p

A SUPPLEMENTARY STUDY GUIDE prepared by Hannah Van Sciver

Book and Lyrics by Brian YorkeyMusic by Tom Kitt

Directed by Terrence J. Nolen

About the Play: Synopsis........................................2 The Creators: Tom Kitt and Brian Yorkey.................3-4

Production History..............................................5-6

Winning the Pulitzer.............................................7-8

Background: Treating Depression.........................9-12

Glossary of Terms..............................................13-14 Meet the Cast.......................................................15 Meet the Creative Team.........................................16

Discussion Questions.............................................17

ABOUT THE PLAY: Synopsis warning: spoilers!

1.

Table of Contents

Act 1

Next to Normal opens in the suburban home of Diana Goodman, her husband Dan, and their two children. They endeavor to start the day like a “normal” family, but things spin out of control as Diana struggles to make sandwiches. Her daughter Natalie finds solace at school in the piano practice room, where she runs into Henry. He is her markedly calmer classmate, who seems to have taken a sudden interest in her. Meanwhile, Dan takes Diana to visit Dr. Fine, who is treating her for bipolar disorder, hallucinations and depression. While Natalie’s romance with Henry slowly blooms, Diana is eventually medicated into a state of emotional numbness. She decides to flush away her medication under the urging of her son. Natalie warily brings Henry home for dinner, but the evening is soured when Diana serves a birthday cake for her son. Dan reveals that their son died sixteen years ago, in his infancy. Doctor Madden suggests hypnosis to treat Diana’s worsening delusions. In the pro-cess of cleaning out her son’s things Diana has a hallucination, and awakes in the hospital with self-inflicted wrist gashes. Doctor Madden recommends electro-shock therapy treatment for Diana’s suicidal and drug-resistant behavior. Dan convinces her it’s her only chance at recov-ery, and she consents. The act ends as the treatment begins.

Act II

While Diana is in treatment for two weeks, Natalie spins out of control, hitting clubs and experimenting with hard drugs. Her relationship with Henry falters, and he tries to invite her to the spring formal dance. When Diana returns home, she has lost nineteen years of her memory. At the suggestion of Doctor Madden, Dan uses different keepsakes to help her recover memories, but leaves out any allusions to the painful parts of her past. Henry arrives to see Natalie, and reminds Diana of someone she can’t quite place. Diana finds her son’s old music box, and slowly recovers memories of him. Henry arrives to pick up Natalie for the dance, but Dan and Diana have an argument, which culminates with Dan smashing the music box. Diana questions Dan’s devotion to her, and Natalie chides Henry, wondering if he’ll be able to handle her if she too goes crazy. Doctor Madden encourages Diana to continue her treatments, but Diana decides she’s had enough. She comes clean to her daughter about both her failings as a mother and Nata-lie’s dead brother, and sends Natalie to meet Henry at the formal. Diana decides to leave Dan so she can begin to work through things on her own. Dan has a breakdown and is visited by their son, who he calls by his name, “Gabe,” for the first time. Dan visits Doctor Madden, and opens up about his own depression, while Diana moves back in with her parents. Though still distressed, she is hopeful that the change will lead to recovery. Natalie and Henry make up, and Natalie and Dan agree to work together to fix their family. Gabe watches from a distance.

ABOUT THE PLAY: Synopsis warning: spoilers!

2.

Brian Yorkey, book and lyrics

As a Pulitzer Prize and Tony Award-winning writer, Brian Yorkey is a household name. But much like his hit musical Next to Normal, Yorkey has had quite the unique path to success. Born in Nebraska, he moved to Seattlewith his family at age ten, where he first developed an interest in theatre. Says Yorkey of his early hobby, “I was mostly just interested in attention, and I was a terrible athlete. So that kind of left drama.” While in high school, he worked at the local Village Theatre, where he learned the business and production side of his craft. Co-founder Robb Hunt was impressed with Yorkey’s drive and ability from a young age. “He’s probably one of the smartest people I’ve ever known—even as a high-school kid. It was clear he would do great things in the world, and it was fortunate for us that he wanted to do musical theater,” says Hunt. After graduation, Yorkey attended Columbia University, where he met Next to Nor-mal composer Tom Kitt. At Columbia, Yorkey served both as artistic director of “The Var-sity Show,” and as a member of the BMI Lehman Engel Musical Theater Workshop. In 2000, Yorkey returned to The Village to serve as associate artistic director. “A big part of my job was helping people try to make their musicals better. My seven years in that job were incredibly productive in learning a respect for which rules you break at your own peril and what it takes to get a musical up and running,” says Yorkey. During those years, Yorkey staged five of his own original musicals, and worked with Kitt on developing the musical which would eventually grow into Next to Normal. Since the success of Next to Normal, Yorkey’s writing career has taken off. He’s writ-ten screenplays for studios such as Paramount, Lionsgate Films and Universal, and he’s cur-rently working on new musicals both with Tom Kitt and with singing legend “Sting.” Yorkey once said with regard to writing, “It’s exponentially harder to write an original musical. Musicals that go wrong can be ridiculous because it’s a ridiculous art form. People bursting into song can be ridiculous. But musicals that go right can be sublime.”

Credits:Theatre-Funny Pages, Making Tracks, The Wedding Banquet, Play It By Heart, A Perfect Fall, Next to Normal

Film and TV-Time After Time, Sluts, Love Undercover, Overture, Chase, The Bears Next Door

Awards-2009 Tony Award for Best Score for Next to Normal co-winner of 2010 Pulitzer Prize for Drama for Next to Normal

The Creators

3.

