Inflammation Associated With Duration of Untreated Unipolar Depression

February 14, 2019 · Posted in Brain Imaging, Course of Illness, Neurobiology · Comment 

depressed woman

Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.

Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.

Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.

Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.

This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.

Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.

In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017.  The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.

Risk Gene for Bipolar Disorder Implicated in Depressed Behaviors and Abnormal Firing of GABA Neurons

February 8, 2019 · Posted in Genetics, Neurobiology · Comment 

DNA

At a 2018 scientific meeting and in a 2017 article in the journal PNAS, researcher Shanshan Zhu and colleagues reported that mice genetically engineered to lack the protein Ankyrin-G in certain neurons showed increases in depression- and mania-like behavior after being exposed to defeat stress (by repeatedly being placed in physical proximity to a larger, more aggressive mouse), which is often used to model human depression.

The researchers targeted the gene ANK3, which is responsible for the production of Ankyrin-G, and has been linked to bipolar disorder in genome-wide association studies. By manipulating the gene, they could eliminate Ankyrin-G in pyramidal neurons in the forebrain, a region relevant to many psychiatric disorders. Pyramidal neurons perform key brain functions, sending nerve pulses that lead to movement and cognition.

The missing Ankyrin-G affected sodium channels (which allow for the flow of sodium ions in and out of cells) and potassium channels. The neurochemical GABA (which typically inhibits nerve impulses) was also dysregulated, resulting in the kind of disinhibition seen in psychosis. Mice showed dramatic behavioral changes ranging from hyperactivity to depression-like behavior (e.g. giving up in a forced swimming test). The hyperactivity decreased when the mice were given treatments for human mania, lithium or valproic acid.

While mutations in the ANK3 gene may disturb sodium channels, another gene linked to depression and bipolar disorder, CACNA1C, affects calcium channels.

In a related study by researcher Rene Caballero-Florán and colleagues that was also presented at the meeting, mice were genetically engineered in such a way that interactions between Ankyrin-G and GABA Type A Receptor-Associated Protein (GABARAP) were disrupted, leading to deficits in inhibitory signaling. These deficits were partially corrected when the mice were treated with lithium.

The study by Caballero-Florán and colleagues used mice with a mutation known as W1989R in the ANK3 gene. Through a program that examines the genes of people with bipolar disorder, the researchers also identified a family with this genetic mutation, including a patient with type I bipolar disorder with recurrent mania and depression who has responded well to lithium treatment.

White Matter Abnormalities in Obesity

January 16, 2019 · Posted in Brain Imaging, Neurobiology · Comment 

obese man

Researcher Ramiro Reckziegel and colleagues reported at a recent scientific meeting that white matter is abnormal in obese adults with bipolar disorder. In a 2018 article in the journal Schizophrenia Bulletin, Reckziegel reported that body mass index (BMI) was associated with reduced fractional anisotropy, a measure of brain fiber integrity, in the cingulate gyrus in patients with bipolar disorder. This finding implies that obesity may play a role in white matter microstructure damage in the limbic system.

White Matter Abnormalities Linked to Irritability in Both Bipolar Disorder and DMDD

January 14, 2019 · Posted in Brain Imaging, Neurobiology · Comment 

white matterAt a 2018 scientific meeting, researcher Julia Linke of the National Institute of Mental Health reported that there were white matter tract abnormalities in young people who had irritability associated with either bipolar disorder or disruptive mood dysregulation disorder (DMDD). Thus, while these two disorders differ in terms of diagnosis, presentation, and family history, they seem to have this neurobiological abnormality in common.

Scientific Mechanisms of Rapid-Acting Antidepressants

January 10, 2019 · Posted in Neurochemistry · Comment 
pyramidal cell

A pyramidal cell (Photo by Bob Jacobs, Laboratory of Quantitative Neuromorphology Department of Psychology Colorado College)

At a recent symposium, researcher Francis McMahon provided electrophysiological evidence that several different types of rapid-acting antidepressants—low-dose ketamine, scopolamine, and rapastinel (a partial agonist of the neurotransmitter NMDA)—act by decreasing the inhibitory effects of GABAergic interneurons on excitatory neurons called pyramidal cells, thus increasing synaptic firing.

Researcher Ronald Duman further dissected these effects, showing that ketamine and its active metabolite norketamine reduce the steady firing rate of GABA interneurons by blocking NMDA receptors, while the partial agonist rapastinel acts on the glutamate neurons directly, and both increase the effects of a type of glutamate receptors known as AMPA. These effects were demonstrated using a virus to selectively knock out GluN2B glutamate receptor subunits in either GABA interneurons or glutamate neurons.

