Inflammation Associated with Cognitive Deficits

October 15, 2019 · Posted in Risk Factors · Comment 

woman thinking

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Katherine E. Burdick and colleagues at Brigham and Women’s Hospital and Harvard Medical School reported that in 240 patients with bipolar disorder who were not currently having a manic or depressive episode, markers of inflammation were associated with cognitive deficits.

Inflammation was associated with cognitive deficits in general, and there were also some relationships between specific inflammatory markers and types of cognitive processing. They found that the inflammatory markers TNF-alpha, TNFR1, and TNFR2 influenced cognitive flexibility. The inflammatory marker VEGF influenced reward processing, while IL-6/IL-6r influenced spatial processing. IL-1beta and IL-1RA influenced social cognition.

Burdick and colleagues found it was important to include both primary and secondary mediators of inflammation in their research “as the effects of the primary pro-inflammatory cytokines can be blocked by a number of decoy receptors and soluble antagonists.” Elevations in these can provide additional information about the function of the immune system.

Editor’s Note: Targeting inflammation with the anti-inflammatory treatments minocycline and celecoxib has been shown to improve depression. Now the role of anti-inflammatory drugs in improving cognition deserves further attention.

Infliximab Helps the Subgroup of Bipolar Depressed Patients Who Faced Adversity in Childhood

October 11, 2019 · Posted in Potential Treatments · Comment 

child with bruised face

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Mike Cosgrove and colleagues described a study of the immune-suppressing drug infliximab in adults with bipolar disorder. The researchers found persistent significant improvements on infliximab only in those with bipolar disorder who also had a history of childhood adversity. Childhood adversity is consistently associated with elevated levels of inflammatory cytokines, and baseline inflammation may be a prerequisite for a positive effect from infliximab, which works by blocking the inflammatory cytokine TNF alpha.

Links Between Mixed Depression, Insulin Resistance, Inflammation, and Cognitive Deficits

August 1, 2019 · Posted in Potential Treatments · Comment 

depressed man with woman

At the 2019 meeting of the International Society for Bipolar Disorders, researcher Roger McIntyre discussed links between obesity, diabetes, and cardiovascular problems; increased inflammation; and decreased functioning of the neural networks involved in cognition. 

He and his colleagues analyzed 121 studies that included empirical research and meta-analyses. McIntyre and colleagues found that patients with higher levels of inflammatory markers have more insulin resistance and cognitive dysfunction. A meta-analysis revealed that the inflammatory markers IL-6, TNF alpha, and CRP were significantly elevated in people with bipolar disorder compared to normal controls, while IL-1B was not.

People with depression who had a few manic traits (mixed depression) were particularly likely to have insulin resistance and elevated levels of pro-inflammatory markers.

People with mixed depression have increases in inflammation and increased incidence of cardiovascular disorder. People experiencing a first episode of mixed depression who are overweight show increased signs of brain aging.

In studies McIntyre and colleagues analyzed, diabetes or pre-diabetes occurred in 50% of depressed patients, and these patients had the greatest amount of cognitive dysfunction.

Treatment

McIntyre noted that taking the antipsychotic drug lurasidone for bipolar depression worked best in both adults and children who had elevated levels of CRP at baseline. The fast-acting antidepressant ketamine also works well in those who show baseline inflammation .

The anti-diabetes drug liraglutide (Victoza, Saxenda) improves mixed depression symptoms and cognition in obesity, diabetes, and mixed depression. Liraglutide belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists or incretin mimetics. They work by increasing insulin release from the pancreas and decreasing excessive glucagon release.

McIntyre now routinely uses liraglutide for cognitive deficits in patients with obesity or diabetes, including patients with mixed depression. It is injected under the skin at 0.6 mg daily, then the dosage is increased to 1.2 mg and then 1.8 mg. Victoza reduces major cardiovascular events in those with type 2 diabetes. The higher-dose Saxenda (3mg) can be used for weight control.

Another anti-diabetes drug, pioglitazine, has also been reported to be helpful in bipolar depression.

McIntyre found that the antibody infliximab, which can be used as an intravenous treatment for chronic inflammation and works by blocking the effects of TNF-alpha, did not improve depression, but did improve cognition.