BRIA

N YO

RKEY

The Creators

Tom Kitt composer

If you leave the New York theatre humming on a given night, it’s likely that Tom Kitt had something to do with it. An extremely prolific Broadway composer, music director, orchestrator, arranger, conductor and musician in his own right, Kitt is also a Pulitzer Prize Winner, a Tony Award Winner, and an Outer Critics Circle Award Winner. Kitt grew up in New York, where he participated in high school theatre productions from a young age. After graduation he studied economics at Columbia College, where he also sang with a cappella group “The Columbia Kingsmen,” and enrolled in the BMI Lehman Engel Musical Theater Workshop. It was there that Kitt first befriended writer Brian Yorkey. Kitt’s Broadway career began in 2002 with the debut of Debbie Does Dallas, for which he composed and arranged some of the music. Since then, Tom Kitt has helped compose and arrange music for a slew of hits, including High Fidelity, Next to Normal, Everyday Rapture and American Idiot, to name a few. And when he’s not working on Broadway, Kitt composes and plays piano in The Tom Kitt Band, and occasionally performs his own songs in one-man shows around New York. Kitt recently finished composing for the new musical adaptation of Bring it On, and is now working on a new musical project with Next to Normal writer Brian Yorkey.

Credits:as Composer-Bring It On The Musical, Everyday Rapture, Next To Normal, High Fidelity, From Up Here, The Winter’s Tale

as Orchestrator, Arranger, Musical Director and Conductor-American Idiot, 13, Hair, Laugh Whore, Urban Cowboy, Debbie Does Dallas, Everyday Rap-ture, Green Day album 21st Century Breakdown

Awards-2008 Outer Critics Circle Award for Outstanding New Score2009 Tony Awards for Best Score and Best Orchestrations2009 Outer Critics Circle Award for Best New Score 2009 Frederick Loewe Award for Dramatic Compositionco-winner of 2010 Pulitzer Prize for Drama

4.

TOM

KITT

SECTION TWO: HISTORY AND CONTEXT

8.

The disorderly history of Next to Normal begins with the meeting of writer Brian Yorkey and composer Tom Kitt at Columbia University in the 1990s. The two were both enrolled in the BMI Lehman Engel Musical Theater Workshop, where they first de-cided to write a musical together. For a first-year final project in 1998, they presented a 10-minute piece called Feeling Electric. The show, which was in fact the very first incar-nation of Next to Normal, came from an idea Yorkey got while watching an NBCDate-line episode on shock therapy. Says Yorkey of the original concept, “We were looking for something that was a little offbeat. We wanted to shake things up and get a rise out of people.” Later, while Yorkey served as artistic director at The Village regional theatre, the pair returned to the project from their college days, reworking the material for a read-ing in 2002. After receiving a grant in 2004, they again reworked the material for a premiere in the New York Musical Theater Fest in 2005. Says Village co-founder Robert Hunt of early versions of Feeling Electric, “We weren’t sure it would ever make it to our mainstage, but it was brilliantly written and very moving and funny and we saw the huge potential. We had absolute belief in what Brian was doing, and wanted to help move that show forward.” Many drafts later, Feeling Electric had grown into a poignant rock-musical. While originally focusing on the more clinical aspects of treatment for depression, it had ex-panded to more broadly address the American family dynamic. The show, now titled Next to Normal, debuted in New York in 2008, with a successful stint at Second Stage. Had Next to Normal followed the usual track, this run would have led to a Broadway opening. However, the show instead moved to the regional Arena Stage in D.C. for further reworking.

Production History The Long Road to Success

Often in the theatre, too much reworking can cause a script to lose both its focus and its novelty. However, for Next to Normal, the winding path it took to Broadway is what allowed it to become a masterpiece. During the final reworking in D.C., a total of nine musical numbers were either cut or replaced, including “Feeling Electric,” the orig-inal title track. Furthermore, the overall attitude of the piece was adjusted. Says Yorkey of the change, “At Second Stage, we agreed we didn’t quite know what the show was yet…It didn’t finally sink in until after our first New York opening (at Rothman’s Second Stage). It’s easy to be snarky about medicine and blame it for failing to solve anything. The more interesting question is: If medicine does the best it can and it’s not enough, what do we do then? How do we live our lives?” The final version of Next to Normal opened at last on Broadway in 2009, starring Alice Ripley, J. Robert Spencer, Jennifer Damiano, Aaron Tveit, Adam Chanler-Berat and Louis Hobson. The show was a hit, snagging both the 2009 Pultizer Prize, as well as the Tony Awards for best score and orchestrations. Looking back on the strange pro-cess, Yorkey comments, “Shows do develop in their own time. Sometimes you just have to keep going and believe the right moment will come.”

Production History: continued

Winning the Pulitzer ~Making History~

Even stranger than Next to Normal’s path to Broadway was its path to the Pul-tizer-Prize for Drama. The show is only the eighth musical in history to earn the much-coveted prize. Furthermore, Next to Normal wasn’t even nominated as a finalist for the award. The Pulitzer Prize was originally established in 1917 in honor of journalist and publisher Joseph Pultizer. The drama award is just one of twenty-one different Pulit-zer Award categories. As stated in official guidelines, the drama award is “for a distin-guished play by an American author, preferably original in its source and dealing with American life.” It also includes a $10,000 prize. While the judging committee accepts submissions for the award, guidelines stipulate that the top honor may be given to a play which is not submitted. Furthermore, a winner does not have to be named every year. (This last occurred in 2006.) In 2010, finalists for the drama prize were The Elaborate Entrance of Chad Deity by Kristoffer Diaz; Bengal Tiger at the Baghdad Zoo by Rajiv Joseph; and In the Next Room or The Vibrator Play by Sarah Ruhl. Jurors included drama critic Charles McNulty, Duke University professor John M. Clum, playwright Nilo Cruz, theatre critic David Rooney and theatre critic Hedy Weiss. The Pulitzer jury chose to recognize Next to Normal for its subject matter, and stated that it “expands the scope of subject matter for musicals.” Next to Normal was the first musical to win the award since Jonathan Larson’s Rent in 1996. Other musicals to earn the Pulitzer include Sunday in the Park With George, A Chorus Line, How to Succeed in Business Without Really Trying and South Pacific.

