Study identifies cognitive benefits of ketamine in patients with treatment-resistant depression

Ket­a­mine mol­e­cules attach them­selves to NMDA neu­ronal recep­tors, which play an impor­tant role in brain plas­tic­i­ty and pre­dic­tive pro­cess­ing. C22H31NO2, CC BY-SA

Which fac­tors deter­mine what we believe about our world, our­selves, our past, and our future? Cog­ni­tive neu­ro­science sug­gests that our beliefs are depen­dent on brain activ­i­ty, specif­i­cal­ly on the way our brains process sen­so­ry infor­ma­tion in order to make sense of our environment.

These beliefs (defined as prob­a­bil­i­ty esti­mates) are cen­tral to our brain’s pre­dic­tive pro­cess­ing func­tion, which enables it to pre­dict the prob­a­bilis­tic struc­ture of the world around us. These pre­dic­tions could even be the fun­da­men­tal build­ing blocks of men­tal states, such as per­cep­tions and emotions.

Many psy­chi­atric dis­or­ders, such as depres­sion and schiz­o­phre­nia, are char­ac­terised by irreg­u­lar beliefs whose ori­gins we still don’t ful­ly under­stand. But if we can iden­ti­fy the cere­bral sys­tems gov­ern­ing them, we could tar­get those very areas in a bid to alle­vi­ate the pain asso­ci­at­ed to these illnesses.

Decoding belief mechanisms in psychiatry

This is one of the find­ings of our study recent­ly pub­lished in the jour­nal JAMA Psy­chi­a­try. For this study, I explored with my team how the dis­so­cia­tive psy­chotrop­ic, ket­a­mine, affects mech­a­nisms of belief updat­ing (i.e., how we change our beliefs upon receiv­ing infor­ma­tion) in patients with treat­ment-resis­tant depression.

While tra­di­tion­al anti­de­pres­sants take weeks to show any results, ket­a­mine – an antag­o­nist mol­e­cule that acts on the NMDA (N‑methyl-D-aspar­tate) recep­tors – pro­duces anti­de­pres­sant effects with­in hours. When admin­is­tered, it also caus­es a dis­so­cia­tive expe­ri­ence of deper­son­al­i­sa­tion typ­i­cal­ly asso­ci­at­ed with a sen­sa­tion of leav­ing the body (known as “autoscopy”).

Giv­en that ketamine’s rapid action and unex­pect­ed dis­so­cia­tive effects make it a poten­tial­ly worth­while option for treat­ing men­tal health prob­lems, we are on a mis­sion to unpack this mys­tery, at the cross­roads between phar­ma­col­o­gy and neuroscience.

Cognitive-affective biases in depression

Accord­ing to the World Health Orga­ni­za­tion, depres­sion affects approx­i­mate­ly 280 mil­lion peo­ple in the world and 700 000 peo­ple die due to sui­cide every year. One of the most spe­cif­ic symp­toms of depres­sion is depres­sive beliefs (e.g., pes­simism, self-dep­re­ca­tion, rejec­tion, and feel­ings of fail­ure), described as “mood-con­gru­ent” beliefs when their con­tent match­es the subject’s affec­tive state.

By influ­enc­ing the patient’s per­cep­tion and action, these beliefs play a vital role in trig­ger­ing the phe­nom­e­non of neg­a­tive auto-rein­force­ment. For exam­ple, the belief that we have been reject­ed by our peers grad­u­al­ly makes us more with­drawn, which in turn rein­forces feel­ings of worth­less­ness. Once this feed­back loop has been closed, it can be dif­fi­cult not to spi­ral downward.

Ever since the pio­neer­ing research of psy­chi­a­trist Aaron Beck, many stud­ies have sug­gest­ed that the ways in which infor­ma­tion is encod­ed in belief net­works accord­ing to their valence (i.e., their pos­i­tive or neg­a­tive nature) could be linked to the emer­gence of depres­sive beliefs.

This inno­v­a­tive research has shown that our brains are like­li­er to encode pos­i­tive infor­ma­tion. Known as “affec­tive bias”, this phe­nom­e­non is respon­si­ble for gen­er­at­ing beliefs that are slight­ly more pos­i­tive than real­i­ty. For instance, we tend to think we are more intel­li­gent, more attrac­tive, bet­ter dri­vers or bet­ter lovers than what is shown in sta­tis­ti­cal reality.

How­ev­er, with depres­sion, this bias dis­ap­pears or flips, with patients tak­ing in more neg­a­tive-valence infor­ma­tion that grad­u­al­ly gen­er­ates gloomi­er beliefs about the world, them­selves, or the future. This phe­nom­e­non of an invert­ed affec­tive bias could well be key to under­stand­ing the ori­gins of depres­sive beliefs.

