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What is already known on this topic?
Patients with bipolar disorder respond differentially to lithium; some predictors of good response, including a family history of such, are known, though their predictive power is modest.1 As other medications are available for this illness, it would be valuable to identify biomarkers, including genetic ones, with greater ability to accurately forecast which patients will respond to lithium and which will not. One prior study examined genetic biomarkers of response and found no significant results.2
What does this paper add?
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Genetic variation in one gene almost entirely determined whether patients with bipolar disorder would respond to lithium or not. The results looked remarkably strong, with positive genetic variants increasing the likelihood of response 74-fold. The authors replicated their findings in two additional samples; the results came out similarly both times.
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The effect, for variants in a gene called glutamate decarboxylase-like 1, was seen in Taiwanese samples. The observed variants are virtually non-existent in European ancestry populations.
Limitations
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Clinical response to lithium was assessed using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder developed by Martin Alda and colleagues (the Alda scale). A portion of this scale targets aspects of the history that make the case less clear. This portion was used to select a ‘cleaner’ subsample for study from a much larger sample of cases available. Thus, those studied are not representative of all patients likely to present for treatment.
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Oddly, the strength of the finding is its biggest limitation. There has been much experience in studying psychiatric and medical ‘phenotypes’ for conditions, including medication response, using the genetic methods reported in this paper; yet there has never been a result with such a large effect. The unusual strength of the finding makes the typical concern about replication in the hands of other investigators especially salient.
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The effective absence of the key variants in European-ancestry populations makes these variants harder to study, given that many of the samples in genetic repositories come from the USA and Europe.
What next in research?
Replication should be sought in east-Asian populations (ethnically comparable to those studied by Chen et al) of bipolar disorder patients who have been assessed for lithium response. Several such groups exist, including some within the Consortium for Lithium Genetics (ConLiGen),3 which reported on attempted replication, using Taiwanese and Japanese samples. The investigators found no association with lithium response for the two most significant markers reported in Chen et al. They conclude with ‘while small effects cannot be ruled out, we can find no support for the existence of a major gene affecting lithium response in Asians.’
Could these results change your practices and why?
No. It would be premature to order genetic testing for these patients now, as we must await the results of additional studies to confirm the findings from Chen and colleagues’ study. However, going forward, if these results were robustly replicated, they would lead to a change in clinician practice, as a laboratory test could be developed to determine who, among east Asians with bipolar disorder, would benefit from lithium and who would not.
Commentary
ABSTRACT FROM Chen CH, Lee CS, Lee MT, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med 2014;370:119–28.
Patients/participants Four hundred and eighteen adults (aged 20–65 years) of Han Chinese descent with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) bipolar I disorder who had been receiving lithium with good adherence for at least 2 years based on lifetime clinical course. Of these, 294 people formed the discovery cohort; 100 people treated for more than 10 years with lithium formed the first replication cohort and 24 people with unsatisfactory response to other mood stabilisers before lithium formed a prospective follow-up cohort.
Setting Twenty-five psychiatric departments in general hospitals and psychiatric institutions in Taiwan; recruitment March 2003–May 2012.
Prognostic factors Single nucleotide polymorphisms (SNPs) identified by genome-wide association analysis in the discovery cohort as being associated with lithium response (Alda scale, higher score indicates better response), and confirmed in the first replication cohort.
Control Not possessing the SNP alleles associated with response.
Follow-up period At least 2 years (prospective follow-up cohort only).
Outcomes
Identification of associated SNPs Two SNPs (rs17026688 and rs17026651) located in the introns of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) showed the strongest associations with lithium response (p=1.66×10−49 and 7.07×10−50, respectively). The OR for response in carriers of the ‘response’ allele of rs17026688 compared to non-carriers was 82.2% (95% CI 36.2% to 195.6%). The sensitivity of the response allele for identifying responders was 93% (95% CI 87.9% to 96.4%), and its positive predictive value was 82.6% (76.3% to 87.9%).
Response in follow-up cohort All 16 carriers of the ‘response’ alleles showed a good response to lithium (total Alda score 8–10), while all eight non-carriers had a poor response (total Alda score 0–3).
Sequencing Resequencing of GADL1 in 94 lithium responders and 94 non-responders from the discovery cohort identified 32 polymorphisms, including a one base pair deletion in intron 8 (IVS8+48delG). This deletion was in complete linkage disequilibrium with rs17026688. In experiments in glioma-derived neural cell lines, the deletion was found to result in production of a shorter GADL1 mRNA transcript missing exons 7 and 8, likely due to alternative splicing.
Footnotes
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Competing interests None.