Spotlight on the Emerging Field of Immunopsychiatry

In recent years, there has been an increasing recognition of the potential role of immune dysfunction in the pathophysiology of psychiatric disorders and vice versa. Along with the well-established link between psychological stress and impaired immunity, for example, study findings suggest a connection between immune dysfunction and psychiatric illnesses including mood and psychotic disorders.^1-3

In a 2021 pooled analysis of 15 cross-sectional studies with a total of 56,351 adults, Frank et al found strong associations between elevated blood levels of C reactive protein (CRP) — a biomarker of systemic inflammation — and a higher risk of several depressive symptoms including appetite changes, low energy, impaired sleep, and diminished interest in activities.²

In addition, longitudinal research has demonstrated bidirectional links between a personal or family history of autoimmune disease and increased risk for psychiatric illness. In a 2019 meta-analysis of 31 studies involving more than 25 million participants, the authors observed a 43% increase in the risk of developing psychotic disorder in patients with a nonneurological autoimmune disease (NNAI), and a 50% increase in the odds of developing NNAI in those with a psychotic disorder.³ 

In the context of COVID-19, cognitive, emotional, and behavioral symptoms may be associated with the effects of infection-related immune changes on the brain.⁴ In studies supported by the National Institutes of Health, animal models suggest that brain inflammation triggered by COVID-19 infection may lead to the mood and cognitive symptoms noted in patients with long COVID.⁵

Such discoveries have given rise to the emerging discipline of immunopsychiatry as part of the broader field of psychoneuroimmunology.³ Researchers are working to elucidate the multifaceted relationship between the immune system and the brain, with the aim to identify targeted treatment strategies for patients who may have immune-mediated psychiatric illness.

To learn more about this growing area of study, we interviewed Robert Dantzer, DVM, PhD, a researcher specializing in the relationship between the immune system and the brain, and Daniel P. Moriarity, PhD, postdoctoral fellow in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, and science and research chair for the California Stress, Trauma, and Resilience (CAL STAR) Network.

What are some key examples of psychiatric conditions that appear to be immune-mediated, and what psychiatric disorders highlight the interplay between the central nervous system and the immune system? 

Dr Dantzer: The best example of a psychiatric condition that is mediated by immunity is represented by the so-called cases of autoimmune psychosis or isolated psychiatric presentations that are positive for neuronal autoantibodies — mainly N-methyl-D-aspartate receptor antibodies — and respond to immunotherapy. A consensus article published in Lancet Psychiatry in 2019 presents what is known and still needs to be learned about this condition.⁶

Other examples of psychiatric conditions that are possibly mediated by interactions between the immune system and the central nervous system include inflammation-associated depression that appears to be more frequent in the case of treatment-resistant depression and could be alleviated by anti-inflammatory agents. Current investigations of this condition advocate the use of a biomarker of inflammation, in the form of elevated circulating C-reactive protein, together with a predominance of somatic symptoms of depression, such as fatigue and reduced motivation, to diagnose this condition and treat it accordingly.²

A possible role of activation of the immune system during pregnancy is also indicated in the pathophysiology of neurodevelopmental disorders such as some forms of schizophrenia and autism spectrum disorder, but this has not yet reached the clinic. 

Dr Moriarity: Atypical immune profiles are seen in many psychiatric disorders, but I think the most high-quality studies of immune-mediated psychiatric symptoms can be seen for depression, and psychosis is up there as well. Depression can be a useful canvas to think about how immune functioning might influence our mental health. Think back to the last time you got really sick or had a strong reaction to a vaccination — you might have felt fatigued, had changes to your appetite, experienced less pleasure, or wanted to see or talk to other people less. As we know, those are also diagnostic criteria of depression.

Why is there a need for a field focused on immunopsychiatry? 

