Is Bipolar Disorder an Autoimmune Disorder?

Hemmo Drexhage, M.D. from Erasmus Medical College presented the November lecture in the Warren Frontiers of Neuroscience Series in Tulsa, Oklahoma.  His presentation was titled "Immunology Meets Psychiatry" and the lecture covered a series of research efforts examining immunological abnormalities in psychiatric conditions.  Here is a summary of my notes from the presentation:

• Although we know genetic factors account for 60-80% of the variance for the schizophrenia and bipolar disease risk, the search for specific genes has been disappointing
• Many genes linked to these two disorders relate to immune function or neurodevelopment
• It might be better to look at patterns of gene expression involving immune function in these disorders compared to controls
• Smith in 1991 proposed the macrophage-T cell theory of psychiatric disorders
• This theory proposed immune cells (monocytes and T cells) are activated in bipolar disorder and schizophrenia
• This upregulation releases abnormal levels of cytokines (inflammatory chemicals) that affect the brain
• This effect directly or indirectly produces symptoms of bipolar disorder and/or schizophrenia

• Drexhage and colleagues research supports the macrophage-T cell theory of psychiatric disorders
• Pro-inflammatory monocyte gene upregulation has been demonstrated in bipolar disorder and depression
• Both disorders upregulate two clusters of gene products but the disorders differ in a third cluster
• The 2C cluster upregulation is found in schizophrenia but not bipolar disorder
• Transcription factors appear important in driving this inflammatory state
• Environmental factors appear key in this inflammation based on a twin study

• So what is this environmental trigger?
• Candidates include viruses, bacteria, diet, toxin, stress
• In animal models, inflammation and increased cytokines during pregnancy cause brain microglial abnormalities and behavioral abnormalities in the offspring
• Antidepressant responders in depression show reduction in inflammatory gene expression to control levels or below
• Gene expression pro-inflammatory effects are also in the periphery (benzodiazepine receptors) and in the brain hippocampus

• High risk children for bipolar disorder (children of bipolar parents) show increased levels of inflammatory markers before the onset of illness
• Inflammatory gene expression studies are hampered by confounders that also increase inflammatory signals--obesity, hyperlipidemia, smoking
• Potential implications are clear
• Anti-inflammatory drugs (i.e. Celebrex or similar) deserve study in these disorders
• Search for viral or bacteria triggers is necessary (i.e. abnormal gut bacterial flora, viral antibody titers)
• Specific patterns of immunological response may be useful diagnostic markers

Photo of a monocyte in a group of red blood cells from Wikipedia courtesy licensed under the Creative Commons Attribution-Share Alike 3.0 Unported, 2.5 Generic, 2.0 Generic and 1.0 Generic license.  Author Bobjgalindo

Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, van Beveren N, Cohen D, Versnel MA, Nolen WA, & Drexhage HA (2010). Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 13 (10), 1369-81 PMID: 20633309


Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, & Drexhage HA (2010). The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert review of neurotherapeutics, 10 (1), 59-76 PMID: 20021321


Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, & Drexhage HA (2008). A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Archives of general psychiatry, 65 (4), 395-407 PMID: 18391128