How ketamine acts on belief systems

We launched our study on the back of a sur­pris­ing clin­i­cal obser­va­tion made at our unit at Paris’s Hôpi­tal de la Pitié-Salpêtrière. When giv­en ket­a­mine as an anti­de­pres­sant, patients with treat­ment-resis­tant depres­sion report­ed feel­ing a strange sen­sa­tion where­by their per­spec­tives on the world seemed to have shift­ed, almost as though their very point of view had been altered.

The neg­a­tive beliefs that they had been car­ry­ing for sev­er­al months appeared to have fad­ed. Some patients even expressed a feel­ing of for­eign­ness, as if their thoughts belonged to some­one else. Even more intrigu­ing­ly, these changes appeared to result from the drug’s anti­de­pres­sant effect, although we still don’t under­stand the causal­i­ty of this.

In light of our patients’ accounts, we sus­pect­ed that ket­a­mine had affect­ed the brain’s belief-updat­ing mech­a­nisms. In an effort to under­stand this phe­nom­e­non, we con­duct­ed an exper­i­ment intend­ed to assess ketamine’s influ­ence on the ways we gen­er­ate beliefs, using pre- and post-treat­ment exper­i­men­tal task and com­pu­ta­tion­al modelling.

Pri­or to the ket­a­mine admin­is­tra­tions, we asked patients and healthy sub­jects to assess their like­li­hood of expe­ri­enc­ing 40 dif­fer­ent future neg­a­tive events (e.g., being bit­ten by a dog or hav­ing a car acci­dent). After being informed of the actu­al occur­rence risks in the gen­er­al pop­u­la­tion, the two groups were again asked to assess the prob­a­bil­i­ty of these events occur­ring in their lives. Results show healthy sub­jects took into account new pos­i­tive facts to update their beliefs, where­as this was not the case for depressed persons.

How­ev­er, this changed only four hours after receiv­ing the first ket­a­mine dose: patients were far less sen­si­tive to neg­a­tive infor­ma­tion and recov­ered their abil­i­ty to update their beliefs. This meant the pos­i­tive affec­tive bias had been restored among patients with treat­ment-resis­tant depres­sion. All the more sur­pris­ing­ly, this effect was direct­ly linked to a reduc­tion in depres­sive symp­toms after one week, which sug­gests that these cog­ni­tive changes may even occur pri­or to clin­i­cal improvement.

Avenues of future research

Fur­ther research is need­ed to under­stand the brain process­es asso­ci­at­ed with these changes, but many clues point to the involve­ment of NMDA recep­tor-medi­at­ed sig­nalling. These neu­ronal recep­tors con­tribute to the brain’s exci­ta­tion-inhi­bi­tion bal­ance, and appear to be essen­tial to pre­dic­tive pro­cess­ing and brain plasticity.

Ketamine’s direct action on the activ­i­ty of these recep­tors may con­sti­tute a direct phar­ma­co­log­i­cal path­way that reg­u­lates pre­dic­tive mech­a­nisms, which would explain the drug’s rapid-onset anti­de­pres­sant effects and its dis­so­cia­tive prop­er­ties. By con­trol­ling the way the brain uses its sen­so­ry build­ing blocks to gen­er­ate beliefs, ket­a­mine could help change the mech­a­nisms behind depres­sive symptoms.

These hypothe­ses open up numer­ous per­spec­tives for devel­op­ing treat­ments tar­get­ing brain pro­cess­ing, or for com­bin­ing these mol­e­cules with aug­ment­ed psy­chother­a­py, pro­to­cols that focus specif­i­cal­ly on belief sys­tems. This goal is at the core of debates in so-called psy­che­del­ic med­i­cine, par­tic­u­lar­ly in treat­ment using psilo­cy­bin, a hal­lu­cino­genic mol­e­cule that also presents rapid anti­de­pres­sant effects. Could this research help bring phar­ma­co­log­i­cal and psy­chother­a­peu­tic approach­es togeth­er in psychiatry?

– Hugo Bot­te­manne is Psy­chi­a­tre à la Pitié-Salpêtrière & chercheur à l’In­sti­tut du Cerveau, Sor­bonne Uni­ver­sité. This arti­cle is based on the results of “Eval­u­a­tion of Ear­ly Ket­a­mine Effects on Belief-Updat­ing Bias­es in Patients With Treat­ment-Resis­tant Depres­sion”, recent­ly pub­lished in JAMA Psy­chi­a­try. The arti­cle was orig­i­nal­ly pub­lished on The Con­ver­sa­tion and trans­lat­ed from the French by Enda Boor­man for Fast For­Word.

To Learn More:

• FDA-approved, Cybin-spon­sored clin­i­cial tri­al to mea­sure ketamine’s impact on the brain via Ker­nel Flow neu­roimag­ing helmet
• Study: Psy­che­delics can pro­mote neur­al plas­tic­i­ty in the pre­frontal cor­tex and expand path­ways for men­tal health