Dr Dantzer: Immunopsychiatry requires the combined effort of immunologists, neurobiologists, neuroimaging specialists, and psychiatrists. It is a field of research that is different from neuroimmunology, due to the distinctive features of psychiatric disorders compared to neurological diseases. It offers an important shift of perspective on the pathophysiology of psychiatric disorders by shifting the usual brain-centric psychiatry perspective — the demonstration that peripheral immune processes can influence brain functions — and by replacing the traditional emphasis on neurotransmission by the tripartite synapse. Although not originating from the field of immunopsychiatry, the demonstration that the brain has a lymphatic system obliges us to reconsider the view of the brain as an immune-privileged organ.⁷

Dr Moriarity: Immunopsychiatry, and psychoneuroimmunology more broadly, are important because it has to do with improving both mental and physical health. These fields are about bidirectional relationships between psychology and the immune system — how our thoughts and behaviors influence our ability to resist and recover from illness and injury, and how immune biology can in turn impact our thoughts and behaviors. By increasing our actionable understanding of how these systems are interrelated, we can hopefully guide interventions for individuals as well as public health efforts.

What are some of the top questions that researchers should explore in this area? 

Dr Dantzer: The top questions in immunopsychiatry are complementary in terms of basic and clinical research. Basic research in immunopsychiatry mainly focuses on mechanisms, investigating the pathways of communication between the immune system and the brain, the role of brain innate immune cells in the relay of the peripheral immune message to the brain, the way these cells interact with neurons, the possible involvement of peripheral immunocytes trafficking into the brain, and the mechanisms by which the immune mediators produced by brain immune cells ultimately impact neuronal networks.⁸

At the clinical level, the main emphasis is on the identification of biomarkers to identify the immune processes that play a role in the development of the psychiatric disorder under consideration and its evolution to chronicity, and the druggable targets that can be used not only to validate the hypothesis of immune causal factors but also to treat the disorder rather than just its symptomatology.

Dr Moriarity: An area of work I’m particularly excited about is the inflammatory phenotyping of mental health — that is, moving beyond thinking about diagnostic categories and exploring how specific the relationship between immune functioning and psychology is.⁹ By clarifying the relevant clinical endpoints, we can design better clinical trials to see how adjunctive immune-modulating treatments — both behavioral and pharmacological — might improve care.

Additionally, there is a lack of immunopsychiatry research investigating these mechanisms in the context of robust, established psychosocial models of risk.¹⁰ We know that things like rumination and worry or social stress are important for mental and immunological health, and we need to explore how inflammation might play a role so we can fold this mechanism into comprehensive treatment plans.

What measures are needed to move this field forward, and what would you recommend to clinicians who are interested in learning more or becoming more involved in these endeavors?

Dr Dantzer: The main measure needed is education. A number of books and review papers on the basic aspects of neuroimmune interactions and their involvement in specific psychiatric disorders are now available. Another important need is the recognition that the brain is not an isolated organ and that psychiatric disorders might have their origin not in the brain but in the rest of the body. An important aspect of immunopsychiatry is the recognition of the role of the gut microbiome — and probably other microbiota — and the investigation of the possibility of treating symptoms of depression by fecal transfer.

Dr Moriarity: As far as reading goes, there are a couple of immunopsychiatric models that are anchored in psychological risk factors that might be good entry points for clinicians interested in learning more about the field. For example, I’ve worked on an immunocognitive model that folds rumination into immunological models of risk, and George Slavich has a great theory on how immunology might be a mechanism explaining how social threat and safety influence psychological outcomes.^11,12

For a more biology-heavy introduction, Andre Miller, Vladimir Maletic, and Charles Raison have a great paper on inflammation and depression.¹³ A recent meta-analysis on psychosocial interventions improving immune outcomes could also be a good entry point.¹⁴

I think clinicians can play a huge role in advancing this field. Clinically, psychosocial interventions can influence immune functioning,¹⁴ so clinicians in interdisciplinary environments who have access to routine biological assessments for their clients could do some really valuable research on how their therapy might influence immune as well as psychiatric outcomes.