Molecular Biology of Depression

October 1, 2015 · Posted in Neurobiology, Risk Factors · Comment 

molecular biology of depressionDysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.

Early Life Experiences are Key

Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.

The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.

CLOCK Genes and Circadian Rhythms

Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.

Fibroblast Growth Factor

Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.

In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.

FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”

Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.

The Human Brain

Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.

In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).

Blood and Now Brain Inflammation Linked to Depression

September 16, 2015 · Posted in Brain Imaging, Risk Factors · Comment 

microgliaThere is growing evidence of a link between inflammation of depression. At the 2015 meeting of the Society of Biological Psychiatry, researcher Jeff Meyer summarized past studies on inflammatory markers. These are measurements, for example of certain proteins in the blood, that indicate the presence of inflammation in the body.

Common inflammatory markers that have been linked to depression include IL-6, TNF-alpha, and c-reactive protein. At the meeting, Meyer reviewed the findings on each of these. Twelve studies showed that IL-6 levels are elevated in the blood of patients with depression. Four studies had non-significant results of link between IL-6 and depression, and Meyer found no studies indicating that IL-6 levels were lower in those with depression. Similarly, for TNF-alpha, Meyer found 11 studies linking elevated TNF-alpha with depression, four with non-significant results, and none showing a negative relationship between TNF-alpha and depression. For c-reactive protein, six studies showed that c-reactive protein was elevated in people with depression, six had non-significant results, and none indicated that c-reactive protein was lower in depressed patients.

Most studies that have linked inflammation to depression have done so by measuring inflammatory markers in the blood. It is more difficult to measure inflammation in the brain of living people, but Meyer has taken advantage of new developments in positron emission tomography (PET) scans to measure translocator protein binding, which illustrates when microglia are activated. Microglial activation is a sign of inflammation. Translocator protein binding was elevated by about 30% in the prefrontal cortex, anterior cingulate cortex, and insula in study participants who showed symptoms of a major depressive episode compared to healthy control participants. The implication is that the depressed people with elevated translocator protein binding have more brain inflammation, probably via microglial activation.

The antibiotic minocycline reduces microglial activation. It would be interesting to see if minocycline might have antidepressant effects in people with depression symptoms and elevated translocator protein binding.

Autopsy Studies Show Brain Inflammation in Unipolar Depression, Bipolar Disorder, and Suicide

September 14, 2015 · Posted in Neurobiology · Comment 

inflammation in the brainDepression and bipolar disorder have been linked to high levels of inflammatory proteins in the blood (namely CRP, IL-1, IL-6, and TNF-alpha), but the relationship between these illnesses and inflammation in the brain has not been well-characterized.

At the 2015 meeting of the Society for Biological Psychiatry, researcher Ghanshyan Pandey discussed findings from autopsy studies of people who died with a diagnosis of unipolar depression or bipolar disorder, and teens who died of suicide. The studies compare data from these ill people with those of controls who are matched for demographic characteristics.

Pandey found that the brains of those who died of unipolar depression and bipolar disorder showed more signs of inflammation compared to the controls. This included elevated levels of the inflammatory proteins IL-1B, IL-6, and TNF-alpha, in addition to elevated levels of the mRNA that leads to their production. Pandey also found that those with depression and bipolar disorder had higher levels of mRNA for the receptors to which TNF-alpha and other inflammatory proteins attach themselves.

Pandey performed similar autopsy studies of teens who died of suicide, the second leading cause of death for this age group, compared to teens who died of other causes. There were more signs of inflammation in the prefrontal cortices of teens who died of suicide. These included mRNA and proteins for IL-1B and TNF-alpha, and IL-6 proteins. In contrast to the ill adults, the teens who died of suicide had lower levels of the receptors for inflammatory proteins than controls. Another type of receptor known as toll-like receptors was higher in the ill teens, particularly the mRNA and proteins TLR3 and TLR4.

Chronic Drug Use and Recovery

August 12, 2015 · Posted in Course of Illness, Neurobiology · Comment 

chronic drug useGeorge Koob, Director of the National Institute on Alcohol Abuse and Alcoholism, discussed the neuroscience of chronic drug use at the 2015 meeting of the Society of Biological Psychiatry. His basic message was that chronic drug use is associated with A) loss of the reward value of the drug and B) a progressive increase in dysphoria and stress when off the drug. Both factors drive craving and drug seeking.

Access to high as opposed to moderate doses of a drug lead to an escalation in drug intake, and associated persistent increases in withdrawal dysphoria, which Koob called “the dark side.”

Koob explained that a month of detoxification is not sufficient, and that people quitting a drug need more time to let dopamine increase and to let levels of corticotropin releasing factor (CRF), which drives the anxiety and dysphoria of withdrawal, normalize. He stressed that for people addicted to opiates, it is important to taper levels of the drug to minimize withdrawal symptoms.

