Il-6 Inhibitor Sirukumab May Improve Anhedonia, But Not General Depression

January 25, 2019 · Posted in Potential Treatments · Comment 

cyclingAt a 2018 scientific meeting, researcher Giacomo Salvadore and colleagues reported that the drug sirukumab, a monoclonal antibody that targets the inflammatory marker Il-6 and that was originally developed to treat rheumatoid arthritis, did not have a statistically significant effect on overall depression compared to placebo. However, by the twelfth week of treatment, sirukumab did have a significant effect on anhedonia (loss of interest or pleasure in activities that one previously enjoyed).

The degree of improvement in anhedonia was significantly correlated with patients’ baseline levels of the inflammatory marker CRP. Since the inflammatory marker that sirukumab targets, Il-6, is one of those most often elevated in depression, it appears that more study of sirukumab would be warranted.

Inflammation Linked to Poor Sleep Quality and Worse Executive Functioning

January 18, 2019 · Posted in Risk Factors · Comment 

man drooling while sleeping

At a recent scientific meeting, researcher Ellen E. Lee and colleagues reported that compared to healthy volunteers, people with bipolar disorder or schizophrenia had elevated levels of inflammatory markers, which were associated with poor sleep. 

According to self-reports, people in the schizophrenia and bipolar disorder group had worse sleep quality than the control group. Those with schizophrenia or bipolar disorder also had significantly higher levels of the inflammatory markers CRP, IL-6, and TNF alpha compared to the healthy volunteers. Among people with bipolar disorder, executive functioning and sleep quality had a strong inverse association to levels of IL-6, such that lower sleep quality and worse executive functioning were associated with higher levels of IL-6. These findings suggest that sleep disturbance and inflammation may have negative consequences for cognitive functioning.

Inflammation is Associated with Antidepressant Treatment Resistance

November 23, 2018 · Posted in Current Treatments, Risk Factors · Comment 

depressed woman

Researcher Ebrahim Haroon and colleagues report in a 2018 issue of Psychoneuroendocrinology that people whose depression failed to respond to at least three different antidepressants in their current episode of depression had higher levels of inflammation than those who had fewer than three failed antidepressant trials. 

The researchers found that patients who had not responded to antidepressants had higher levels of the inflammatory markers TNF-alpha, TNF-alpha receptor 2, and Il-6. The inflammatory marker CRP was also significantly elevated in these patients when statistical analyses that excluded body mass index (BMI) were used.

Haroon and colleagues reported that a third of all patients with major depressive disorder fail to respond to currently available antidepressant treatments, and that inflammation may be to blame because it interferes with the neurotransmitter systems that antidepressants target.

Editor’s Note: These data indirectly support the use of anti-inflammatory drugs to augment the effects of antidepressants in patients with treatment resistant depression.  A caution that may be very important is to assess evidence of inflammation at baseline, as some data suggest that people with low CRP may, for example, do more poorly with a blocker of TNF-alpha, while people with high CRP at baseline (over 3 pg/ml) show good improvement.

Inflammatory Marker IL-6 is Elevated in People with Depression and Those with a History of Childhood Trauma

November 21, 2018 · Posted in Risk Factors · Comment 

verbal abuse of a child

In a 2018 article in the journal Psychiatry Research, researcher Ana Munjiza and colleagues reported that the inflammatory marker IL-6 was higher in 64 depressed people than in 53 non-depressed people, and that levels of IL-6 among people in the depressed group were significantly correlated with scores on a questionnaire in which participants reported traumas experienced in childhood. They reported more physical abuse, physical neglect, and emotional abuse.

Munjiza and colleagues indicate that trauma in childhood is a risk factor for depression in adulthood, as other researchers have suggested, and that inflammation could mediate the relationship between childhood adversity and depression.

Editor’s Note: IL-6 has been associated with antidepressant treatment resistance. IL-6 is secreted from white cells in the blood and from monocytes from the bone marrow in response to stress. It enters the brain and starts an inflammatory cascade that induces depressive behaviors. Animal studies have shown that if IL-6 secretion is blocked, depressive-like behaviors do not occur.

Another indicator of inflammation is CRP, and elevations in CRP have been associated with poor response to selective serotonin reuptake inhibitor (SSRI) antidepressants, and better response to the noradrenergic tricyclic antidepressant nortriptyline and the dopamine active antidepressant bupropion.

Treatments for depressed people with histories of childhood trauma may include psychotherapy, somatic therapies such as repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and medication. More research is needed to determine the optimal treatment regimens for this subgroup of depression sufferers, including whether anti-inflammatory drugs could play a helpful role in preventing or treating depression. People with elevated inflammatory markers (such as IL-6, CRP, IL-1, or TNF-alpha) are likely to be better candidates for adjunctive anti-inflammatory treatments than those with normal or low baseline levels of inflammation.

Psychotherapy Improved Depression, Reduced Inflammation

December 21, 2016 · Posted in Current Treatments · Comment 

supportive expressive psychodynamic therapy

A recent study shows that psychotherapy can not only improve depression symptoms, but may also reduce the inflammation that often accompanies them.

Researcher Jean Pierre Oses and colleagues randomly assigned participants with depression to receive Supportive-Expressive psychodynamic therapy, which is designed to help patients understand conflictual relationship patterns, or an alternative therapy. Among the 47 participants who received Supportive-Expressive therapy, depression improved significantly after 16 sessions, and blood levels of the inflammatory markers interleukin-6 and TNF alpha also dropped.

The research was presented at the 2016 meeting of the Society of Biological Psychiatry.

Meta-Analysis Shows Inflammation is Common in Unipolar Depression, Bipolar Depression, and Schizophrenia

December 19, 2016 · Posted in Risk Factors · Comment 

inflammation in 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

December 15, 2016 · Posted in Risk Factors · Comment 

cardiovascular healthBipolar 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

December 14, 2016 · Posted in Brain Imaging, Neurobiology · Comment 

brain inflammation

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.

IL-6 in Blood and Bone Marrow Linked to Lack of Resilience to Stress

December 8, 2016 · Posted in Risk Factors · Comment 

stress and inflammation

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.

Certain Types of Inflammation and BMI Predict Depression

December 6, 2016 · Posted in Course of Illness, Risk Factors · Comment 

BMI and inflammation predict chronic illness

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.

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