Home Featured Post Debunking the “chemical imbalance” theory yet not throwing out the antidepressant baby with the bathwater

Debunking the “chemical imbalance” theory yet not throwing out the antidepressant baby with the bathwater

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A recent study found incon­sis­tent evi­dence link­ing the neu­ro­trans­mit­ter sero­tonin to depres­sion. In an arti­cle for The Con­ver­sa­tion, the authors of the study con­clud­ed that it is impos­si­ble to say that tak­ing SSRI anti­de­pres­sants is worth­while. But is it safe to con­clude that sero­tonin is not involved in depres­sion or that mod­ern anti­de­pres­sants aren’t help­ful in treat­ing the condition?

Depres­sion is a com­mon and seri­ous life-lim­it­ing con­di­tion. Low mood and loss of enjoy­ment are its core symp­toms, but many unique symp­tom com­bi­na­tions can lead to a diag­no­sis. Two peo­ple with depres­sion can have very dif­fer­ent symptoms.

The roots of depres­sion are var­ied and peo­ple can have very dif­fer­ent rea­sons for their symp­toms. Psy­cho­log­i­cal trau­ma is a well-estab­lished risk fac­tor. And inflam­ma­tion is increas­ing­ly recog­nised as a like­ly cause in many research studies.

Many genet­ic fac­tors have also been iden­ti­fied, each with a very small effect. There are prob­a­bly thou­sands of small genet­ic effects with each per­son hav­ing an almost unique com­bi­na­tion that can increase the risk of depression.

These risk fac­tors explain why some peo­ple get depres­sion more often than oth­ers, but mul­ti­ple risk fac­tors are often report­ed by peo­ple with depres­sion, and it is not usu­al­ly pos­si­ble to con­clude which – if any – led to their symptoms.

Depres­sion, like many con­di­tions defined chiefly by its symp­toms, is unlike­ly to be a sin­gle con­di­tion with a sim­ple set of dis­crete caus­es. Sim­i­lar­ly, it is unlike­ly that there would be a sin­gle ther­a­py or drug that would treat all peo­ple effec­tive­ly. But the diverse symp­toms and risk fac­tors under­ly­ing depres­sion do not mean we lack effec­tive treatments.

Anti­de­pres­sants were dis­cov­ered ini­tial­ly by repur­pos­ing a drug used to treat tuber­cu­lo­sis, with lit­tle under­stand­ing of its effects on the brain.

Ini­tial research revealed that anti­de­pres­sants increased the quan­ti­ty of sero­tonin and nora­dren­a­line in the brain. These find­ings formed the basis of a the­o­ry of depres­sion, known as the monoamine hypoth­e­sis, which sug­gests that insuf­fi­cient lev­els of these neu­ro­trans­mit­ters are an under­ly­ing mech­a­nism of depres­sion that can be cor­rect­ed with antidepressants.

This sim­plis­tic expla­na­tion of depres­sion and its treat­ment has been met with con­flict­ing data and jus­ti­fi­able scep­ti­cism, and sev­er­al alter­na­tive the­o­ries of depres­sion and anti­de­pres­sants have been proposed.

For more than a decade, few researchers and health pro­fes­sion­als would refer to depres­sion as a sim­ple “chem­i­cal imbal­ance”. Yet it would be unwise to dis­miss the role of sero­tonin entire­ly, as there remains some evi­dence for its involve­ment in depres­sion. Although lim­it­ed access to liv­ing human brain tis­sue means that direct con­fir­ma­tion of serotonin’s role in depres­sion is difficult.

Our lim­it­ed under­stand­ing of both depres­sion and anti­de­pres­sant treat­ment has led the authors of the above­men­tioned study to ques­tion whether anti­de­pres­sants are a help­ful approach to treat­ment. These cri­tiques are not new, but they incor­rect­ly imply that an under­stand­ing of the mech­a­nism is nec­es­sary for effec­tive treatment.

In con­trast, the cor­ner­stone for iden­ti­fy­ing effec­tive treat­ments is the ran­domised con­trolled tri­al (the gold stan­dard of clin­i­cal research), which has been wide­ly applied to the study of anti­de­pres­sants and psy­chother­a­pies. This type of study can reli­ably tell us whether a treat­ment works or not – even if we have no idea why the treat­ment is effective.

Ran­domised con­trolled tri­als of thou­sands of depressed peo­ple have shown beyond rea­son­able doubt that anti­de­pres­sant drugs are effec­tive in depres­sion. Stud­ies of peo­ple with depres­sion treat­ed with anti­de­pres­sants can also pro­vide impor­tant infor­ma­tion on how treat­ments deliv­er their ben­e­fits and may in future pro­vide impor­tant infor­ma­tion on why some peo­ple respond more than others.

Con­di­tions defined large­ly by their symp­toms are dif­fi­cult to research and treat, but this has not pre­vent­ed the devel­op­ment of effec­tive treatments.

Depres­sion is usu­al­ly man­aged effec­tive­ly with anti­de­pres­sants or by talk­ing treat­ments, such as cog­ni­tive behav­iour ther­a­py, despite an incom­plete under­stand­ing of the con­di­tion and how these treat­ments work.

We can­not know if treat­ments address the under­ly­ing prob­lem because we haven’t yet iden­ti­fied what that is. To imply that SSRI anti­de­pres­sants may not be worth­while is to mis­un­der­stand an evi­dence base that says the very opposite.

Steadi­ly, we are begin­ning to under­stand more about the caus­es of depres­sion and iden­ti­fy sub­types, or “depres­sions”, that have more spe­cif­ic mech­a­nisms and treatments.

Our under­stand­ing of depres­sion and its treat­ment has been advanc­ing for more than a cen­tu­ry and shows no signs of slow­ing. Iden­ti­fy­ing the caus­es and new treat­ments for depres­sion is dif­fi­cult but essen­tial if we are to address one of the most com­mon caus­es of dis­abil­i­ty worldwide.

– This arti­cle was orig­i­nal­ly pub­lished on The Con­ver­sa­tion. Andrew M McIn­tosh is Pro­fes­sor of Bio­log­i­cal Psy­chi­a­try at the Uni­ver­si­ty of Edin­burgh, and Cathryn Lewis is Pro­fes­sor of Genet­ic Epi­demi­ol­o­gy & Sta­tis­tics at King’s Col­lege London.

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