In addition to CRF, dynorphin also plays a role in chronic drug abuse. This opiate peptide acts at kappa opiate receptors and is associated with anxiety, dysphoria, and psychosis as opposed to morphine, which acts at mu opiate receptors and is associated with euphoria and decreased pain. Koob found that administration of the kappa opiate antagonist norbinaltorphimine (nor-BNI) blocks dose escalation of methamphetamine and brings abstinence-related compulsive drug seeking back to baseline.

Chronic Stress Makes You Stupid

August 10, 2015 · Posted in Neurobiology · Comment 

chronic stress

At the 2015 meeting of the Society of Biological Psychiatry, Bruce McEwen, professor of neuroscience at Rockefeller University, gave an overview of stress’s effect on the brain. He explained that “chronic stress makes you stupid,” and said that while one can compensate for the effects of chronic stress, one cannot reverse them.

Short-term stress can be helpful, increasing cortisol, with generally positive effects. When stress lasts longer, the chronic increase in cortisol starts to cause problems: impaired memory, endangered neurons, decreased bone and muscle, and metabolic abnormalities.

McEwen said that chronic stress shrinks the dendrites in the medial prefrontal cortex and the hippocampus. A healthy prefrontal cortex is necessary for new learning and memory.

Chronic stress also enlarges the orbital frontal cortex and the amygdala. An oversized orbital frontal cortex can induce habits, making a person susceptible to repetitive thinking and obsessions, addictions, or other compulsive behavior. An oversized amygdala can provoke fear and anxiety.

Editor’s Note: Stress can make people more susceptible to substance abuse, which in turn leads to losses in cortical control.

Neuropsychological Deficits After Concussion Are Correlated with White Matter Abnormalities

July 31, 2015 · Posted in Brain Imaging · Comment 
DTI scan

DTI brain scan can show damage to white matter following a concussion.

Many people suffer problems with mental functioning after an apparent concussion (otherwise known as mild traumatic brain injury, or mTBI) that does not show abnormalities on traditional brain imaging measures such as the MRI. New technology called diffusion tensor imaging (DTI) shows that the integrity of white matter tracts may be disturbed by concussions. White matter comprises parts of the brain where myelin wraps around axons, as opposed to grey matter, which reflects the presence of neuronal cell bodies.

In a longitudinal study published in the Journal of Neurotrauma, Vigneswaran Veeramuthu and colleagues compared 61 people with an mTBI to 19 healthy controls. The mTBI participants had their neuropsychological faculties assessed an average of 4.35 hours after their trauma, and participated in DTI scans an average of 10 hours after the trauma. Both the neuropsychological assessment and the DTI scan were repeated six months later. When the acute and follow-up assessments were compared to the same assessments in control participants, the two groups showed differences in numerous white matter tracts at the six-month mark. There was also an association between the degree of abnormality observed on the DTI scans and decrements in performance on the tests of neuropsychological functioning both immediately after the trauma and six months later.

The researchers concluded that their results “provide new evidence for the use of DTI as an imaging biomarker and indicator of [white matter] damage occurring in the context of mTBI, and [the results] underscore the dynamic nature of brain injury and possible biological basis of chronic neurocognitive alterations.”

Editor’s Note: People should be aware of these findings, which confirm earlier studies, and begin rehabilitative treatment as soon as possible after a concussion. New research should target white matter tract changes, with the goal of secondary prevention, i.e. limiting damage to the brain after a traumatic injury has occurred. There are several promising drugs that can prevent damage if administered immediately after an mTBI, including the antioxidant supplement N-acetylcysteine (NAC), which has shown promise in preliminary clinical and laboratory studies, and many others, including lithium and valproate, as reported by De-Maw Chuang and this editor Robert M. Post in a 2015 article in the Journal of Neurology and Stroke titled “Preventing the Sequelae of Concussions and Traumatic Brain Injury.”

Serotonin 5-HT7 Receptors: Why Should We Care About Them?

June 12, 2015 · Posted in Neurochemistry · Comment 


5-HT7 is a type of receptor activated by the neurotransmitter serotonin. Some of the most potent effects of lurasidone (Latuda), an atypical antipsychotic with antidepressant effects in bipolar depression, and vortioxetine (Brintellix), a unique antidepressant for unipolar depression that also has positive effects on cognition, occur through the blockade of 5-HT7 receptors. The atypical antipsychotics aripiprazole and sulpiride also act on 5-HT7 receptors.

Researcher Agnieszka Nikiforuk summarized the research to date on 5-HT7 receptors in the journal CNS Drugs in 2015.

The receptors play a role in regulating sleep and circadian rhythms, which may explain why drugs that target them can be helpful in depression. Drugs that target 5-HT7 receptors have also improved learning and memory.