7.

8.

Winning the Pulitzer ~Past Winners~

2011-12: Water by the Spoonful, Quiara Alegría Hudes 2010-11: Clybourne Park, by Bruce Norris2009-10: Next to Normal, by Brian Yorkey and Tom Kitt 2008-09: Ruined, by Lynn Nottage2007-08: August: Osage County, by Tracy Letts2006-07: Rabbit Hole, by David Lindsay-Abaire2005-06: No award2004-05: Doubt, by John Patrick Shanley2003-04: I Am My Own Wife, by Doug Wright2002-03: Anna in the Tropics, by Nilo Cruz2001-02: Topdog/Underdog, by Suzan-Lori Parks2000-01: Proof, by David Auburn1999-00: Dinner with Friends, by Donald Margulies1998-99: Wit, by Margaret Edson 1997-98: How I Learned To Drive, by Paula Vogel1996-97: No award1995-96: Rent, by Jonathan Larson1994-95: The Young Man From Atlanta, by Horton Foote1993 94: Three Tall Women, by Edward Albee1992-93: Angels in America: Millennium Approaches, by Tony Kushner1991-92: The Kentucky Cycle, by Robert Schenkkan1990-91: Lost in Yonkers, by Neil Simon1989-90: The Piano Lesson, by August Wilson1988-89: The Heidi Chronicles, by Wendy Wasserstein1987 88: Driving Miss Daisy, by Alfred Uhry1986-87: Fences, by August Wilson1985-86: No award1984-85: Sunday in the Park With George, by James Lapine and Stephen Sondheim1983-84: Glengarry Glen Ross, by David Mamet1982-83: ‘night, Mother, by Marsha Norman1981 82: A Soldier’s Play, by Charles Fuller1980-81: Crimes of the Heart, by Beth Henley1979-80: Talley’s Folly, by Lanford Wilson1978-79: Buried Child, by Sam Shepard1977-78: The Gin Game, by D.L. Coburn1976-77: The Shadow Box, by Michael Cristofer1975-76: A Chorus Line, by Michael Bennett, James Kirkwood, Nicholas Dante, Marvin Hamlisch and Edward Kleban1974-75: Seascape, by Edward Albee1973 74: No award1972-73: That Championship Season, by Jason Miller1971-72: No award 1970-71: The Effect of Gamma Rays on Man-in-the-Moon Mari-golds, by Paul Zindel1969-70: No Place to Be Somebody, by Charles Gordone1968-69: The Great White Hope, by Howard Sackler1967-68: No Award 1966-67: A Delicate Balance, by Edward Albee1965-66: No Award 1964-65: The Subject Was Roses, by Frank D. Gilroy1962-64:No Award

1961-62: How to Succeed in Business Without Really Trying, by Frank Loesser and Abe Burrows 1960-61: All the Way Home, by Tad Mosel1959-60: Fiorello! by George Abbott, Jerome Weidman, Jerry Bock, and Sheldon Harnick 1958-59: J.B., by Archibald MacLeish1957-58: Look Homeward, Angel, by Ketti Frings1956-57: Long Day’s Journey Into Night, by Eugene O’Neill1955-56: The Diary of Anne Frank, by Frances Goodrich and Albert Hackett 1954-55: Cat on a Hot Tin Roof, by Tennessee Williams1953-54: The Teahouse of the August Moon, by John Patrick1952-53: Picnic, by William Inge1951-52: The Shrike, by Joseph Kramm1950-51: No award1949-50: South Pacific, by Richard Rodgers, Oscar Hammer-stein II and Joshua Logan1948-49: Death of a Salesman, by Arthur Miller1947-48: A Streetcar Named Desire, by Tennessee Williams1946-47: No award1945-46: State of the Union, by Howard Lindsay and Russel Crouse1944-45: Harvey, by Mary Chase1943-44: No award1942-43: The Skin of Our Teeth, by Thornton Wilder1941-42: No award1940-41: There Shall Be No Night, by Robert E. Sherwood1939-40: The Time of Your Life, by William Saroyan1938-39: Abe Lincoln in Illinois, by Robert E. Sherwood1937-38: Our Town, by Thornton Wilder1936-37: You Can’t Take It With You, by Moss Hart and George S. Kaufman1935-36: Idiot’s Delight, by Robert E. Sherwood1934-35: The Old Maid, by Zoe Akins1933-34: Men in White, by Sidney Kingsley1932-33: Both Your Houses, by Maxwell Anderson1931-32: Of Thee I Sing, by George S. Kaufman, Morrie Ryskind and Ira Gershwin1930-31: Alison’s House, by Susan Glaspell1929-30: The Green Pastures, by Marc Connelly1928-29: Street Scene, by Elmer Rice1927-28: Strange Interlude, by Eugene O’Neill1926-27: In Abraham’s Bosom, by Paul Green1925-26: Craig’s Wife, by George Kelly1924-25: They Knew What They Wanted, by Sidney Howard1923-24: Hell-Bent fer Heaven, by Hatcher Hughes1922-23: Icebound, by Owen Davis1921-22: Anna Christie, by Eugene O’Neill1920-21: Miss Lulu Bett, by Zona Gale1919-20: Beyond the Horizon, by Eugene O’Neill1918-19: No award1917-18: Why Marry?, by Jesse Lynch Williams1916-17: No award

THE UNIVERSITIES

12.

