Patients with a primary humoral immunodeficiency (PID) are 91% more likely to have a psychiatric disorder and 84% more likely to exhibit suicidal behavior, compared against those without the condition, new research shows.Results showed that this association, which was stronger in women, could not be fully explained by comorbid autoimmune diseases or by familial confounding.These findings have important clinical implications, study investigator Josef Isung, MD, PhD, Centre for Psychiatry Research, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.Clinicians managing patients with PID "should be aware of this increased association with psychiatric disorders and perhaps screen for them," said Isung.The study was published in the November issue of JAMA Psychiatry.Registry StudyMounting evidence suggests immune disruption plays a role in psychiatric disorders through a range of mechanisms, including altered neurodevelopment. However, little is known about the neuropsychiatric consequences resulting from the underproduction of homeostatic antibodies.PIDs involve a deficiency in antibody production, mainly affecting immunoglobulin, "or the humoral aspect of the immune system," said Isung. They're associated with an increased risk for recurrent infections and of developing autoimmune diseases.The immunodeficiency can be severe, even life threatening, but can also be relatively mild. One of the less severe PID types is selective IgA deficiency, which is linked to increased infections within the mucosa-associated lymphoid tissue (MALT), an important immune barrier.Experts have long suspected that infections within the MALT are associated with certain forms of psychopathology in children, particularly obsessive-compulsive disorder and chronic tic disorders.While patients with this selective IgA subtype may be at some increased risk for infection and autoimmune disease, their overall health otherwise is good, said Isung.The prevalence of PIDs ranges from about 1:250 to 1:20,000, depending on the type of humoral immunodeficiency, although most would fall into the relatively rare category, he added.Using several linked national Swedish registries, researchers identified individuals with any PID diagnosis affecting immunoglobulin levels, their full siblings, and those with a lifetime diagnosis of selective IgA deficiency. In addition, they collected data on autoimmune diseases.The study outcome was a lifetime record of a psychiatric disorder, a suicide attempt, or death by suicide.Strong Link to AutismResearchers identified 8378 patients (59% women) with PID affecting immunoglobulin levels (median age at first diagnosis, 47.8 years). They compared this group with almost 14.3 million subjects without PID.In those with PID, 27.6% had an autoimmune disease vs 6.8% of those without PID, a statistically significant difference (P < .001).About 20.5% of those with PID and 10.7% of unexposed subjects had at least one diagnosis of a psychiatric disorder.In a model adjusted for year of birth, sex, and history of autoimmune disease, subjects with PID had a 91% higher likelihood of any psychiatric disorder (adjusted odds ratio [AOR] 1.91; 95% CI, 1.81 - 2.01; P < .001) vs their counterparts without PID.The AORs for individual psychiatric disorders ranged from 1.34 (95% CI, 1.17 - 1.54; P < .001) for schizophrenia and other psychotic disorders to 2.99 (95% CI, 2.42 - 3.70; P < .001) for autism spectrum disorders (ASDs)It's unclear why the association with PID was strongest for autism, "but being a neurodevelopmental disorder, maybe autism is logically more associated with this type of disruption," said Isung.Research suggests that immunologic disruption may play a role in ASD, either through altered maternal immune function in utero or through immune disruption after birth, the researchers note.Compared to those without PID, individuals with it had a significantly increased likelihood of any suicidal behavior (AOR, 1.84; 95% CI, 1.66 - 2.04, P < .001) as well as individual outcomes of death by suicide and suicide attempts.The association with psychiatric disorders and suicidal behavior was markedly stronger for exposure to both PID and autoimmune disease than for exposure to either of these alone, which suggest an additive effect for these immune-related conditions.Sex Differences"It was unclear to us why women seemed particularly vulnerable," said Isung. He noted that PIDs are generally about as common in women as in men, but women tend to have higher rates of psychiatric disorders.The analysis of the sibling cohort also revealed an elevated risk for psychiatric disorders, including ASD and suicidal behavior, but to a lesser degree."From this we could infer that at least part of the associations would be genetic, but part would be related to the disruption in itself," said Isung.An analysis examining selective IgA subtype also revealed a link with psychiatric disorders and suicidal behavior, suggesting this link is not exclusive to severe PID cases."Our conclusion here was that it seems like PID itself, or the immune disruption in itself, could explain the association rather than the burden of illness," said Isung.However, he acknowledged that the long-term stress and mental health fallout of having a chronic illness like PID may also explain some of the increased risk for psychiatric disorders.This study, he said, provides more evidence that immune disruptions affect neurodevelopment and the brain. However, he added, the underlying mechanism still isn't fully understood.The results highlight the need to raise awareness of the association between immunodeficiency and mental illness, including suicidality among clinicians, patients, and advocates.These findings may also have implications in patients with other immune deficiencies, said Isung, noting, "it would be interesting to further explore associations with other immunocompromised populations."No SurprisesCommenting on the findings for Medscape Medical News, Igor Galynker, MD, professor of psychiatry at Icahn School of Medicine at Mount Sinai, New York City, said the study was "very well-done" and used "reliable and well-controlled" databases.However, he added, the results "are neither particularly dramatic nor conclusive" as it makes sense that medical illnesses like PID would "increase risk of psychopathology," said Galynker.PID patients are much more likely to have contact with clinicians and to receive a psychiatric diagnosis, he said."People with a chronic illness are more stressed and generally have high incidences of depression, anxiety, and suicidal behavior. In addition to that, they may be more likely to be diagnosed with those conditions because they see a clinician more frequently."However, that reasoning doesn't apply to autism, which manifests in early childhood and so is unlikely to be the result of stress, said Galynker, which is why he believes the finding that ASD is the psychiatric outcome most strongly associated with PID is "the most convincing."Galynker wasn't surprised that the association between PID and psychiatric illnesses, and suicidal behaviors, was stronger among women."Women attempt suicide four times more often than men to begin with, so you would expect this to be more pronounced" in those with PID.The study was supported by grants from the Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institute; Stockholm Care Services; the Soderstrom Konig Foundation; and the Fredrik & Ingrid Thurings Foundation.Isung and Galynker have disclosed no relevant financial relationships.JAMA Psychiatry. November 2020 issue. Full textFor more Medscape Psychiatry news, join us on Twitter and Facebook