New research clarifies how trauma in early life can lead to obesity in adolescence. In a study of 160 young people between the ages of 9 and 15, researcher Janitza Montalvo-Ortiz and colleagues identified seven sites in the genome where DNA methylation predicted body mass index (BMI) in adolescence. The researchers also collected information on family traumas that occurred during the participants’ childhoods and found that DNA methylation and family trauma such as child abuse interacted to predict BMI.
Epigenetics describes the ways life experiences can change how easily DNA is turned on or off. While the genes coded by DNA sequences one inherits from one’s parents never change, the structure of DNA can change. DNA methylation is one type of epigenetic change that refers to the addition of methyl groups to promoter regions of DNA in response to life events.
In this research, which was presented at the 2016 meeting of the Society of Biological Psychiatry, Montalvo-Ortiz and colleagues found that the site of DNA methylation with the strongest link to BMI in adolescence was a gene called MAP2K3. This gene had previously been linked to obesity, but this is the first time DNA methylation at this site has been linked to both obesity and childhood trauma. Other relevant gene sites where DNA methylation occurred include ANKRD2, CPXM2, NUBPL, and RFK.
At the 2016 meeting of the Society of Biological Psychiatry, researcher Femke Lamers and colleagues presented findings from the Netherlands Study of Depression and Anxiety. The inflammatory markers interleukin-6 and CRP were elevated in people with current major depression. These measures were correlated with BMI, a measure of body weight. High levels of interleukin-6 at the beginning of the study predicted who would have a chronic course of illness.
Editor’s Note: Previous studies have found that elevated levels of CRP predicted a future mood episode in people at high risk for bipolar disorder due to a family history of the illness.
These studies suggest that it might be useful to assess levels of these inflammatory markers (CRP, interleukin-1, interleukin-6, and TNF-alpha) in young people who are at high risk for bipolar disorder. Factors that put someone at high risk include a family history of depression or bipolar disorder, a history of adversity in childhood (abuse, neglect, loss of a parent, etc.), and preliminary symptoms.
Several interventions are available that may reduce the likelihood that someone at risk for bipolar disorder will go on to develop the illness. Family interventions such as the Family Focused Therapy developed by researcher David Miklowitz are helpful. In a 2013 study in the Journal of the American Academy of Child and Adolescent Psychiatry, Miklowitz reported that Family Focused Therapy outperformed treatment as usual for youth at risk for bipolar disorder.
Measures of inflammation might provide additional rationale for beginning interventions in youth at high risk for mood disorders. In addition to family interventions, omega-3 fatty acid supplementation is a low-risk option that is supported by some positive data. Since BMI was implicated in the study by Lamers and colleagues, keeping weight under control might also have some benefit.
For adults with depression who want to keep their weight under control, the combination of the antidepressant bupropion XR (150–300mg/day) and naltrexone (50mg/day), an opiate antagonist medication normally used to fight addictions, has been effective.
In a talk at the 2015 meeting of the International Society for Bipolar Disorder, researcher David Bond reported that 75% of patients in a study of first episode mania had unhealthy body mass indices (BMIs). Forty percent were overweight while thirty-five percent were obese. Higher weight was associated with greater illness severity. Bond said that in other studies obesity has been associated with less time well and a greater risk of relapse into depression.
Obese patients also had lower brain volume, worse memory, and a greater risk of developing early onset dementia compared to other patients. Those who were overweight or obese had a 35% higher risk of developing Alzheimer’s disease.
In a different talk at the same meeting, researcher Roger McIntyre reported that among patients with bipolar disorder, those who were obese have greater cognitive problems and more evidence of inflammation than those who were not obese. He has seen indirect antidepressant effects and other health benefits following weight loss from bariatric surgery.
Many patients with schizophrenia do not reach full remission on antipsychotic drugs alone. The anticonvulsant drug topiramate (Topamax) has shown some promise as an adjunctive treatment for schizophrenia. To clarify the results of studies of topiramate, researcher Christoph Correll and colleagues performed a meta-analysis of nine randomized, placebo-controlled clinical trials of the drug. They found that when topiramate was added to antipsychotic treatment, it improved both positive and negative symptoms of schizophrenia, and it also led to reduced weight.
Editor’s Note: Topiramate might also be useful for patients with schizophrenia who have the common comorbidities of alcohol and cocaine abuse, since in other studies of patients with these primary disorders, topiramate was helpful.
