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CHICAGO -- North­west­ern Medicine sci­en­tists have dis­cov­ered a new path­way in the brain that can be ma­nip­u­lated to al­le­vi­ate de­pres­sion. The path­way of­fers a promis­ing new tar­get for de­vel­op­ing a drug that could be ef­fec­tive in in­di­vid­u­als for whom other an­tide­pres­sants have failed.

New an­tide­pres­sant op­tions are im­por­tant be­cause a sig­nif­i­cant num­ber of pa­tients don’t ad­e­quately im­prove with cur­rently avail­able an­tide­pres­sant drugs. The life­time preva­lence of ma­jor de­pres­sive dis­or­der is be­tween 10 to 20 per­cent of the pop­u­la­tion.

“Iden­ti­fy­ing new path­ways that can be tar­geted for drug de­sign is an im­por­tant step for­ward in im­prov­ing the treat­ment of de­pres­sive dis­or­ders,” said Sarah Brooker, the rst au­thor and an M.D./Ph.D stu­dent at North­west­ern Univer­sity Feinberg School of Medicine.

The aim of the North­west­ern study was to bet­ter un­der­stand how cur­rent an­tide­pres­sants work in the brain. The ul­ti­mate goal is to nd new ones that are more ef­fec­tive for peo­ple not cur­rently get­ting relief from ex­ist­ing drugs.

In the study, sci­en­tists dis­cov­ered for the rst time that an­tide­pres­sant drugs such as Prozac and tri­cyclics tar­get a path­way in the hip­pocam­pus called the BMP sig­nal­ing path­way. A sig­nal­ing path­way is a group of mol­e­cules in a cell that work to­gether to con­trol one or more cell func­tions. Like a cas­cade, af­ter the rst mol­e­cule in a path­way re­ceives a sig­nal, it ac­ti­vates an­other mol­e­cule and so forth un­til the cell func­tion is car­ried out.

Re­searchers showed that Prozac and tri­cyclics in­hibit this path­way and, thereby, trig­ger stem cells in the brain to pro­duce more neu­rons. Th­ese par­tic­u­lar neu­rons are in­volved in mood and mem­ory for­ma­tion. But the sci­en­tists didn’t know if block­ing the path­way con­trib­uted to the drugs’ an­tide­pres­sant ef­fect be­cause Prozac acts on mul­ti­ple mech­a­nisms in the brain.

Af­ter con­firm­ing the im­por­tance of the BMP path­way in de­pres­sion, North­west­ern sci­en­tists tested a brain pro­tein, Nog­gin, on de­pressed mice. Nog­gin is known block the BMP path­way and stim­u­late new neu­rons, called neu­ro­ge­n­e­sis.

Sci­en­tists in­jected Nog­gin into the mice and ob­served the ef­fect on mood by test­ing for de­pres­sion and anx­i­ety be­hav­ior. A sign of de­pres­sion in mice is a ten­dency to hang hope­lessly when held by the tail, rather than try­ing to get up­right. Af­ter re­ceiv­ing Nog­gin, mice en­er­get­i­cally tried to lift them­selves up, whereas con­trol mice were more likely to give up and be­come im­mo­bile.

The mice were then put in a maze with se­cluded (safe) and open (less safe) spaces. The Nog­gin mice were less anx­ious and ex­plored more mazes than the con­trol mice.

“The bio­chem­i­cal changes in the brain that lead to de­pres­sion are not well un­der­stood, and many pa­tients fail to re­spond to cur­rently avail­able drugs,” Kessler said. “Our nd­ings may not only help to un­der­stand the causes of de­pres­sion, but also may pro­vide a new bio­chem­i­cal tar­get for de­vel­op­ing more ef­fec­tive ther­a­pies.”

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