Psychotic Symptom Severity in BPAD Inversely Linked to Lithium Response

woman with emotional problems, blurry
woman with emotional problems, blurry
The severity of psychotic symptoms in patients with bipolar affective disorder correlated inversely with the response to lithium therapy.

The severity of psychotic symptoms in patients with bipolar affective disorder (BPAD) correlated inversely with response to lithium therapy, according to a study published in JAMA Psychiatry. Other findings suggested that the antigen presentation pathway and inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-4 (IL-4), and interferon gamma (IFNγ) may play a biological role in lithium treatment response in BPAD.

BPAD and schizophrenia can be difficult to distinguish clinically during episodes of acute illness because of overlapping psychotic symptoms. In addition, these two disorders have a 68% shared genetic variation — the highest among all pairs of psychiatric disorders. However, while lithium is not effective in schizophrenia and may result in lithium-induced neurotoxic effects in patients with the disorder, ≥70% of patients with BPAD respond to lithium.

These observations prompted the current study. Bernhard T. Baune, PhD, MD, MPH, discipline of psychiatry, School of Medicine, University of Adelaide, Australia, and the International Consortium on Lithium Genetics investigated how patients with BPAD with a high genetic susceptibility for schizophrenia as indicated by their schizophrenia polygenic score (PGS) would respond to lithium compared with patients with BPAD with a low PGS for schizophrenia.  The investigators also explored the genetic and molecular foundations of identified associations between schizophrenia and response to lithium.

From 2008 to 2013, the investigators genotyped and assessed 2586 patients with BPAD who had received lithium treatment for long-term response to treatment. Patients with BPAD with a low polygenic load for schizophrenia responded to lithium, while patients with a high load responded poorly. A cross-trait GWAS meta-analysis identified 15 genetic loci within protein-coding genes that appear to have overlapping outcomes in schizophrenia risk and treatment response to lithium in BPAD. These findings suggest that the HLA antigen system may be involved in genetic susceptibility to schizophrenia and treatment response to lithium.

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Limitations of the study include the use of a retrospective measure of response to lithium, the fact that the polygenic load for schizophrenia accounted for only 1% of the observed variation in treatment response, and the fact that the study was not designed to determine definitive mechanistic answers.

The investigators argue that their findings have important implications for the treatment of BPAD and for future research. They also contend that these findings support the idea that responsiveness to lithium may represent a true psychiatric endophenotype.


International Consortium on Lithium Genetics (ConLi*Gen). Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study [published online November 9, 2017]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.3433