Background: Treating Depression

Post-Prozac Nation: The Science and History of Treating DepressionBy SIDDHARTHA MUKHERJEE, Published: April 19, 2012 in The New York Times

Few medicines, in the history of pharmaceuticals, have been greeted with as much exultation as a green-and-white pill containing 20 milligrams of fluoxetine hydrochloride — the chemical we know as Prozac. In 1988, a year after the Food and Drug Administration approved Prozac, 2,469,000 prescriptions for it were dispensed in America. By 2002, that number had risen to 33,320,000. By 2008, antidepressants were the third-most-com-mon prescription drug taken in America.Fast forward to 2012 and the same antidepressants that inspired such enthusiasm have become the new villains of modern psychopharmacology. In fact, the very theory for how these drugs work has been called into ques-tion. For decades, a central theory in psychiatry has been that antidepressants worked by raising serotonin lev-els in the brain. Prozac and Paxil were thought to increase serotonin levels, thereby strengthening the signals between nerve cells — as if a megaphone had been inserted in the middle.But this theory has been widely criticized. Is the “serotonin hypothesis” of depression really dead? The lat-est research suggests that serotonin is, in fact, central to the functioning of mood, although its mechanism of action is vastly more subtle and more magnificent than we ever imagined. Prozac, Paxil and Zoloft may never turn out to be the “wonder drugs” that were once advertised. But they have drastically improved our under-standing of what depression is and how to treat it.

In the autumn of 1951, doctors treating tubercular patients at Sea View Hospital on Staten Island with a new drug — iproniazid — observed sudden transformations in their patients’ moods and behaviors. The wards — typically glum and silent, with moribund, lethargic patients — were “bright last week with the happy faces of men and women,” a journalist wrote. If the men and women at Sea View were experiencing an awaken-ing, then a few hundred miles south, others at Duke’s hospital encountered its reverse. In 1954, a 28-year-old woman was prescribed Raudixin to control her blood pressure. A few months later, she returned to the hos-pital, complaining of crying spells, dullness and lethargy. She felt futile, guilty and hopeless, she told her doc-tors. A few months later, when she returned, the sense of futility had turned into hostility. The “feeling blue,” as another patient described it, persisted until the drug was discontinued.Psychiatrists and pharmacologists were quick to note these bizarre case reports. It was around this same time that scientists were learning that the brain itself was immersed in a soup of chemicals. By the late 1960s, evi-dence suggested that signals between neurons were carried by several chemicals, including the neurotrans-mitter serotonin. Might iproniazid and Raudixin have altered the levels of some neurotransmitters in the brain, thereby changing brain signaling and affecting mood? Strikingly so, scientists found. Raudixin — the “feeling blue” drug — drastically lowered the concentration of serotonin and closely related neurotransmitters in the brain. Conversely, drugs known to increase euphoria, like iproniazid, increased those levels.These early findings led psychiatrists to propose a radical new hypothesis about the cause and treatment of de-pression. Depression, they argued, was a result of a “chemical imbalance” of neurotransmitters in the brain. In the normal brain, serotonin shuttled between mood-maintaining neurons, signaling their appropriate function. In the depressed brain, this signal had somehow gone wrong.Powerful vindication for this theory came from the discovery of new medicines that specifically elevated sero-tonin concentrations. The first such drug, Zimelidine, was created by a Swedish researcher, Arvid Carlsson. Fol-lowing Carlsson’s lead, pharmaceutical chemists threw their efforts and finances into finding serotonin-enhanc-ing drugs, and the new giants of the antidepressant world were born in rapid succession. Prozac was created in 1974. Paxil appeared in 1975, Zoloft in 1977.

In 2003, in Boston, I began treating a 53-year-old woman with advanced pancreatic cancer. The suddenness of the diagnosis struck her like an intravenous anesthetic, instantly numbing everything. Most disturbing, I watched as she lapsed into self-neglect. This grief, of course, was fully provoked by the somberness of her diagnosis, but she recognized something troubling in her own reaction and begged for help. I contacted a psy-chiatrist. With her consent, we prescribed Prozac.

ants. The study vindicated Kirsch’s conclusions but only to a point. In patients with moderate or mild depres-sion, the benefit of an antidepressant was indeed small, even negligible. But for patients with the most severe forms of depression, the benefit of medications over placebo was substantial. Like Dorothy, these patients most likely still experienced sorrow, but they experienced it in ways that were less self-destructive or paralyz-ing. As Solomon wrote: “The opposite of depression is not happiness, but vitality, and my life, as I write this, is vital.”These slippery, seemingly contradictory studies converge on a surprisingly consistent picture. First, patients with severe depression tend to respond most meaningfully to antidepressants, while patients with moderate or mild depression do not. Second, in a majority of those who do respond, serotonin very likely plays an im-portant role, because depleting serotonin in depressed patients often causes relapses. And third, the brain-as-soup theory — with the depressed brain simply lacking serotonin — was far too naïve.

As is often the case in science, a new theory emerged from a radically different line of inquiry. In the late 1980s, a neuroscientist named Fred Gage became interested in a question that seemed, at first, peripheral to depression: does the adult human brain produce new nerve cells?The dogma in neurobiology at the time was that the adult brain was developmentally frozen. But Gage and

13.

Background: continuedIn the first weeks, we waited watchfully, and nothing happened. But when I saw her again in the clinic after a month and a half, there were noticeable changes. Yet she still felt sad beyond measure, she said. The drug certainly affected many of the symptoms of depression, yet had not altered the subjective “feeling” of it.Any sane reader of this case would argue that a serotonin imbalance was not the initiating cause of Dorothy’s depression; it was, quite evidently, the diagnosis of a fatal disease. Pause for a moment, though, to consider the physiology of a heart attack. A heart attack can be set off by a variety of causes — yet aspirin is an effec-tive treatment of a heart attack regardless of its antecedent cause. Why? Because a heart attack, however it might have been provoked, progresses through a common, final pathway: there must be a clot in a coronary artery that is blocking the flow of blood to the heart. Might major depression be like a heart attack, with a central common pathway and with serotonin as its master regulator?But such a line of inquiry can’t tell us whether the absence of serotonin causes depression. For that, we need to know if depressed men and women have measurably lower levels of serotonin or serotonin-me-tabolites (byproducts of serotonin breakdown), in their brains. In 1975, pathologists performed autopsies on depressed patients to measure serotonin levels. The initial findings were suggestive: depressed patients typically tended to have lower levels of brain serotonin compared with controls. But in 1987, when research-ers in Scandinavia performed a similar experiment with newer tools to measure serotonin more accurately, serotonin levels were found to be higher in depressed patients. In 1994, male subjects at McGill University in Montreal were given a chemical mixture that lowered serotonin. Doctors then measured the fluctuations in the mood of the men as serotonin levels dipped in the blood. Though serotonin was depleted, most of them experienced no significant alterations in their mood.At first glance, these studies seem to suggest that there is no link between serotonin and depression. But an important fact stands out in the McGill experiment: lowering serotonin does not have any effect on healthy volunteers with no history of depression, but serotonin-lowering has a surprisingly brisk effect on people with a family history of depression. Other experiments showed that though depressed patients generally didn’t have consistently lower levels of serotonin, suicidal patients often did. Might contemplating suicide be the most extreme form of depression? Or is it a specific subtype of mood disorder that is distinct from all the other forms? And if so, might depression have multiple subtypes — some inherently responsive to treatment with serotonin-enhancing drugs and some inherently resistant?

