For first-episode psychosis with NMDA blood antibodies, conventional treatment may be best course

Patients with anti-NMDA receptor antibodies respond to antipsychotic drug


Philadelphia, December 17, 2020

Psychosis is among the most haunting – and mysterious – of human psychiatric conditions. In recent years, a new neurological disorder has been described in a small number of patients with new-onset psychosis, called anti-NMDA receptor antibody encephalitis, in which self-generated antibodies attack a critical type of receptor needed for neural signaling in the brain.

Patients with these new-onsets often go on to develop seizures, movement disorders, and even coma. Researchers have now taken a closer look at patients with psychosis – but without any of these other symptoms – who carry anti-NMDA receptor antibodies, which are associated with the disease, and whether conventional treatments are effective for treating their psychosis. This new study appears in Biological Psychiatry, published by Elsevier.

“In the last decade there has been a surge of interest in the possibility that psychotic disorders might somehow be caused by autoimmunity, where the body mounts an immune response against its own tissues,” explains lead author of the study, Thomas Pollak, PhD, Institute of Psychiatry, Psychology and Neuroscience, King’s Health Partners, King’s College London, London, UK. “We now know that specialized immune molecules called antibodies can target the NMDA receptor in the brain and cause psychosis as part of a neurological disorder called anti-NMDA receptor encephalitis – as movingly described by Susannah Cahalan in her book Brain on Fire,” an investigative memoir.

The autoimmune disease often strikes young adults (similar to other forms of psychosis), and psychosis can appear suddenly without any previous indication of psychiatric illness. The enigmatic condition is highly treatable with immunotherapy, a treatment used for autoimmune disorders, however immunotherapy does carry its own set of risks.

The success of immunotherapy for anti-NMDA receptor encephalitis has led some to jump to the conclusion that, in patients with recent first-episode psychosis, the presence of the antibodies in blood alone may warrant immunotherapy. In addition, antipsychotic medications have been thought not to be effective for psychosis caused by anti-NMDA receptor encephalitis and some side effects may be more severe in these patients. Therefore, the best treatment course for patients who do not meet criteria for encephalitis, but who have detectable anti-NMDA receptor antibodies in their blood, remains controversial.

Now, Dr. Pollak said, “this new study shows that antipsychotics worked just as well in patients with these antibodies in their blood as in patients who did not have them.”

The new work focused on nearly 400 patients with first episode psychosis (FEP) from an ongoing study of schizophrenia in Europe. Of the 387 enrolled, 15 (about 4 percent) were “seropositive,” meaning they carried the anti-NMDA receptor antibodies. The authors hypothesized that seropositive individuals might have a shorter duration of untreated psychosis before seeking treatment, because, with anti-NMDA receptor encephalitis, psychosis can arise so suddenly. That was the case, but, once in treatment, symptoms did not differ significantly between patients with and without the antibodies.

In addition, seropositive and seronegative patients responded similarly to a four-week course of the antipsychotic medication amisulpride on two measures of psychotic symptoms. Likewise, side effects were similar in the two groups. Together, the findings indicate that there is no reason not to treat FEP patients with anti-NMDA receptor antibodies in their blood with antipsychotic medications. It remains unclear whether the antibodies contribute to psychosis in such patients, or whether they are present coincidentally.

Consistent with recently published guidelines, the findings support the view that “doctors should not offer immunotherapy for patients who have NMDA receptor antibodies detectable in their blood but not in their cerebrospinal fluid – at least until well-controlled trials of immunotherapy in this group have been completed,” Dr. Pollak explained. “For now, these patients need to be further investigated for signs of brain inflammation with MRI, EEG and a lumbar puncture before immunotherapy is even considered. Unfortunately, it is not as simple as just doing a blood test. The search for biomarkers of treatment response in psychosis continues.”

John Krystal, Editor of Biological Psychiatry, said of the research, “These are early days in this work, but the current findings suggest that the presence of antibodies against NMDA glutamate receptors does not alter the effectiveness or tolerability of traditional antipsychotic medications. Perhaps, the next question to ask is whether these patients benefit distinctively from medications that more directly facilitate NMDA glutamate receptors.”

“Psychotic disorders can have a devastating impact on patients and their families,” said Philip McGuire, MD, PhD, senior author of the new study. “While many patients are helped by treatment with antipsychotic medication, in about a third of patients this is ineffective. Unfortunately, at present, it is not possible to predict whether a patient will show a good response to treatment or not. If there was a test that could predict treatment response, patients who are unlikely to benefit from conventional treatment could be offered an alternative treatment.”

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Notes for editors
The article is "Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis," by Thomas Pollak, Angela Vincent, Conrad Iyegbe, Ester Coutinho, Leslie Jacobson, Dan Rujescu, James Stone, Julie Jezequel, Veronique Rogemond, Stefane Jamain, Laurent Groc, Anthony David, Alice Egerton, Rene Kahn, Jerome Honnorat, Paola Dazzan, Marion Leboyer, Philip McGuire (https://doi.org/10.1016/j.biopsych.2020.11.014). It appears as an Article in Press in Biological Psychiatry, published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at Biol.Psych@sobp.org or +1 254 522 9700. Journalists wishing to interview the authors may contact Thomas Pollak at thomas.pollak@kcl.ac.uk or +44 207 848 5135.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry
Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

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Media contact
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Biol.Psych@sobp.org