And the most commonly prescribed antidepressants, SSRIs (selective serotonin reuptake inhibitors) - once hailed as wonder drugs - do not work for a significant number. They also have a range of potential side-effects, including insomnia, sexual problems and difficulty coming off them.
But now a Cambridge University psychiatrist suggests there is a radical way to transform this gloomy picture. Professor Edward Bullmore believes the root of the problem is inflammation. In his book, The Inflamed Mind, he argues that depression is not a mental, but a physical, illness caused by inflammation - which opens up the possibility of entirely new approaches to treating it.
Inflammation is the body’s first line of defence: it occurs when the immune system’s messenger molecules (cytokines) alert white blood cell “shock troops” (macrophages) to attack and destroy invaders - such as bacterial infection.
As part of the immune response, the blood vessels expand to bring more blood to the damaged area to repair it.
The most obvious signs of inflammation are the redness and swelling that occur when you cut yourself, for instance.
High levels of inflammation are now known to be associated with most chronic diseases, including diabetes and cancer, as well as rheumatoid arthritis and asthma.
And as Bullmore sets out in his book, it seems that inflammation is linked with depression, too.
The idea is that if you treat the inflammation, the depression is alleviated.
For decades, drug treatment for depression had been largely limited to SSRI drugs that raised the amount of the brain chemical serotonin, which is known to be associated with positive feelings.
The thinking was that depressed people didn’t have enough serotonin.
But if this inflammation theory is proven right, in the foreseeable future patients could be leaving their GP surgery with a much more varied package to help with low mood.
There had long been hints that inflammation could play a part in depression.
For instance, after being vaccinated - designed to cause an immune response - people often complain of feeling tired and lacking motivation.
It was a consultation with a woman with severe arthritis when he was a young hospital doctor in 1989 - about the time SSRIs first came on the market - that made Bullmore start to think about a link between inflammation and depression.
Her swollen, painful hands made the diagnosis of arthritis obvious; but then, instead of immediately writing a prescription for an anti-inflammatory painkiller, he asked how she felt.
“Quietly but clearly, she told me she had very low levels of energy,” he writes.
“Nothing gave her pleasure any more; her sleep was disturbed and she was preoccupied by pessimistic thoughts.” All classic signs of depression.
He diagnosed not one but two disorders, though at the time he didn’t link it with inflammation.
It’s a classic problem in medicine.
When two disorders come together, are they separate, or does one cause the other? Was the constant pain and difficulty moving what made her depressed or did the inflammation that damaged her joints play a part?
It was an idea that went against the conventional understanding.
That is: that the immune system was blocked from acting on the brain by the blood brain barrier - effectively a filter that keeps out many com- pounds carried in the blood.
But within a few years, research showed that immune system cells and proteins could get through the blood brain barrier, and studies on animal brains revealed that these immune cells could behave like the most undisciplined militia, blasting the territory they were supposed to be protecting.
This research showed that nerve cells in the brain exposed to the immune system’s messenger cells, the cytokines, were likely to die and networks of cells became less able to learn and lay down memories. But this was different from the havoc wreaked in arthritic hands, not least because the lack of pain receptors in the brain meant it wasn’t painful.
The immune troops also made use of a form of protein called tryptophan, which is normally turned into the “feel good” chemical serotonin, to make toxic damaging compounds instead.
This could be why SSRIs don’t benefit depressed patients with high levels of inflammation - because the raw material for making serotonin isn’t available.
However, about 80% of depressive episodes are connected with stress, says Bullmore, citing the example of a man who starts divorce proceedings being 10 times more likely to suffer depression than the general population.
So the link between inflammation and depression looks very plausible.
Bullmore says we need to move on - from seeing depression as all in the mind or all in the brain to a response of the whole human self to the challenges of survival in a hostile world.