We may not understand how serotonin-enhancing antidepressants work, but do we know whether they work at all? In 1997, a psychologist, Irving Kirsch, currently at the Harvard Medical School, set out to look at the placebo effect in relation to depression. To measure this effect, Kirsch combined 38 trials that included pa-tients who had been given antidepressants, placebos or no treatment and then applied mathematical reason-ing to estimate how much the placebos contributed to the improvements in mood. He found that 75 percent of an antidepressant’s effect could have been obtained merely by taking the placebo. Kirsch came to believe that pharmaceutical companies were exaggerating the benefits of antidepressants by selectively publishing positive studies while suppressing negative ones.In 2010, researchers revisited Kirsch’s analysis using six of the most rigorously conducted studies on antide-pressants. The study vindicated Kirsch’s conclusions but only to a point. In patients with moderate or mild depression, the benefit of an antidepressant was indeed small, even negligible. But for patients with the most severe forms of depression, the benefit of medications over placebo was substantial. These slippery, seemingly contradictory studies converge on a surprisingly consistent picture. First, patients with severe depression tend to respond most meaningfully to antidepressants, while patients with moder-ate or mild depression do not. Second, in a majority of those who do respond, serotonin very likely plays an important role, because depleting serotonin in depressed patients often causes relapses. And third, the brain-as-soup theory - with the depressed brain simply lacking serotonin - was far too naïve.

In the late 1980s, a neuroscientist named Fred Gage became interested in a question that seemed, at first, peripheral to depression: does the adult human brain produce new nerve cells? The dogma in neurobiology at the time was that the adult brain was developmentally frozen. But Gage and other scientists revisited old findings and discovered that adult mice, rats and humans did, in fact, experience the birth of new neurons -

Background: continued - but only in two very specific parts of the brain: in the olfactory bulb and in the hippocampus.Could there be a connection between emotion and neuronal birth in the hippocampus? To find out, Gage and his collaborators began to study stressed mice. When mice are chronically stressed they demonstrate behavioral symptoms like anxiety and lethargy and lose their sense of adventurousness, features that mimic aspects of human depression. Researchers found that in these mice, the burst of nerve cells in the hippocam-pus also diminished. The converse turned out to be true as well. When mice are housed in an “enriched” environment they become more active and adventurous. They explore more; they learn faster; they seek pleasure. Enrichment, in short, acts behaviorally like an antidepressant. When Gage examined the brains of these enriched mice, he found that more neurons were being born in the hippocampus.At Columbia University, another neuroscientist, René Hen, was intrigued by Gage’s studies. Hen, working with other researchers, began to investigate the link between Prozac and nerve growth. The birth of neurons in the mice takes about two or three weeks - about the same time it takes for antidepressants to take effect. Might the psychiatric effects of Prozac and Paxil be related to the slow birth of neurons and not serotonin per se? Hen began to feed his mice Prozac. Over the next few days, their behaviors changed: anxiety they had exhibited decreased, and the mice became more adventurous. And newborn neurons appeared in the hip-pocampus in precisely the location that Gage found with the environmentally enriched mice. But when Hen selectively blocked the birth of neurons in the hippocampus, the adventurousness and the food-exploration instincts of the Prozac-fed mice vanished. Prozac’s positive effects, in other words, depended on the birth of nerve cells in the hippocampi of these mice. In 2011, Hen and his colleagues repeated these studies with depressed primates. When Hen measured neuron birth in the hippocampi in depressed monkeys, it was low. When he gave the monkeys antidepressants, the depressed symptoms abated and neuron birth resumed. Blocking the growth of nerve cells made Prozac ineffective.Hen’s experiments have profound implications for psychiatry and psychology. Antidepressants like Prozac and Zoloft, Hen suggested, may transiently increase serotonin in the brain, but their effect is seen only when new neurons are born. Might depression also be a degenerative disease — an Alzheimer’s of emotion, a dementia of mood? And how, exactly, might the death of neurons in the tiny caul of the hippocampus cause this disorder of mood? And how, then, does the birth of cells heal this feeling?

