Fluctuations in White Matter in Adolescents with Bipolar Disorder May Indicate Cardiovascular Risk
During functional magnetic resonance imaging (fMRI) of the brain, data on physiological fluctuations in white matter are collected. These fluctuations are caused by cardiac pulses, cerebrovascular dysfunction, and other factors. Increasing fluctuations have been linked to cognitive impairment with age.
Vascular problems in adults with bipolar disorder have been linked to cerebrovascular disease, a group of conditions that affect bloodflow to the brain. In a recent study, researcher Arron W. S. Metcalfe and colleagues used data on physiological fluctuations in white matter (usually a nuisance variable) to assess the vascular health of teens with bipolar disorder. Compared to 32 age-, IQ-, and sex-matched controls, 32 adolescents with bipolar disorder had more fluctuations in white matter in three different clusters in the brain.
These white matter fluctuations are a possible early indicator of susceptibility to cerebrovascular disease in teens with bipolar disorder. Patients with depression and bipolar disorder are at increased risk for cardiovascular disease, so maintaining a good diet, exercising regularly, and assessing blood pressure, cholesterol, and lipid levels is recommended. See page __ where we describe research showing teens with bipolar disorder have stiffer artery walls.
Teens with Bipolar Disorder Have More Inflammation, Cardiovascular Risks
Bipolar disorder has been linked to cardiovascular disease. New research by Jessica Hatch and colleagues shows that inflammation may be at the root of this connection. At the 2016 meeting of the Society of Biological Psychiatry, the researchers showed that teens with bipolar disorder have higher levels of inflammatory marker interleukin 6.
Hatch and colleagues assessed the blood of 60 teens with bipolar I or II disorder and 20 healthy controls for a variety of biomarkers, including the inflammatory proteins interleukin 6, interleukin 10, and TNF alpha; VEGF, which is responsible for the production of new blood vessels; and brain-derived neurotrophic factor (BDNF), which protects neurons. The researchers also assessed the participants’ cardiovascular health, performing the carotid intima media thickness test to estimate how much plaque is in the arteries, and measuring how well the patients’ arteries dilate in response to changes in bloodflow.
Participants with bipolar disorder had higher levels of interleukin 6 than healthy controls, regardless of whether their bipolar illness was symptomatic. Low BDNF was linked to greater carotid intima thickness in participants with symptomatic bipolar disorder, and vascular measurements suggest a possible mechanism by which bipolar disorder increases cardiovascular risk.
Brain Inflammation Found in Autopsy Studies of Teen and Adult Suicides
Suicide and depression have both been linked to elevated levels of inflammatory cytokines in the blood and cerebrospinal fluid. A recent study finds that these inflammatory markers are also elevated in the brains of teens and depressed adults who died from suicide.
In autopsy studies, researcher Ghanshyam N. Pandey measured levels of the inflammatory cytokines interleukin-1beta, interleukin 6, and TNF-alpha in the brains of teen suicide victims, and compared these to the brains of teens who died from other causes. Pandey also measured levels of interleukin-1beta, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and TNF-alpha in the prefrontal cortex of depressed adult suicide victims and compared them to levels in adults who died of other causes.
There were abnormalities in the inflammatory markers in the brains of those who died from suicide compared to their matched controls. The suicide victims had higher levels of interleukin-1beta, interleukin 6, and TNF-alpha than the controls. Among the adults, levels of the anti-inflammatory cytokine interleukin 10 were low in the suicide victims while levels of Toll-like receptors (TLR3 and TLR4), which are involved in immune mechanisms, were high.
Brain inflammation has also been observed in positron emission tomography (PET) scans of depressed patients, where signs of microglial activation can be observed. Elevated inflammatory cytokines are also found in the blood of some people with bipolar disorder, depression, and schizophrenia.
Pandey presented this research at the 2016 meeting of the Society of Biological Psychiatry.
