The drug explained the disease
If raising a brain chemical lifts mood, maybe low levels cause depression. That inference, published in 1965, is where the chemical-imbalance story starts.
We have not finished checking this source. No judgement either way. how we score evidence
Caveat on this rating: The serotonin pairing is mandatory wherever this claim appears and is carried in the body as well as here. Moncrieff et al. 2022 (Mol Psychiatry, doi 10.1038/s41380-022-01661-0, PMID 35854107) found no consistent evidence of an association between serotonin and depression; Jauhar and colleagues replied in the same journal (doi 10.1038/s41380-023-02095-y) that the conclusion is overstated on grounds of method and interpretation. This is not settled in either direction. Schildkraut 1965 (Am J Psychiatry 122:509-522, doi 10.1176/ajp.122.5.509, PMID 5319766) is named but NOT quoted: its full text could not be read during verification, so the two-lines-of-evidence characterisation is taken from Hillhouse and Porter 2015, which is the row's citation.
The chemical-imbalance story was reasoned backward from the drugs. Nobody found a deficiency in patients first and then built a medicine to correct it.
Significant findings
In 1965 Joseph Schildkraut set out the catecholamine hypothesis: mood runs on a family of brain chemicals.
A 2015 history names the two lines of evidence it rested on. One was what the drug reserpine did to those chemicals; the other was how antidepressants work.
Both were facts about drugs. Neither was a measurement taken from a depressed person.
The serotonin version became the public shorthand. A 2022 umbrella review of that literature reported "no consistent evidence" of an association between serotonin and depression.
That review was contested in print. Jauhar and colleagues replied in the same journal that its conclusion is overstated. Both halves belong on this page.
Worth asking
Whether a medication helps you and why it helps are separate questions with separate evidence.
Ask what outcome yours is expected to produce and by when, rather than which chemical it adjusts. Nothing here is a reason to stop. Stopping abruptly can be dangerous, so any change belongs in a prescriber conversation with a taper plan.
Source
A brief history of the development of antidepressant drugs: From monoamines to glutamate — Hillhouse TM, Porter JH (2015)
Read the source: https://doi.org/10.1037/a0038550
DOI: 10.1037/a0038550
How this was scored
- Study design
- not recorded
- Funding
- not recorded
- Published in
- not recorded
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
We have not finished checking this source, so there is no scoring to show yet. “We have not checked this yet” and “this is disputed” are different statements, so no scored band is shown rather than a low one.
Read the full scoring rubric, including what it can't tell you.
Published August 31, 2026.
Questions
How strong is the evidence behind this?
Resolv rates this source "not yet assessed". We have not finished checking this source. No judgement either way. One caveat travels with that badge: The serotonin pairing is mandatory wherever this claim appears and is carried in the body as well as here. Moncrieff et al. 2022 (Mol Psychiatry, doi 10.1038/s41380-022-01661-0, PMID 35854107) found no consistent evidence of an association between serotonin and depression; Jauhar and colleagues replied in the same journal (doi 10.1038/s41380-023-02095-y) that the conclusion is overstated on grounds of method and interpretation. This is not settled in either direction. Schildkraut 1965 (Am J Psychiatry 122:509-522, doi 10.1176/ajp.122.5.509, PMID 5319766) is named but NOT quoted: its full text could not be read during verification, so the two-lines-of-evidence characterisation is taken from Hillhouse and Porter 2015, which is the row's citation. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
A brief history of the development of antidepressant drugs: From monoamines to glutamate — Hillhouse TM, Porter JH (2015). DOI: 10.1037/a0038550. The full source is linked on this page so you can read it yourself.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.