Herpesvirus may lead to bipolar, depression

An international team of scientists led by Bhupesh Prusty — from the
Department of Microbiology at the University of Würzburg in Germany —
discovered that in the brains of people who lived with bipolar and major
depression, a class of neurons called Purkinje cells was infected with
the herpesvirus HHV-6A.
Purkinje neurons are inhibitory brain cells located in the human cerebellum, which is
the brain area responsible for controlling movement, muscles, balance,
and posture.
However, some research has also tied this brain region to language, cognition, and mood.

Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders Frontiers in microbiology

Ketamine nasal spray rapidly relieves depression and suicidal thoughts, finds trial | The Independent

People with serious mental illness could one day be offered a nasal
spray of ketamine after a clinical trial showed the drug can rapidly
tackle bouts of severe depression and suicidal thoughts.
In just a matter of hours, doctors, and the patients themselves,
measured a significant improvement in symptoms of patients classed as
being at high risk of suicide.
The trial of antidepressant esketamine by Yale University researchers
and the manufacturer, Janssen, suggests it could be effective in
bridging the gap where conventional antidepressants take weeks to
be fully effective.

Depression is a physical illness which could be treated with anti-inflammatory drugs, scientists suggest

 "Depression could be treated using anti-inflammatory drugs, scientists now believe, after determining that it is a physical illness caused by a faulty immune system.

Around one in 13 people in Britain suffers from anxiety or depression and last year the NHS issued 64.7 million prescriptions for antidepressants, double the amount given out a decade ago.

Current treatment is largely centred around restoring mood-boosting chemicals in the brain, such as serotonin, but experts now think an overactive immune system triggers inflammation throughout the entire body, sparking feelings of hopelessness, unhappiness and fatigue.

It may be a symptom of the immune system failing to switch off after a trauma or illness, and is a similar to the low mood people often experience when they are fighting a virus, like flu."



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Esketamine produces rapid effects in treatment-resistant depression - Medical News Today

A new study in Biological Psychiatry reports that esketamine, a component of the general anesthetic ketamine, shows rapid and significant improvement in depressive symptoms in patients who do not respond to currently available therapies. The study aimed to demonstrate the efficacy and safety of esketamine in hopes to fulfill a long-awaited clinical need for therapies that can crack treatment-resistant depression.

Ketamine piqued researchers' interest when a study demonstrated that low doses of the drug have rapid antidepressant effects, alleviating symptoms within just 2 hours. This stood in stark contrast to conventional antidepressant drugs, which can take 1 to 3 months to produce an effect. In addition, ketamine appeared to work in patients who did not see improvement in symptoms with conventional antidepressant drugs, about one third of patients with major depressive disorder."

Prenatal BPA exposure linked to anxiety and depression in boys -- ScienceDaily

Boys exposed prenatally to a common chemical used in plastics may be more likely to develop symptoms of anxiety and depression at age 10-12. The new study by researchers at the Columbia Center for Children's Environmental Health (CCCEH) within the Mailman School of Public Health examined early life exposure to the chemical Bisphenol A (BPA). Results are published in the journal Environmental Research.

Cat scratches, not bites, are associated with unipolar depression--cross-sectional study. - PubMed - NCBI

A recent study performed on 1.3 million patients showed a strong association between being bitten by a cat and probability of being diagnosed with depression. Authors suggested that infection with cat parasite Toxoplasma could be the reason for this association.


METHOD:
A cross sectional internet study on a non-clinical population of 5,535 subjects was undertaken.


RESULTS:
The subjects that reported having been bitten by a dog and a cat or scratched by a cat have higher Beck depression score. They were more likely to have visited psychiatrists, psychotherapists and neurologists in past two years, to have been previously diagnosed with depression (but not with bipolar disorder). Multivariate analysis of models with cat biting, cat scratching, toxoplasmosis, the number of cats at home, and the age of subjects as independent variables showed that only cat scratching had positive effect on depression (p = 0.004). Cat biting and toxoplasmosis had no effect on the depression, and the number of cats at home had a negative effect on depression (p = 0.021).

 CONCLUSIONS:
Absence of association between toxoplasmosis and depression and five times stronger association of depression with cat scratching than with cat biting suggests that the pathogen responsible for mood disorders in animals-injured subjects is probably not the protozoon Toxoplasma gondii but another organism; possibly the agent of cat-scratched disease - the bacteria Bartonella henselae."



