative to traditional drug therapies for some mental health disorders, flawed features of study design have cast doubt on their conclusions. These include small sample sizes, failure to compare psilocybin to other drugs or placebos, and difficulties with blinding (shielding participants from information about which drug or dosage they are taking).

    The recent trial addresses several of these issues with a sample size of 233 patients with treatment-resistant depression recruited across ten countries in North America and Europe. It also features the crucial element of double-blinding, a procedure that ensures neither the investigator nor the participant knows which treatment or dose is provided. Participants received one of three psilocybin doses: 25, 10, or 1 milligram (treated as an inactive dose, equivalent to a placebo) The study investigators then assessed participants’ depressive symptoms over time.

    As early as two days after taking the highest dose of psilocybin, participants' depression scores markedly improved, an effect that endured up to six weeks. Twelve weeks after treatment, approximately 24 percent of high-dose recipients maintained an improved mental state compared to 10 percent from the “placebo” group.

    These findings offer evidence that psilocybin might help treat severe depression. Nonetheless, the authors flagged several side-effects of high dosage, ranging from mild symptoms, such as headaches, nausea, and fatigue, to rare, but serious, adverse effects, such as suicidal ideations and self-harm. These severe symptoms affected 11 high-dose recipients, compared to just a single patient from the inactive dose group. The observation suggests potential cause for concern, and the FMF team looks forward to these preliminary results being discussed in greater detail in a peer-reviewed publication.

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  • Depression is associated with muscle loss in older adults. journals.plos.org
    Aging Depression Muscle Dementia

    Sarcopenia, the loss of muscle mass with age, is related to falling, poor oral health, and chronic disease. Sarcopenia is a progressive disorder, but early interventions with diet and exercise may improve health outcomes. Authors of a new report investigated the relationship between sarcopenia progression, depression, dementia, and hypertension.

    Body composition shifts across the lifespan, with a progression toward lower muscle mass and increased fat mass after age of 60. Because fat and muscle participate in whole-body metabolism and hormone signaling, this shift in body composition contributes to the development of age-related diseases. Previous research has reported a link between sarcopenia, cognitive impairment, and depressive symptoms in older Korean men, but research is needed in additional demographic groups.

    The authors collected data from more than 750 adults aged 60 years and older living in Japan. Participants completed surveys to measure depression and dementia status and underwent a physical examination that included the measurement of blood pressure, height, muscle mass, grip strength, and walking speed. The investigators classified participants as having sarcopenia if they had low skeletal muscle index (i.e., the ratio of the muscle in a person’s arms and legs to their height), poor grip strength, and slower walking speed. They defined pre-sarcopenia as having a low skeletal muscle index with normal grip strength and walking speed. Finally, they classified participants with a normal skeletal muscle index as robust.

    Sarcopenia was associated with increased age and depression severity, but reduced hypertension. Compared to robust participants, those with pre-sarcopenia were more likely to have depression and hypertension. However, sarcopenia was not associated with dementia, which the authors noted may have been due to the small number of participants (only 49) with dementia.

    The authors suggested that future research should explore strategies for management of depression, dementia, and hypertension in the prevention of sarcopenia.

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  • Plasma levels of BDNF lower in women with history of suicide attempts. www.sciencedaily.com
    Brain Depression BDNF

    Suicide is a major public health concern, claiming the lives of nearly 800,000 people worldwide each year. A history of a suicide attempt is a robust predictor of a future attempt. Findings from a 2017 study suggest that plasma levels of BDNF are a marker for suicidality.

    BDNF is a protein that plays critical roles in the creation and functioning of neurons and the ability of synapses to strengthen or weaken over time. Low BDNF levels are associated with an increased risk for depression.

    The participants in the study included 34 women with a history of suicide attempt and 39 without (average age, 33 years). The women were matched based on age, ethnicity, family income, body mass index, and cigarette smoking history. The authors of the study assessed the women’s mental health history and current status and took blood samples to determine BDNF levels.

    Thirty (88 percent) of the women who had attempted suicide had a lifetime history of major depressive disorder. Of these, 14 (40 percent) met the criteria for current major depressive disorder. The women with a history of suicide attempt had lower levels of BDNF than women without a history of suicide – a difference that was maintained even after taking into account other potential psychiatric or demographic factors. The authors of the study posited that lower BDNF levels represent a trait-like biochemical indicator of suicide risk and might be relevant for suicide prevention.

    Other biochemical indicators of suicide have been identified, as well. For example, markers of accelerated extrinsic aging have been observed in the blood of suicide completers. Age acceleration is a phenomenon that occurs when an individual’s epigenetic age exceeds their chronological age. Learn more about epigenetic aging in this overview article.

