Not a day goes by with­out a sig­nif­i­cant depression-related announce­ment. Yes­ter­day, one could read that Older Women More Likely to Suf­fer Depres­sion (than Older Men; in the Wash­ing­ton Post). Today, we see that St. Jude Start­ing Trial On Brain Stim­u­la­tion For Depres­sion (CNN). A few days ago, Blue Cross of Cal­i­for­nia Launched Mater­nity Depres­sion Pro­gram (press release).

Time to step back and ask our­selves ques­tions such as, “What is going On”, “What is Depres­sion”, “What Treat­ments Work, and What is the Lat­est Research”. For­tu­nately, thanks to our col­lab­o­ra­tion with Greater Good Mag­a­zine, Jill Sut­tie offers a fas­ci­nat­ing answers to those questions-and more. Enjoy.

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Clos­ing the Circuit

Helen Mayberg’s research could rev­o­lu­tion­ize depres­sion treatment.

— By Jill Suttie.

At some point in their lives, 5 to 12 per­cent of Amer­i­can men and 10–25 per­cent of women will suf­fer an episode of depres­sion, mak­ing it the most com­monly diag­nosed men­tal dis­or­der today. Unlike nor­mal sad­ness, which passes with time, depres­sion feels unstop­pable and causes peo­ple to lose inter­est in nearly all activ­i­ties. Because it affects a person’s abil­ity to eat, sleep, work, and func­tion nor­mally, it exacts a huge cost on the econ­omy, esti­mated at $30 bil­lion dol­lars annu­ally. The cost in human suf­fer­ing can­not be measured.

Mil­lions of peo­ple diag­nosed with depres­sion turn to med­ica­tion as a treat­ment, and many of the most pop­u­lar depres­sion med­ica­tions Prozac, Zoloft, and Paxil, to name a few work by chang­ing the chem­istry of the brain, increas­ing or decreas­ing the speed of infor­ma­tion exchanged between cells. How they alle­vi­ate depres­sion is not well under­stood, but the drugs are widely pre­scribed and, accord­ing to some experts, not always for good reason.

“Most peo­ple who are depressed go to their MD’s and are pre­scribed med­ica­tion, which is easy to take and usu­ally well-tolerated,” says Helen May­berg, an Emory Uni­ver­sity neu­rol­o­gist. “But only about 30 per­cent of peo­ple who take meds get bet­ter. Why?”

May­berg believes the answer may lie in her research. For years, May­berg has stud­ied how neural path­ways are dis­rupted dur­ing men­tal ill­ness, espe­cially depres­sion. Using the newest scan­ning tech­nolo­gies, she is mak­ing ground­break­ing dis­cov­er­ies about how depres­sion is wired in the brain and she is devel­op­ing a new tech­nol­ogy that can lit­er­ally “rewire” the brain to over­come depres­sion. If suc­cess­ful, her exper­i­ments could rev­o­lu­tion­ize the field of depres­sion treatment.

Explor­ing Area 25

May­berg first became inter­ested in brain scan­ning and depres­sion when she was a research fel­low at Johns Hop­kins Uni­ver­sity in the mid-1980s. There, she stud­ied stroke vic­tims and patients with Parkinson’s and Huntington’s dis­eases all of whom are at higher risk for depres­sion and dis­cov­ered some­thing inter­est­ing: Brain scans of depressed patients dis­played a unique activ­ity pat­tern. The frontal lobes of the brain the parts asso­ci­ated with higher cog­ni­tive processes, like how we inter­pret our expe­ri­ences and emo­tions always dis­played lower activ­ity lev­els. They didn’t in non-depressed patients.

“It made us real­ize that depres­sion is not nec­es­sar­ily due to a chem­i­cal imbal­ance, as peo­ple have thought for years, but might be due to a wiring pat­tern in the brain that has gone wrong,” says May­berg. Build­ing on this insight, May­berg has spent her career try­ing to learn more about the wiring of the depressed brain. Using scan­ning tech­niques, she’s stud­ied how brain activ­ity changes before and after treat­ment. In one line of research, May­berg found that depressed patients who improved after tak­ing Prozac for six weeks showed increased activ­ity in their frontal lobes, again sug­gest­ing this region plays a role in depres­sion. But she also made another, unex­pected dis­cov­ery: Activ­ity in the sub­gen­ual cin­gu­late a band of brain tis­sue known as “Area 25″ that lies deep within the frontal cor­tex and is part of the emo­tion con­trol cen­ter of the brain went down in all the patients who recovered.