Brain Volumes Affected by Type and Timing of Childhood Abuse
Maltreatment during childhood has been linked to brain changes and mental illness. In a study by researcher Carl M. Anderson and colleagues that was presented at the 2016 meeting of the Society of Biological Psychiatry, maltreatment at particular ages was statistically linked to deficits in the size of certain brain areas in young adulthood.
The brain areas under examination are critical for the regulation of emotion and behavior, and this research suggests that early experiences can stunt their development, perhaps through altered production of synapses or via the synaptic pruning process that occurs during preadolescence. The details, summarized below, are perhaps less important than the overall finding that maltreatment in childhood affects brain volume, and this effect varies based on the timing and type of maltreatment. Abuse and neglect earlier in life affected the left side of the brain, while later maltreatment affected the right side.
Severity of physical abuse at age 3 affected the volume of the ventromedial prefrontal cortex in women. Physical abuse at ages 3 and 8 in men affected left ventromedial prefrontal cortical volume, while later abuse at ages 7 and 12 predicted volume of the right side.
In women, dorsal anterior cingulate area on the left was predicted by physical abuse at age 5 and by emotional neglect at ages 7 and 11. Later emotional neglect at ages 15 and 16 and physical abuse by a peer at age 10 was associated with smaller right dorsal anterior cingulate. In men, smaller left dorsal anterior cingulate area was predicted by physical neglect at age 2 and emotional abuse by a peer and witnessing abuse of a sibling at ages 5 and 10, and right area by physical neglect at age 12.
Early Life Stress Affects Volume of the Hippocampus
New research shows that there are crucial periods of early life in which a stressful event can reduce hippocampal volume in adolescence. In a study presented at the 2016 meeting of the Society of Biological Psychiatry, Kathryn L. Humphreys and colleagues found that children who experienced a significant stressor before age 8 had smaller hippocampi in early adolescence than children who did not have a significant stressor early in life.
The severity of the stressors that occurred when children were between the ages of 0 and 2 predicted the volume of the hippocampus later in life. This was true to a lesser extent for stressful events that occurred between the ages of 3 and 5. No effect was seen for stressful events that took place between the ages of 6 and 8.
The period of sensitivity to stressful events between ages 0 and 2 and its effects on hippocampal volume could influence a variety of psychiatric outcomes in conditions such as depression and post-traumatic stress disorder (PTSD).
Amygdala Hyperactivity Linked to Family History of Depression
In new research presented at the 2016 meeting of the Society of Biological Psychiatry, researcher Tracy Barbour and colleagues revealed that youth with a family history of depression showed more amygdala activation in response to a threat than people without a family history of depression. This amygdala hyperactivity was linked to low resilience to stress and predicted worsening depressive symptoms over the following year.
In the study, 72 non-depressed youth were shown images of cars or human faces or cars that seemed to loom in a threatening way. Brain scans showed increased amygdala activity in participants with a family history of depression compared to those without such a history.
The amygdala is an almond-shaped part of the brain in the temporal lobe that has been linked to emotional reactions and memory, decision-making, and anxiety.
IL-6 in Blood and Bone Marrow Linked to Lack of Resilience to Stress
Rodents who are repeatedly defeated by larger animals often exhibit depression-like behaviors. In new research that researcher Georgia E. Hodes presented at the 2016 meeting of the Society of Biological Psychiatry, animals who are susceptible to these social defeat stress behaviors showed immune irregularities, including high levels of the inflammatory marker interleukin-6.
An intervention to prevent the mice from secreting interleukin-6 in blood and bone marrow took away their susceptibility to social defeat stress. When bone marrow from rodents with no interleukin-6 was transplanted into susceptible mice, the recipients showed resilience to social defeat stress. Conversely, a transplant from susceptible mice to those mice without IL-6 led to social defeat stress in the previously “immune” mice.
This research shows that the peripheral immune system, including blood and bone marrow, plays an important role in depression-like behaviors in mice.
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Child Abuse Linked to Adolescent Obesity
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.
Certain Types of Inflammation and BMI Predict Depression
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.
