rs1387923 — NTRK2 NTRK2/TrkB 3'UTR variant

3' UTR variant in the TrkB receptor gene affecting NTRK2 expression; associated with treatment-resistant depression susceptibility and lithium/mood-stabilizer response through BDNF signaling pathway effects

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The BDNF Receptor That Gates Your Brain's Neuroplasticity

NTRK2 encodes TrkB (tropomyosin receptor kinase B), the primary receptor for brain-derived neurotrophic factor (BDNF)11 brain-derived neurotrophic factor (BDNF)
A protein that promotes neuronal survival, growth, and synaptic plasticity — often called the brain's "fertilizer" because of its role in keeping neurons healthy and connected. When BDNF binds TrkB, it triggers intracellular signaling cascades that determine whether neurons form new connections, survive cellular stress, or respond to antidepressants. NTRK2 is consistently implicated in depression genetics — not just as a risk gene, but as a mechanistic hub that explains why some people respond to certain treatments and others don't.

The rs1387923 variant sits in the 3' untranslated region (3' UTR) of the NTRK2 gene — a region that controls mRNA stability and translation efficiency22 mRNA stability and translation efficiency
The 3' UTR contains binding sites for microRNAs and RNA-binding proteins that regulate how much TrkB protein gets made from each mRNA copy. Rather than changing the TrkB protein structure, this variant likely alters how much receptor is produced in neurons, particularly during stress or when antidepressants engage the BDNF pathway.

The Mechanism

TrkB receptor density matters. When BDNF is released from active neurons, it needs sufficient TrkB on the target cell surface to trigger synaptic plasticity33 synaptic plasticity
The ability of synapses to strengthen or weaken over time, which underlies learning, memory, and mood regulation. A 3' UTR variant affecting mRNA stability could reduce TrkB surface expression in a dose-dependent manner — so G-allele homozygotes may have chronically lower TrkB availability. This would blunt the neurotrophic response to BDNF, impair hippocampal neurogenesis (which is disrupted in depression), and reduce the brain's ability to reorganize after stress.

Critically, many antidepressants — including SSRIs, SNRIs, ketamine, and even lithium — exert part of their effect by upregulating BDNF and potentiating TrkB signaling44 upregulating BDNF and potentiating TrkB signaling
These drugs don't just adjust neurotransmitter levels; growing evidence shows they directly enhance TrkB sensitivity and downstream plasticity signaling. A variant reducing TrkB expression may therefore blunt the response to these treatments — a mechanistic basis for treatment resistance.

The Evidence

The strongest evidence for rs1387923 comes from a multicenter prospective study of Han Chinese patients with major depressive disorder55 multicenter prospective study of Han Chinese patients with major depressive disorder
Li et al. Journal of Psychiatric Research, 2013, n=948 MDD patients followed longitudinally. Investigators found that the rs1387923+rs1565445 two-SNP haplotype conferred a 1.41-fold increased risk of treatment-resistant depression (p = 0.0014). When BDNF rs6265 was added to form a four-locus model, gene-gene interaction was the strongest predictor of treatment resistance in the entire cohort.

In bipolar disorder, a 2007 pharmacogenetics study66 2007 pharmacogenetics study
Bremer et al. Molecular Diagnostics and Therapeutics, n=184 lithium responders vs. non-responders found significant interactions between rs1387923, rs1565445, and lithium response, particularly when combined with suicidal ideation as a comorbidity. The same NTRK2 variants also appeared in a 2013 bipolar I study77 2013 bipolar I study
Wang et al. Journal of Molecular Neuroscience, n=579 examining mood stabilizer (lithium and valproate) response.

A 2020 Polish case-control study88 2020 Polish case-control study
Suchanek-Raif et al. Disease Markers, n=192 schizophrenia patients, 264 controls found that the G/G genotype at rs1387923 was specifically associated with increased schizophrenia risk in men, while A/A homozygosity was protective. This sex-specific pattern highlights that TrkB signaling interacts with sex hormones in determining psychiatric vulnerability.

