Psychiatric Prodrome in Anti-NMDAR-Associated Encephalopathy: Clinical and Pathophysiologic Considerations

To present a review of the literature on the clinical presentation and pathophysiology of anti-N-methyl-d-aspartate receptor encephalopathy (ANMDARE) with attention to both the more commonly recognized psychotic symptom prodrome and the less well-understood depressive symptom prodrome.

The search for clinical neuropsychiatric phenomena and proposed mechanisms involved in ANMDARE pathophysiology was conducted in PubMed. English-language articles published up to September 2019 were identified using a combination of the following search terms: N-methyl-d-aspartate, anti-NMDA receptor encephalitis, schizophrenia, psychosis, depression, major depressive disorder, bipolar I disorder, bipolar II disorder, anxiety, and posttraumatic stress disorder.

From 150 articles identified from the initial search, the 73 most relevant clinical studies, reviews, and case reports related to the study objectives were included.

Sources were individually analyzed by the 3 authors for the most clinically relevant information.

The pathophysiology and mechanisms involved in anti-NMDA receptor antibody delivery to the brain are incompletely characterized, but antibody binding appears to involve the GluN1 subunit in most cases. Psychotic symptoms are the most commonly recognized components of prodromal psychiatric illness in ANMDARE, which may lead to an initial diagnosis of schizophrenia. In addition to psychotic symptoms, there are reports of depressive symptoms occurring before the emergence of, co-occurring with, or instead of psychotic symptoms in ANMDARE.

In addition to the better-known psychotic prodrome, depressive symptomatology can occur in ANMDARE patients. ANMDARE should be considered in patients with initial presentation of either psychotic or atypical depressive illnesses. Early recognition of these psychiatric prodromal states as antecedents to ANMDARE could lead to improved diagnosis and better management of this potentially life-threatening autoimmune disorder.