The Role of Autoantibodies in Untreated Psychosis

Joseph Dalmau, MD, PhD

Previously-believed idiopathic psychiatry or neurologic conditions may be driven by symptoms produced by autoantibodies affecting neurotransmitters, according to a new presentation that evidences about 2 centuries of clinical trends.

In a virtual presentation as part of the American Psychiatric Association’s (APA) Spring Highlights Meeting 2020, Joseph Dalmau, MD, PhD, discussed the role of synaptic autoantibodies in driving psychiatric disease and psychosis.

As the Professor at the Catalan Institute for Research and Advanced Studies at the University of Barcelona, and Adjust Professor of Neurology at the University of Pennsylvania noted, the link from the immune system and psychosis has “long been suspected.”

Dalmau drew a timeline reaching back to the 19th century, showing the evolution of clinical understanding of the immune system-psychosis association: the discovery that typhoid malaria might cure psychosis in 1876; the use of inoculated malarial parasite to treat psychosis in patients with syphilis starting in 1927; the use of CSF antibodies against brain structures in schizophrenia in 1937; the observed risk of schizophrenia in adult offspring of women pregnant during a past decades’ influenza pandemic in 1988; and the finding of psychiatric symptoms in novel antibody-mediated encephalitis in 2005.

The linkage is still being established in current research. For example, Dalmau noted, anti-NMDA receptor (NMDAR) encephalitis—a condition more common in children and young adults—has been observed to develop Immunoglobulin G (IgG) antibodies that ultimately alter patients’ memory, behavior, cognition, and psychosis.

Initial symptoms of the disease can be insomnia, anxiety, catatonic features or psychosis—meaning patients can be quickly admitted to psychiatry wards or clinics where the disease would not be suspected. If patients are then treated with standard antipsychotic therapy, they could be at risk for severe adverse events.

Though the frequency of psychiatric episodes among patients with anti-NMDAR encephalitis is uncommon—just 4% of patients observed in a 2008 trial presented such symptoms—the severity of their progression is troubling. Dalmau explained patients with properly untreated psychiatric features almost always prove to follow-up seizures, dyskinesias, and even dysautonomia.

Dalmau shared he and his colleagues’ go-to acronym for diagnostic clues of anti-NMDAR encephalitis in patients with new-onset psychiatry symptoms: ‘SEARCH F NDMAR A."

• Sleep dysfunction
• Excitement; disinhibition; alternating manic and depressive behaviors
• Agitation/aggression
• Rapid onset
• Children and young adult predominance
• History of psychiatric disease absent
• Fluctuating catatonia
• Negative and positive symptoms at presentation
• Memory deficit
• Decrease of verbal output/mutism
• Antipsychotic intolerance
• Rule out neuroleptic malignant syndrome (NMS)
• Antibodies and additional tests

Dalmau recommended physicians pursue electroencephalogram (EEG), magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) testing in potential patients.

“Although the disease is potentially lethal, most patients respond to immunotherapy and treatment of the tumor (if this applies),” he wrote.

In considering treatment other than immunotherapy, supportive care and psychiatric therapy should be prioritized. Dalmau noted benzodiazepines are tolerable, while other antipsychotics including quetiapine and olanzapine are more likely intolerable.

The session, “The Role of Synaptic AutoAntibodies in Psychiatric Disease,” was presented online during APA 2020.