Researcher Ben Goldstein reported at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry that children with bipolar disorder have levels of inflammatory markers in the same range as people with inflammatory illnesses, such as rheumatoid arthritis. In his research, increases in the inflammatory marker c-reactive protein (CRP) occurred in proportion to the severity of manic symptoms in the children.
Goldstein also discussed cognitive dysfunction, which is often seen early in the course of childhood onset bipolar disorder. Goldstein described studies showing that this type of cognitive dysfunction consists of a decrease in reversal learning, a measure of cognitive flexibility. Elevated CRP was significantly associated with deficits in a child’s composite score for reversal learning.
Together these data suggest that inflammation could play a role in disease disability and cognitive dysfunction in childhood bipolar disorder.
Researcher Andrea Danese discussed the influence of childhood maltreatment on inflammation in a symposium at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry. Danese indicated that inflammation is part of the normal immune system, which includes the blood brain barrier, recognition of self- versus non-self proteins, activation of cytokines and endothelial cells, and response by phagocytes and acute phase proteins. In an acute phase inflammatory response, the liver secretes proteins including c-reactive protein (CRP) and fibrinogen into the blood, where their levels can be measured.
Normal amounts of inflammation can be protective, while excessive or persistent inflammation can be damaging and pathological. The inflammatory cytokines interferon gamma and tumor necrosis factor (TNF alpha) induce an enzyme called indoleamine oxidase (IDO) that shunts the amino acid tryptophan away from its normal path, which yields serotonin, so that it instead yields kynurenine and then kynurenic acid, which inhibits the action of glutamate at NMDA receptors. Kynurenine can also be hydroxylated and turned into quinolinic acid, which activates glutamate NMDA receptors and causes toxicity.
In addition, inflammatory cytokines such as interleukin six (Il-6) can cross the blood brain barrier and directly influence neurotransmission. Meta-analyses have shown that inflammatory markers CRP, IL-6, IL-1, and IL-1 Ra all increase significantly in depression. A direct demonstration of the relationship between inflammation and depression is the finding that when hepatitis C is treated using the inflammatory treatment interferon gamma, there is about a 30% incidence of depression, which responds to the antidepressant paroxetine.
Stress can also increase the activity of the sympathetic nervous system, driving inflammation, and decrease parasympathetic activity, resulting in further inflammation. In addition, glucocorticoid receptor resistance can develop, enhancing depression, and increasing inflammation. Thus there are multiple ways inflammation can develop.
Danese described a study from New Zealand in which 1000 participants were observed over several decades—from childhood through age 38. The small percentage of participants who experienced maltreatment as children (aged three to eleven) showed a linear increase in CRP in adulthood as a function of their histories of previous child maltreatment. The maltreatment included parental rejection in 14%, sexual abuse in 12%, harsh discipline in 10%, changing caretakers in 6%, and physical abuse in 4%. Childhood maltreatment was also associated with some unfortunate outcomes in adulthood, including lower socioeconomic status, more major depression, more persistent depression, more cardiovascular risk, and more smoking. In other studies, Danese found that compared with controls, patients with depression alone, and patients with maltreatment alone, a greater number of patients with both depression and maltreatment (about 30%) had elevated CRP.
Danese noted that in a study by Ford et al. (2004), recurrent depressions, but not single depressions, were also significantly associated with increased CRP. In a meta-analysis by Nanni et al. in the American Journal of Psychiatry in 2012, Danese and colleagues found that across multiple studies, childhood maltreatment was associated with a twofold increase in the incidence of depression and a twofold increase in the persistence of depression (chronic depression or treatment resistance). The traditional optimal treatment for depression, combined psychotherapy and pharmacotherapy, was also significantly less effective in those with histories of childhood maltreatment. However, psychotherapy alone was equally effective in those with and without childhood maltreatment.
Together these data suggest that childhood maltreatment, partly through an inflammatory pathway, results in multiple difficulties in adulthood, including depression and treatment resistance. These data speak to the importance of attempting to prevent maltreatment in the first place, and ameliorating its consequences should it occur.
Editor’s Note: In a 2014 article in the Journal of Nervous and Mental Disorders, this editor Robert Post and colleagues reported that childhood adversity (verbal, physical, or sexual abuse) is associated with increases in medical comorbidities in adult patients with bipolar illness, and it is likely that inflammation could play a role in some of these medical conditions.