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  • Bipolar disorder patients experience generalized impaired cellular resilience and broad reductions in BDNF that may contribute to the disease www.sciencedaily.com
    Brain Depression Stress BDNF

    From the article:

    Effective neuronal plasticity also depends on neurotrophins, which are regulatory factors that promote development and survival of brain cells. Brain-derived neurotrophic factor (BDNF) is the neurotrophin mostly found in the brain. It has been extensively investigated in bipolar disorder patients and has been suggested as a hallmark of bipolar disorder. Indeed, some studies have shown that the levels of BDNF in the serum of bipolar disorder patients are reduced whenever patients undergo a period of depression, hypomania, or mania. Other studies have shown that regardless of mood state, bipolar disorder patients present reduced levels of BDNF. Overall, changes in BDNF levels seem to be a characteristic found in bipolar disorder patients that may contribute to the pathophysiology of the disease.

    Immediate early genes:

    Immediate early genes (IEGs) are a class of genes that respond very rapidly to environmental stimuli, and that includes stress. IEGs respond to a stressor by activating other genes that lead to neuronal plasticity, the ability of brain cells to change in form and function in response to changes in the environment. Ultimately, it is the process of neuronal plasticity that gives the brain the ability to learn from and adapt to new experiences.

    One type of protein produced by IEGs is the so-called Early Growth Response (EGR) proteins, which translate environmental influence into long-term changes in the brain. These proteins are found throughout the brain and are highly produced in response to environmental changes such as stressful stimuli and sleep deprivation. Without the action played out by these proteins, brain cells and the brain itself cannot appropriately respond to the many stimuli that are constantly received from the environment.

    […]

    in a previous study done by the group in 2016, one type of IEG gene known as EGR3, that normally responds to environmental events and stressful stimuli, was found repressed in the brain of bipolar disorder patients, suggesting that when facing a stressor, the EGR3 in bipolar disorder patients does not respond to the stimulus appropriately. Indeed, bipolar disorder patients are highly prone to stress and have more difficulties dealing with stress or adapting to it if compared to healthy individuals. What the research group is now suggesting is that both EGR3 and BDNF may each play a critical role in the impaired cellular resilience seen in bipolar disorder, and that each of these two genes may affect each other’s expression in the cell. “We believe that the reduced level of BDNF that has been extensively observed in bipolar disorder patients is caused by the fact that EGR3 is repressed in the brain of bipolar disorder patients. The two molecules are interconnected in a regulatory pathway that is disrupted in bipolar disorder patients,”

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  • Seasonal variation in Nrf2 antioxidant pathway influence winter depression-like behavior in fish. neurosciencenews.com
    Depression Sulforaphane NRF2 Traditional Medicine

    Seasonal affective disorder (SAD) is a form of depression that is influenced by seasonal changes in weather and daylight. It commonly occurs in the dark, cool days of winter but can occur during other times of the year, as well. Approximately 10 percent of people worldwide experience SAD. A new study suggests that seasonal variation in the Nrf2 antioxidant pathway regulates winter depression-like behavior in fish.

    Nrf2 (short for nuclear factor erythroid 2-related factor 2) is a cellular protein that regulates the expression of antioxidant and stress response proteins. Nrf2 functions within a biological pathway called Keap1-Nrf2-ARE, where it switches on the transcription of various cytoprotective proteins that protect against oxidative damage triggered by injury and inflammation.

    The authors of the study exposed medaka, a type of fish that exhibits seasonal SAD-like differences in its behavior to either summer- or winter-like conditions. Then they examined the metabolites produced in their brains. They found evidence that winter-like conditions altered levels of 68 metabolites, some of which are associated with depression. In particular, winter-like conditions reduced levels of glutathione, a powerful antioxidant compound produced by the body’s cells. Glutathione helps prevent inflammation, a key driver in depression.

    Then the study authors analyzed gene expression in the fish and found that winter-like conditions altered signaling pathways that are implicated in depression, including Nrf2. Results of a chemical screen indicated that celastrol, a plant-based compound commonly used in traditional Chinese medicine, activated Nrf2 signaling, which in turn induced the activity of Nrf2 target genes, including glutathione.

    These findings demonstrate that celastrol could be beneficial in treating some of the symptoms associated with seasonal depression by switching on the activity of antioxidant pathways such as Nrf2. Interestingly, sulforaphane, an isothiocyanate compound derived from broccoli, is the most potent naturally occurring inducer of Nrf2 activity. Watch this clip featuring sulforaphane expert Dr. Jed Fahey in which he describes the importance of the Nrf2 pathway.

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