The de­pres­sion-in­flam­ma­tion link

North & South - - Contents - BY DONNA CHISHOLM

As science re­veals the depth of the con­nec­tion be­tween the im­mune sys­tem and de­pres­sion, are we on the brink of a treat­ment rev­o­lu­tion?

As science re­veals the depth of the con­nec­tion be­tween the im­mune sys­tem and de­pres­sion, are we on the brink of a treat­ment rev­o­lu­tion? Donna Chisholm in­ves­ti­gates.

When the black dog turned up again last year, Kathryn Moake didn’t waste any time in tam­ing it. She went straight to her GP. “I could be one of those mid­dle-aged women who dis­ap­pears from home and is found hid­ing be­hind a bush,” she told the doc­tor. She was tear­ful, anx­ious, and felt her life was out of con­trol.

At 51, the Christchurch pri­mary school teacher knew how bleak things could be­come if her de­pres­sion wasn’t con­trolled. As a young mother, she’d had an al­most over­whelm­ing urge to step in front of on­com­ing cars. “The only rea­son I didn’t do it was be­cause my five-year- old and 18- month- old daugh­ters were with me and I didn’t want them to see it.”

Fol­low­ing that doc­tor’s visit in March last year, she be­gan to join the dots be­tween her men­tal and phys­i­cal health. Af­ter years of low iron lev­els and ex­treme fa­tigue, and more re­cently rum­bling di­ges­tive symp­toms, she was fi­nally di­ag­nosed with coeliac dis­ease, an au­toim­mune dis­or­der that causes an in­flam­ma­tory re­sponse in the gut to di­etary gluten. She also had symp­toms of ir­ri­ta­ble bowel.

What if her de­pres­sion, coeliac dis­ease and bowel symp­toms were re­lated, linked to a mis­fir­ing im­mune sys­tem that was turn­ing her body against it­self, in both her gut and her brain?

It’s a ques­tion that’s gained re­newed mo­men­tum with the re­cent re­lease of The In­flamed Mind, a book by Cam­bridge Uni­ver­sity psy­chi­a­trist Pro­fes­sor Ed­ward Bull­more, which de­tails ev­i­dence of the emerg­ing role of in­flam­ma­tion in de­pres­sion – and nails down the cof­fin lid on the no­tion that body and mind are sep­a­rate.

He says the idea that the blood­brain bar­rier is an im­per­me­able “Ber­lin Wall” is one in which West­ern medics have been in­doc­tri­nated; it con­tin­ues to in­form their think­ing that de­pres­sion is “all in the mind”. Even rel­a­tively young doc­tors still be­lieve it, he told North & South. “Peo­ple of my vin­tage who went through med­i­cal train­ing had it drummed into them, and med­i­cal ed­u­ca­tion changes so slowly,” he says. “If you’re trained in the West­ern med­i­cal tra­di­tion, you’re prob­a­bly the tough­est au­di­ence – but talk­ing to pa­tients, it’s easy.”

Amid the sci­en­tific and med­i­cal re­search in the book, Bull­more re­lates two per­sonal sto­ries that have in­formed his work. The first hap­pened when, while train­ing as a physi­cian in 1989, he saw pa­tient “Mrs P”, a woman in her late 50s who had the in­flam­ma­tory au­toim­mune dis­ease rheuma­toid arthri­tis. She was so painfully swollen and dis­fig­ured, she found it dif­fi­cult to walk and when Bull­more ques­tioned her about her state of mind, he found she was also de­pressed. He re­ported this to his se­nior physi­cian, who was unim­pressed.

“De­pressed? Well, you would be, wouldn’t you?” he said.

It didn’t oc­cur to ei­ther of them, writes Bull­more, that the woman’s de­pres­sion might be a phys­i­cal re­sponse to her in­flam­ma­tion, rather than a psy­cho­log­i­cal re­ac­tion to her pain and dis­abil­ity.

Bull­more’s sec­ond anec­dote refers to his re­cent root canal surgery, which he says caused a tem­po­rary bout of lethargy, so­cial with­drawal and mor­bid thoughts. “My tooth had been in­fected by some bac­te­ria; my gums had be­come in­flamed in re­sponse to that in­fec­tion; the den­tists’ drilling and scrap­ing… had the short-term dis­ad­van­tage of mak­ing my gums even more in­flamed and in­creas­ing the risk of the bac­te­ria spread­ing from my tooth into my blood­stream. [ It] amounted to a chal­lenge to my body’s in­tegrity, a threat to my sur­vival and a clar­ion call to my im­mune sys­tem to step up its in­flam­ma­tory re­sponse.”

