A 2016 study by Peter S. Bloomfield and colleagues in the American Journal of Psychiatry used PET scans to compare the activity of microglia, immune cells in the central nervous system, in healthy controls, people with schizophrenia, and those at high risk for the illness. It found that both people with schizophrenia and those at high risk had greater brain inflammation than the healthy controls.
The study was the first to show that microglial activity was elevated in people at high risk (who showed some preliminary symptoms of schizophrenia). The finding had a large effect size.
Microglial activity was also correlated with symptom severity in the high-risk participants. Increased microglial activity was not linked to depression, suggesting that it is specific to the development of psychosis.
These findings resemble those of other recent studies showing increased inflammation in people at high risk for psychosis.
The study suggests that increased microglial activity occurs before a first episode of psychosis. That means it could help identify people who may develop schizophrenia. The findings also suggest that anti-inflammatory treatment could theoretically be used to prevent psychosis.
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
There is mounting evidence from animal studies and epidemiological research that an infection during pregnancy may increase the risk of schizophrenia in the offspring. A recent study by Alan Brown and colleagues presented at the 2015 meeting of the Society of Biological Psychiatry used a large dataset from the Finnish Prenatal Study of Schizophrenia to compare medical data from the mothers of 777 people with schizophrenia (630 with schizophrenia and 147 with schizoaffective disorder) to data from the mothers of 777 healthy people.
The study’s biobank contained blood samples taken from the mothers in early to mid-pregnancy, which the researchers used to determine the mothers’ levels of C-reactive protein (CRP), an indicator of inflammation. Higher levels of CRP were associated with increased risk of schizophrenia in the offspring. When the researchers analyzed the findings by sex of the offspring, the link between prenatal infection and schizophrenia risk was significant in males, but not females. The effect was also stronger among offspring born after their due date than those born at or before their due date.
Epigenetics is the process by which environmental factors affect the way a person’s genes are transcribed. These changes, which may include the addition or subtraction of methyl groups from DNA, change the DNA’s structure (how tightly it is wound around the histones that give it shape) but not its sequence. These structural changes, which affect how easily the DNA is transcribed, can then be passed on to future generations. A new study by Ulrike Stadlbauer and colleagues presented at the Society of Biological Psychiatry explored a particular pathway by which an infection in a pregnant mouse can lead to behavioral changes in three following generations of mice.
Pregnant mice were given injections that produced an infection. A first generation of offspring were interbred to create a second generation of offspring, and these were interbred to create a third generation of offspring. The first generation of offspring had epigenetic changes in methylation and hydroxymethylation to promoter regions of two enzymes that regulate synthesis of the neurotransmitter GABA, and these epigenetic changes were associated with reduced mRNA expression of these two genes.
All three generations of offspring had deficits in social interaction, short-term memory, and cued fear conditioning. Interestingly, the second and third offspring generations also exhibited depression-like behavior that had not been present in the original mothers or the first generation of offspring.
Editor’s Note: This is another fascinating demonstration of how environmental occurrences, which can include stressors, exposure to drugs, and now immune challenges, can have effects across generations, likely through epigenetic changes that persist in ova or sperm. Amazingly, it turns out that the environment can change traits in future generations, not by inducing changes to gene sequences, but through epigenetic changes to the structure of DNA or histones that persist across generations.
A study currently in progress indicates that the anti-inflammatory COX-2 inhibitor celecoxib (better known as the arthritis treatment Celebrex) may aid in the treatment of bipolar depression. In a panel session on inflammation at the 2015 meeting of the Society of Biological Psychiatry, researcher Angelos Halaris reported results from the first 26 participants.
Participants were taking mood stabilizers for bipolar disorder and became depressed. They received either 20mg/day of the selective serotonin reuptake inhibitor antidepressant escitalopram (Lexapro) plus either 200mg twice a day of celecoxib or placebo for a total of eight weeks. Those participants who received celecoxib showed greater and more rapid reductions in depression symptoms than those who received placebo.