Increasing AMPA activity increases synapse number and function and also increases network connectivity, which can reverse the effects of stress. Duman and colleagues further showed that when light is used to modulate pyramidal cells (a process called optogenetic stimulation) in the medial prefrontal cortex, different effects could be produced. Stimulating medial prefrontal cortex cells that contained dopamine D1 receptors, but not D2 receptors, produced rapid and sustained antidepressant effects. Conversely, inhibiting these neurons blocked the antidepressant effects of ketamine. Stimulating the terminals of these D1-containing neurons in the basolateral nucleus of the amygdala was sufficient to reproduce the antidepressant effects. These data suggest that stimulation of glutamate D1 pyramidal neurons from the medial prefrontal cortex to the basolateral nucleus of the amygdala is both necessary and sufficient to produce the antidepressant effects seen with ketamine treatment.

Researcher Hailan Hu reported that NMDA glutamate receptors drive the burst firing of lateral habenula (LHb) neurons, which make up the depressogenic or “anti-reward center” of the brain and appear to mediate anhedonic behavior (loss of interest or enjoyment) in animal models of depression. Ketamine blocks the burst firing of the LHb neurons, which disinhibits monoamine reward centers, enabling ketamine’s rapid-onset antidepressant effects. This may occur because inhibitory metabotropic glutamate receptors (mGluR-2) are activated, decreasing the release of glutamate.

MGluR-2 may also help explain the antidepressant effects of acetyl-L-carnitine supplements. L-carnitine is an amino acid that is low in the blood of depressed patients. The supplement acetyl-L-carnitine (ACL) activates the DNA promoter for mGluR-2, increasing its production and thus decreasing excess glutamate release. The acetyl group of the ACL binds to the DNA promoter for mGluR-2, thus this process seems to be epigenetic. Epigenetic mechanisms affect the structure of DNA and can be passed on to offspring even though they are not encoded in the DNA’s genetic sequence.

Inflammation and Depression: Treatment Implications

November 19, 2018 · Posted in Neurobiology · Comment 

inflammation in the brainVladimir Maletic of the University of South Carolina School of Medicine Greenville gave a plenary talk at the 2018 meeting of the North Carolina Psychiatric Association that described a variety of ways that inflammation can drive depression.

Maletic explained that stress can increase neurotransmitters that activate brain macrophages, increase NFkB (a protein that controls DNA transcription and cell survival), and increase brain inflammation, evidenced by elevated levels of the inflammatory markers IL-1b, IL-6, TNF-alpha, and C-reactive protein (CRP). These signs of inflammation are associated with changes in brain function and connectivity that are consistent with depression, fatigue, and cognitive slowing.

Inflammation measured outside of the brain and spinal cord is associated with increased activity of the insula (a key brain sensor and modulator of emotions), disconnection between the prefrontal cortex and the reward circuits in the nucleus accumbens, and decreased function and structural changes to the hippocampus (critical for memory).

Maletic also explained that inflammation changes the way the amino acid tryptophan is metabolized. Normally tryptophan is converted into kyneurenic acid, which prevents excitotoxicity and has anticonvulsant effects. Stress can lead to tryptophan being metabolized instead into quinolinic acid, which is neurotoxic and has been linked to certain psychiatric disorders and neurodegenerative processes. This in turn impairs synaptic functioning, including increasing glutamate and decreasing brain-derived neurotrophic factor (BDNF), impairing a type of glia called oligodendroglia (which produce myelin), and the formation of new neural connections.

These findings have several important implications for treatment. Increases in inflammation have been linked to the atypical type of depression characterized by increased appetite, weight gain, and increased sleep rather than the more classic presentation of depression that includes loss of appetite, weight loss and insomnia. Thus, weight gain, waist circumference, and body mass index (BMI) are correlated with inflammation and can signal a poor response to medications (including the rapid-acting antidepressant ketamine and some other antidepressants). If someone with unipolar depression has high levels of CRP, they tend to have a poorer response to selective serotonin reuptake inhibitor (SSRI) antidepressants, and may respond better to the noradrenergic tricyclic antidepressant nortryptyline, the serotonin and norepinephrine reuptake inhibitors (SNRIs), and the dopamine active antidepressant bupropion.