Typ­i­cally, those symp­toms would have been ex­plained away in psy­cho­log­i­cal, not im­muno­log­i­cal terms: the close en­counter with the den­tist was a re­minder he was lit­er­ally get­ting long in the

tooth, trig­ger­ing a pe­riod of “ra­tio­nal pes­simism”. It was far more likely, he writes, that he was de­pressed be­cause he was in­flamed.

In­flam­ma­tion is, of course, part of the im­mune sys­tem’s nor­mal healthy re­sponse to help us heal af­ter in­jury or in­fec­tion; the same process can be trig­gered by acute or chronic stress. We can also feed the body’s in­flam­ma­tory re­sponses with a poor diet, in­ac­tiv­ity and dis­rupted sleep. But some­times, when the body fires up that re­sponse, it can’t al­ways dampen it down again, lead­ing to au­toim­mune con­di­tions such as Mrs P’s rheuma­toid arthri­tis and Kathryn Moake’s coeliac dis­ease. But what hap­pens when that in­flam­ma­tion af­fects the brain as well as the body?

Since the book, Bull­more has been in­un­dated by ques­tions from pa­tients with de­pres­sion, ask­ing whether sim­ple anti-in­flam­ma­to­ries such as ibupro­fen or as­pirin might be the holy grail of treat­ment. They’re not, he says: the drugs have side ef­fects that may be harm­ful, and so far, there’s lit­tle clin­i­cal ev­i­dence they would al­le­vi­ate de­pres­sion. But, he points out in the book, there’s no fi­nan­cial in­cen­tive for drug com­pa­nies to con­duct ex­pen­sive clin­i­cal tri­als for de­pres­sion be­cause the medicines are off-patent any­way.

Bull­more be­lieves about a third of cases of ma­jor de­pres­sion have an in­flam­ma­tory link, and that’s where he’d be tar­get­ing re­search into new treat­ments. How­ever, the only rou­tine blood test for in­flam­ma­tory mark­ers mea­sures C-re­ac­tive pro­teins, which are pro­duced in the liver and rise in re­sponse to in­flam­ma­tion. It’s a blunt tool, and in­creased lev­els could sig­nal any­thing from gum dis­ease to heart dis­ease. “This isn’t ready for prime­time in terms of peo­ple go­ing to their doc­tor and get­ting a test that is de­signed to pick out an in­flam­ma­tory mech­a­nism that con­trib­utes to de­pres­sion, but I don’t think this is go­ing to be the only test avail­able in fu­ture.”

The biomark­ers that are thought to have a much more im­por­tant role in sig­nalling de­pres­sion are what’s known as pro-in­flam­ma­tory cy­tokines (see side­bar, page 36), and they are more dif­fi­cult and more ex­pen­sive to mea­sure.

Auck­land men­tal health nurse prac­ti­tioner Anna El­ders, a cog­ni­tive be­havioural ther­a­pist, be­lieves a blood test might be su­per­flu­ous any­way. “Once you start look­ing at the holis­tic pic­ture, you al­most don’t need to go down that route. You find out this per­son has der­mati­tis, had child­hood asthma or eczema and ir­ri­ta­ble bowel. There’s a host of in­flam­ma­tory-type symp­toms so it would be un­likely there’d be no in­flam­ma­tion, whether it shows up in the blood or not.”

El­ders, who’s worked in men­tal health for 17 years and is a pro­fes­sional teach­ing fel­low at Auck­land Uni­ver­sity, es­ti­mates in­flam­ma­tion is a con­trib­u­tor in about half of the pa­tients she sees with de­pres­sion. “In those who re­port more life­long men­tal health prob­lems, who were first de­pressed in child­hood or ado­les­cence, there is a real clin­i­cal pic­ture of in­flam­ma­to­ry­driven au­toim­mune con­di­tions, poor qual­ity of life and cur­rent stress.”