One subject of research into 5-HT7 receptors is whether better results come from blocking the receptors or stimulating them.

Blockade of 5-HT7 receptors has improved depression-like symptoms in animals and enhances the effects of sub-therapeutic doses of antidepressants. In other animal studies, stimulation of the receptors has appeared promising for the prevention of age-related cognitive decline.

Calcium Channel May Be Responsible for Circadian Rhythm Abnormalities in Bipolar Disorder

April 1, 2015 · Posted in Neurobiology · Comment 

circadian rhythms

Genetic variation in L-type calcium channel genes have been linked to bipolar disorder. Since calcium plays an important role in circadian rhythms, abnormalities in the calcium channel in bipolar disorder could explain some of the circadian rhythm disturbances patients with bipolar disorder exhibit. New research by Michael McCarthy and colleagues shows that calcium channels in general, and the gene CACNA1C in particular, affect signaling pathways that regulate circadian rhythms in both human and animal cells. The researchers also found that calcium channels affected how lithium changes circadian rhythms, suggesting a mechanism by which the treatment may work. They suggest that drugs that affect the L-type calcium channel may be promising treatments for bipolar disorder.

Editor’s Note: The L-type calcium channel blocker nimodipine has had antidepressant, antimanic, and anticycling effects in some patients with bipolar disorder in small studies both by Peggy Pazzaglia and colleagues (including this author Robert Post) and a larger randomized study by Haroon R. Chaudhry.

The clinical effects of nimodipine results thus align with studies linking the CACNA1C gene to bipolar illness and its early onset, increased expression of the gene in the brain of bipolar patients in autopsy studies, increased levels of calcium in white cells of bipolar patients, and a variety of other neurobiological phenomena observed in normal controls carrying the risk gene.

The new link found between CACNA1C and circadian rhythms further links the L-type calcium channel abnormality and bipolar disorder, as well as the therapeutic effects of the L-type calcium channel blocker nimodipine. This drug deserves further study, especially in those with the genetic variation in CACNA1C that has been linked to bipolar disorder.

Brain Activity Differentiates Youth with Bipolar Disorder from Youth with Unipolar Depression

March 24, 2015 · Posted in Brain Imaging, Diagnosis · Comment 

stressed teen girl

Both bipolar disorder and unipolar depression often begin in childhood or adolescence, but it can be difficult to distinguish the two using symptoms only. People with bipolar illness may go a decade without receiving a correct diagnosis. Researcher Jorge Almeida and colleagues recently performed a meta-analysis of previous studies to determine what neural activity is typical of children with bipolar disorder versus children with unipolar depression while processing images of facial emotion. They found that youth with bipolar disorder were more likely to show limbic hyperactivity and cortical hypoactivity during emotional face processing than youth with unipolar depression. Almeida and colleagues hope that this type of data may eventually be used to diagnose these disorders or to measure whether treatment has been successful.

Connections Between Stress and Substance Use May Be Mediated By Corticotropin-Releasing Factor

March 13, 2015 · Posted in Neurobiology · Comment 

brainResearchers hope to map out the neurocircuitry by which stress leads to compulsive drug taking. A recent study by Klaus Miczek and colleagues examined different rodents’ responses to the stress of being repeatedly placed in the cage of a larger, more aggressive rodent, developing what is known as defeat stress, a set of behaviors that mimic human depression. Mice and rats showed increases in the stress hormone corticosterone that did not diminish over repeated run-ins with a larger animal. Rodents who were exposed to this stress became sensitized to cocaine or amphetamine, showing hyperactivity that increased each time they accessed the drug (the opposite of a tolerance response). Some also “binged” on cocaine, which they were able to self-administrate by pushing a lever to receive infusions. The mice and rats that went through the social defeat showed elevated levels of dopamine in the nucleus accumbens, the brain’s reward center. Levels were related to the severity of their stressful experience.

Later the rodents had a choice between water and a 20% alcohol solution. The researchers determined what type of stress led the rodents to consume the alcohol solution instead of the water. The maximal effect was seen in two types of mice that suffered an attack of less than five minutes that resulted in a moderate number of attack bites (30); this resulted in the mice consuming large amounts (15–30 g/kg/day) of the alcohol solution. Earlier sensitization to cocaine or amphetamine did not predict later alcohol or cocaine self-administration.

When the researchers injected the rodents with antagonists of the receptors for corticotropin-releasing factor, a hormone and neurotransmitter important in stress response, prior to each episode of social defeat, the rodents did not escalate their cocaine or alcohol self-administration, indicating that CRF plays an essential role in the process by which stress makes animals prone to using substances.

In related research by Camilla Karlsson and colleagues, IL-1R1 and TNF-1R, the receptors for two inflammatory cytokines, mediated the effects of social stress on escalated alcohol use in mice.

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