There is some good news. Read more

Depression and Suicidal Thoughts Linked to Brain Inflammation

February 14, 2018 · Posted in Neurobiology · Comment 

depressed man

A 2017 article by Sophie E. Holmes and colleagues in the journal Biological Psychiatry reports that people with major unipolar depression, especially those with suicidal thoughts, have higher levels of the inflammatory marker translocator protein than do healthy individuals.

The participants with depression and suicidal thinking had high levels of translocator protein in the anterior cingulate cortex, which suggests that inflammation is affecting microglia.

Many studies have found links between different indicators of inflammation and mood disorders, leading researchers to speculate whether targeting the immune system could be an effective way to treat mood disorders. Patients with high levels of inflammation often fail to respond to typical treatments for depression.

Some previous research has found evidence of microglial activation in the brains of people who died from suicide.

The small study by Holmes and colleagues used positron-emission tomography, or PET scans, to observe evidence of translocator protein levels in the brain in 14 medication-free participants in a major depressive episode and 13 healthy volunteers. Those with depression, and particularly those with suicidal thoughts, showed more evidence of neuroinflammation.

Link Clarified Between Gut Microbes and Emotions

February 12, 2018 · Posted in Neurobiology · Comment 

mice exercising

A 2017 article in the journal Microbiome suggests that gene-regulating molecules called microRNAs in the brain may be the link between microbes in the gut and emotions.
The research by Alan E. Hoban and colleagues looked at mice raised in a sterile, microbe-free environment. These mice had fewer anxiety-like behaviors than mice raised among the usual bacteria, viruses, and fungi. This finding implies that the microbiome—the trillions of microbes that live in and around our bodies—affects brain functions. In this case, the affected regions were the prefrontal cortex and the amygdala, which both play a role in the detection and response to fearful stimuli. These regions showed alterations in the level of microRNAs present.

When Hoban and colleagues introduced microbes into the animal’s systems, some microRNAs did not bounce back, suggesting that there may be a crucial window early in life when the presence of microbes is needed for the brain to develop normally.

In general, this research shows that microRNAs are key to understanding the link between the microbiome and the brain.

Type of Trauma Affects Gene Transcription Effects in PTSD

January 22, 2018 · Posted in Neurobiology · Comment 

PTSDIn a 2017 article in the journal Neuropsychopharmacology, researcher Michael S. Breen and colleagues analyzed five separate studies of post-traumatic stress disorder (PTSD) and found that sex and type of trauma affected the immunological pathways that changed with PTSD. People with PTSD showed disruptions in gene expression in specific immunological pathways depending on what type of trauma they had experienced.

Men exposed to combat traumas showed downregulation in a pathway related to wound healing, while men who were exposed to interpersonal traumas had upregulation in a signaling pathway mediated by the inflammatory marker IL-12. Women exposed to interpersonal traumas showed upregulation of two pathways—one related to lipid metabolism and the other related to MAPK (or mitogen-activated protein kinase) activity.

The participants with PTSD also showed a lot of the same disruptions across all types of trauma, including disruptions that affected cytokine, innate immune, and type 1 interferon pathways.

These data show that immune dysregulation and inflammatory pathways play a role in the pathophysiology of PTSD.

Different Types of Trauma Affect Brain Volume Differently

October 16, 2017 · Posted in Neurobiology · Comment 

brain volume

Post-traumatic stress disorder (PTSD) has been associated with decreased volume of gray matter in the cortex. Research by Linghui Meng and colleagues has revealed that the specific types of trauma that precede PTSD affect gray matter volume differently.

At the 2016 meeting of the Society for Neuroscience, Meng reported that PTSD from accidents, natural disasters, and combat led to different patterns of gray matter loss. PTSD from accidents was associated with gray matter reductions in the bilateral anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). PTSD from natural disasters was linked to gray matter reductions in the mPFC and ACC, plus the amygdala and left hippocampus. PTSD from combat reduced gray matter volume in the left striatum, the left insula, and the left middle temporal gyrus.

Meng and colleagues also found that severity of PTSD was linked to the severity of gray matter reductions in the bilateral ACC and the mPFC.

In a 2016 article in the journal Scientific Reports, Meng and colleagues reported that single-incident traumas were associated with gray matter loss in the bilateral mPFC, the ACC, insula, striatum, left hippocampus, and the amygdala, while prolonged or recurrent traumas were linked to gray matter loss in the left insula, striatum, amygdala, and middle temporal gyrus.

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