May­berg won­dered whether there might be a spe­cific kind of inter­ac­tion between these brain regions that led to depres­sion. She spec­u­lated that a high level of activ­ity in Area 25 might depress activ­ity in the frontal lobes, which would pre­vent the frontal lobes from reg­u­lat­ing the dis­tress­ing thoughts that con­tribute to depres­sion. But later she stud­ied patients who had recov­ered from depres­sion using cog­ni­tive behav­ioral ther­apy (CBT), a form of talk ther­apy where patients are taught how to iden­tify neg­a­tive think­ing pat­terns and replace them with more pos­i­tive ones. In that study, patients who recov­ered had com­pletely dif­fer­ent results: Activ­ity went down in the frontal lobes instead of up, and activ­ity in Area 25 did not change.

These two seem­ingly con­tra­dic­tory results sug­gested to May­berg that depres­sion is not caused by a sin­gle brain activ­ity pat­tern, but by a brain activ­ity pat­tern that is dif­fer­ent for dif­fer­ent patients. Area 25 and the frontal lobes, she thought, form an inter­ac­tive cir­cuit in the brain, work­ing together to mod­u­late mood; in depressed patients, parts of the cir­cuit are either over-active or under-active. Med­ica­tion and CBT both appear to work by cor­rect­ing the bal­ance between the frontal lobes and Area 25: Med­ica­tion tar­gets Area 25 so that it doesn’t inhibit the frontal lobes, whereas CBT tar­gets the frontal lobes directly, mak­ing them less active. The impli­ca­tion to May­berg was that dif­fer­ent patients would require dif­fer­ent treat­ments, depend­ing on their par­tic­u­lar brain circuitry.

These con­clu­sions are bol­stered by numer­ous stud­ies of treat­ment effec­tive­ness, accord­ing to Steve Hol­lon, a pro­fes­sor at Van­der­bilt Uni­ver­sity and an expert in the field of depres­sion research. The com­bi­na­tion of CBT and med­ica­tion, explains Hol­lon, is con­sid­ered the most effec­tive treat­ment for depres­sion to date, and this mix of treat­ments has proven to be bet­ter at alle­vi­at­ing depres­sion than either treat­ment alone. If each treat­ment affects the brain dif­fer­ently as Mayberg’s work sug­gests it fol­lows that the com­bined treat­ment would have the best chance of induc­ing recov­ery for the great­est num­ber of patients because it would help those who would ben­e­fit from one or the other treat­ment, as well as patients who might respond best to a mix­ture of the two.

“Mayberg’s research is help­ing iden­tify for us what is going on in depres­sion at the neural level, how CBT and med­ica­tion affect the brain,” says Hol­lon. “She’s really on the cut­ting edge of where the field of depres­sion research needs to go.”

Rad­i­cal recoveries

May­berg moved to Emory Uni­ver­sity in 2003, where she is now work­ing with patients she calls the “ter­mi­nally depressed” those who’ve gone through mul­ti­ple treat­ment approaches and still haven’t recov­ered. In one recent, trail­blaz­ing study, she took six ter­mi­nally depressed patients and, using a new tech­nol­ogy called “deep brain stim­u­la­tion” (DBS), embed­ded wires in their brains at Area 25. The wires were attached to a bat­tery, which acted like a pace­maker, deliv­er­ing a steady but adjustable cur­rent to the wire. Imme­di­ately, patients reported some relief from their symp­toms, and their symp­toms con­tin­ued to improve over the weeks that followed.

“Four patients 60 per­cent recov­ered from their depres­sion. It was incred­i­ble,” says May­berg. “These are peo­ple who’d suf­fered for years, whose depres­sion was con­sid­ered intractable.” After a few months, May­berg also saw activ­ity increase in their frontal lobes, sug­gest­ing that stim­u­la­tion to Area 25 helped restore bal­ance to their brains’ cir­cuitry. Four years later, those four patients still have their wires intact and are still in remis­sion. Most have either stopped using med­ica­tion or have greatly reduced their dosage. Accord­ing to May­berg, their new chal­lenge is to learn how to adjust to being healthy. “Now they need to know what it’s like to have a bad day. Before, every day was a bad day,” she says.

As impres­sive as these results are, DBS is clearly not for every­one. May­berg offered it to peo­ple who, unlike most depressed patients, had not improved after years of try­ing other, more con­ven­tional treat­ments. And of course, even among peo­ple who might ben­e­fit from DBS when all other options fail, many will resist such an inva­sive treat­ment. Hus­seini Manji, a neu­ro­sci­en­tist and the direc­tor of the National Insti­tute of Men­tal Health’s Anx­i­ety and Mood Dis­or­ders Pro­gram, says that while he sees Mayberg’s DBS results as promis­ing, he ques­tions the prac­ti­cal­ity of imbed­ding elec­trodes in patients’ brains. “She has helped nar­row down where we need to inter­vene in the depressed brain,” says Manji. “But wouldn’t it be ideal if we could do the same thing chem­i­cally, to avoid brain surgery?”