If an answer to these questions exists, it may emerge from the work of Helen Mayberg, a neuroscientist at Emory University. Mayberg has been mapping anatomical areas of the brain that are either hyperactive or inactive in depressed men and women. Tracing such sites led her to the subcallosal cingulate, a minuscule bundle of nerve cells that sit near the hippocampus and function as a conduit between the parts of the brain that control conscious thinking and the parts that control emotion. Think of the subcallosal cingulate as a po-tential traffic intersection on the road between our cognitive and emotional selves. When Mayberg stimulated this area of the brain with tiny bursts of electricity using probes in patients resistant to antidepressant therapy, she found remarkable response rates: about 75 percent of them experienced powerful changes in their moods during testing. Seconds after stimulation began, many patients, some of them virtually catatonic with depression, reported a “sudden calmness” or a “disappearance of the void.” The stimulator can be implanted in patients and works like a depression pacemaker: it continues to relieve their symptoms for years.At first glance, Mayberg’s studies would appear to bypass the serotonin hypothesis. After all, it was electrical, not chemical, stimulation that altered mood. But the response to Mayberg’s electrical stimulation also seemed to be linked to serotonin. The subcallosal cingulate is particularly rich in nerve cells that are sensitive to sero-tonin. Researchers found that if they blocked the serotonin signal in the brains of depressed rats, the pace-maker no longer worked.A remarkable and novel theory for depression emerges from these studies. Perhaps some forms of depres-sion occur when a stimulus - genetics, environment or stress - causes the death of nerve cells in the hippo-campus. In the nondepressed brain, circuits of nerve cells in the hippocampus may send signals to the sub-callosal cingulate to regulate mood. In the depressed brain, nerve death in the hippocampus disrupts these signals - with some turned off and others turned on - and they are ultimately registered consciously as grief and anxiety. When the hippocampus malfunctions, perhaps emotional pain can be generated and amplified out of context.

An antidepressant like Paxil or Prozac, these new studies suggest, is most likely not acting as a passive signal-strengthener. Rather, it appears to change the wiring itself. Neurochemicals like serotonin still remain central to this new theory of depression, but they function differently: as dynamic factors that make nerves grow, perhaps forming new circuits. There are, undeniably, important gaps in this theory. As the clinical trials show unequivocally, only a fraction of the most severely depressed patients respond to serotonin-enhancing anti-

An antidepressant like Paxil or Prozac, these new studies suggest, is most likely not acting as a passive signal-strengthener. Rather, it appears to change the wiring itself. Neurochemicals like serotonin still remain central to this new theory of depression, but they function differently: as dynamic factors that make nerves grow, perhaps forming new circuits. There are, undeniably, important gaps in this theory. As the clinical trials show unequivocally, only a fraction of the most severely depressed patients respond to serotonin-enhancing antidepressants. Nor does the theory explain why “talk therapies” work in some patients and not in others, and why the combination of talk and antidepressants seems to work consistently better than either alone. But the most profound implications have to do with how to understand the link between the growth of neurons, the changes in mood and the alteration of behavior. Perhaps antidepressants like Pro-zac and Paxil primarily alter behavioral circuits in the brain - particularly the circuits deep in the hippocam-pus where memories and learned behaviors are stored and organized - and consequently change mood. In time, the insights generated by these new theories of depression will most likely lead to new antidepres-sants: chemicals that directly initiate nerve growth in the hippocampus or stimulate the subcallosal cingu-late. Our current antidepressants are thus best conceived not as medical breakthroughs but as technological breakthroughs. They are chemical tools that have allowed us early glimpses into our brains and into the biology of one of the most mysterious diseases known to humans.

Siddhartha Mukherjee is an assistant professor of medicine in the division of medical oncology at Colum-bia University. He is the author of “Emperor of All Maladies: A Biography of Cancer.” Editor: Ilena Silverman

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Glossary of TermsBipolar Disorder - a mental condition characterized by rapid swings between very good moods, ir-ritability, and manic depression.Schizophrenia - a mental disorder that makes it difficult to separate fantasy from reality. It also impairs one’s ability to think clearly, have normal emotional responses, and act normally in social situations. Psychotherapy - a general term for addressing mental health concerns by talking with a psychologist or other mental health provider.Psychoparmacology - the branch of pharmacology that deals with the study of the actions, effects, and development of psychoactive drugs.Electroconvulsive Therapy/Electroshock Therapy/ECT - a procedure in which electric currents are passed through the brain, deliberately triggering a brief seizure. ECT seems to cause changes in brain chemistry that can immediately reverse symptoms of certain mental illnesses, often working when other treatments are unsuccessful.Eye Movement Desensitization Reprocessing/EMDR - an integrative form of psychotherapy, which includes aspects of psychodynamic and cognitive behavioral therapies.Transcranial Magnetic Stimulation/TMS - a relatively non-invasive procedure that involves placing a device on the skull, containing a coil of wire that carries electricity and produces a magnetic field. The flow of electricity through the device causes neurons to become either more or less active.Zoloft (Sertraline) - a drug used to treat depression, obsessive-compulsive disorder, panic attacks, posttraumatic stress, and social anxiety disorder. It increases the amount of serotonin in the brain.Paxil (Paroxetine) - a drug used to treat depression, panic disorder, social anxiety disorder, obses-sive-compulsive disorder, generalized anxiety disorder, and posttraumatic stress. Like Zoloft, it in-creases the amount of serotonin in the brain.Buspar (Buspirone) - an anti-anxiety medicine that affects chemicals in your brain. It’s used in the treatment of anxiety disorders.Xanax (Alprazolam) – a drug that reduces nervous tension by slowing down the movement of po-tentially unbalanced chemicals in the brain. It is used to treat anxiety disorders, panic disorders and anxiety caused by depression.Depakote (Divalproex Sodium) - affects chemicals in the body that may be involved in causing sei-zures.Klonopin (Clonazepam) – affects chemicals in the brain that may cause anxiety. It is used to treat sei-zure disorders or panic disorder.Prozac/Sarafem/Fontex (Fluoxetine) - an antidepressant used for the treatment of major depression, obsessive-compulsive disorder, bulimia nervosa, panic disorder and premenstrual dysphoric disorder.Ativan (Lorazepam) - used to relieve anxiety. It works by slowing activity in the brain, allowing for relaxation.Valium (Diazepam) - affects chemicals in the brain that may become unbalanced and cause anxiety. It’s used to treat anxiety disorders, alcohol withdrawal symptoms, and muscle spasms.Aderol/Adderall - used for the treatment of attention deficit hyperactivity disorder (ADHD) and narco-lepsy. It is commercially available and legal only in the United States.Risperdal (Risperidone) - used to treat the symptoms of schizophrenia, mania, bipolar disorder, ag-gression, self-injury and sudden mood changes in adults and teenagers. It works by changing the activity of specific natural substances in the brain.Robitussin (Guaifenesin) - used to relieve chest congestion. It works by thinning the mucus in the air passages to make it easier to cough up the mucus and clear the airways.Lithium - used to treat and prevent episodes of mania in people with bipolar disorder. It works by decreasing abnormal activity in the brain.