The study will continue, and Halaris and colleagues will also observe whether measures of inflammation in patients’ blood are correlated with the patients’ responsiveness to the combined treatment with escitalopram and celecoxib.
There 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.
In a new study by ESM Eurelings and colleague in the journal International Psychogeriatrics, the inflammatory marker C-reactive protein differentiated between older people with symptoms of apathy versus symptoms of depression. Higher levels of C-reactive protein were found in those with symptoms of apathy. The researchers concluded that apathy may be a manifestation of mild inflammation in elderly people.
Omega-3 fatty acids are found in some green vegetables, vegetable oils, and fatty fish. There is some evidence that omega-3 fatty acid supplements can reduce depression, but researchers are trying to clarify which omega-3s are most helpful, and for whom. A new study in Molecular Psychiatry suggests that depressed people with higher inflammation may respond best to EPA omega-3 fatty acids compared to DHA omega-3 fatty acids or placebo. Researchers led by M.H. Rapaport divided people with major depressive disorder into “high” and “low” inflammation groups based on their levels of the inflammatory markers IL-1ra, IL-6, high-sensitivity C-reactive protein, leptin, and adiponectin. Participants were randomized to receive eight weeks of treatment with EPA omega-3 supplements (1060mg/day), DHA omega-3 supplements (900mg/day), or placebo.
While overall treatment differences among the three groups as a whole were negligible, the high inflammation group improved more on EPA than on placebo or DHA, and more on placebo than on DHA. The authors suggest that EPA supplementation may help relieve symptoms of depression in people whose depression is associated with high inflammation levels, a link common among obese people with depression.
Editor’s Note: These data add to a study by Rudolph Uher et al. in which people with high levels of C-reactive protein responded better to the tricyclic antidepressant nortriptylene, while those with low levels of the inflammatory marker responded better to the selective serotonin reuptake inhibitor antidepressant escitalopram.
Events like surgery or heart attacks that cause inflammation can lead to cognitive deficits or depression for months or years afterward, even though the direct effects of inflammation wear off within weeks. In a recent study, Natalie Tronson and colleagues subjected mice to surgical heart attack, sham surgery, or no operation, and observed how well they absorbed new learning eight weeks later.
Both male and female mice had impairments in fear learning following surgical heart attacks. Female mice that received sham surgery also showed deficits in fear learning. When the researchers dissected the mice, analyzing their blood and hippocampi after the eight-week period, inflammatory cytokine measures had normalized as expected, but the researchers found other abnormalities.
Intracellular signaling was dysregulated, and there had been epigenetic changes in cells of the hippocampus. (Epigenetic changes refer to those that change the structure of DNA, such as how tightly it is wound, rather than its sequence. For example, the addition of acetyl groups to DNA or the histones around which it is wound.) The researchers observed increased histone acetylation and phospho-acetylation following the heart attacks.
The researchers concluded that a systemic inflammatory event, such as heart attack or surgery, can cause long-term memory impairment and changes in mood through epigenetic mechanisms. They compared the findings to those of other studies in which normal aging and memory-impairing treatments such as chemotherapy had also been associated with increases in histone acetylation or decreases in histone deacetylase activity.
Stressors in early life can contribute to the risk of developing mood disorders. Given that many treatments for mood disorders work by blocking the serotonin 5-HT transporter, Nicole Baganz and colleagues designed a study to see whether an early life stressor, in this case maternal separation, would affect immune processes that in turn affect serotonin signaling.
In this study as in many before it, mice that were removed from their mothers exhibited behaviors that resembled human anxiety and depression. They were also found to have elevated messenger RNA for several inflammatory cytokines (including IL-1beta and IL-6) in their brain and blood. Mice that had a gene for the interleukin-1 receptor (IL-1R) removed exhibited neither the depressive behavioral effects nor the changes in cytokine levels following maternal separation, showing that the IL-1R gene plays a necessary role in the signaling process that leads to this type of depression. Levels of the stress hormone corticosterone in the blood did not differ in the mice with and without the IL-1R gene.
The researchers concluded that early life stressors can cause lifelong changes in inflammatory cytokine levels in mice.