Gene* | Drug-class | Use in bipolar disorder | Trial on BD population | CPIC level of evidence | FDA label |
---|---|---|---|---|---|
CYP2D6 | Second-Generation Antipsychotics (SGAs) | Positive association of CYP2D6 genotype and tardive dyskinesia (Fleeman et al. 2011) | No | Not included | No |
SGAs | Positive association of CYP2D6 genotype and weight gain (Fleeman et al. 2011) | No | Not included | No | |
Aripiprazole | Changes in serum concentrations in poor metabolizers (Hendset et al. 2007) | No | B | Actionable | |
Risperidone | Changes in serum concentrations in poor metabolizers (Eum et al. 2016) | No | B | Informative | |
Tricyclic Antidepressants | Association of changes in serum concentrations with metabolizer phenotype (Hicks et al. 2017) | No | A, Guideline | Informative | |
Selective Serotonin Reuptake Inhibitors (SSRIs) | Association of changes in serum concentrations with metabolizer phenotype (Hicks et al. 2015) | No | C-D, Guideline | Informative | |
Antidepressant induced mania (AIM) in 3 poor metabolizer bipolar patients (Sanchez-Iglesias et al. 2016) | Yes (mixed) | Not included | No | ||
CYP2C19 | Tricyclic Antidepressants | Association of changes in serum concentrations with metabolizer phenotype (Hicks et al. 2017) | No | A, Guideline | No |
Citalopram, Escitalopram | Association of changes in serum concentrations with metabolizer phenotype (Hicks et al. 2015) | No | A, Guideline | Actionable | |
Escitalopram | A retrospective study of 2087 gentoyped patients showed that poor and ultrarapid CYP2C19 metabolizers seem to predict greater switching from escitalopram to another agent (Jukic et al. 2018) | Multiple Diagnosis | Not included | No | |
Sertraline | Association of changes in serum concentrations with metabolizer phenotype (Hicks et al. 2015) | No | B, Guideline | No | |
HLA-B | Carbamazepine | There is a strong recommendation by the CPIC of not to use carbamazepine in carbamazepine naive patients, with HLA-B*15:02 positive subjects given a “Greater risk of carbamazepine-induced SJS/TEN”. Proceed with caution in HLA-B*15:02 negative subjects, depending on HLA-A*31:01 genotype; there may be an average risk in negative vs. Higher risk in positive alleles (Phillips et al. 2018) HLA-B variants have been associated with carbamazepine induced agranulocytosis/granulocytopenia in European populations (Goldstein et al. 2014) | No | A | Actionable |
CYP2C9 | Valproate | The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity (Monostory et al. 2019) | No | No | No |
GRIK4 | Citalopram | Initial modest association observed in the STAR*D trial (Paddock et al. 2007). Meta-analysis results showed that the C allele appeared more frequently than the T allele in responders to treatment (OR: 1.22; 95% CI 1.035–1.445; z = 2.36; p = 0.018) (Kawaguchi and Glatt 2014) | No | Level D | No |
Haloperidol | Early and modest evidence of association with antimanic effect of haloperidol in BD (Drago et al. 2013) | Yes | No | No | |
DRD2 | Aripiprazole, Risperidone | C/C homozygotes improved in positive symptoms more than the T carriers during 12 weeks of treatment with aripiprazole or risperidone, C/C homozygotes developed more akathisia during treatment with aripiprazole, rolactin elevation in males treated with risperidone, in that C/C homozygotes had lower elevation of prolactin compared to the T carriers (Zhang et al. 2015) | First-episode psychosis | C (Risperidone) | No |
Antipsychotics | A meta-analysis of 698 schizophrenia patients, found that Del allele carrier of the -141C Ins/Del polymorphism, were significantly associated with poorer antipsychotic drug response, compared to the Ins/Ins genotype, OR = .65, p = 0.03 (Zhang et al. 2010) | No | C (Risperidone) | ||
SLC6A4 | Antidepressants | A meta-analysis of 1034 bipolar patients and antidepressant remission rates reported reduced anti-depressive remission rates in S-carriers of the serotonin transporter promoter polymorphism (OR = 0.64, p = .006, I2 = 0.0%) (Rao et al. 2019) | Yes | Not included | No |
A 6-study (453 bipolar patients) meta-analysis demonstrated a marginally significant evidence of association of the S allele with AIM (OR = 1.35; 95% CI 0.99–1.85; P = 0.059) (Frye et al. 2015) | Yes | Not included | No | ||
EPHX1 | Carbamazepine | Carriers of the SCN1A IVS5-91GA variant or of EPHX1 c.337TC variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71 ± 0.28 vs 1.11 ± 0.69 μgmL per mgKg for SCN1A IVS5-91 AA vs GG and 0.76 ± 0.16 vs 0.94 ± 0.49 μgmL per mgKg for EPHX1 c.337 CC vs TT; P0.05 for both) (Daci et al. 2015) | No | D | No |
HLA-A | Carbamazepine | Due to “Greater risk of carbamazepine-induced SJS/TEN” by CPIC, proceed with caution in HLA-B*15:02 negative subjects, depending on HLA-A*31:01 genotype; there may be an average risk in negative vs. Higher risk in positive alleles (Phillips et al. 2018) | No | A | Actionable |
HTR2A | Antidepressants | A meta-analysis found association of greater antidepressant response in major depressive disorder, for the dominant models of rs6313 5HTR2A-T > C polymorphism (OR = 1.62; 95% CI 1.21–2.18; P = 0.008) and rs7997012G > A (OR = 1.92; 95% CI 1.02–3.61; P = 0.044) (Lin et al. 2014) | No | D | No |
HTR2C | Clozapine, Olanzapine, Risperidone | A meta-analysis found significant association betwen the C allele of the HTR2C rs1414334:C > G polymorphism (OR = 2.44; 95%CI [1.48, 4.00]; P = 0.0004; I2 = 0), the HTR2C -697 G/C polymorphism (OR = 1.54; 95%CI [0.99, 2.40]; P = 0.05; I2 = 0), and olanzapine/clozapine/risperidone-induced metabolic syndrome (Ma et al. 2014) | No | D | No |
OPRM1 | Naltrexone | Several trials have found an association between the A118G rs1799971 polymorphism and naltrexone response (Patriquin et al. 2015), review | No | C/D | No |
ABCB1 | Antidepressants | Multiple genetic variants have been explored. Mixed evidence of association with less dose for remission, response, time to remission and remission in treatment of unipolar depression with antidepressants. The majority of evidence found associations with side effects and tolerability. (For a comprehensive review see (Bruckl and Uhr 2016) | No | A/B | No |
COMT | SSRIs | Significant association between rs13306278 and remission (P = 0.038) in 1914 depressed patients from STAR*D genotyped for COMT (Ji et al. 2012) | No | C | No |
CYP3A5 | Alprazolam | In a study of 19 healthy volunteers, CYP3A5 non-expressors had a lower alprazolam clearance compared carriers of the CYP3A5*1/*1 and CYP3A5*1/*3 alleles (Park et al. 2006) | No | C | No |
UGT1A4 | Lamotrigine | A meta-analysis found no associations between concentration to dose ratio (CDR) values and different polymorphisms of UGT1A4. The non-pediatric population showed a non-significant trend of association between UGT1A4 142T > G WT and higher CDR (Kim and Kim 2019) | No | D | No |