In individuals with major depressive disorder (MDD), particularly those who experience suicidal thinking, levels of translocator protein (TSPO), a marker of microglial inflammation, are increased, new research shows.
Investigators from the University of Manchester, United Kingdom, found significantly higher levels of TSPO in patients with MDD than in healthy control persons. Levels were particularly high in the anterior cingulate cortex (ACC), which suggests microglial activation. TSPO was also particularly elevated in the insula in patients with depressed and suicidal thoughts compared with those who did not have suicidal thoughts.
“The evidence for a link between depression and inflammation is quite compelling now, and there is also mounting evidence for a link between suicide and inflammation across a range of mental disorders,” lead investigator Peter S. Talbot, MD, told Medscape Medical News.
“If we can learn more about these links, it may lead to more effective prevention or treatments of depression and suicidal thinking by targeting specific aspects of the inflammatory process,” he added.
The study was published online August 12 in Biological Psychiatry.
The Living Brain
Inflammation in depression is a “promising avenue of research for new treatment strategies, based on evidence that at least a subset of individuals with MDD have higher levels of peripheral proinflammatory cytokines,” the authors write.
Previous research has found a high prevalence of depression in patients with inflammatory medical disorders, and there is evidence that inflammation may be associated with lack of response to antidepressants.
Peripheral inflammation can cause an inflammatory response in the brain in which the metabolism of tryptophan “is diverted from the production of serotonin to kynurenine, which is subsequently converted into the neurotoxic quinolinic acid by activated microglia and infiltrating macrophages and monocytes,” they note.
Research on animal models has supported this understanding of the neuroinflammatory pathway. Postmortem studies have found increased levels of quinolinic acid in the ACC of individuals with depression who had died by suicide. In addition, microglial and astrocytic activation has been found in the ACC, the thalamus, and the frontal cortex of patients with depression.
Evidence of an association between neuroinflammation ― specifically, microglial activation ― and suicidality has been based on postmortem studies. No previous research has specifically investigated the association between neuroinflammation and suicidality in living patients.
Positron-emission tomography (PET) scans and radioligands specific for the 18-kDa TSPO, a mitochondrial protein that is upregulated in activated glial cells, provide a useful index for measuring neuroinflammation in living patients.
The researchers set out “to investigate brain TSPO availability in MDD and to explore factors that might be associated with heightened inflammation” using the “prototypical” TSPO radioligand [11C] (R )-PK11195 to measure brain TSPO availability in nonsmoking, medically healthy, and antidepressant-naive or antidepressant-free patients with moderate to severe depression.
Three areas of the brain were chosen as the focus of the study: the ACC, the prefrontal cortex (PFC), and the insula. These areas were chosen because in aprevious study, TSPO levels in these areas were to be significantly elevated in patients with depression. These areas also play a role in mood regulation, and previous research has found that the ACC has a role in the association between inflammation and depression.
Markers of Inflammation
A secondary aim of the study was to explore the associations between brain TSPO levels, symptom severity, suicidal ideation, exercise levels, childhood adversity, and peripheral markers of inflammation.
“Most of the previous evidence is based on blood tests and postmortem brain samples, and relatively little has been known so far about what is going on in the living brain during a major depressive episode or suicidal thinking,” said Dr Talbot.
“PET is such an important imaging technique because it allows us to measure levels of a range of chemicals in the living brain and can provide evidence for microglial activation, which is, in turn, evidence for the presence of an inflammatory process in the brain,” he said.
To investigate these associations, the researchers compared 14 patients with moderate to severe MDD with 13 sex- and age-matched health control persons. The patients were 15 to 55 years old and had been diagnosed on the basis of DSM-IV criteria as having moderate to severe MDD. Depression was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) (mean score ± SD = 31 ± 4) and the Hamilton Depression Rating Scale (HDRS) (mean score ± SD = 20 ± 3). Seven of the 13 control persons were men (mean age of control persons ± SD = 33 ± 11 years).
Patients were required to be either antidepressant-naive or to have been free of antidepressant use for at least 8 months. All participants were required to be nonsmokers and to be medically healthy, as determined on the basis of on clinical history, physical examination, routine blood tests, and urine toxicology.
The researchers measured the participants’ body mass index (BMI), degree of childhood adversity (assessed using the Childhood Adversity Questionnaire), physical exercise (measured by the Godin Leisure-Time Exercise Questionnaire), and the levels of several inflammatory markers of inflammation in plasma (tumor necrosis factor–α [TNF-α], interleukin-6 [IL-6], IL-8, IL-1β, and C-reactive protein [CRP]).
TSPO availability ([11C] (R)-PK11195 binding potential [BPND]) across the hypothesized regions (ACC, PFC, and insula) was higher by a mean of 39% in the patients with MDD than in the control persons. The finding was statistically significant (MANOVA, main effect of group: F 3,23 = 5.63, P = .005).