In a poster at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Larissa Portnoff reported that NF-kB, a marker of inflammation that can be measured in two types of white blood cells (lymphocytes and monocytes), was significantly elevated in adolescents who had bipolar disorder compared to healthy control participants.
Several other inflammatory markers have been linked to bipolar disorder, including c-reactive protein (CRP) and TNF alpha. The new data about NF-kB suggests that another inflammatory pathway is overactive in the disorder. NF-kB levels did not correlate with the severity of manic or depressive symptoms, as do levels of some other inflammatory markers.
C-reactive protein, or CRP, is a protein found in blood plasma, the levels of which rise in response to inflammation. In a recent study, levels of CRP were able to predict which of two antidepressants a patient was more likely to respond to.
The 2014 article by Rudolph Uher et al. in the American Journal of Psychiatry reported that low levels of CRP (<1 mg/L) predicted a good response to the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) while higher levels of CRP predicted a good response to the tricyclic antidepressant nortriptyline, a blocker of norepinephrine reuptake.
The research was part of the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured in the blood of 241 adult men and women with major depressive disorder. In the article the researchers say that CRP and its interaction with medication explained more than 10% of the individual variance in response to the two antidepressants.
If these findings can be replicated with these and similarly acting drugs, it would be a very large step in the direction of personalized medicine and the ability to predict individual response to medications.
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.)
Some people have found that gluten-free or casein-free diets have improved their intestinal, autoimmune, or neurological symptoms. (Casein is a protein found in mammals’ milk. Cow milk is high in casein while human milk proteins are 20–45% casein.) One explanation for the good effects of these diets is that peptides that are released during digestion of these foods can create epigenetic changes in gene expression, adding methyl groups to DNA strands that increase inflammation.
As infants transition from getting all of their nutrition from the placenta to using their gastrointestinal tract, their diet may lead to epigenetic modifications that affect their health later in life. Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Methyl or acetyl groups can be added to DNA or the histones around which it is wound.
When a person digests casein (from either human or animal milk) or gliaden (a protein derived from wheat), peptides are released that activate opioid receptors, modulating the uptake of the amino acid cysteine in neurons and in the gastrointestinal tract. This decrease in cysteine uptake is associated with drop in the antioxidant glutathione and a methyl donor (a molecule with a reactive methyl group that can easily become part of another molecule) called S-Adenosyl methionine.
In addition to decreasing cysteine uptake, the peptides also increase DNA methylation and create epigenetic changes in genes involved in redox (changes in oxidation) and methylation homeostasis.
These processes are described in a 2014 article by Malav S.Trivedi et al. in the Journal of Nutritional Biology. Trivedi et al. conclude that milk and wheat can change antioxidant activity and gene expression. Differences in the peptides in human and cow milk may explain developmental differences between children who are breastfed and those who receive formula.
The decrease in antioxidants caused by peptides from wheat and milk can predispose people to inflammation and oxidation, explaining why wheat- or casein-free diets might be useful.
Links between inflammation and depression continue to be identified in new research. Researcher N. Vogelzangs et al. reported in a 2014 article in Neuropharmacology that inflammatory and metabolic dysregulation in antidepressant users predicted an outcome of depression two years later. Elevated levels of the marker of inflammation Il-6, low HDL (or “good”) cholesterol, high triglycerides, and high blood sugar were associated with poor response to medication and chronicity of depression. Of 315 people treated with antidepressants (average age 43), 138 were in remission at 2 years, while 177 (56.2%) were still depressed. People with four or more types of inflammatory or metabolic dysregulations had a 90% chance of still being depressed at 2 years.
Among inflammatory markers including CRP and TNF-alpha, IL-6 alone was associated with chronic depression. Il-6 can cross the blood-brain barrier. We have previously reported that researcher Scott Russo found that in rats in a depression-like state known as defeat stress (brought about by repeated defeat by a larger rodent), blocking Il-6 can prevent depressive behaviors such as social avoidance or loss of preference for sucrose.
Like inflammation, metabolic abnormalities also complicate depression. Lipid dysregulation and hyperglycemia are associated not only with depression persistence, but also with the new onset of depression in humans.
Vogelzangs et al. conclude that these data “ suggest that inflammatory and metabolic dysregulation worsens depression course owing to reduced [antidepressant] response and that alternative intervention treatments may be needed for depressed persons with inflammatory and metabolic dysregulation.”
