Inflammation Associated with Cognitive Deficits
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.
Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments
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.
Clinical Vignettes from Dr. Elizabeth Stuller
Dr. Elizabeth Stuller, a staff psychiatrist at the Amen clinics in Washington, DC and CEO of private practice Stuller Resettings in Baltimore, MD, provided this editor (Robert M. Post) with several interesting anecdotal observations based on her wide clinical experience with difficult-to-treat mood disordered patients.
- Stuller has used low-dose asenapine (Saphris), e.g. half a pill placed under the tongue, for depressed patients with alcohol use problems who have trouble getting to sleep. She has also used asenapine for rapid calming of agitated patients in her office.
- Stuller has also had success with the use of the atypical antipsychotic drug brexpiprazole (Rexulti) for patients with bipolar depression and low energy. She typically uses 0.5 mg/day for women and 1 mg/day for men. Stuller finds that there is little weight gain or akathisia with brexpiprazole.
- She has had success with the drug Nuedexta, which is a combination of dextromethorphan and quinidine and is approved for the treatment of sudden uncontrollable bouts of laughing or crying, known as pseudobulbar affect, which can occur as a result of neurological conditions or brain injuries. It is a combination of an NMDA antagonist and a sigma receptor agonist. Stuller starts with the 20mg dextromethorphan/10 mg quinidine dose once a day and increases to twice a day in week two. She finds it useful for behavioral effects of traumatic brain injury (TBI), anxiety resulting from the use of synthetic marijuana (sometimes called spice), and psychosis not otherwise specified. Stuller also finds that some patients appear to respond well to Nuedextra but not minocycline, or vice versa.
Editor’s Note: Note that these are preliminary clinical anecdotes conveyed in a personal communication, and have not been studied in clinical trials, thus should not be relied upon in the making of medical decisions. All decisions about treatment are the responsibility of a treating physician.
Anti-Inflammatory Treatments Look Promising for Bipolar Depression
Inflammation has been linked to both unipolar and bipolar depression. New research shows that anti-inflammatory treatments may reduce bipolar depression, for which few treatments exist.
Researchers led by Jonathan Savitz divided people with bipolar depression into four groups. One group received two placebos, another received minocycline (a drug with neuroprotective and immune-modulating properties) plus a placebo, the third received aspirin plus a placebo, and the final group received both minocycline and aspirin. Of the 64 participants, those who took both minocycline and aspirin were most likely to respond to treatment and to enter remission. In people with body mass indexes (BMIs) above the median of 30, a sign of greater inflammation, 100% of those who received both anti-inflammatory drugs responded to treatment, compared to 36% of those who received aspirin alone, 33% of those who received minocycline alone, and 25% of those who received two placebos.
Dosages of the drugs were 100mg twice a day for minocycline and 81mg twice a day for aspirin. Savitz and colleagues believe that aspirin and minocycline must work particularly well together, and are modifying their study to more directly compare use of the two anti-inflammatory drugs together to the absence of anti-inflammatory treatments.
Blood and Now Brain Inflammation Linked to Depression
There is growing evidence of a link between inflammation of depression. At the 2015 meeting of the Society of Biological Psychiatry, researcher Jeff Meyer summarized past studies on inflammatory markers. These are measurements, for example of certain proteins in the blood, that indicate the presence of inflammation in the body.
Common inflammatory markers that have been linked to depression include IL-6, TNF-alpha, and c-reactive protein. At the meeting, Meyer reviewed the findings on each of these. Twelve studies showed that IL-6 levels are elevated in the blood of patients with depression. Four studies had non-significant results of link between IL-6 and depression, and Meyer found no studies indicating that IL-6 levels were lower in those with depression. Similarly, for TNF-alpha, Meyer found 11 studies linking elevated TNF-alpha with depression, four with non-significant results, and none showing a negative relationship between TNF-alpha and depression. For c-reactive protein, six studies showed that c-reactive protein was elevated in people with depression, six had non-significant results, and none indicated that c-reactive protein was lower in depressed patients.
Most studies that have linked inflammation to depression have done so by measuring inflammatory markers in the blood. It is more difficult to measure inflammation in the brain of living people, but Meyer has taken advantage of new developments in positron emission tomography (PET) scans to measure translocator protein binding, which illustrates when microglia are activated. Microglial activation is a sign of inflammation. Translocator protein binding was elevated by about 30% in the prefrontal cortex, anterior cingulate cortex, and insula in study participants who showed symptoms of a major depressive episode compared to healthy control participants. The implication is that the depressed people with elevated translocator protein binding have more brain inflammation, probably via microglial activation.
The antibiotic minocycline reduces microglial activation. It would be interesting to see if minocycline might have antidepressant effects in people with depression symptoms and elevated translocator protein binding.
Another promising open study of minocycline in bipolar depression
Joanna Soczynska in Roger McIntyre’s lab at the University of Toronto presented a poster at the 2014 meeting of the International College of Neuropsychopharmacology (CINP) on the anti-inflammatory and neuroprotective antibiotic minocycline.
Twenty-seven patients with a major depression received minocycline in addition to the medications they were already being prescribed. Dosage was 100mg twice a day. Treatment with adjunctive minocycline was associated with significant improvement on several scales that measure depression severity.
Editor’s Note: What was particularly interesting was that a subset of patients achieved complete remission, raising the question whether these patients might have markers of inflammation that would predict this excellent response. The authors concluded that the “results provide a rationale for testing minocycline’s efficacy in a larger randomized, placebo-controlled trial.”
Exactly this type of study was proposed a year ago by researcher Andy Nierenberg and given the best marks by a National Institute of Mental Health review committee but was turned down for funding because the National Institute of Mental Health has implemented a new initiative, Research Domain Criteria (RDoC), that lays out new criteria for research, limiting funding to those studies that focus on a molecular target that spans several diagnoses.)
Antibiotic Minocycline Could Improve Bipolar Depression
In an abstract presented at the 2013 meeting of the Society of Biological Psychiatry, Iosifescu et al. reported that the antibiotic minocycline, which has showed anti-inflammatory, neuroprotective, and mitochondrial-sparing effects in animal models, brought about improvement in patients with bipolar depression. Doses of 100mg to 300mg per day were successful in this small open study.
There are some positive placebo-controlled data in patients with schizophrenia who were prescribed this antibiotic. However, until now it had not been studied in bipolar disorder. The preliminary data reported here suggest that controlled double-blind studies of this agent are needed in bipolar depression.
The abstract (#497) can be found in the 2013 convention supplement (9S) to the journal Biological Psychiatry.
Inflammation and Oxidative Stress in Bipolar Disorder
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders conference in Sao Paulo, Brazil in March reported new data relevant to inflammation and oxidative stress. Both inflammation and oxidative stress increase risk of cardiovascular disorders, and patients with inadequately treated mood disorders lose 10 or more years of life expectancy from cardiovascular disorders compared to the general population. Inflammation and oxidative stress may also contribute to the symptoms, evolution, and progression of the mood disorders themselves.
It is possible that these two processes could become new targets for therapeutic intervention in addition to more traditional psychopharmacological drugs that primarily target the neurotransmitters dopamine, norepinephrine, serotonin, and the neurotrophic factor BDNF. Read more