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Gut Bacteria Consumes Neurochemical (GABA) Linked To Depression

A recently-discovered strain of gut bacteria has been found to consume GABA, a neurochemical found in the brain. The neurotransmitter has a calming effect on the brain, and the bacteria’s reliance on GABA could explain how the microbiome has an effect on mood.

The bacterial species found in the gut – called KLE1738 – was found to grow in culture only when supplemented with GABA molecules. “Nothing made it grow, except GABA,” said Philip Strandwitz, a postdoctoral research associate from Northeastern University in Boston. Strandwitz and his colleagues presented their findings at the annual meeting of the American Society for Microbiology, in June.

This is the first time a bacterial species has been found which uses a neurotransmitter as an energy source. As GABA calms down brain activity by inhibiting signals between nerve cells, the researchers were surprised to find that it’s necessary for some microbial life.

Ketamine lifts depression via a byproduct of its metabolism | National Institutes of Health (NIH)

"A chemical byproduct, or metabolite, created as the body breaks down ketamine likely holds the secret to its rapid antidepressant action, National Institutes of Health (NIH) scientists and grantees have discovered.  This metabolite singularly reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative, or addictive side effects associated with ketamine. It may work via AMPA receptor stimulation rather than by NMDA receptor antagonism.



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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment: Immunity

Highlights
•Viruses induce depressive behavior and ISG15 expression at the blood-brain barrier
•IFNAR1 expression on neural cells is not involved in IFN-β-induced sickness behavior
•IFNAR1 expression on brain endothelial and epithelial cells drives behavioral changes
•Brain endothelia- and epithelia-derived CXCL10 inhibits hippocampal synaptic plasticity

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy."



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Body’s defenses against common viruses may mess up neurons, spark depression | Ars Technica

Getting sick is definitely a bummer. But besides feeling icky and being stuck in bed, viral infections may cause us to actually be depressed. While scientists have been clued into this connection for a while, there was little data on how everyday viral infections, like the flu, might mess with our moods.

Now, data from a new mouse study shows that common viruses may spur sadness by causing the cells that line the blood-brain barrier to release signals that hush the chatter between neurons in the area of the brain responsible for mood. The findings, published this week in the journal Immunity, may finally explain the link between infections and mental health problems, and it could point researchers towards new strategies for treating depression and other mood disorders.

Researchers have been collecting hints of the connection between mental health and infections for years. Though it was first dismissed as people simply being blue about getting sick, doctors now accept that there is a condition called “sickness behavior.” This condition is marked by cognitive deficits, drowsiness, general malaise, and other depression-like symptoms in those with an infection. Moreover, in a 2013 Danish study, researchers found that people who had been treated for a severe infection were 62 percent more likely to suffer from mood disorders. Perhaps related, those that had an autoimmune disease were 45 percent more likely to have such a mental health issue."



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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment: Immunity

 Highlights 

•Viruses induce depressive behavior and ISG15 expression at the blood-brain barrier
•IFNAR1 expression on neural cells is not involved in IFN-β-induced sickness behavior
•IFNAR1 expression on brain endothelial and epithelial cells drives behavioral changes
•Brain endothelia- and epithelia-derived CXCL10 inhibits hippocampal synaptic plasticity

Summary 

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy."



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Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host|[rsquo]|s metabolism : Molecular Psychiatry

"Major depressive disorder (MDD) is the result of complex gene–environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with ‘depression microbiota’ derived from MDD patients resulted in depression-like behaviors compared with colonization with ‘healthy microbiota’ derived from healthy control individuals. Mice harboring ‘depression microbiota’ primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host’s metabolism."



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A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression : Molecular Psychiatry

 "Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders."



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Cat scratches, not bites, are associated with unipolar depression - cross-sectional study. - PubMed - NCBI

 A recent study performed on 1.3 million patients showed a strong association between being bitten by a cat and probability of being diagnosed with depression. Authors suggested that infection with cat parasite Toxoplasma could be the reason for this association.

METHOD:

A cross sectional internet study on a non-clinical population of 5,535 subjects was undertaken.

RESULTS:

The subjects that reported having been bitten by a dog and a cat or scratched by a cat have higher Beck depression score. They were more likely to have visited psychiatrists, psychotherapists and neurologists in past two years, to have been previously diagnosed with depression (but not with bipolar disorder). Multivariate analysis of models with cat biting, cat scratching, toxoplasmosis, the number of cats at home, and the age of subjects as independent variables showed that only cat scratching had positive effect on depression (p = 0.004). Cat biting and toxoplasmosis had no effect on the depression, and the number of cats at home had a negative effect on depression (p = 0.021).