It’s dif­fi­cult to pull apart the rel­a­tive weight of the var­i­ous clin­i­cal driv­ers. “I de­scribe it to pa­tients like the old game of Pick-up Sticks. You hold them and let them go, and then get this messy ar­ray of in­ter-con­nect­ed­ness, know­ing that when you shift one, five oth­ers move at the same time. It helps us think about the true holis­tic na­ture of how we op­er­ate as hu­man be­ings, but it pro­vides a great chal­lenge to how we ap­proach treat­ment.”

She’s dis­cussed the po­ten­tial role of in­flam­ma­tion with pa­tients for the past two or three years. “Many have a mix­ture of amaze­ment at be­ing given a pic­ture that makes a lot of sense, to tie things to­gether to help them un­der­stand why life has been such a chal­lenge. They can feel a bit daunted by it and some are very frus­trated that no one has talked to them

about it in this way be­fore. But it gives them a lot of hope be­cause they see a bunch of dif­fer­ent ways they can in­ter­vene with their health and shift the way their fu­ture might look.”

An­tide­pres­sants work well for some, but her pa­tients with in­flam­ma­tion of­ten have a poorer re­sponse to the drugs and more side ef­fects. El­ders says at this stage, she looks to di­etary and life­style in­ter­ven­tions be­fore rec­om­mend­ing pa­tients be tested for in­flam­ma­tion.

As a nurse prac­ti­tioner, she can pre­scribe an­tide­pres­sants, but has also tried mi­cronu­tri­ent sup­ple­ments, which have been the sub­ject of years of re­search by Ju­lia Ruck­lidge’s team at Can­ter­bury Uni­ver­sity. Ruck­lidge, a pro­fes­sor of clin­i­cal psy­chol­ogy, has found the mi­cronu­tri­ents im­proved the well­be­ing of peo­ple with ADHD and she’s now re­cruit­ing par­tic­i­pants for a new trial to test their ef­fec­tive­ness in peo­ple with anx­i­ety and de­pres­sion.

ONE OF THE more con­tentious sug­ges­tions in Bull­more’s book is that we be­come more in­flamed nat­u­rally as we age, and ac­cord­ingly, be­come more anx­ious and de­pressed. Other ex­perts dis­agree, cit­ing what’s known as the hap­pi­ness “u-curve”, re­flect­ing the fact we have the high­est rates of de­pres­sion and anx­i­ety in our youth and old age, but a pe­riod of rel­a­tive mood sta­bil­ity and well­be­ing in our mid­dle years.

While we may be prone as we age to chronic con­di­tions in­volv­ing de­gen­er­a­tion, those con­di­tions aren’t nec­es­sar­ily in­flam­ma­tion re­lated, says Auck­land Uni­ver­sity As­so­ciate Pro­fes­sor Roger Booth, a spe­cial­ist in psy­choneu­roim­munol­ogy, the study of how the mind and ner­vous and im­mune sys­tems in­ter­act. Booth be­lieves we are years away from rou­tinely us­ing anti-in­flam­ma­to­ries in pa­tients with de­pres­sion, point­ing to the need for re­search to iden­tify which pa­tients might re­spond to the treat­ment, which treat­ments would work, and also the pos­si­ble down­sides.

“In­flam­ma­tion is a use­ful process that anti- in­flam­ma­to­ries dampen down. Long-term dampening will have ad­verse ef­fects, so it’s not go­ing to be a case of, ‘I’ll be okay with my de­pres­sion if I take this [anti-in­flam­ma­tory] pill for the rest of my life.’ I don’t think we are any­where close to that sort of thing.”

Long-term, for ex­am­ple, it could stop the im­mune sys­tem re­spond­ing ef­fec­tively to life- threat­en­ing in­fec­tions. “What we don’t know is whether a short course of an anti-in­flam­ma­tory would re­set the cir­cuitry so when you came off it, all was well, or it was man­age­able with life­style changes. Anti-in­flam­ma­to­ries are go­ing to change a num­ber of path­ways, some of which we know a bit about and some we don’t know enough about, and that’s likely to end up caus­ing a whole lot of other prob­lems.”

Twenty years ago, the in­flu­ence of the im­mune sys­tem on the ner­vous sys­tem wasn’t thought to be par­tic­u­larly sig­nif­i­cant, he says. “Now, the two are very much en­meshed and novel path­ways of un­der­stand­ing emerge, as well as po­ten­tially novel treat­ments. But then we run the risk of say­ing, ‘We’ve got this magic bul­let that will solve every­thing.’ It won’t be that sim­ple.”

