Be on Lookout for Autoimmune-Influenced Psychosis

The COVID-19 crisis has highlighted how an infection and the body’s immune response can impact a multitude of organs, including the brain. During the virtual APA Spring Highlights Meeting in April, Josep Dalmau, M.D., Ph.D., described how an individual’s immune response can trigger a rare neurological disorder known as anti-NMDA receptor encephalitis.

Dalmau is a senior investigator at the Catalan Institute for Research and Advanced Studies at the University of Barcelona and an adjunct professor of neurology at the University of Pennsylvania. He said he hoped his session would raise awareness that psychosis can emerge via a variety of mechanisms.

Dalmau’s interest in anti-NMDA receptor encephalitis began when he treated four young women who presented with delusions and hallucinations coupled with abnormal movements and seizures. These women were later determined to have ovarian tumors.

As reported in a 2008 paper, Dalmau and his colleagues discovered that the culprit behind these varied symptoms was an antibody attacking the NMDA receptor, which binds the neurotransmitter glutamate. These antibodies disrupt normal brain signaling and lead to swelling.

Since that initial discovery, Dalmau has studied over 500 patients with anti-NMDA receptor encephalitis and developed a portrait of this disorder. The disease evolves in stages. Psychiatric symptoms, including psychosis, insomnia, mania, and/or memory deficits typically emerge first. Neurological problems like abnormal movement and seizures manifest about one to four weeks after that, at which point patients deteriorate to the point of needing intensive care. Like the initial four women studied, many patients have a tumor which likely contributes to the development of autoantibodies. In some cases, however, viral infection may lead to the development of the autoantibodies.

Treatment of anti-NMDA receptor encephalitis can vary by patient but typically involves steroids coupled with plasma transfusions; if a tumor is identified, it is removed. Recovery can be slow, with patients continuing to experience residual memory or motor problems for months, Dalmau noted. Relapse rates are less than 10% after two years.

Dalmau said that the profile of symptoms caused by NMDA-receptor autoantibodies are intriguing since they resemble symptoms seen in patients with schizophrenia.

Many studies have pointed to overactive dopamine receptors as the major mechanism underlying schizophrenia. Other research has implicated NMDA receptor dysfunction in contributing to schizophrenia, particularly nonpsychotic symptoms like social withdrawal or cognitive difficulty.

These connections led Dalmau to explore how frequently NMDA-receptor antibodies have been found in people with schizophrenia. A study he published 2017 in Nature Communicationslooked at blood samples of about 150 people with schizophrenia. He found that 19% of these patients had NMDA-receptor antibodies compared with 3% of healthy controls. He noted these are not the same antibodies that cause NMDA-receptor encephalitis and their concentration was low, so it remains unclear if these antibodies are contributing to schizophrenia.

Dalmau concluded his talk by providing some thoughts on how psychiatrists might determine whether a patient presenting for the first time with psychosis has anti-NMDA receptor encephalitis. He encouraged psychiatrists to be on the lookout for young patients with no family history of psychosis who present with symptoms of insomnia and agitation, as these may be warning signs of this disorder.

Another way to determine whether a patient has first-episode psychosis versus anti-NMDA receptor encephalitis may be to evaluate a patient’s serial dependence in visual working memory (the brain’s ability to store certain visual cues for quick retrieval). “Autoimmune-affected patients develop working memory problems, but they have less dysfunction in serial dependence compared with people with schizophrenia,” he said.

Identifying potential autoimmune problems early can help physicians provide better long-term management, but it also impacts acute symptom care, Dalmau continued. “We have to be careful about antipsychotics, because many autoimmune patients are intolerant toward these medications,” Dalmau cautioned. He noted that quetiapine or olanzapine might be the best options. On the other hand, patients with autoimmune disorders can often tolerate benzodiazepines well, which may also help to reduce symptoms of insomnia in these patients. ■

“Anti-NMDA-receptor Encephalitis: Case Series and Analysis of the Effects of Antibodies” is posted here.

“Dynamic Disorganization of Synaptic NMDA Receptors Triggered by Autoantibodies From Psychotic Patients,” is posted here.