It is noteworthy that a 2014 meta-analysis of the anti-inflammatory drug celecoxib (Celebrex) published by Farhad Faridhosseini et al. in Human Psychopharmacology, showed that the drug, often prescribed for arthritis, is effective for unipolar depression when added to patients’ regular treatment.
It remains to be ascertained whether celecoxib’s effects are seen in depression in general, or if they pertain only to the 30% of depressed patients who show inflammation at baseline. Typical markers of inflammation include Il-6, CRP, TNFa, and Il-1.
Statins, prescribed to lower cholesterol, also have anti-inflammatory effects, and are also effective in preventing depression.
Determining treatment approaches for those patients showing signs of inflammation or metabolic irregularities remains a high priority for study. The preliminary data noted here suggest that treating these dysregulations in those with depression may be useful.
There is increasing evidence of a link between mood disorders and inflammation in the body.
At the 2014 meeting of the International Society for Bipolar Disorders, Shang-Ying Tsai discussed increases in measures of inflammation that occur in bipolar disorder as a function of the clinical state of depression, mania, or euthymia (remission). He found that in both mania and depression, there were elevations in various markers of inflammation: STNF-R1, CRP, IL-Ira and SLR-2r. However, SLR-2r showed some particularly interesting results. In mania, elevation of SLR-2r, a marker of cell-mediated inflammation, was state-related, meaning it increased during an episode of mania and remained normal during euthymia. In depression, SLR-2r elevation was trait-related, or persistently elevated (even in remission).
Editor’s Note: This study adds to a growing list of studies that confirm the presence of inflammation in patients with bipolar disorder compared to normal controls, including a 2012 article by Tsai in the Journal of Affective Disorders. How elevations in inflammatory markers in a given individual should direct specific types of treatment intervention remains to be further clarified.
While the reasons why one person develops bipolar disorder and another does not remain mysterious, the current thinking is that genes contribute some risk while immunological abnormalities contribute other risks. Researchers have identified certain antibodies whose levels spike during an episode of mania, as if the patient is having an immune reaction. These are referred to as biomarkers or inflammatory markers.
While various biomarkers for mania have been identified, until recently their effects had only been examined independently. A 2013 article by Dickerson et al. published in the journal PLOS ONE examined four biomarkers in combination. Each was a type of antibody: to the NR peptide of the NMDA receptor, to gliadin (a protein derived from gluten), to Toxoplasma gondii (a parasitic protozoan), and to Mason-Pfizer Monkey Virus. Measures of these four types of antibodies made up a combined inflammation score for participants in the study.
The study compared 57 patients presenting with a manic episode with 207 non-psychiatric controls and 330 patients who had had recent onset of psychosis, schizophrenia, or bipolar depression. The combined inflammation score of the mania group was significantly higher than the other groups at the time of hospital admission and at the time of evaluation several days later. It had returned to normal (i.e. not different from the other groups) at followup six months later, although those with the highest combined inflammation scores were at risk for re-hospitalization during that period.
The findings of this study suggest that hospitalization for mania is associated with immune activation, and the level of this activation predicts subsequent re-hospitalization. Treatments for mania that target this inflammatory response should be investigated.
There is mounting evidence that inflammation and metabolic problems are related to depression. A recent study by Vogelzangs et al. in the journal Neuropsychopharmacology examined 313 patients being treated for depression to see whether levels of inflammatory markers in the blood and metabolic factors such as cholesterol, blood pressure, and waist circumference predicted whether those patients would still (or again) be diagnosable with depression two years later.
Several factors predicted later depression, including high levels of the inflammatory marker interleukin-6, low HDL (“good”) cholesterol, higher than normal triglycerides, and high blood glucose (hyperglycemia).
People who had four or more types of inflammatory or metabolic abnormalities had almost twice the odds of having chronic depression. Among those study participants who had only recently begun taking antidepressant medication, having four or more of these risk factors made them almost 7 times more likely to be depressed during follow-up.
One explanation for the connection between inflammatory and metabolic dysregulation and depression is that inflammation and metabolic problems worsen and complicate a patient’s depression and reduce the patient’s responsiveness to traditional antidepressants. Alternative ways of treating these patients aimed at their inflammation and metabolism may be necessary.