That, at least, is some­thing all the ex­perts we spoke to agree with. Psy­chi­a­trist Richard Porter, pro­fes­sor and head of the de­part­ment of psy­cho­log­i­cal medicine at the Otago Med­i­cal School in Christchurch, says one is­sue of many as­so­ci­ated with the rou­tine use of an­ti­in­flam­ma­to­ries in de­pres­sion is that no one knows at what level in­flam­ma­tion should be treated.

“There is in­creas­ing ev­i­dence that in­flam­ma­tion is im­por­tant as a factor in de­pres­sion, but it’s too com­plex a dis­ease to de­ter­mine one root cause.” He be­lieves in­flam­ma­tion is prob­a­bly “very im­por­tant” in more se­vere de­pres­sion. “Milder de­pres­sion is of­ten a psy­cho­log­i­cal re­sponse to stress, with fewer bi­o­log­i­cal ab­nor­mal­i­ties in brain and body.”

But Porter says he’d be likely to rec­om­mend the use of choles­terol-low­er­ing statins in peo­ple with de­pres­sion who had, for ex­am­ple, some risk fac­tors for car­dio­vas­cu­lar dis­ease. “Statins are quite sig­nif­i­cantly anti-in­flam­ma­tory. GPS would have dif­fer­ent thresh­olds for rec­om­mend­ing statins and some would be quite con­ser­va­tive, but my ad­vice would be to be less con­ser­va­tive if a pa­tient has a his­tory of de­pres­sion.”

Some of the big­gest stud­ies in the world of drug treat­ments, in­clud­ing statins, for in­flam­ma­tory-re­lated de­pres­sion are be­ing done across the ditch, at Mel­bourne’s Deakin Uni­ver­sity, un­der the lead­er­ship of renowned neu­ro­sci­en­tist and psy­chi­a­trist Pro­fes­sor Michael Berk. He told North & South that Deakin has three or four clin­i­cal tri­als un­der­way. In one just com­pleted in­volv­ing the old an­tibi­otic minocy­cline, which also re­duces in­flam­ma­tion, the re­searchers were able to show an­tide­pres­sant ef­fects. They’ve also shown an amino acid called N-acetyl cys­teine, which has anti-in­flam­ma­tory and an­tide­pres­sant prop­er­ties, is use­ful for schizophre­nia and bipo­lar dis­or­der, and pos­si­bly de­pres­sion as well.

Deakin did the first epi­demi­o­log­i­cal stud­ies show­ing statins can re­duce the risk of de­pres­sion, and re­searchers there are just fin­ish­ing a clin­i­cal trial on the ef­fec­tive­ness of statins and as­pirin in youth de­pres­sion. A fur­ther study on the use of as­pirin to pre­vent de­pres­sion is sched­uled for anal­y­sis by the end of the year. A num­ber of in­ter­na­tional stud­ies have also shown promis­ing re­sults with the arthri­tis drug cele­coxib (Cele­brex), which can boost the ef­fec­tive­ness of an­tide­pres­sants.

One of Deakin’s most ro­bust pieces of work has been re­search show­ing how improving diet – in­creas­ing vegetable, fruit, wholegrain, legumes, fish and nut con­sump­tion while re­duc­ing sweets and pro­cessed foods – can ease de­pres­sion. Last year, Deakin’s Food and Mood Cen­tre pub­lished the re­sults of a 12-week ran­domised con­trolled trial show­ing that a third of those on a di­etary regime went into re­mis­sion for their de­pres­sion, com­pared to only 8% who had so­cial sup­port alone.

Berk says that, as a clin­i­cian, he’d be far more likely to rec­om­mend an­tide­pres­sants, psy­chother­apy, ex­er­cise, smok­ing ces­sa­tion and diet mod­i­fi­ca­tion be­cause the risks are min­i­mal.

“It’s too early in the piece to rec­om­mend anti-in­flam­ma­tory strate­gies. I don’t think the ev­i­dence, as ex­cit­ing as it is, is ro­bust enough for clin­i­cians to do rou­tinely, and re­mem­ber, there is an op­por­tu­nity cost. When­ever you tell peo­ple to do some­thing, most peo­ple will ad­here to one or two rec­om­men­da­tions and not oth­ers. If you tell them to do five things, they are not go­ing to do five things.”

