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

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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