The highest increase was found in the ACC (67%); smaller elevations were found in the PFC (29%) and the insula (24%).
Univariate tests conducted on individual regions found that the elevation in ACC was of large effect size and was statistically significant (F 1,25 = 5.99, P = .022; partial η 2 = 0.193; Cohen’s d = 0.95). The elevations in the PFC and the insula had small effect sizes and did not reach statistical significance.
“Surprising” Difference in Suicidal Patients
To analyze the effects of suicidal ideation on TSPO availability, the researchers stratified patients into those with and those without current suicidal thoughts (n = 9 and n = 5, respectively).
There were no significant difference in age, sex, BMI, or injected mass of radiotracer between the two MDD subgroups, and they were well matched for overall disease severity with respect to scores on the MADRS and HDRS.
The researchers found significant differences in TSPO availability among the groups (control persons, patients with suicidal thinking, and patients without suicidal thinking) across all three regions (MANOVA, main effect of group: F6,46 = 4.22, P = .002).
Univariate tests on the individual regions found statistical significance and large effect size in the ACC (F 2,24 = 9.91, P = .001; partial η 2 = 0.452) and the insula (F 2,24 = 4.59, P = .021; partial η 2 = 0.277) and trend significance in the PFC (F 2,24 = 3.15, P = .061; partial η 2 = 0.208).
Pairwise comparisons showed that TSPO availability in the ACC and the insula was significantly higher in patients with suicidal thinking than in those without suicidal thinking and that availability trended higher in the PFC. In addition, TSPO availability in the ACC was also significantly higher in patients with suicidal thinking than healthy control subjects.
The researchers found no significant correlations between BPND in any of the regions and symptom severity, illness duration, BMI, childhood adversity, or any of the peripheral inflammatory markers.
Likewise, there were no differences in concentration of peripheral inflammatory markers between patients with and those without suicidal thoughts. However, there was a negative correlation in patients with MDD between BPND in the ACC and their degree of physical exercise that reached trend significance (r = −0.47, P = .07).
“One surprising aspect of the results was the size of the difference in microglial activation between the suicidal and nonsuicidal depressed patients,” Dr Talbot commented.
“In one way, it’s not surprising, because it fits with the previous nonimaging literature. But I was surprised that the effect was so large that we could identify it so clearly in such relatively small subgroups,” he said.
He cautioned that because the groups were relatively small, the findings should be regarded as “preliminary and in need of confirmation in a larger study, but they are an important first step in helping us learn more about the links between suicidality and inflammation in the living brain.”
Commenting on the study for Medscape Medical News, Jonathan P. Godbout, PhD, professor in the Neuroscience Institute for Behavioral Medicine Research, Ohio State Wexner Medical Center, Columbus, described the study as “a good starting point to say inflammation in depression is real and is a target for intervention” because “we need ways to determine neuroinflammation in living, breathing human beings instead of relying on postmortem studies.”
He cautioned that although TSPO is a well-validated, established marker of microglial activation, it is only one inflammatory marker among many, and “there is a lot more to microglial activation than change in a single marker.”
Nevertheless, “it is nice to have imaging techniques that can detect inflammation in humans,” said Dr Godbout, who was not involved in the study.
The research has important clinical implications, he stated. “I think scans like this can one day be used diagnostically, although they are expensive, because if you can identify the cell type generating inflammation in the brain, you have a target for intervention.”
Dr Talbot added that there are some take-home messages for practicing clinicians even now.
“Although PET scans for microglial activation are not yet at a point where they can be used diagnostically or to help guide treatment, there are lifestyle changes that patients with depression could take immediately that are broadly anti-inflammatory and may be helpful in reducing the intensity of their depression over time.”
These include smoking cessation; reducing weight, cholesterol, and blood pressure if they are elevated; and increasing physical exercise, since “our findings showed a trend for those depressed patients who had the highest levels of physical exercise to have the lowest levels of brain microglial activation.”
He noted that there are important implications for future research.
“The link between suicidality and microglial activation is intriguing and needs to be confirmed in a larger study with depressed patients and also investigated in a range of other disorders in which the risk of suicide is increased, such as bipolar disorder and schizophrenia,” he said.
If anti-inflammatory drugs prove effective in treating depression and suicidality, “it is likely that their effectiveness will be in particular subgroups of patients rather than all patients.” Research would be needed to identify those patients most likely to benefit from them.
Lastly, “it will be important to investigate whether nonmedication treatments for depression, such as CBT and lifestyle changes, can have anti-inflammatory effects in the brain as part of their mechanism of effectiveness.”
Financial support for the study was provided by Karl Herholz and the University of Manchester’s Magnetic Resonance Imaging Facility. The authors have disclosed no relevant financial relationships.
Biol Psychiatry. Published online August 12, 2017. Abstract