Today's landmark findings call into question society's ever-growing reliance on antidepressants like Prozac.
Millions of patients take selective serotonin reuptake inhibitors, designed to boost levels of the 'feel-good' chemical.
University College London researchers argue, however, that there's 'no convincing evidence' that depression is caused by an imbalance of the chemical.
One academic involved in the study described the findings as 'eye-opening', and that 'everything I thought I knew has been flipped upside down'.
Lead author Professor Joanna Moncrieff, a psychiatrist, said: 'The popularity of the "chemical imbalance" theory has coincided with a huge increase in the use of antidepressants.
'Thousands suffer from side effects of antidepressants, including severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise.
'We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance.
'It is high time to inform the public that this belief is not grounded in science.'
One in six British adults and roughly 13 per cent of Americans take antidepressants, figures suggest.
NHS data shows there has been a surge in prescriptions doled out in England, with 8.3million patients taking them in 2021/22, 6 per cent more than the previous year.
The most common are SSRIs such as fluoxetine (Prozac), citalopram (Cipramil) and sertraline (Lustral).
Serotonin helps carry signals in the brain and is thought to have a positive influence on mood, emotion and sleep.
They are preferred to other types of antidepressants because they cause fewer side effects. Yet they can still lead patients taking them to experience anxiety, diarrhoea, dizziness and blurred vision.
Depressed patients can also be hit by crippling withdrawal symptoms when they try to come off the pills.
At the same time, a raft of studies have suggested they don't work any better than a placebo.
The UCL study, published in the journal Molecular Psychiatry, analysed 17 previous reviews dating back to 2010 and consisting of dozens of individual trials.
It does not prove SSRIs don't work. However, it does suggest the drugs don't treat depression by fixing abnormally low serotonin levels.
SSRIs have no other proven way of working, Professor Moncrieff and colleagues said.
Comment: Perhaps not proven, but a mechanism is theorized:
Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated...
These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.
She added: 'We can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.
'We do not understand what antidepressants are doing to the brain exactly.
'Giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.'
Studies used in the review involved hundreds of thousands of people from various countries.
They found there was no difference in serotonin levels between people diagnosed with depression and healthy people, despite polls suggesting up to 95 per cent of the public believing this is the case.
Artificially lowering serotonin levels in healthy volunteers also did not lead them to developing depression.
And over the long-term, powerful SSRIs may actually have the opposite effect as to what is intended.
Co-author Dr Mark Horowitz said: 'I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures.
'Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down.'
However, other experts have criticised the study's conclusions.
The Royal College of Psychiatrists (RCP) urged people with depression to continue taking their medication.
'Antidepressants will vary in effectiveness for different people,' a spokesperson said.
'And the reasons for this are complex, which is why it's important that patient care is based on each individual's needs and reviewed regularly.
'Continued research into treatments is important to help us better understand how medications work as well as their effectiveness.
'We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their GP.'
Dr Michael Bloomfield, another psychiatrist at UCL, called the findings 'unsurprising' given how complex a condition depression is.
'Depression has lots of different symptoms and I don't think I've met any serious scientists or psychiatrists who think that all causes of depression are caused by a simple chemical imbalance in serotonin,' he said.
However, he said it was still possible for SSRIs to help treat depression even if they didn't address the root cause.
'Many of us know that taking paracetamol can be helpful for headaches and I don't think anyone believes that headaches are caused by not enough paracetamol in the brain,' he said.
'The same logic applies to depression and medicines used to treat depression.
'There is consistent evidence that antidepressants can be helpful in the treatment of depression and can be life-saving.'
Professor Allan Young, director of the Centre for Affective Disorders at the Institute of Psychiatry, said the review 'does not change' the evidence that antidepressants work.
An analysis of NHS data published this month found the number of antidepressants doled out to 13 to 19-year-olds rose by a quarter between 2016 and 2020.
It included prescriptions up to the end of 2020, following a year of national Covid lockdowns and school and university closures.
An increasing amount of evidence is beginning to accrue showing that restrictions took a heavy toll on young people's mental health.
The NHS data โ obtained through a Freedom of Information (FOI) request โ also showed antidepressants use rose sharply among adults in their 20s.
Mental health and children's charities told MailOnline the data was an 'alarming sign' of a mental health crisis in Britain.
They warned some young people may have been given drugs by GPs because they can't get counselling due to pandemic backlogs.
" These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.There are a lot of "inflammatory" effects people are exposed to today, perhaps a poor diet being #1, along with alcohol, and the overuse of medications generally. Also, since Pharma never studies the interactions of all the vaccines they are injecting people with over a lifetime, that may be another part of the puzzle.
Depressed people seem to be suffering from energy blockages in their bodies, between the body/gut and the control center/brain - and they are "depressed" because they do not feel fully "normal". While they still know they are not fully normal, so are still "depressed" - their brain is getting more stimulation directly from the action of the SSRI which doesn't fix the blockage issue, but makes their brain feel a little more normal. Treats a symptom, but doesn't fix the real issue.