The Journal of the American Medical Association
July 23, 2014
Activation of the immune system is the body’s natural reaction to infection or tissue damage, but when this protective response is prolonged or excessive, it can play a role in many chronic illnesses, not only of the body, but also of the brain.
“Psychiatric and neurodevelopmental disorders are being thought of more and more as systemic illnesses in which inflammation is involved,” noted Eric Hollander, M.D., of Montefiore Medical Center and Albert Einstein College of Medicine, New York City. The cause of increased inflammation in these conditions isn’t always clear, but it has become a hot topic of investigation.
Hollander, who spoke at the annual meeting of the American Psychiatric Association held here in May, was among several investigators who discussed how immune-inflammatory mechanisms can go awry and contribute to the development of depression, schizophrenia, and autism, insights that are leading to novel experimental approaches for these and other disorders.
Cytokines in Depression
“The notion that inflammation plays a role in neuropsychiatric disorders really caught fire in the context of depression,” said Andrew Miller, M.D., of Emory University School of Medicine, Atlanta.
This idea came from early studies showing that patients with depression, regardless of their physical health status, exhibited cardinal features of inflammation, including increases in inflammatory cytokines in the blood and cerebral spinal fluid.
The inflammatory cytokines interleukin-6 and tumor necrosis factor (TNF), as well as the acute-phase reactant c-reactive protein (CRP), are the most reliable biomarkers of increased inflammation in patients with depression, said Miller.
Interestingly, there seems to be a special relationship between inflammation and treatment-resistant depression (TRD), which occurs in about one-third of all depressed patients, said Miller. Patients who don’t respond to antidepressant therapy tend to show an increase in inflammatory markers. Data indicate that these inflammatory molecules can sabotage and circumvent the mechanisms of action of conventional antidepressant therapy.
Given the association of inflammatory cytokines with TRD, researchers set out to test the therapeutic potential of inhibiting inflammatory cytokines in this subset of patients. Administration of a TNF antagonist has been shown to improve depressed mood in patients with other disorders, such as psoriasis and Crohn disease, suggesting that this approach might help reverse depressive symptoms in otherwise healthy patients with TRD.
In a recent proof-of-concept study, Miller and his colleagues gave infusions of the monoclonal antibody infliximab, a TNF antagonist, to 60 adults with major depression that was at least moderately resistant to medication (Raison CL et al. JAMA Psychiatry. 2013;70:31-41). Based on the hypothesis that an anticytokine strategy might be effective only in patients with high inflammation before treatment, the researchers also measured CRP and other inflammatory biomarkers at baseline and throughout the study.
Infliximab did not prove to be more effective than placebo in treating TRD in the study. In fact, overall, those treated with placebo did better than those who received infliximab, said Miller. However, when patients were stratified on the basis of inflammatory biomarkers, those patients with high baseline measurements (plasma CRP concentrations >5 mg/L) had the best response to infliximab.
These results indicate that a simple test for a peripheral blood biomarker of inflammation like CRP might predict which patients would respond to immune-targeted therapy for depression, said Miller. “It’s one of the first studies in psychiatry connecting a biomarker to treatment response,” he noted.
In a subsequent study, Miller’s team compared gene expression profiles of the participants who responded to infliximab with those who did not respond. Within 6 hours after the first infusion of infliximab, the researchers were able to distinguish responders from nonresponders (Mehta D et al.Brain Behav Immun. 2013;31:205-215).
Miller’s group has also been working to identify the brain regions and pathways that are targeted by inflammatory cytokines, such as interferon-alpha—work that may lead to more personalized treatment options for patients with depression, he said (Capuron L et al. Arch Gen Psychiatry. 2012;69:1044-1053).
Anti-Inflammatory Treatment in Schizophrenia
A role for the inflammatory process is also being explored in schizophrenia, noted Norbert Müller, M,D, Ph,D of Ludwig Maximilian University of Munich, Germany.
The influence of infectious agents on the pathogenesis of schizophrenia, as well as on other psychiatric disorders, has been discussed for decades, and prenatal and postnatal infections are considered risk factors for schizophrenia. Research in prenatal infections indicates that the culprit is not a specific infectious agent, but rather the maternal immune response (Krause D et al. World J Biol Psychiatry. 2010;11:739-743).
Data from a 30-year population-based register study indicate that inflammation coming from either infection or autoimmunity is a risk factor for schizophrenia, not only during development but also later in life (Benros ME et al. Am J Psychiatry. 2011;168:1303-1310). The risk seems to increase in a dose-dependent manner, with the risk increasing along with the number of infections, for example, said Müller.
