Rats Exposed to Jet Fuel Pass Epigenetic Changes on to Third Generation
A recent study of rats showed that exposure to hydrocarbons (jet fuel JP-8) can bring about disease not just in the rats who were exposed, but also in subsequent generations. Epigenetics is the study of how environmental events or biochemical changes can affect the structure of DNA, e.g. by attaching extra methyl groups. (These kinds of “epimutations” are separate from the inherited genetic makeup we receive from our parents, but new evidence suggests that some can be passed on to future generations.)
When first generation female rats were exposed to jet fuel, third generation rats showed 33 different examples of DNA methylation as well as obesity.
Previous research has shown similar signs of transgenerational transmission of disease resulting from first generation exposure to chemicals such as bisphenol A, phthalates, dioxins, and pesticide mixtures.
The Impact of Obesity on Brain and Behavior
In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, K. Sim and colleagues discussed the impact of increased body mass index on the integrity of white matter in the brain during a first episode of mania. The researchers found significant abnormalities in white matter integrity in the temporal pole and occipital brain regions in overweight and obese patients compared to patients of normal weight. These data highlight the need to clarify the neural mechanisms that link obesity and poorer functional outcomes in bipolar disorder.
Other investigators have reported that bipolar patients with obesity have a less robust response to naturalistic treatment compared to those of normal weight. At least one study suggested that patients with overweight and obesity experience more cognitive difficulties.
Editor’s Note: The pathophysiological mechanisms involved in the relationship between weight and brain function are not yet clear, although one possibility is that in obese patients, some fat cells in the abdominal area become too big to survive and are scavenged by other cytokine-producing cells. These inflammatory cytokines are then able to cross the blood-brain barrier, enter the brain, and affect neuronal functioning. Whether a mechanism like this is at play in relation to these particular findings remains for further investigation.
Nonetheless, these data suggest the importance of good diet, exercise, and other means of maintaining a good body weight in order to attempt to avoid some of the adverse associations of obesity with deficits in cognition, white matter integrity, and treatment outcome.
Obesity and Bipolar Disorder: News from the American Academy of Child and Adolescent Psychiatry
At the annual meeting of the American Academy of Child and Adolescent Psychiatry in Toronto in October 2011, a symposium on the impact of obesity on the course of childhood onset bipolar illness was held.
Typical Treatment of Bipolar Disorder in Youth
David Axelson described the typical outcome of bipolar illness and the medications used during naturalistic treatment. The data came from the large collaborative Course and Outcome of Bipolar Illness among Youth (COBY) study, in which he and his colleagues followed 255 patients with bipolar I disorder (BP I), 30 patients with bipolar II (BP II), and 153 patients with bipolar not otherwise specified (BP NOS) for a mean of 5 years. He discussed only BP I children at the symposium.
The study initially followed 270 BP I children for a mean of 582 weeks. They ranged in age from 7 to 17 years (average 14.4 years). Ninety-three percent of the children were treated with one or more antimanic (AM) agents. These included atypical antipsychotics (AA) in 77%, valproate or carbamazepine in 44%, and lithium in 47%. Antidepressants (ADs) were used in 46% of the children, stimulants in 43%, and benzodiazepines in 21%. Sixty percent had been on two classes of antimanic medications concurrently at some point.
A univariate analysis showed that older children received smaller amounts of antipsychotics and more anticonvulsants and lithium. Variables associated with better response, that is, a rating of either much or very much improved on the Clinical Global Impressions scale for bipolar disorder (CGI-BP), included older age and treatment with atypical antipsychotics. Those who had comorbid attention deficit hyperactivity disorder (ADHD) or psychosis at baseline did more poorly. Mean symptom scores were better when the children received any anti-manic treatment including an atypical or lithium, but worse when they received valproate or carbamazepine.
These data are similar to those from other prospective treatment outcome studies in childhood-onset bipolar I illness. Taken together they all suggest that the illness is difficult to treat and stabilize even when multiple medicines are used in combination.