Still, Manji com­mends May­berg for mak­ing impor­tant con­tri­bu­tions to the sci­en­tific under­stand­ing and treat­ment of depres­sion. Like May­berg, he thinks that brain scans could help iden­tify sub­groups of peo­ple who would ben­e­fit from cer­tain forms of treat­ment, espe­cially if these treat­ments are used in com­bi­na­tion with one another. “It may be that one needs chem­i­cal treat­ments to bring one­self back to a time when the brain wiring went wrong, and then cog­ni­tive restruc­tur­ing to rewire the brain so that it can fol­low a more pos­i­tive path­way,” he says.

At the National Insti­tute of Men­tal Health, Manji and a team of researchers are busy try­ing to develop chem­i­cal treat­ments that would work more effi­ciently than what’s cur­rently on the mar­ket. They are search­ing for a “smart mol­e­cule,” a chem­i­cal that would more accu­rately tar­get the parts of the brain impli­cated in depres­sion. So far, they’ve had luck with ket­a­mine, a med­ica­tion that, in higher doses, can be used as an anes­thetic. In a study he con­ducted with ter­mi­nally depressed patients, pub­lished in 2006, 71 per­cent of those patients receiv­ing a sin­gle intra­venous dose of ket­a­mine showed improve­ment within one day. This com­pares favor­ably against cur­rent pop­u­lar depres­sion med­ica­tions, which tend to take weeks to work. But ket­a­mine has severe side-effects, includ­ing hal­lu­ci­na­tions, which makes it unten­able as a med­ica­tion for the gen­eral pub­lic. Still, Manji believes that its fast action shows that researchers are on the right track.

“Cur­rent med­ica­tions may be work­ing at an indi­rect mol­e­c­u­lar tar­get in the brain, which is why there is such a lag time,” says Manji. “We need to move 20 steps beyond, to tar­get the exact cir­cuit in the brain that’s caus­ing depression.”

Hol­lon agrees that med­ica­tion for depres­sion needs to be refined. “Cur­rently, we put peo­ple with depres­sion on med­ica­tion and usu­ally keep them there,” he says. “But what we don’t know and we need to know is who needs to stay on med­ica­tion and who can come off of it.” Hol­lon hopes that Mayberg’s research will improve under­stand­ing of what is hap­pen­ing to patients’ brains as they progress through the heal­ing process, so that psy­chol­o­gists can select not only the best course for treat­ment, but the best treat­ment over time.

Get­ting there

Mean­while, May­berg is busy recruit­ing more patients to do another DBS study. She is also involved in a large-scale project to see whether brain scans of depressed patients can be used to pre­dict the best treat­ment for those patients. If suc­cess­ful, her exper­i­ments could trans­form depres­sion treat­ment. “If we knew that a par­tic­u­lar brain pat­tern indi­cated what type of treat­ment a patient would best respond to, it could save them years of unsuc­cess­ful treat­ment,” says May­berg. It could also elim­i­nate the need for drug treat­ment for some patients, and help those who resist med­ica­tion because of per­sonal beliefs or adverse side effects, she adds.

Despite these advances, May­berg says the research has a long way to go.

“We can’t be so arro­gant that we think we know exactly what a pat­tern of activ­ity in the brain means,” says May­berg. “When I see Area 25 light up because the per­son is sad, I still don’t know if that’s gen­er­at­ing the sad­ness, or if that’s the sig­nal try­ing to turn off the sad­ness.” She hopes that 10 years from now, bet­ter tech­nol­ogy will enable sci­en­tists to uncover more spe­cific infor­ma­tion about the neural cir­cuitry of depres­sion and other men­tal dis­or­ders, and that future treat­ment approaches will involve tar­get­ing spe­cific areas of the brain rather than flood­ing it with non­spe­cific drugs, like Prozac.

In the mean­time, May­berg is cau­tiously opti­mistic. “We need to move away from a one-size-fits-all approach to men­tal ill­ness,” she says. “I think we’re get­ting there.”

— Jill Sut­tie, Psy.D., is Greater Good’s book review edi­tor and a free­lance writer. Copy­right Greater Good. Greater Good Mag­a­zine, based at UC-Berkeley, is a quar­terly mag­a­zine that high­lights ground break­ing sci­en­tific research into the roots of com­pas­sion and altruism.

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