McIntyre also supports the use of acetyl-L-carnitine, a potential adjunctive treatment that can reverse the insulin resistance that often occurs with obesity and thus could theoretically improve cognition.

McIntyre described preliminary literature suggesting the effectiveness of drugs such as statins, calcium channel blockers, and biguanides such as the diabetes treatment metformin in reducing inflammation.

Bariatric surgery to reduce the size of the stomach was another option discussed by McIntyre. He said the intervention is safe for patients with bipolar disorder and can help them recover cognitive function.

McIntyre noted that offspring of a mother with obesity have decreased response to sensory cues, reward preference, cognitive control, and motor control. Obesity and the inflammation that goes along with it apparently affect offspring via epigenetic mechanisms, meaning obesity may change the structure of inherited DNA (without changing its sequence).

Obesity Associated with Inflammation and Brain Abnormalities

July 1, 2019 · Posted in Risk Factors · Comment 

obese family

At the 2019 meeting of the International Society for Bipolar Disorders, researcher David J. Bond reviewed the data on the multiple adverse effects of obesity in patients with bipolar disorder. These include increased cardiovascular risk, poorer response to treatment, brain abnormalities, and decreased cognitive function, which is correlated with the degree of overweight.

Editor’s Note: These data emphasize the importance of starting a nutritious diet early in life and sustaining it through adulthood, avoiding the drugs most associated with weight gain such as clozapine and olanzapine, and facilitating weight loss with drugs. There are several treatments that can aid in weight loss. One is the diabetes treatment metformin, starting at a high dose of 500mg twice daily, and increasing to 1000mg twice daily if tolerated. The anticonvulsants topiramate or zonisamide also promote weight loss. The most effective option is a combination of the antidepressant bupropion sustained release (at a dose of 150–300mg) plus the anti–substance abuse drug naltrexone (50mg). This combination was associated with a loss of 10% of body weight over 12 weeks in women with diabetes.

Rich Western Diet Reprograms Immune Cells in Mice

June 4, 2019 · Posted in Risk Factors · Comment 

fat mouse

A 2018 article by Anette Christ and colleagues in the journal Cell describes the process by which a Western diet can trigger changes to the immune system in mice. The mice fed a calorically rich Western diet started to show systemic inflammation. Blood measures of inflammation returned to normal after the mice resumed their regular diet, but their immune responses remained heightened, as if the immune system had been trained to overreact.

The vast majority of deaths in Western cultures are caused by noncommunicable diseases such as type 2 diabetes and cardiovascular disease, which have been linked to lifestyle factors such as diet and exercise. The immune system has two wings: one that responds to specific pathogens, and one that mounts general protection against infection and is triggered by immune signaling receptors. However, according to Christ and colleagues, in addition to reacting when microbes are present, this second wing may also respond to “sterile” danger signs, such as consumption of a Western diet. The immune system may become trained to react this way chronically, something that the researchers believe may trigger inflammation in noncommunicable diseases.

The Western diet triggered epigenetic changes to the mice’s immune system. Epigenetic changes are ones that affect the structure of DNA, for example how tightly it is packaged. In the case of the Western diet, these changes resulted in a heightened immune system that launched strong inflammatory responses in reaction to even small stimuli. Myeloid cells from bone marrow were reprogrammed to proliferate and provide a stronger immune response.

The researchers also took human monocyte cells trained with LDL (“bad”) cholesterol and stimulated them with lipopolysaccharide (an inflammatory compound made of fat and sugar). The cells showed a heightened immune reaction similar to that seen in the mice.

Mice genetically engineered to lack the inflammasome NLRP3, which activates inflammatory responses, did not show the systemic inflammation or the enhanced myeloid activity when fed the Western diet, so Christ and colleagues believe NLRP3 may play an important role in mediating the immune response to the Western diet.

Inflammation Associated With Duration of Untreated Unipolar Depression

February 14, 2019 · Posted in Brain Imaging, Course of Illness, Neurobiology · Comment 

depressed woman

Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.

Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.

Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.

Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.

This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.

Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.

In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017.  The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.

Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments

February 5, 2019 · Posted in Current Treatments · Comment 
CRP

C-reactive protein (CRP)

C-reactive protein, or CRP, is a marker or inflammation that has been linked to depression and other illnesses. People with high levels of CRP respond differently to medications than people with lower CRP, so assessing CRP levels may help determine which medications are best to treat a given patient.

