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* Surprising trial results lead to rethinking of depression
* Disorder now seen as cluster of distinct conditions
* Neuroscientists say understanding brain circuitry is key
* Depression affects more than 350 million people
By Kate Kelland, Health and Science Correspondent
LONDON, Sept 9 (Reuters)- As Susan sits chatting to a nursein a London clinic, a light tapping sound by her head signalsthat parts of her brain are being zapped by thousands of tinyelectro-magnetic pulses from a machine plugged into the wall.
The 50 year-old doctor is among growing ranks of people withso-called treatment-resistant depression, and after 21 yearsfighting a disorder that destroyed her ability to work and attimes made her want to "opt out of life", this is a last resort.
Until recently, Susan and others like her had effectivelyreached the end of the road with depression treatments, havingtied the best drugs medical science had to offer, engaged inhours of therapy, and tried cocktails of both.
But a renaissance in research into depression prompted bysome remarkable results with highly experimental treatments haschanged the way neuroscientists see the disorder and is offeringhope for patients who had feared there was nowhere left to go.
Their drive to find an answer has taken neuroscientists touncharted waters - researching everything from psychedelic magicmushrooms, to the veterinary tranquilizer ketamine, to magneticstimulation through the skull, to using electrical implants - abit like a pacemaker for the brain - to try and reset thiscomplex organ's wiring and engender a more positive outlook.
Their sometimes surprising findings have in turn taught themmore about depression - leading to a view of it not as a singlemental illness but a range of disorders each with distinctmechanisms, yet all producing similarly debilitating symptoms.
"The thinking about depression has been revitalised," saidHelen Mayberg, a neurologist at Emory University in Atlanta inthe United States.
"We have a new model for thinking about psychiatric diseasesnot just as chemical imbalance - that your brain is a just bigvat of soup where you can just add a chemical and stir - butwhere we ask different questions - what's wrong with brainchemistry and what's wrong with brain circuits."
ADD A CHEMICAL AND STIR?
There's little doubt that until this new breath of hope,depression had been going through a bad patch.
Affecting more than 350 million people, depression is rankedby the World Health Organisation as the leading cause ofdisability worldwide. In extreme cases, depressed people killthemselves. Around a million people commit suicide every year,the majority due to unidentified or untreated depression.
Treatment for depression involves either medication orpsychotherapy - and often a combination of both. Yet as thingsstand, as many as half of patients fail to recover on theirfirst medication, and around a third find no lasting benefitfrom any medication or talking therapy currently available.
High hopes for "wonder" drugs like Prozac, Seroxat andothers in their class of selective serotonin reuptake inhibitors(SSRIs) in the 1980s and 1990s were dimmed by studies in the2000s that showed they helped a proportion of people, but leftat least 30 percent of patients little or no better than before.
And as chronically depressed patients move from trying onedrug to the next, or one type of therapy to another, their hopestoo dim as it becomes clear that failing to get better with eachdepressive bout in turn also ups their chances of relapse.
For Susan, the battle seemed never ending.
When she was at her lowest, she dreaded each day, says shewas "frightened of everything" and overwhelmed even bystraightforward tasks like making a meal for her two children.
"I was taking double doses of antidepressants - two types atonce - and because I was also very agitated I was on (thesedative) chloral hydrate to help me sleep," she told Reuters.
"So I was on this massive amount of medication, but with noeffect whatsoever on my depression. Nothing was working."
Desperate to help patients like Susan, and alarmed by newsof some pharmaceutical firms such as GlaxoSmithKline abandoning research and development in depression because it wasproving too hard to find new drugs that could turn a profit, doctors began looking for new approaches.
"We often encounter patients who say 'I've tried a millionthings and nothing seems to be working'," said Rafael Euba, aconsultant psychiatrist at the London Psychiatry Centre(LPC)where Susan was treated. "We want to instil a feeling ofhope."
ELECTRO-THERAPY
In Susan's case, past experience with a controversialelectrical intervention - electro convulsion therapy (ECT) -which she says was what eventually clawed her back from hersevere depression 17 years ago, lead her to investigate thelatest in electrical treatments - so-called repetitivetranscranial magnetic stimulation, or rTMS
Approved by medicines regulators in the United States and inEurope it is a painless treatment that uses electro-magneticinduction to activate an area of the brain that psychiatristsknow is involved in the regulation of mood.
Unlike ECT, which gained notoriety in the 1975 Americandrama film One Flew Over the Cuckoo's Nest, rTMS it does notinduce "shock", but is far more targeted, delivering a pulse toneurons in the brain and that makes them fire again.
