Schizophrenia traits negatively predict lithium response in bipolar disorder

Naveed Saleh, MD, MS, for MDLinx | May 15, 2018

Bipolar patients with a genetic risk for schizophrenia are less likely to respond to lithium treatment, according to new research published in JAMA Psychiatry.

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Bipolar patients who have significant genetic risk variants for schizophrenia are likely to have a poor therapeutic response to lithium, researchers have found.

Experts estimate that the shared genetic variation between bipolar disorder and schizophrenia is 68%, which exceeds that of any other dyad of psychiatric illnesses. Although bipolar disorder and schizophrenia are closely linked, lithium doesn’t work in patients with schizophrenia. Thus, increased schizophrenia trait loading in bipolar patients may be tied to poor treatment response to lithium.
 
“We aimed to investigate whether patients with BPAD [bipolar affective disorder] who had a high genetic susceptibility for schizophrenia (SCZ), expressed by their SCZ polygenic score (PGS), would respond better or more poorly to lithium compared with patients with BPAD who had a low PGS for SCZ,” wrote corresponding author Bernhard T. Baune, PhD, MD, MPH, Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia, and coauthors. “In addition, we set out to explore the genetic and molecular underpinnings of any identified association between SCZ and treatment response to lithium.”

Genetic factors appear to play a role in patients’ therapeutic response to lithium. Three genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) linked to lithium response in BPAD, implicating different genetic loci.

The researchers suggested that in addition to GWAS, polygenic analysis may also help elucidate the clinical efficacy of lithium. Polygenic analysis “quantifies the combined effects of genetic variants across the whole genome on a given clinical outcome, computed as a weighted summation of effect sizes of multiple independent polymorphisms.”

This study consisted of three steps:

  1. The team tested whether PGS for schizophrenia is significantly linked to treatment response in 2,043 patients with bipolar type 1 and 543 patients with bipolar type 2 disorder.
  2. The researchers used a cross-trait GWAS meta-analysis to identify individual genetic variants shared between schizophrenia and response to lithium in bipolar patients.
  3. The researchers characterized genetic variants identified in the second step and examined shared biological pathways forming the basis of genetic susceptibility to schizophrenia and lithium treatment response in bipolar patients.

Notably, the researchers analyzed overlapping SNPs that met genome-wide significance in the meta-GWAS for biological context using the Ingenuity Pathway Analysis (IPA) platform.

After analyzing the data, the researchers found an inverse association between schizophrenia genetic loading risk variants and long-term response to lithium in bipolar patients. By employing cross-trait meta-GWAS and IPA, they also demonstrated “that genetic variants in the HLA antigen region, the antigen presentation pathway, and inflammatory cytokines such as TNF, IL-4 and IFNγ could play a biological role in treatment response to lithium in BPAD.”

“We show for the first time, to our knowledge, that genetic characterization has the potential to aid the stratification of patients with BPAD into those who respond and those who do not respond to lithium, prior to initiation of treatment,” Dr. Baune and coauthors wrote. “The findings underscore the importance of careful assessments of patients’ family psychiatric histories in the context of treatment selection.”

The researchers acknowledged that one limitation of this study was that the schizophrenia polygenic load represented a small percentage of the observed variation in lithium treatment response in bipolar patients.

“For future clinical translation,” the researchers concluded, “a high genetic loading for SCZ risk variants could be used in conjunction with clinical parameters to determine the likelihood of nonresponse to lithium treatment in BPAD.”

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