The genetics here is real, weak and spread across hundreds of positions. The pharmacogenomics is the useful part, and it answers a narrower question than the tests sold on it claim: how much of a drug you are exposed to, never which antidepressant will work for you.
Depression is common, treatable and heritable in the way most common conditions are: many positions each contributing a very small amount, none of them decisive. The largest studies have found more than a hundred independent variants, and together they explain a small fraction of who becomes depressed. There is no depression gene, and the honest reading of the genetics is that it describes populations rather than people.
What genetics does have to say to an individual is about medicines, and it says less than most people have been told.
It can tell you about dose. Two enzymes, CYP2D6 and CYP2C19, clear most antidepressants. People at the extremes of either — clearing very slowly or very fast — reach concentrations well outside what a standard dose intends. Too much means side effects that make people stop; too little means taking a drug that was never going to reach a working level. CPIC publishes dosing guidance on exactly this.
It cannot tell you which drug will work. This is the distinction that consumer "find the right antidepressant for you" tests blur, and it is worth being blunt about. CPIC's 2023 guideline looked at SLC6A4 and HTR2A — the two genes those tests lean on hardest — and recommended against using them to guide therapy. Whether a particular antidepressant will lift a particular person's depression is not currently predictable from a genotype.
So the useful sentence is narrow and true: genotype can change the dose and the odds of tolerating a drug. Choosing the drug remains a clinical judgement.
Depression is diagnosed by interview rather than measured, and the same diagnosis covers people whose illnesses look quite different. That makes the phenotype noisy, and a noisy phenotype needs enormous samples to find small effects. The studies here ran to hundreds of thousands of people, and the variants they found still shift risk by amounts too small to matter to any individual.
The two positions on this page are narrower still: each comes from a study of depression under a specific circumstance — one in people without trauma exposure, one interacting with stressful life events. Read them as research findings about how the question was asked, not as anything about a reader.
The enzymes, and what they do to which drugs. CYP2C19 converts tertiary-amine tricyclics into secondary amines; CYP2D6 clears both forms and most SSRIs to some degree. Fluvoxamine, paroxetine and fluoxetine also inhibit these enzymes themselves, so one antidepressant can change how another drug is handled — an interaction that has nothing to do with genotype and is more often the explanation.
What SLC6A4 and HTR2A are, and why they keep appearing. They encode the serotonin transporter and a serotonin receptor, which makes them the obvious candidates and the ones most heavily marketed. The evidence for using them to select a drug has not held up, and the current CPIC guideline recommends against it.
Depression is not one thing. Genetic studies find partial overlap with bipolar disorder, schizophrenia and anxiety — several of the positions in this catalogue are labelled with more than one of those at once. That overlap is a real finding about the categories, not an error in the data.
Nothing here is diagnostic or urgent. If you are unwell, the useful step is a clinician. If you are already on an antidepressant, do not change it on the strength of a page — stopping abruptly is unsafe and the risk is immediate, where any genetic consideration is not.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Major Depressive Disorder comes down to these specific, well-studied positions — not a diagnosis.
THRB · rs138272922
See detailed info →BMP2 · rs10485715
See detailed info →Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| CYP2D6 | Tricyclic antidepressants (amitriptyline, nortriptyline, clomipramine, desipramine, doxepin, imipramine, trimipramine) | Tricyclics are handled by two enzymes working in sequence: CYP2C19 turns a tertiary amine such as amitriptyline, clomipramine, doxepin, imipramine or trimipramine into its secondary amine — which is itself an active drug, and in two cases a drug prescribed in its own right, nortriptyline and desipramine — and CYP2D6 clears both. A CYP2D6 poor metaboliser accumulates more drug than intended and is more likely to stop because of dry mouth, sedation or a racing heart; an ultrarapid metaboliser may never reach a useful level. A CYP2C19 poor metaboliser shifts the balance towards the parent drug. CPIC recommends avoiding a tricyclic or halving the starting dose at these extremes, with therapeutic drug monitoring if one is used anyway. What this does not do is say which antidepressant will work. It is about dose and side effects; efficacy is a clinical judgement no genotype currently predicts. Nothing here should be used to start, stop or change a medicine — stopping an antidepressant abruptly is unsafe. (CPIC Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 update (Clin Pharmacol Ther 2017, PMID 27997040); original guideline PMID 23486447.) |
No, and the tests sold on that promise lean hardest on two genes — SLC6A4 and HTR2A — that CPIC’s 2023 guideline recommends against using to guide therapy. What genotype can inform is dose and the likelihood of side effects, through CYP2D6 and CYP2C19. Which drug helps remains a clinical judgement.
They tell you essentially nothing on their own. Depression is spread across hundreds of positions of very small effect, and these two come from studies of depression under particular circumstances rather than of depression in general.
Partly. Twin studies usually put heritability around a third — real, and much lower than schizophrenia or bipolar disorder. Most people with a depressed parent or sibling never develop it.
Not on the strength of a page. Stopping an antidepressant abruptly is unsafe, and that risk is immediate where a genetic consideration is not. If a result seems relevant, take it to the person prescribing.
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