Because of the apparent involvement of inflammatory processes in schizophrenia, the use of anti-inflammatory compounds for the disorder has received increasing attention. A number of studies carried out in the past decade using cyclooxygenase-2 (COX-2) inhibitors in addition to antipsychotic medication have shown a therapeutic effect for the disorder.
Müller noted that timing seems to influence response to this anti-inflammatory therapy because no benefit was seen in a study involving patients who had a long duration of disease (Rapaport MH et al.Biol Psychiatry. 2005;57:1594-1596).
Rather, the most compelling data was for anti-inflammatory therapies carried out in the early phase of the disorder: a recent meta-analysis showed an advantage of COX-2 inhibitors only among patients who had a short duration of the disorder (Nitta M et al.Schizophr Bull. 2013;39:1230-1241).
“From an immunologic point of view, this fits very well,” said Müller. “If you have chronic inflammation, it’s more or less impossible to treat effectively with a short-term anti-inflammatory therapy,” he said.
Müller’s group is also beginning to use interferon γ to activate the cellular arm of immunity (type 1 response), which appears to be blunted in most patients with schizophrenia. The work is only in early stages but so far has shown some promise.
Inflammatory Mechanisms in Autism
A hyperactive immune system is also postulated to play a role in people with autism spectrum disorder (ASD). Increases in proinflammatory cytokines have been found both in the cerebrospinal fluid of patients with ASD and in postmortem brain tissue from deceased patients with autism, said Montefiore’s Hollander.
The association between immune dysfunction and ASD has led researchers to test several novel treatments that target inflammatory mechanisms to alleviate some symptoms of ASD.
One of these mechanisms involves the gut microbiome. “We can think about certain bacteria and parasites in the gut as helping to dampen the chronic inflammatory response, and that a lack of favorable gut parasites allows proinflammatory cytokines to prevail,” said Hollander.
When the microbiome is deprived, as the “hygiene hypothesis” contends has happened in developed countries, it may lead to a lack of control of the immune system. This could help explain why developed countries have higher rates of autoimmune conditions, although other factors—such as underdiagnosis—could also contribute to the lower rates in low- and middle-income countries.
Hollander and his colleagues have focused on trying to beef up the microbiome in people with ASD by introducing a medicalized parasite, Trichuris suis ova (TSO), the eggs of a porcine whipworm.Trichuris suis ova is safe in humans, does not multiply in the host, is not transmittable by contact, and is cleared from the system spontaneously.
Trichuris suis ova works by tamping down the proinflammatory response to increase its survival within the host. It has been studied with some success in autoimmune diseases such as Crohn disease and inflammatory bowel disease and appears to achieve its effects by shifting the balance of T-regulator and T-helper cells and their respective cytokines, said Hollander.
Hollander’s group has been carrying out a small preliminary study of TSO in 10 high-functioning adults with ASD who were able to give informed consent. All participants had a family or personal history of some kind of a seasonal or food allergy or a family history of autoimmune problems.
The aim of identifying this subset of people with ASD was to stratify the study population according to signs of immune dysfunction. In this way, researchers can study a more homogeneous group of people within what is considered a very heterogeneous illness, said Hollander.
In a 28-week, double-blind, randomized, crossover study, the patients received TSO for 3 months (2500 eggs every 2 weeks) followed 4 weeks later by placebo treatment for 3 months. After the first 12-week phase of TSO or placebo, the patients entered a 4-week washout before beginning the second 12-week phase.
The researchers used several measurements to assess symptoms, including stereotypy (self-stimulatory behavior), repetitive behavior, and rigidity or craving for sameness. In their interim analysis of this pilot study, they demonstrated the feasibility and safety of using TSO in an adult population with autism and have found a potential benefit from treatment in all these domains.
Hollander’s team is in the process of launching a new study of this same approach in a pediatric population with ASD, based on the idea that early intervention in developmental disorders is optimal.
In a different therapeutic approach, Hollander and his colleagues studied 10 children with ASD who had a history of symptom improvement when they had fevers. All the children spent alternate days soaking in a hot tub at 102°F (to mimic fever) or at 98°F (control condition).
The children showed improvements on the days when their body temperature was raised to 102°F, compared with the days they were bathed at 98°F. Benefits were seen particularly in restricted and repetitive behavior as well as social behavior, said Hollander.
The mechanism of action is under investigation, but researchers conjecture that raising the body’s temperature either through fever or a hot tub bath releases anti-inflammatory signals that can bring about the observed behavioral effects.
Future studies need to be done to replicate many of these findings. But researchers suggest the data represent a step toward personalizing therapies for psychiatric and neurodevelopmental disorders and provide promise for the development of inflammatory biomarkers and treatment approaches for patients who are responsive to immune-targeted therapies.