High baseline levels of CRP (3–5pg/ml) predict a poor response to selective serotonin reuptake inhibitor antidepressants (SSRIs) and to psychotherapy, and are associated with increased risk of recurrent depression, heart attack, and stroke.

However, high baseline CRP predicts a better response to the antidepressants nortriptyline and bupropion. High CRP is also associated with better antidepressant response to infliximab (a monoclonal antibody that inhibits the inflammatory cytokine TNF alpha), while low levels of CRP predict worsening depression upon taking infliximab.

High baseline CRP also predicts good antidepressant response to intravenous ketamine (which works rapidly to improve treatment-resistant depression), minocycline (an anti-inflammatory antibiotic that decreases microglial activation), L-methylfolate (a supplement that can treat folate deficiency), N-acetylcysteine (an antioxidant that can improve depression, pathological habits, and addictions), and omega-3 fatty acids (except in people with low levels of DHA).

High baseline CRP also predicts a good response to the antipsychotic drug lurasidone (marketed under the trade name Latuda) in bipolar depression. In people with high baseline CRP, lurasidone’s positive results have a huge effect size of 0.85, while in people with low CRP (<3pg/ml) the improvement on lurasidone has a smaller effect size (0.35).

In personal communications with this editor (Robert M. Post) in 2018, experts in the field (Charles L. Raison and Vladimir Maletic) agreed that assessing baseline CRP levels in a given patient could help determine optimal strategies to treat their depression and predict the patient’s responsiveness to different treatment approaches.

At a 2018 scientific meeting, researchers Cynthia Shannon, Thomas Weickert, and colleagues reported that high baseline levels of CRP were associated with symptom improvement in patients with schizophrenia when they were treated with the drug canakinumab (marketed under the trade name Ilaris). Canakinumab is a human monoclonal antibody that targets the inflammatory cytokine interleukin-1 beta (Il-1b). Il-1b is elevated in a subgroup of patients with depression, bipolar disorder, or schizophrenia, and CRP levels are an indication of the associated inflammation.

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.

High Baseline Levels Of C-Reactive Protein Predict Better Response To Lurasidone in Bipolar Depression

December 5, 2018 · Posted in Current Treatments · Comment 

depressed woman

In a study presented at the 2017 meeting of the International Society for Affective Disorders, Charlies L. Raison and colleagues examined whether baseline levels of the inflammatory marker C-reactive protein (CRP) affected antidepressant response to the antipsychotic drug lurasidone in bipolar depression. The participants were divided into three double-blind groups: one received 20–60mg/day of lurasidone, another received 80–120 mg/day of lurasidone, and the third received placebo over a period of six weeks. The effect was dramatic—in people with CRP levels above 5 mg/L at the beginning of the study, lurasidone (at either dosage level) had a very large effect size (d=0.85), while in people with baseline CRP levels below 5 mg/L the effect size was smaller (d=0.35).

Interestingly, 118 of the participants (24.5%) had CRP levels above 5mg/L at baseline, indicating a substantial amount of inflammation was present in a quarter of the bipolar depressed patients. Higher levels of CRP at baseline were correlated with better improvement on specific items on the Montgomery–Åsberg Depression Rating Scale (MADRS): “lassitude” (or lack of energy), “apparent sadness,” “reported sadness,” and “pessimistic thoughts.” Raison and colleagues concluded: “These findings suggest that the efficacy of lurasidone in patients with bipolar depression may in part be linked to the inflammatory status of patients prior to treatment. If confirmed in prospective investigations, [the results of a wide-range CRP assay] may prove useful as a predictive biomarker that could help optimize the use of lurasidone for the treatment of patients with bipolar depression.”

Editor’s Note: In many instances, high levels of CRP predict a poor response to treatment (such as to selective serotonin reuptake inhibitor antidepressants (SSRIs) in unipolar depression), so these findings are of considerable interest. They also suggest the untested possibility that lurasidone has anti-inflammatory effects, as those with high levels of inflammation at baseline often respond better to drugs with direct anti-inflammatory effects such as celecoxib (Celebrex) or the antioxidant N-acetylcysteine (NAC).

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