Meta-Analysis Shows Inflammation is Common in Unipolar Depression, Bipolar Depression, and Schizophrenia
In a symposium at the 2016 meeting of the Society of Biological Psychiatry, Mark Hyman Rapaport described the results of his research group’s meta-analysis of studies comparing levels of inflammation in the blood of people with unipolar depression, bipolar depression, and schizophrenia. Rapaport and colleagues determined that people acutely ill with any of the three illnesses showed abnormally high levels of certain inflammatory proteins. These included: interleukin-1beta, interleukin-6, TNF alpha, and c-reactive protein. Those who were chronically ill showed elevations in interleukin-6.
These data are consistent with increasing evidence that inflammation also occurs in the brain. Brain inflammation can be observed by measuring translocator protein binding, a measure of brain microglial activation, using positron emission tomography (PET) scans.
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.
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.
Emotional Abuse Increases Inflammation
Trauma in childhood is a risk factor for depression, and both childhood trauma and depression have been linked to increased inflammation. In a study presented at the 2016 meeting of the Society of Biological Psychiatry, Sarah R. Horn and colleagues found that emotional abuse in childhood predicted high levels of inflammation measured in the blood in adulthood.
Horn and colleagues took blood samples from 35 people with treatment-resistant depression and 28 healthy control subjects. The researchers measured inflammatory markers in the blood and also interviewed the participants about any physical, sexual, or emotional abuse they experienced in childhood. Among all the participants, emotional abuse was linked to elevated levels of several inflammatory markers, including interleukin-6, interleukin-10, interleukin-1a, interleukin-15, and fractalkine.
The researchers suggest that more research is needed to clarify the link between early trauma, depression, and inflammation. How elevated inflammation in people with a history of abuse may influence the effectiveness of different psychotherapies and medications for depression remains to be determined.
Inflammation Linked to Non-Response to Antidepressants
In a symposium on inflammation’s role in psychiatric disorders at the 2016 meeting of the Society of Biological Psychiatry, researcher Carmine Pariante reviewed the considerable literature indicating that major depression is often associated with measures of inflammation. Depression has been linked to elevated blood levels of the inflammatory proteins interleukin-1, interleukin-6, TNF alpha, and c-reactive protein, with about one-third of depressed patients having an elevated level of at least one of these proteins. People with elevated inflammatory markers are also less likely to respond to traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs).
Pariante reported that in depressed people, interleukin-6 is also elevated in cerebrospinal fluid in addition to blood, suggesting that inflammation in depression extends to the central nervous system. Increased secretion of interleukin-6 has been linked to depressive behaviors in mice exposed to stress.
There is some hope that anti-inflammatory treatments can help patients who do not respond to traditional antidepressant treatment. Some anti-inflammatory medications that may eventually be used to treat depression with inflammation include the COX-1 inhibitor aspirin, the COX-2 inhibitor celecoxib (Celebrex), or the antibiotic minocycline. Each of these approaches gained some support in preliminary clinical trials, but it has not yet been established that these anti-inflammatory treatments produce a better response in people with elevated inflammatory markers.
Inflammation Linked to Post-Stroke Depression
A 2016 study in the journal Psychoneuroendocrinology confirms that high levels of inflammatory cytokines in the blood are linked to higher risk of depression following a stroke.
The study, by Hee-Ju Kang and colleagues, followed 222 stroke sufferers for one year. Two weeks following the stroke, their levels of inflammatory cytokines IL-6 and IL-18 were measured. They were also assessed for depression both at the two-week point and one year later. The researchers also observed whether or not the participants were treated with statins, which are often prescribed to lower stroke risk and also have anti-inflammatory effects.
Those participants who had depression following their strokes (either at two weeks or at one year) tended to be older, to have a history of depression or stroke, to have a more severe stroke, and to have a stroke location toward the front of the brain.
Having any depression following the stroke was associated with higher levels of IL-6 and IL-18. This was particularly true of those participants who were not taking a statin. Among those taking statins, the statins may have interfered with the link between inflammatory cytokines and post-stroke depression. In the statin group, the only significant finding was a link between levels of IL-6 and depression at the two-week mark.
Repeated Sports Injuries Linked to Brain Inflammation
Professional football players face repeated mild traumatic brain injuries throughout their careers, and may face a variety of brain impairments, from depression to dementia, as a result.
A recent study by researcher Jennifer Coughlin and colleagues clarified how these impairments may be caused by repeated brain impacts. The researchers used positron emission tomography (PET) scans to observe the volume of translocator protein, a marker of brain injury and repair, in the brains of seven active or recently retired National Football League (NFL) players. Compared to healthy, athletic volunteers who were age-matched to the NFL players, the NFL players showed greater volume of translocator protein in several brain regions, including the left and right thalamus, the left and right temporal poles, and the brainstem.
It is not yet clear whether the increased volume of translocator protein is a sign of the brain’s attempts to repair itself, or whether it shows deterioration toward chronic traumatic encephalopathy. Translocator protein is also considered a marker of microglial activation, which occurs with inflammation.
High levels of translocator protein have also been seen in patients with depression and schizophrenia.
Lithium Treatment Reduces Inflammation, Mania-Like Behavior in Rats
Patients with bipolar disorder often show increases in signs of inflammation, including levels of the proteins IL-2, IL-4, Il-6, IL-10 and tumor necrosis factor in their blood. Lithium is the most effective treatment for bipolar disorder, but it is not yet clear how it works. A recent study by researcher Joao de Quevado and colleagues determined that lithium can reduce the same inflammatory markers in rats.
Rats were treated with amphetamine to induce mania-like behavior, which was accompanied by increases in some of the same inflammatory markers in the blood and brain that are increased in people with bipolar disorder. Lithium treatment reduced both the manic behavior and levels of these inflammatory proteins in the rats.
The researchers concluded that lithium may treat mania by reducing inflammation.
Yoga Therapy Improves Depression and Inflammation
Drug treatment for major depression can produce remission in 35–50% or patients. The others may need additional interventions, and some mind-body techniques have been successful. A recent randomized study by Anup Sharma and colleagues found that Sudarshan Kriya Yoga (SKY) decreased depression at one and two months when added to participants’ regular treatments. Participants who received the yoga treatment also showed reductions in inflammation in the blood, including lower levels of the inflammatory proteins TNF-alpha, IL-10, and CRP.
