The Serotonin Hypothesis: Depression as a Chemical Imbalance

While I’ve always thought that we may be overprescribing SSRIs (selective serotonin reuptake inhibitors, a type of antidepressant) to people who are feeling blue, I thought the science was chrystal clear that low serotonin levels caused depression. I was therefore highly surprised when I learnt that there is no consistent evidence that depression is caused by lowered serotonin activity or concentrations. The shaky scientific foundation for SSRIs, which have been aggressively marketed by the pharmaceutical industry in direct to consumer ads since 1987 when Eli Lilly launched Prozac, is the serotonin hypothesis.

First proposed by psychiatrist Joseph Schildkraut in 1965, the hypothesis linked depression with low levels of noradrenaline, a neurotransmitter that mobilizes the brain and body for action. Researchers soon started focusing on serotonin as the real culpit, but the science around it was plagued by flawed methodology and inconsistent results. Attempts to induce depression by depleting serotonin levels failed to produce consistent findings and huge increases in brain serotonin, achieved by administering high doses of L-tryptophan, proved ineffective at relieving depression.

Flash forward to the nineties, Prozac quickly became the blockbuster drug of the decade, featuring everywhere on American television and in magazines as a miracle medicine by popularizing the idea that our moods are neurochemical. The marketing term chemical imbalance took hold of the public imagination, as seen in an early advertisement for Zoloft, Pfizer’s SSRI released in 1991, where the narrator states that “depression may be related to an imbalance of naturally occuring chemicals between nerve cells and the brain.” The key word here is may, because even though neuroscience is a rapidly advancing research field, there is no scientifically established ideal chemical balance of serotonin, let alone an identifiable pathological imbalance.

I wasn’t alone in having been misled by the pharmaceutical industry into believing that low serotonin levels were a leading cause of depression that could be medicated. According to a systemic review published in Nature in 2022, 80% or more of the general public now believed that depression was caused by a chemical imbalance. In reviewing the evidence for the serotonin hypothesis, the authors concluded that even though it had been so influential – and remained so with textbooks still giving it qualified support, and general practicioners as well as leading researches endorsing it to the point where it formed the basis for much empirical research – there was no convincing evidence to support that depression was associated with, or caused by, lower serotonin concentrations or activity. The review also brought up alternative explanations for the effects of SSRIs, including the idea that they work by an amplified placebo effect or through their ability to blunt or restrict emotions in general.

Further evidence for the placebo effect was obtained by the clinical psychologist Irving Kirsch and his colleagues, when by using the Freedom of Information Act, they pulled the data from all clinical trials of SSRIs submitted to the FDA by pharmaceutical companies. When the published and unpublished trials were pooled, the placebo duplicated about 80% of the antidepressant response. This extremely high rate of placebo response is not found in the treatment of well-studied chemical imbalances, such as insulin deficiency, and thus casts further doubt on the serotonin hypothesis.

Contrary to these scientific findings, with research now indicating that depression likely stems from multiple complex factors, SSRIs remain the first line of treatment for mood disorders alongside psychotherapy. Some scientists are strongly advising against this practice – as a study published in the BMJ Evidence-Based Medicine in 2020 concluded “the harmful effects of SSRIs seem to outweigh the possible small benefits.” The authors, which included Kirsch, recommended against treating adults with major depressive disorder with antidepressants until valid evidence had shown that the potential beneficial effects outweighed the harmful ones.

Perhaps Lord Warner, former Minister of State at the UK Department of Health, said it best when he expressed his doubtful mind in Parliament with the words “I have some concern that sometimes we do, as a society, wish to put labels on things which are just part and parcel of the human condition.” What troubled Lord Warner, and what should perhaps trouble all of us, is that we’re moving towards an increasingly medicalised society, one where there is a pill for every ill.