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Mozart - a prolific and influential composer of the Classical era. He composed over 600 works, many of which are acknowledged as pinnacles of symphonic, concertante, chamber, operatic, and choral music. He is among the most enduringly popular of classical composers.Oscar Peterson - a Canadian jazz pianist and composer. He released over 200 recordings, won eight Grammy Awards, and received other numerous awards and honours over the course of his career. He is considered to have been one of the greatest jazz pianists of all time,Beethoven - a German composer and pianist, and a crucial figure in the transition between the Classi-cal and Romantic eras in Western art music. He remains one of the most famous and influential com-posers of all time. Miles Davis – a trumpet player who was at the forefront of several major developments in jazz music, including bebop, cool jazz, hard bop, modal jazz, and jazz fusion.One Flew Over the Cuckoo’s Nest - a novel written by Ken Kesey. Set in an Oregon psychiatric hospi-tal, the narrative serves as a study of the institutional process and the human mind as well as a critique of Behaviorism and a celebration of humanistic principles. Published in 1962, the novel was adapted into a Broadway play and a film.Sylvia Plath - an American poet, novelist and short story writer. After suffering from depression from the age of twenty and a marital separation, Plath committed suicide in 1963.Francis Farmer - an American stage and screen actress. She is perhaps best known for sensationalized and fictional accounts of her life, particularly her involuntary commitment to a mental hospital.

Glossary: continued

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Meet the Cast.JAMES BARRY (Dan) - Next to Normal is James’s Philly theatre debut! Broadway: Bloody Bloody Andrew Jackson. NY: Sive (Irish Rep), It’s A Wonderful Life: A Live Radio Play (Queens Theatre), Bloody Bloody Andrew Jackson (The Public). Regional: Man of La Mancha with Terrence Mann (Connecticut Rep), Wittenberg (Chester Theatre Co), Pumpboys & Dinettes (New Theatre, kansas City), The Full Monty (Drury Lane, Chicago), Two by Friel (after Chek-hov) (Irish Rep, Chicago), Bomb-itty of Errors (Syracuse Stage), and several productions at his home away from home, The Berkshire Theatre group, where favorite credits include The Caretaker, A Thousand Clowns & The Who’s Tommy. RACHEL CAMP (Natalie) - Next to Normal is Rachel’s Arden debut! Recent credits: Buddy - The Buddy Holly Story (Walnut Street Theatre), Slip/Shot (Flashpoint Theatre Co.), The Great American Trailer Park Musical (11th Hour/Montgomery Theatre Co.), The Three Musketeers (People’s Light & Theatre Co.). Rachel won the 2011 Barrymore Award for Outstanding Sup-porting Actress in a Musical for her work in The 25th Annual Putnam County Spelling Bee at Theatre Horizon. Upcoming: Winter Wonderettes at 11th Hour Theatre Company and Marty in Grease at the Walnut Street Theatre.

MICHAEL DOHERTY (Henry) - Michael was last seen at The Arden as Posner in The History Boys. Recently, he finished a successful run of an original Philly Fringe piece entitled, Jeff Coon and Ben Dibble Must Die (Los Jarochos). Off-broadway: Dublin By Lamplight (Inis Nua/ 59E59; Winner best Ensemble- 1st Irish Fest. Awards). Regional: Mr. Hart and Mr. Brown (People’s Light), The 25th Annual Putnam County Spelling Bee (Theatre Horizon; Barry-more- Supporting Actor/Ensemble), The Great American Trailer Park Musical (Montgomery Theater/11th Hour), Our Show of Shows (1812 Productions), and more. Up next: Assistance at the Wilma Theater.

KRISTINE FRAELICH (Diana) - Kristine was last seen at the Arden as Dot/Marie in Sunday in thePark with George. Other credits include Eva Peron in Evita (Walnut Street); Betty Gow in Baby Case (Arden); Narrator in Joseph...Dreamcoat and Ellen in Miss Saigon at Lenape Perform-ing Arts Center. Broadway: Frank Wildhorn’s The Civil War, Narrator in the first national tour of Joseph....Dreamcoat. Performed with Jason Robert Brown in Songs for a New World in Concert at Symphony Space. ROBERT HAGER (Gabe) - Robert is making his Arden debut! Broadway: How to Succeed in Business..., Bye Bye Birdie, Spring Awakening. National Tour/Regional: Spring Awakening, Scrooge: The Musical, The Who’s Tommy, Jesus Christ Superstar. He has been involved in many workshops and readings. Robi is also pursuing his solo singer-songwriting career and gives solo concerts regularly in the NYC area.

BRIAN HISSONG (Doctor Madden/Doctor Fine) - Brian last appeared at the Arden in Sunday in the Park With George and Winesburg, Ohio (Barrymore Award for Outstanding Leading Actor in a Musical). A proud graduate of the University of Michigan and a member of Actor’s Equity, other credits include leading roles at the York Theatre, Paper Mill Playhouse, good-speed Opera House, TUTS, Lincolnshire Marriott, MTWichita, Arkansas Rep, WVPT, and Tony in the international tour of West Side Story.