A 2013 article by Smith et al. in the journal Diabetes, Obesity, and Metabolism reports that obese patients treated with the combination of bupropion (Wellbutrin) and naltrexone (Revia) had excellent weight loss and reduction in body fat compared to those treated with either drug alone or with placebo. The combination resulted in about a 14% reduction in body fat, while placebo, bupropion alone, and naltrexone alone each brought about only a 3-4% reduction.
Editor’s Note: Researcher Roger McIntyre is an expert on the metabolic syndrome in patients with bipolar illness and has been using this combination with success in patients with mood disorders. He finds the combination of bupropion and naltrexone more helpful than the anticonvulsants topiramate (Topomax) or zonisamide (Zonegran) or the anti-diabetes drug metformin.
Since obesity and the metabolic syndrome occur in approximately 40 to 50% of bipolar patients and significantly increases cardiovascular risks such as heart attack and stroke, and since bupropion is widely used in the treatment of bipolar depression, this combination appears worthy of consideration for those with obesity. Its use should be accompanied by a good diet and an exercise regimen. Decreasing cardiovascular risk is a very important component of the treatment of bipolar disorder, and the combination of bupropion and naltrexone could have substantial benefits.
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.
A study published in the Journal of Child and Adolescent Psychopharmacology in late 2011 reviewed the various weight and metabolic side effects of drugs like olanzapine, clozapine, risperidone, quetiapine, and aripiprazole.
Across 34 published head-to-head and placebo-controlled studies in youth with psychotic and bipolar disorders, weight gain ranged from 3.8 to 16.2 kg with olanzapine (n=353), 0.9-9.5 kg with clozapine (n=97), 1.9-7.2 kg with risperidone (n=571), 2.3-6.1 kg with quetiapine (n=133), and 0-4.4 kg with aripiprazole (n=451).
According to Heartwire, an article in the New England Journal of Medicine indicates that having any of these risk factors increases the likelihood of cardiovascular disease later in life. The more risk factors one has, the greater the increase in risk.
Across the whole meta-analysis, participants with no risk factors at age 55 (total cholesterol level: <180 mg/dL;
blood pressure: <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking; nondiabetic) had drastically better odds
of avoiding death from cardiovascular disease through the age of 80 than participants with two or more major risk
factors (4.7% vs 29.6% among men and 6.4% vs 20.5% among women).
People with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal MI (Editor’s Note: myocardial infarction, or heart attack) (3.6% vs 37.5% among men, <1% vs 18.3% among women) and fatal or nonfatal stroke (2.3% vs 8.3% among men,
5.3% vs 10.7% among women), compared with those with two or more risk factors.
What this article does not mention is that depression is a risk factor for coronary artery disease, and should be treated just as aggressively and persistently as the other cardiovascular risk factors.
Also as we’ve written before in the BNN, exercise is one element of a healthy life style that can positively affect all of these risk factors. Starting a healthy diet and exercise regimen in middle age will have long-term positive effects and reduce risks later in life.
Andre Pikalov and colleagues from Sunovion Pharmaceuticals Inc. reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 on the weight and metabolic effects seen in short- and long-term trials of the atypical antipsychotic lurasidone (Latuda) in schizophrenia. The studies compared lurasidone to olanzapine (Zyprexa, at 15mg), haloperidol (Haldol, at 10mg), and placebo. Doses of lurasidone ranged from 20-120mg administered once daily. Short-term treatment for six weeks was associated with changes in weight and metabolic indices similar to those of placebo, while participants taking olanzapine gained substantial amounts of weight and had increases in triglycerides and cholesterol. Changes in glucose and hemoglobin A1C were similar on lurasidone, haloperidol, and placebo, but higher on olanzapine. In the long-term sample, mean weight gain on lurasidone at 12 months was 0.71 kg and metabolic parameters remained relatively unchanged.
Editor’s note: Multiple posters at the meeting composed a substantial body of evidence concerning acute and long-term studies of lurasidone, which shows that the drug has a weight and metabolic profile relatively similar to placebo and more favorable than that of olanzapine.
Although lurasidone has not been studied acutely or in the long term in patients with bipolar disorder, the safety profile of this drug in schizophrenia indicates that it may eventually be useful for acute and long-term treatment strategies in bipolar disorder. All typical and atypical antipsychotic drugs that have been approved for treatment of schizophrenia have subsequently been shown to have efficacy in acute mania, and given lurasidone’s similar actions in blocking dopamine receptors, there is little reason to expect that this drug will be any different. The results of actual studies of this drug in mania and depression are eagerly awaited.