Is depression a chemical imbalance?

A 2022 umbrella review gathered the principal lines of research: serotonin and its main metabolite in body fluids, receptor and transporter measurements, tryptophan depletion studies, and genetic association work.

It found no consistent evidence that depression is associated with lowered serotonin concentration or activity, and the large genetic studies found no association between the serotonin transporter gene and depression.

The review is not a demonstration that serotonin is irrelevant to mood. Its case is that the specific claim people were told was not supported by the literature it was said to rest on.

A reply in the same journal from psychiatric researchers argued that it overstated that case, leaving out tryptophan depletion results in depressed people not taking antidepressants and misreading the imaging. What the reply defends is a role for serotonin in people vulnerable to or suffering from depression, a smaller claim than a chemical imbalance.

A 2018 network meta-analysis of 522 trials and 116,477 participants, covering 21 antidepressants, found all of them more effective than placebo in acute treatment of major depression in adults, with differences between drugs in efficacy and in how well they were tolerated.

The margin is modest, and the paper says so itself. Odds of response ran from 1.37 to 2.13 times placebo depending on the drug, and the summary effect on symptom scores was 0.30 standard deviations, with a credible interval of 0.26 to 0.34.

The usual reply is that an average hides the people who respond dramatically. That has been tested, by asking whether outcomes vary more on the drug than on placebo, and twice the extra variation was not there. A 2022 analysis of individual patients in trials submitted to the US Food and Drug Administration read the same kind of data differently: its model found three kinds of response, and put a large response at 24.5 per cent on the drug against 9.6 per cent on placebo. Outcomes do differ between people. Whether the drug is what differs for some of them is still argued from the same trials.

A drug that works is not evidence for the theory that inspired it. Aspirin was in use for more than seventy years before its mechanism was found in 1971.

Candidate accounts include effects on neural plasticity, and early effects on how emotional and social information is processed rather than on mood directly. Neither is settled, and the review that sets them out argues they may be complementary rather than rival.

Onset is also slower than the change in neurotransmitter levels, which was an awkward fact for the original theory from early on.

Depression is defined by a list of symptoms, and the list can be satisfied many ways. Among 3,703 patients entering the STAR*D study there were 1,030 distinct symptom profiles, and about half of those profiles belonged to one patient each.

A category assembled that way may not correspond to a single biological state. That would explain a literature full of effects that are real on average and inconsistent in detail, which is what this literature looks like.

There is no biological test for it. A review of prospective biomarkers, across imaging, immune markers, neurotrophic factors and hormones, found none that predicted onset or recurrence once patients already diagnosed were set aside. Diagnosis is by description, treatment is by trial, and the relationship between the experience, the brain and the circumstances a person is in is not understood.

Saying so is not the same as doubting that the condition is real, and the people who most need that distinction made carefully are the ones living with it.