Meet the Creative TeamTERRENCE J. NOLEN (Director) is co-founder and Producing Artistic Director of Arden Theatre Company. Favorite Arden productions include all-Philadelphia casts of August: Osage County; Death of a Salesman; The Grapes of Wrath and Hedda Gabler and such musicals as Sweeney Todd; Pacific Overtures; Falsettos; Vio-let; and Caroline, or Change. Terry has been nominated for 24 Barrymore Awards for his directing work at the Arden and received awards for The Baker’s Wife; Sweeney Todd; Opus; Winesburg, Ohio; Assassins and Something Intangible. He directed Michael Hollinger’s Opus at Primary Stages in New York and was nomi-nated for a Lucille Lortel Award for Outstanding Director. His short film The Personal Touch was nominated for an Emmy Award. JORGE COUSINEAU (Scenic and Video Designer) has designed sound and video for over forty shows here at the Arden, highlights include Clybourne Park, The Threepenny Opera and Sunday In The Park With George. Jorge also composes music and designs sets for many other theater companies in and around Philadelphia, such as the Wilma, 1812 Productions, Theatre Exile and New Paradise Laboratories.

THOM WEAVER (Lighting Designer) Arden: 9 productions. Philadelphia area: Wilma, People’s Light, Lantern, Walnut, Headlong, Delaware Theatre Company, InterAct, Azuka, Curtis Opera, New Paradise Laboratories, Theatre Exile, 1812, Pennsylvania Shakespeare Festival, and Flashpoint Theatre Company, where he is Artistic Director. Other credits: Theatre J, Shakespeare Theatre, Cal Shakes, Children’s Theatre Company, Roundhouse, CENTERSTAGE, Folger Theatre, Cincinnati Playhouse, Hangar, Cleveland Playhouse, Syracuse Stage, berkshire Theatre Festival, Williamstown, Asolo, Signature Theater Company, Lincoln Center Festival, Spoleto, Pitts-burgh Public Theatre, and Yale Rep. 2011 Barrymore for In the Next Room, 14-time Barrymore Award nomi-nee, Helen Hayes nominee, and winner of the 2007 AUDELCO Award.

DANIEL PERELSTEIN (Sound Designer) is a freelance sound designer, composer, and musical director in Philadelphia. Previous designs at Arden: Robin Hood, Women in Jep; Upcoming: Pinocchio. Recent designs at Wilma, Live Arts, Walnut, Peoples Light, kimmel Center, PlayPenn, Azuka, Lantern,Theatre Horizon, Flash-point, others. Resident designer for Bearded Ladies Cabaret. ALISON ROBERTS (Costume Designer) is starting her thirteenth season as the Arden’s Costume Supervisor. She has a BA in Theatre Arts from Rowan University and an MFA in Costume Design and Technologyfrom Illinois State University. Next up this season, she will design A Raisin in the Sun. You can see her free-lance design work with Theatre Exile and Philadelphia Young Playwrights later this year. ERIC EBBENGA (Musical Director) is thrilled to return to the Arden, where he has music directed The Three-penny Opera; Sunday in the Park with George; Candide; Assassins (Barrymore Award); Caroline, or Change; Sweeney Todd and Pacific Overtures. Other recent shows include The Light in the Piazza (Barrymore award); Grey Gardens; Ordinary Days and the Philadelphia and west coast premieres of The Scottsboro Boys. NIKI COUSINEAU (Choreographer) is a Philadelphia based choreographer and dancer. She co-directs Sub-circle, a company she founded with Jorge Cousineau in 1998. Their work together transforms theatrical and site-specific spaces, merging dance, sound, set design, lighting and film. Niki is a recipient of a Pew Fellow-ship and was recently a choreographic fellow at MANCC in Tallahassee, Florida. She is excited to return to the Arden after working on Sunday in the Park with George.

SARAH OLLOVE (Assistant Director/Dramaturg) is excited to be back at the Arden for her seventh production. A freelance dramaturg, she is a graduate of the ART/MXAT Institute for Advanced Theatre Training. She has worked nationally with companies including ART, Signature Theatre, the Flea, and Woolly Mammoth. Local dramaturgy credits include work with Theatre Exile, PTC, the Bearded Ladies, Gas & Electric Arts, and she is the Resident Dramaturg at Azuka Theatre.

ALEC E. FERRELL (Stage Manager) is happy to be joining the Arden for their 25th Anniversary Season. Past Arden credits include: August: Osage County; A Moon for the Misbegotten; Ghost-Writer (World Premiere); Blue Door; Rabbit Hole; My Name Is Asher Lev (World Premiere); Robin Hood; Charlotte’s Web; The Flea and the Professor (World Premiere). Other work with PlayPenn, PTC@Play, the Eugene O’Neill Theater Cen-ter, Theatre Horizon.

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Discussion Questions1. Do you think Kitt and Yorkey’s portrayal of a depressed housewife is realistic? Is it a compassionate portrait?

2. Do you think the story favors one generational perspective over another? Does it seem to favor one gender over the other?

3. Dr. Fine and Doctor Madden are traditionally played by the same actor. Why do you think this choice was made? What does it suggest about Diana’s perception of treat-ment?

4. During the show, Natalie turns to drugs as a way of coping with her family situation. Who is to blame for her downward spiral? Is everyone to blame? No one?

5. Next to Normal tackles the complex dialogue that exists surrounding pharmaceuti-cal and therapeutic treatments for depression. What do you think the play’s ultimate stance is regarding treatment? What’s your stance, personally?

6. Diana’s dead son, Gabe, haunts the stage throughout the action of the play. Howev-er, it isn’t until late in Act 2 that Dan acknowledges him. Does Dan’s acknowledgement of Gabe represent a positive step in his grieving process, or a sharp turn towards mad-ness?

7. In Act 2, Natalie expresses her concern that she will one day be like her mother. She says, “I might end up crazy,” and Henry replies that “Crazy is perfect..so I will be perfect for you.” Do you think Natalie will end up struggling with depression like her mother? Do you think Henry will remain supportive?

8. At the close of the show, Diana leaves Dan to sort out her life, and the cast joins in singing “There will be light.” What do you think of this ending? Is it optimistic? Is it re-alistic?

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