Toward Biological Subtypes in Schizophrenia: Potential Role of NMDA-Receptor Antibodies

We are, in the end, a sum of our parts, and when the body fails, all the virtues we hold dear go with it.

-Susannah Cahalan,
Brain on Fire: My Month of Madness¹

I had the opportunity to attend the 4th Biennial Conference of the Schizophrenia International Research Society (SIRS), held April 5-9, 2014, in Florence, Italy. The theme of the meeting was “Fostering Collaboration in Schizophrenia Research.” Approximately 1500 delegates from across the globe attended the meeting, and there were about 300 oral presentations and over 800 poster presentations. One of my “take-home messages” from the meeting (a sentiment echoed by other attendees from my department) was the absence of a major breakthrough in the field with regard to diagnosis or treatment. Nonetheless, through my lens as an eternal optimist, despite the lack of seminal findings, there is evidence of progress.

One potential impediment to progress in schizophrenia research is the use of symptom-based diagnosis, which itself was not designed for biological validity. Towards “precision medicine for psychiatry,” the NIMH Research Domain Criteria project aims for a diagnostic system based on improved understanding of the biological and psychosocial basis of mental disorders.²

Another “take-home message”: the immunology of schizophrenia has become a credible area of research focus-one that is fast-moving towards translation of findings into therapeutic interventions. At the SIRS meeting, I attended a symposium titled “Potential Role of NMDA-Receptor Antibodies in Schizophrenia,” in which the question was asked, “Is NMDA-receptor encephalitis a schizophrenia subtype?”³ And while the jury is still out regarding a definitive answer, the question itself represents an important step towards “precision medicine” and an improved understanding of the pathophysiology of psychotic symptoms.

As presented by Dr Johann Steiner at the University of Magdeburg (Germany), NMDA receptor encephalitis is due to IgG antibodies against the NR1a subunit of the N-methyl-D-aspartate receptor, which cause receptor internalization and decreased (glutamatergic) neurotransmission. The majority of affected patients are young women, often with a comor-bid ovarian teratoma. Psychosis is a common early (within about 2 weeks) feature, frequently characterized by disorganized behavior or catatonia. A progressive disorder, NMDA receptor encephalitis is responsive to early immunotherapy (eg, intravenous immunoglobulin, corticosteroids, plasmapheresis).

NMDA receptor encephalitis has received increased media attention, in part through New York Post writer Susannah Cahalan, who chronicled her experience with the disorder in her best-selling book Brain on Fire: My Month of Madness.¹

Dr Belinda Lennox from Oxford University (United Kingdom) presented data on milder, “incomplete” forms of NMDA receptor encephalitis with isolated psychotic symptoms. That is, affected persons present with signs and symptoms of first-episode psychosis: their peripheral blood is positive for NMDA receptor antibodies, but there are no other neurological signs or symptoms suggestive of encephalitis (eg, fever, seizures). In a cohort of 110 patients with first-episode psychosis, Dr Lennox has identified 8 who tested positive for NMDA receptor antibodies, with another 20 identified by ad hoc screening. Compared with patients without NMDA receptor antibodies, those who tested positive for antibodies had higher levels of psychopathology (including prominent affective symptoms and suicidality), cognitive impairment, and movement disorders, and they were less likely to have used marijuana in the previous month. Patients who were antibody-positive had normal brain MRI scans and no evidence of progressive encephalopathy, tumors, or other autoimmune disorders.

In a “proof-of-concept” approach, 10 of these patients were entered into an open/clinician choice treatment study. Five received immunotherapy (corticosteroids or plasma exchange) and the other 5 were treated with antipsychotics. Following treatment, all of the patients who received immunotherapy had decreased antibody levels and a decrease on the Modified Rankin Scale (a measure of disability), without worsening of psychosis. By contrast, among those treated with antipsychotics, antibody levels were unchanged in 3 and decreased in the other 2 patients post-therapy.