The chronic, low-grade in­flam­ma­tion that’s as­so­ci­ated with de­pres­sion is not only linked to stress and poor diet, says Berk, but to many other fac­tors, in­clud­ing in­ac­tiv­ity, obe­sity, smok­ing, den­tal caries, sleep dis­tur­bance, al­ler­gies, vi­ta­min- D de­fi­ciency and leaky gut.

AHH, AT LAST, that G-word. The Gut. No story ex­plor­ing the causes of ill­ness these days seems com­plete with­out a nod to our mi­cro­biome – and de­pres­sion is no ex­cep­tion, with gut bac­te­ria pro­duc­ing an es­ti­mated 90% of the body’s sero­tonin, a neu­ro­trans­mit­ter that has a key role in reg­u­lat­ing mood.

The state of the gut mi­cro­biota has been as­so­ci­ated with schizophre­nia, autism, anx­i­ety and ma­jor de­pres­sion. At birth, babies in­herit their mi­cro­biota from their moth­ers, but diet in the first three years of life also plays a crit­i­cal role in de­ter­min­ing the mi­cro­biome foot­print in adult­hood. Hav­ing that foot­print doesn’t mean it’s im­pos­si­ble to al­ter, though – di­etary changes can re­duce the level of in­flam­ma­tory mark­ers in the bowel in just two weeks.

Sci­en­tists ac­knowl­edge it can be dif­fi­cult to sep­a­rate cause and ef­fect – does men­tal ill health cause a poor diet rather than the other way around? – but most stud­ies that have in­ves­ti­gated whether the ill­ness comes first have so far ruled it out. Last year, the Pro­bi­otics in Preg­nancy Study of more than 400 Auck­land and Welling­ton women, funded by the Health Re­search Coun­cil and Fon­terra and run by Auck­land Uni­ver­sity, found that those who took a pro­bi­otic daily dur­ing preg­nancy and for six months af­ter birth halved their risk of clin­i­cally sig­nif­i­cant anx­i­ety.

In 2009, the Dunedin Mul­ti­dis­ci­plinary

One of the more con­tentious sug­ges­tions in Bull­more’s book is that we be­come more in­flamed nat­u­rally as we age, and ac­cord­ingly, be­come more anx­ious and de­pressed.

Health and De­vel­op­ment Study re­ported that adults at 32 were twice as likely to have in­flam­ma­tion and de­pres­sion if they’d been mal­treated as chil­dren – al­though not all of the study par­tic­i­pants who had de­pres­sion were also in­flamed. The study found that even mild in­creases in in­flam­ma­tion lev­els ap­peared to pre­dict in­creased risk of heart dis­ease in ap­par­ently healthy peo­ple.

Study di­rec­tor Pro­fes­sor Richie Poul­ton told North & South that when the team ex­am­ined the ex­ist­ing science be­fore its anal­y­sis, it was a con­fused pic­ture; de­pres­sion was as­so­ci­ated with in­flam­ma­tion in some stud­ies, but not all. “We then rea­soned that what might link the two was a third factor – specif­i­cally, a his­tory of child mal­treat­ment – be­cause it’s well known that ad­ver­sity in child­hood can raise the risk of heart dis­ease in later life as well as in­crease the like­li­hood of de­vel­op­ing de­pres­sion. That’s ex­actly what we found: it was only those de­pressed adults who had a his­tory of child­hood mal­treat­ment that had sig­nif­i­cantly high lev­els of sys­temic in­flam­ma­tion in their fourth decade of life.”

The Dunedin pa­per sug­gested that doc­tors rou­tinely as­sess de­pressed pa­tients for child­hood mis­treat­ment to iden­tify those with el­e­vated risk of in­flam­ma­tion and po­ten­tially poor health. Poul­ton says the study will fur­ther ex­am­ine the in­ter­ac­tions be­tween phys­i­cal, so­cial and psy­cho­log­i­cal fac­tors in ill health when its as­sess­ment of par­tic­i­pants, now aged 45, is fin­ished early next year.