Obesity and Mood Disorders in Youth
Another speaker, Ben Goldstein, indicated that in the scientific literature, obesity has been associated with a higher number of depressive episodes and longer length of depression, more recurrences of depression, more anxiety disorders, increased numbers of hospitalization, more suicide attempts, and worse functional outcomes. In the same group of patients discussed by Axelson above, 42% were overweight or obese, compared to a 34% incidence in the general population of children in this age range.
Factors associated with overweight included substance abuse, a history of physical abuse, prior hospitalization, and being on 2 or more medications. Those who were overweight or obese spent more time ill in a manic or depressive episode. Read more
Inflammation and Mood Disorders
There is increasing evidence of a link between inflammation, brain function, and treatment resistance in the mood disorders. Obesity is also linked to inflammatory processes and thus may contribute to the development of treatment resistance in both unipolar and bipolar mood disorders.
Causes of Inflammation
Obesity is one factor that can lead to increases in inflammation. When people gain weight, the size of fat cells can increase to the point that the cells are deprived of oxygen and disintegrate. Then macrophages and other cells come in to sweep up the remaining particles of the fat cells. These scavenger cells then become activated and produce more regulatory chemicals called cytokines. The cytokines produced in the periphery (in the body outside the brain) can then enter the brain and affect brain function in a process that may ultimately be linked to fatigue, depression, and other adverse mood and behavior states that contribute to treatment resistance. There is a two-way street: the brain can influence the body and what goes on in the body can influence the brain.
Other factors that can lead to increases in inflammation and eventually to treatment resistance in the unipolar and bipolar mood disorders include early life stress, medical illness, and anxiety and personality disorders.
Anti-Inflammatory Treatments
Given the close links between inflammation and depression (discussed in BNN Volume 15, Issue 1 from 2011), Andrew H. Miller of Emory University decided to test a specific anti-inflammatory agent called infliximab (a TNF monoclonal antibody that inhibits TNF alpha actions) as an antidepressant. One sign of inflammation is a C-reactive protein (CRP) level of 2mg/L or greater. The effect of infliximab on the population of treatment refractory depressed patients who participated in Miller’s study was not significant on the whole, but the drug did have significantly greater antidepressant effects than placebo in those patients with the highest levels of CRP. The investigators believe this demonstrates the principle that a drug that inhibits TNF alpha may be useful in patients with the greatest degree of inflammation.
Other approaches to anti-inflammatory mechanisms are also being pursued, including use of aspirin, COX-2 inhibitors, and the antibiotic minocycline. Minocycline has anti-inflammatory and neuroprotective effects and has been reported to have positive effects in cognition and negative symptoms of schizophrenia.
The Evolving Omega-3 Fatty Acid Story: The Icing on the Cake (And Why It Shouldn’t Be Eaten)
Omega-3 fatty acids are important for brain development and function and are essential to the human diet since they cannot be synthesized by the body. Omega-3 fatty acids are derived from canola oil, walnuts, flax seed oil, leafy vegetables, and especially fish. The main omega-3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They have anti-inflammatory effects, unlike omega-6 fatty acids, which are pro-inflammatory. The omega-6 fatty acids come from soy, peanuts, corn oil, and meats, and are associated with increases in obesity, myocardial infarction, and stroke.
In a recent review of the literature, John Davis and Joe Hiblen found that diets that include high levels of omega-3 fatty acids are associated with decreased incidence of depression, suicide, and cardiovascular disease. The researchers performed a meta-analysis of all the prospective depression treatment studies of omega-3 fatty acids compared to placebo. They found that EPA had antidepressant effects in humans, with moderate effect size and a high degree of statistical significance. DHA, however, did not appear to have an antidepressant effect, and pure DHA was even associated with some worsening of depression.
Editor’s note: This meta-analysis helps clarify some of the ambiguities in the literature about the antidepressant efficacy of the omega-3 fatty acids, clarifying that EPA alone is an effective antidepressant. The one study that did not find antidepressant effects with EPA was carried out by the Bipolar Collaborative Network, in which I am an investigator. Our study, published in an article by Keck et al., showed that 6g of EPA was not significantly more effective than placebo in bipolar depression or in rapid cyclers. However, there is some indication that 6g may be too high a dose of EPA, and most of the recommendations now suggest using 1-2g of either EPA or an EPA/DHA combination. Read more
