North & South - - Cover Story Part One -

How can in­flam­ma­tion, the body’s phys­i­cal re­sponse to in­jury and in­fec­tion, pos­si­bly lead to de­pres­sion? To un­der­stand the in­flam­ma­tory process, it’s nec­es­sary to un­der­stand the role of a few key play­ers in our im­mune sys­tem: macrophages, cy­tokines and lym­pho­cytes.

Macrophages fire up when the body en­coun­ters a for­eign in­vader. They break down sub­stances such as bac­te­ria and dish them up to the lym­pho­cytes to tar­get and de­stroy them. The macrophages also pro­duce pro­teins called cy­tokines, which have ei­ther proor anti-in­flam­ma­tory ef­fects (and, con­fus­ingly, some­times both). It’s a group of pro-in­flam­ma­tory cy­tokines – in­ter­leukin 1, tu­mour necro­sis factor (Tnf)-al­pha and in­ter­leukin 6 – that has ex­cited the in­ter­est of sci­en­tists in­ves­ti­gat­ing the links be­tween in­flam­ma­tion and de­pres­sion.

Typ­i­cally, these cy­tokines are used as sig­nals to turn on some later as­pects of the im­mune sys­tem, and their pro­duc­tion tends to in­crease when we need them, and re­duce when we don’t.

Here’s where some fas­ci­nat­ing an­i­mal stud­ies come in. Rats in­jected with in­fec­tious bac­te­ria tend to with­draw from so­cial con­tact, move less, and have dis­turbed sleep and eat­ing be­hav­iour – symp­toms com­monly seen in de­pres­sion. But you don’t need to in­fect a rat with the ac­tual bac­te­ria to see this sort of sick­ness be­hav­iour: in­ject­ing a rat with cy­tokines alone will pro­duce the same ef­fect, sug­gest­ing it’s not the germ it­self that makes the an­i­mal sick, but the im­mune re­sponse to it.

Re­search has also shown that if a bac­te­rial toxin is in­jected into the rat, the toxin it­self won’t get into the brain – the blood–brain bar­rier will pre­vent that – but the in­flam­ma­tory sig­nals from the re­sponse to the toxin will.

The brain’s macrophages, known as mi­croglial cells, pick up those sig­nals and start pro­duc­ing cy­tokines, which in turn dam­age nerve cells in sur­round­ing tis­sue. The re­sult, says Ed­ward Bull­more in The In­flamed Mind, is that nerve cells die or shrink, and the sup­ply of neu­ro­trans­mit­ters such as sero­tonin (which are pro­duced in the brain as well as the gut) is dis­rupted. “Not only can an­gry mi­croglial cells kill nerve cells in their im­me­di­ate neigh­bour­hood, they can also block the re­gen­er­a­tive process that would form new nerve cells in their place.”

The fact that the cy­tokines change the way neu­rons make and re­lease sero­tonin may also ex­plain why peo­ple who are in­flamed re­spond less well to tra­di­tional SSRI an­tide­pres­sants, which pro­long the amount of time sero­tonin stays in the synapse (the com­mu­ni­ca­tion junc­tion be­tween neu­rons). “When in­flam­ma­tion re­duces the amount of sero­tonin re­leased into the synapses, it is ef­fec­tively pulling in the op­po­site di­rec­tion to SSRIS.”

ANTI-TNF drugs have been used in rheuma­toid arthri­tis since the late 1990s, and Bull­more’s book notes the ex­pe­ri­ences of doc­tors and nurses treat­ing pa­tients with the early in­fu­sions of one drug, in­flix­imab (Rem­i­cade).

“They knew the pa­tient would feel better and be full of grat­i­tude al­most im­me­di­ately. It was so pre­dictable that it had a nick­name. They called it the Rem­i­cade high. It’s ex­actly what you’d ex­pect if cy­tokines caused de­pres­sion: that anti- cy­tokines should be anti- de­pres­sant; that a shot of anti-tnf should make peo­ple with in­flamed minds feel high.”

The point was also proved in re­verse, when pa­tients with hep­ati­tis B be­ing treated with in­ter­feron, an in­flam­ma­tory cy­tokine to boost the im­mune re­sponse to the hep­ati­tis virus, be­came de­pres­sive. “This is not a side ef­fect, but a sign that the treat­ment is hav­ing its in­tended ef­fect of stim­u­lat­ing an in­flam­ma­tory re­sponse. This hap­pens to peo­ple who were not de­pressed im­me­di­ately be­fore the in­ter­feron in­jec­tion. Their ex­pe­ri­ence pro­vides some of the clear­est ev­i­dence in hu­mans that an in­flam­ma­tory stim­u­lus can cause de­pres­sion.”

C-re­ac­tive pro­teins and proin­flam­ma­tory cy­tokines are all present at higher lev­els in peo­ple who have de­pres­sion than in peo­ple who don’t. They’re also higher in other dis­or­ders such as obe­sity, di­a­betes and car­dio­vas­cu­lar dis­ease. But while they are markedly higher in con­di­tions such as blood poi­son­ing, they’re only mildly to mod­er­ately raised in peo­ple with de­pres­sion.

Of course, it’s not just in­fec­tion and in­jury that spark an in­flam­ma­tory re­sponse, but also stress, poverty and ad­verse child­hood ex­pe­ri­ences.

Left: an il­lus­tra­tion of a tu­mour necro­sis factor (Tnf)-al­pha, a proin­flam­ma­tory pro­tein that’s thought to be linked to de­pres­sion.

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