A pathway-level perspective comes from a UK population-based imaging study99 UK population-based imaging study
Juhasz et al. Biological Psychiatry, 2011, n>2,000 examining nine variants across the CREB1-BDNF-NTRK2 signaling axis. NTRK2 variants amplified the effect of childhood adversity on lifetime depression risk, consistent with the gene's role as a plasticity gate: in people with adequate TrkB signaling, early-life stress may be buffered; with reduced TrkB function, the same stress produces lasting neurobiological changes.

Practical Actions

For those carrying the G allele — particularly G/G homozygotes — the actionable insight is that your BDNF pathway may have a reduced amplification gain, meaning both therapeutic interventions and lifestyle factors that work through BDNF are especially important to maximize. Aerobic exercise is the most consistently effective strategy for increasing both BDNF secretion and TrkB expression in humans, with neuroimaging studies showing hippocampal volume increases that parallel BDNF upregulation. For those who haven't responded to first-line antidepressants, the evidence linking this variant to treatment-resistant depression supports proactive escalation to augmentation strategies — particularly lithium augmentation, where NTRK2 genotype has shown predictive value in pharmacogenetic studies.

Ketamine and ketamine-based treatments (esketamine) work through rapid BDNF/TrkB pathway activation and represent a mechanistically rational escalation option for G/G carriers with treatment-resistant depression.

Interactions

The most important interaction is with BDNF rs6265 (Val66Met). Studies consistently find that rs1387923 risk genotypes combine with BDNF rs6265 to produce gene-gene interactions stronger than either variant alone. In the Li et al. 2013 cohort, the four-locus model (rs1387923 + rs1565445 + rs2769605 + BDNF rs6265) was the key predictor of treatment-resistant depression — suggesting the entire BDNF→TrkB signaling axis needs to be considered together.

The rs1565445 variant is in linkage disequilibrium with rs1387923 and is typically analyzed as part of the same haplotype block. Carriers who also carry rs2769605 represent a higher-risk subgroup with compounded NTRK2 signaling reduction.

Drug Interactions

lithium dose_adjustment literature
valproate reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard TrkB Expression Normal

Reference genotype with typical TrkB receptor expression

You carry two copies of the A allele, the GRCh38 reference allele at this position. About 28% of people share this genotype. The available evidence suggests this genotype is associated with lower depression treatment resistance compared to G-allele carriers, and is the protective genotype in the schizophrenia association studies. Your TrkB receptor expression is likely in the typical range, supporting normal BDNF signaling and neuroplasticity responses.

AG Intermediate TrkB Variant Intermediate

One copy of the risk allele — moderately elevated depression vulnerability

The codominant inheritance pattern at this locus means heterozygotes have intermediate outcomes. In population studies, AG carriers show intermediate frequencies of treatment resistance between AA and GG homozygotes. The variant likely affects TrkB receptor density on neuronal membranes through altered mRNA stability — one functional copy of the A allele provides partial buffering against the G-allele's effect on expression.

The practical significance for heterozygotes depends heavily on genetic context — particularly BDNF rs6265 (Val66Met) status. AG carriers who also carry BDNF Val/Met or Met/Met may have more pronounced TrkB pathway reduction than either variant predicts alone, as the ligand (BDNF) and receptor (TrkB) effects compound.

GG Elevated TrkB Risk Variant High Risk

Two copies of the risk allele — substantially elevated treatment-resistant depression risk

The GG genotype places you in the highest-risk group at this locus. The mechanism involves the 3' UTR location of this variant — a region rich in microRNA binding sites that regulate mRNA lifetime and translation efficiency. Two copies of the G allele may substantially reduce TrkB surface expression on neurons, limiting the downstream signaling available when BDNF is released during antidepressant treatment, exercise, or psychotherapy.

This matters most for treatment selection. Antidepressants that work primarily by upregulating BDNF secretion (SSRIs, SNRIs) may be less effective if the TrkB receptor they rely on is underexpressed. Lithium augmentation has specific pharmacogenetic evidence at this locus (Bremer et al. 2007), and ketamine — which bypasses some of the BDNF-dependency by directly activating TrkB through an allosteric mechanism — may be particularly effective for GG carriers with treatment-resistant depression.

Sex differences are also documented: G/G was specifically associated with schizophrenia risk in men in the Suchanek-Raif 2020 study, with the NTRK2+BDNF haplotype being protective specifically in women. This suggests the TrkB pathway intersects with sex-hormone-dependent neuromodulatory systems.