At the LPC - currently the only place in Britain wherepatients can get rTMS - a treatment course can be anything from3 to 6 weeks of half an hour a day, five days a week.
It isn't cheap. The treatment costs 1,500 pounds ($2,300)per week, with the average course lasting four weeks. And somepatients also need weekly or fortnightly "maintenance" sessionsbeyond that.
Patients put on a white fabric cap and the electro-magneticcoil is positioned over the part of the brain that needs help -normally the left dorso-lateral prefrontal cortex, which is afew inches above the temple beneath the skull.
"Unlike with other psychiatric treatments, patients tend tofind this experience quite pleasant," said Euba. "All you get isa slight tingling on the scalp - and some people like thatbecause it's a physical sensation that something is happening."
Although they are from a controlled trial and show only asnapshot of the couple of dozen patients treated and monitoredat one clinic, Euba's results so far have been striking.
Of 24 patients with depression ranging from mild to severewho received rTMS at the LPC, 18 of them - or 75 percent - gotcompletely well and were classed as being in remission. Two moreresponded to treatment but did not get completely well, and onlyfour - 17 percent - did not respond.
DEEP BRAIN STIMULATION
Mayberg and her colleagues in the United States had alsobeen intrigued by the potential for electrical stimulation toease severe depression, but they went in deeper.
After the success of using deep brain stimulation (DBS)devices made by firms such as Medtronic to treat tremorsin patients with Parkinson's disease, her team conducted a trialusing them in a small number of patients who'd had depressionfor decades and had not been helped by numerous different drugs.
Electrical stimulation devices were implanted into thebrains of patients with severe depression and bipolar disorder.
"In this treatment the stimulation continues all the time -they implant the "pacemaker" and leave it switched on for years- and only sometimes they have to change the battery," saidJonathan Roiser, a reader in cognitive neuroscience atUniversity College London.
According to study results published in the Archives ofGeneral Psychiatry journal last year, the number of patients whohad responded to treatment after two years was very high - at 92percent - and the proportion who were completely well and inremission from their depression was 58 percent.
For psychiatrists more used to seeing patients fail againand again to get better on any kind of treatment, these resultswere unheard-of. "It was a remarkable finding," says Roiser.
Yet it's not just the brain's wiring that is getting moreattention. Chemistry, too has thrown up some exciting results.
Researchers who looked, for example, at the veterinarytranquilizer ketamine - or "Special K" as it is called as aparty drug - found that in some patients with depression itdramatically reduced their symptoms, sometimes within hours -and kept their mood stable for several weeks after treatment.
Inspired by these uplifting findings, several drug firms,including Roche, AstraZeneca and Johnson &Johnson's Janssen unit, are in the early or mid stagesof developing ketamine derivatives into what they hope willbecome successful new antidepressants.
DEFINE SUBTYPES AND TREAT ACCORDINGLY
Experts say the success these new and some stillexperimental treatments for depression emphasizes there-thinking of it as not one but a cluster of disorders.
"We now have this increasingly influential model of what iscausing mental health problems like depression - one focussed onthe brain circuits," said Roiser.
"We've learnt a lot about how these circuits operate, whatkind of cognitive tasks they are involved in, how they interactand how they are connected to each other."
More evidence of this came in a recent study in the Journalof the American Medical Association in which researchers foundthat brain scans of depressed patients could help predictwhether they would be more likely to respond to treatment withanti-depressant drugs or with psychotherapy.
The study focussed on a part of the brain known as theinsula, which plays a role in influencing emotions.
It found that in patients whose scans showed their insulaconsumed an excess of glucose, psychotherapy was more likely tohelp. In patients whose insula were less active, consuming lessglucose, antidepressants were more successful.
"Our gut tells us there are subtypes (of depression), andthis shows that if you look the brain, you should define thebiology and treat accordingly - just as we do in other branchesof medicine (like cancer or diabetes)," said Mayberg.
Far from being defeated by the emergence of depression as amore complex a disorder than first assumed, scientists say therenaissance in research is based in confidence that deeperknowledge will ensure new and better treatments can be found.
Roiser confesses to feeling "extremely excited andoptimistic" about the future of treating mental illnesses.
"We're in a movement away from the traditional psychologicaland biological explanations for depression - which lookincreasingly outdated and simplistic - and we're in the middleof specifying these disorders in terms of their underlying braincircuits," he said. "That's a much better position than we werein 20 years ago."