Dr Takashi Kanbayashi from Akita University (Japan), also pre-sented prevalence data on NMDA receptor antibodies. He found that 8 of 120 patients with schizophrenia or schizoaffective disorder tested positive for antibodies, but also 4 of 12 patients with narcolepsy with psychosis and 2 of 120 patients with neurosis/depression were antibody-positive. Among the 8 patients with schizophrenia/schizoaffective dis-order and positive antibody tests, all were women, half had catatonia, and 3 had ovarian teratomas. Dr Kanbayashi’s group also found that ECT may be an effective treatment option for affected patients.

The final symposium presenter was Dr Hannelore Ehrenreich from the Max Planck Institute (Germany). She presented data from the Göttingen Research Association for Schizophrenia (GRAS) collection, which comprised 1081 patients with schizophrenia and 1325 controls. They found a 10.5% prevalence of positive NMDA receptor antibody tests in patients with schizophrenia but, importantly, a similar prevalence in controls. Increasing age was associated with an increasing prevalence of positive antibody tests, as were a common genetic variant (rs524991) and past influenza infection.

The discussant for the symposium was Dr Souhel Najjar, a neurologist from New York University, who diagnosed schizophrenia in writer Susannah Cahalan and treated her. He outlined some of the future challenges in this area of research.

What are the implications of this symposium for practicing clinicians? Should we be routinely ordering anti-NMDA receptor IgG antibody tests for our patients with schizophrenia? Probably not, especially since there is not a “standardized” assay for these antibodies and patients may have antibodies for one isotype but not others (ie, either IgG, IgM, or IgA antibodies). Furthermore, Dr Ehrenreich found an approximately 10% prevalence of these antibodies in healthy controls, making the significance of their presence less clear. But I admit to ordering NMDA IgG antibody tests for some of my patients-particularly those early in the course of illness and with prominent disorganization or catatonia. My rationale is that the risks of a blood draw are minimal, 1 in 10 to 20 patients will test positive, and a positive test could significantly affect or change treatment and prognosis.

Even in the absence of routine testing, this symposium was a strong reminder that as clinicians, we need to consider a broad differential diagnosis for patients presenting with first-episode psychosis. As a researcher, the symposium inspired me as we strive to better understand the pathophysiological underpinnings of symptoms of psychosis, and offered evidence that immunology is coming to the fore in schizophrenia research. Regardless of the definitive outcome on the association with NMDA receptor antibodies, these efforts represent progress towards biologically defined subtypes of the disorder we call schizophrenia. And that, most certainly, is a virtuous pursuit I hold dear.

Disclosures:

Dr Miller is Associate Professor (effective July 1, 2014) in the department of psychiatry and health behavior at Georgia Regents Uni-versity in Augusta. His current research focuses on inflammation/cytokines as a potential clinical state and relapse predictive marker in schizophrenia, and is funded by an NIMH K23 Mentored Patient-Oriented Research Career Development Award and the NIH Clinical Loan Repayment Program Award. He has been recognized with several young investigator awards, the 2010 Laughlin Fellowship from the American College of Psychiatrists, and a 2011 Exemplary Psychiatrist Award from the National Alliance on Mental Illness. He has received support from the NIH Clinical Research Loan Repayment Program, speaker fees for grand rounds from Emory University and the Zucker-Hillside Hospital, reimbursement for travel/accommodations/meeting expenses from Georgia Regents University, and honoraria for a survey from Insight Consulting and MDLinx.com.

References:

1. Cahalan S. Brain on Fire: My Month of Madness. London: Penguin Books, Ltd; 2013.

2. Insel TR. The NIMH Research Domain Criteria (RDoC) project: precision medicine for psychiatry. Am J Psychiatry. 2014;171:395-397.

3. Steiner J, Ehrenreich H, chairpersons. Symposium. Potential role of NMDA-receptor antibodies in schizophrenia: overlap and distinction from NMDA-receptor encephalitis. Presented at: 4th Schizophrenia International Research Society Conference; April 5-9, 2014; Florence, Italy.