CONCLUSIONS:

Absence of association between toxoplasmosis and depression and five times stronger association of depression with cat scratching than with cat biting suggests that the pathogen responsible for mood disorders in animals-injured subjects is probably not the protozoon Toxoplasma gondii but another organism; possibly the agent of cat-scratched disease - the bacteria Bartonella henselae.

Molecular Psychiatry - Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression

Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=−0.47,P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=−0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=−0.33 to −0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.

Neurotransmitters Produced During Depression May Boost Pro-Inflammatory Molecules and Increase Risk of Heart Disease, Diabetes, Chronic Pain | Brain & Behavior Research Foundation (Formerly NARSAD)

Consuming highly refined carbohydrates increases risk of depression -- ScienceDaily

"The study by James Gangwisch, PhD and colleagues in the department of psychiatry at Columbia University Medical Center (CUMC) looked at the dietary glycemic index, glycemic load, types of carbohydrates consumed, and depression in data from more than 70,000 postmenopausal women who participated in the National Institutes of Health's Women's Health Initiative Observational Study between 1994 and 1998.

Consumption of carbohydrates increases blood sugar levels to varying degrees, depending on the type of food ingested. The more highly refined the carbohydrate, the higher its score on the glycemic index (GI) scale. The GI scale, which goes from 0-100, measures the amount of sugar found in the blood after eating. Refined foods such as white bread, white rice, and soda trigger a hormonal response in the body to reduce blood sugar levels. This response may also cause or exacerbate mood changes, fatigue and other symptoms of depression.

The investigators found that progressively higher dietary GI scores and consumption of added sugars and refined grains were associated with increased risk of new-onset depression in post-menopausal women. Greater consumption of dietary fiber, whole grains, vegetables and non-juice fruits was associated with decreased risk. This suggests that dietary interventions could serve as treatments and preventive measures for depression. Further study is needed to examine the potential of this novel option for treatment and prevention, and to see if similar results are found in the broader population."



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Scientists show a link between intestinal bacteria and depression

In this study, researchers subjected mice to early life stress with a procedure of maternal separation, meaning that from day three to 21, newborn mice were separated for three hours each day from their mothers and then put back with them.

First, Bercik and his team confirmed that conventional mice with complex microbiota, which had been maternally separated, displayed anxiety and depression-like behaviour, with abnormal levels of the stress hormone corticosterone. These mice also showed gut dysfunction based on the release of a major neurotransmitter, acetylcholine.

Then, they repeated the same experiment in germ-free conditions and found that in the absence of bacteria mice which were maternally separated still have altered stress hormone levels and gut dysfunction, but they behaved similar to the control mice, not showing any signs of anxiety or depression.

Study links brain inflammation triggered by chronic pain to anxiety and depression -- ScienceDaily

In work with rodents, Catherine Cahill, associate professor of
anesthesiology & perioperative care at UCI, Christopher Evans of
UCLA's Brain Research Institute, and colleagues discovered that
pain-derived brain inflammation causes the accelerated growth and
activation of immune cells called microglia. These cells trigger
chemical signals within neurons that restrict the release of dopamine, a
neurotransmitter that helps control the brain's reward and pleasure
centers.

Molecular Signatures of Major Depression: Current Biology

Adversity particularly in early life, can cause illness. Clues to the responsible
mechanisms may lie with the discovery of molecular signatures of stress,
some of which include alterations to an individual’s somatic genome.
Here, using genome sequences from 11,670 women, we observed a highly
significant association between a stress-related disease, major
depression, and the amount of mitochondrial DNA (p = 9.00 × 10⁻⁴², odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10⁻¹⁴,
odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mitochondrial DNA amount were associated with adverse life events, conditional
regression analyses showed the molecular changes were contingent on the
depressed state. We tested this hypothesis with experiments in mice,
demonstrating that stress causes both molecular changes, which are
partly reversible and can be elicited by the administration of
corticosterone. Together, these results demonstrate that changes in the
amount of mitochondrial DNA and telomere length are consequences of stress and
entering a depressed state. These findings identify increased amounts of
mtDNA as a molecular marker of MD and have important implications for
understanding how stress causes the disease.