Bull­more says the emerg­ing links be­tween stress and in­flam­ma­tion help to bring to­gether the bi­o­log­i­cal and psy­choso­cial sides of the de­pres­sion equa­tion. “The key thing is the mech­a­nism. If we say stress causes de­pres­sion, it’s a bit like say­ing light causes vi­sion – there’s a whole se­quence of events in the mid­dle but we don’t yet un­der­stand all the in­ter­ven­ing stages.

He says a “care­ful doc­tor” in 2018 is likely to steer a pa­tient away from ex­ist­ing anti-in­flam­ma­tory drugs, to­wards treat­ment of the un­der­ly­ing con­di­tion. “Pe­ri­odon­ti­tis, lit­er­ally in­flam­ma­tion around the teeth, would be top of my list of cul­prits if I was in­flamed and de­pressed. This is a low-grade chronic in­fec­tion that can eas­ily get for­got­ten be­cause most doc­tors don’t think about it, and most den­tists aren’t paid to think about the links be­tween gum dis­ease and de­pres­sion.”

Gas­troin­testi­nal dis­tur­bances, such as ir­ri­ta­ble bowel (as in Kathryn Moake’s case) or in­ter­mit­tent col­i­tis, are also likely sus­pects, he says, with so-called “leaky gut” al­low­ing bac­te­ria through the in­testi­nal wall to cause in­flam­ma­tion in the body. The con­di­tion would be ex­ac­er­bated if the im­mune sys­tem is al­ready on high alert be­cause of a de­prived or abu­sive child­hood.

Moake is still bat­tling her ir­ri­ta­ble bowel symp­toms, but af­ter more than a year on an­tide­pres­sants, says her low mood is un­der con­trol, even af­ter a mar­riage break­down. She’s con­fi­dent child­hood stress isn’t a cause of her de­pres­sion – “we were very lucky to have a lovely child­hood with awe­some par­ents and every­thing we needed” – but she’s plan­ning to re­turn to her doc­tor to have her in­flam­ma­tory mark­ers tested.

“I prob­a­bly haven’t been as ro­bust as I would have been if I hadn’t had the in­flam­ma­tory stuff go­ing on,” she says.

In the mean­time, she’s ex­plor­ing nat­u­ral ways to im­prove her health. “I’m try­ing re­ally hard with sleep, and I’ve given up all caf­feine and al­co­hol – not that I drank much be­fore.” She says she’d never “go it alone” by try­ing over-the­counter anti-in­flam­ma­to­ries. “You’ve got to be work­ing along­side some­one who knows what they’re do­ing.”

It might be too early for pa­tients such as Moake, but Bull­more says a “best­case sce­nario” would re­sult in “de­ci­sive moves” in treat­ment within five or 10 years. “Maybe we’ll see new drugs that, un­like the old ones, are not vaguely sup­posed to work equally well for ev­ery­one, but are sci­en­tif­i­cally pre­dicted to work par­tic­u­larly well for some.

“We could be on the cusp of a rev­o­lu­tion. I might be wrong, but I think it has al­ready be­gun.” +

Christchurch pri­mary school teacher Kathryn Moake sus­pects her de­pres­sion, coeliac dis­ease and bowel symp­toms may be re­lated.

Auck­land men­tal health nurse prac­ti­tioner and cog­ni­tive be­havioural ther­a­pist Anna El­ders es­ti­mates in­flam­ma­tion con­trib­utes to de­pres­sion in about half her pa­tients.

Pro­fes­sor Michael Berk says the ev­i­dence for an­ti­in­flam­ma­tory strate­gies is “ex­cit­ing” but not yet ro­bust enough for clin­i­cians to use rou­tinely.

Cam­bridge Uni­ver­sity psy­chi­a­trist Pro­fes­sor Ed­ward Bull­more be­lieves about a third of cases of ma­jor de­pres­sion have an in­flam­ma­tory link.

The Dunedin Mul­ti­dis­ci­plinary Health and De­vel­op­ment Study led by Pro­fes­sor Richie Poul­ton (above left) has linked child­hood mal­treat­ment with later in­flam­ma­tion and de­pres­sion. Auck­land Uni­ver­sity As­so­ciate Pro­fes­sor Roger Booth (above right) says the im­mune and ner­vous sys­tems are “en­meshed” and re­search could lead to novel treat­ments.


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