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Making the Three Tenors Sing By Alen J. Salerian Special to The Washington Post Tuesday , June 20, 2000 During my first session with Sarah, a married, 40-year-old lawyer, she complained about frustrating failures she had experienced in treatment of her depression. "After all this therapy and all these medications, I still don't feel like getting out of bed in the morning," she said. She leaned forward and gently placed a piece of paper on my desk. It was a printout of all the medications she had taken during the past two years: Zoloft at 200 mg for six months. Prozac at 60 mg for three months. Sixty mg of Paxil for six months, then 400 mg of Wellbutrin for three months. Serzone at 600 mg for two months. Finally, 1,500 mg of lithium for two months. There were two- or three-week breaks between medications. She had seen several doctors. Her frustration was understandable. But her worry changed to surprise when I suggested that, instead of continuing to try different drugs in sequence, she pursue a "combination strategy" - taking more than one of these drugs at a time. A combination strategy was something I'd been sharing with medical students and patients for years. It arises from understanding the role of what I call "the three tenors," the three key neurotransmitters in the brain that regulate mood - serotonin, dopamine and norepinephrine. As an opera lover, I like to see them as voices singing in the mind. When they sing in harmony and balance, they can make a person feel comfortable in life. But when one of the tenors is out of sync, the music can be disturbing, even frightening. It may be ordinary knowledge for a psychiatrist to appreciate how each neurotransmitter works - that serotonin regulates worry and anger, that dopamine is critical for initiative and pleasure and that norepinephrine controls alertness and energy. But this information is rarely shared with those being treated. It should be, because it is often the foundation for a successful treatment, one that manages to work even after many others have failed. A little history is helpful. From the days when the first antidepressant, iproniazid, was serendipitously discovered in the 1950s, many advances have occurred in the treatment of depression. Yet the central biological challenge has remained the same: how to make one, two or all three tenors sing in harmony. The first group of antidepressants, called tricyclics and monoamine oxidase inhibitors, were an effective but unfriendly bunch. They indeed helped all three tenors sing vibrantly, but they produced very unpleasant noises along the way. To reach their effective levels, one had to suffer horrible side effects. For example, the trycyclic antidepressant Elavil caused such intense drowsiness that many patients reported feeling like zombies. Other medications caused dry mouth, constipation, sedation and other less severe problems. The introduction in 1988 of Prozac, the first drug of a class called selective serotonin reuptake inhibitors, or SSRIs, marked a significant breakthrough in treatment. It was based on the discovery that elevating serotonin levels was crucial in alleviating depression. Prozac was the first "designer" antidepressant, which selectively targeted serotonin alone. Consequently it produced significantly fewer and less severe side effects than its predecessors. Thanks to the subsequent development of the many similarly targeted SSRIs, by the late 1990s American psychiatrists had at least 20 antidepressants to choose from to treat depression. Most psychiatrists quickly learned that Prozac and Paxil would increase serotonin but would not alter norepinephrine or dopamine, whereas Wellbutrin would elevate brain dopamine concentrations without much effect on serotonin. And Effexor would increase both norepinephrine and serotonin. Regardless of the mechanism or action, all were considered similarly efficacious--which is to say sometimes they worked and sometimes they didn't. Gradually among American psychiatrists, a simple protocol was adopted to treat cases of depression: Choose an antidepressant that treated one lead tenor. If that didn't work, try another. And keep trying different ones until the desired effect was achieved. Yet most researchers agreed that even with the best combination of psychotherapy and the most effective single medication, still roughly 30 percent of individuals with depression would not improve. Luckily for patients like Sarah, in the last several years many quiet discoveries have been made in the clinical practice of psychiatry. First, it was discovered that not all antidepressants are effective for severe depressions. Also, that antidepressants with dual action - those that influenced two tenors, like serotonin and norepinephrine - often performed better than the antidepressants that target a solo tenor. And further, that combining antidepressants often worked better than using a single one. Sarah's case illustrates the point. I asked Sarah to tell me more about her depression. "What troubles you most?" "Worry," she responded. "I keep thinking I'm going to miss something important. That I'm going to hurt somebody. In reality I know I do a good job as a criminal attorney, yet I'm afraid I'm going to screw up. I know there's no basis for it, but the fear of hurting one of my clients paralyzes me. There are days when I can't even leave home because of it." Sarah stared into her lap, then looked up at me. "So what can you do for me?" "What I can do for you is put you on Paxil and Wellbutrin." "I've tried both and neither worked," she said. "Not to mention that Paxil made me sleepy and edgy." "Your medication history indicates that you never took these medications in combination. And there is good evidence that what we call 'augmentation therapy' works better." She was skeptical. She said this sounded very "aggressive," and wondered whether she was my "guinea pig" in an experiment. Six weeks later, after trying the regimen, Sarah had fully recovered. "I cannot tell you how good and worry-free I feel," she said. "It's like a burden has been lifted." But recovery had not been an easy ride - or without a change in course. Extreme fatigue and nausea troubled her, yet once she had decided to try the combination therapy, she wasn't going to stop her medical trial. By the end of the fourth week - a reasonable point to evaluate the overall response to treatment - Sarah had reported being "60 percent better" but said she still lacked energy and zip. I recommended she add Adderall - an amphetamine-like medication often used to treat attention deficit disorder - to further boost her dopamine. And finally, Sarah's tenors began to sing, thanks to a combination of Wellbutrin, Paxil and Adderall. Sarah is not an exception. I've treated hundreds of patients who have responded well to combination strategies. Recent research is also promising for the use of various hormones - such as testosterone, estrogen, DHEA and thyroid hormones - to augment the efficacy of various antidepressants. Again, augmentation therapy appears to be a novel way to stimulate a pleasant mood. A few things about treating depression are clear. Poor response to treatment should always be a reason to search for a new strategy. And it is critical to educate patients about the chemistry of mood and how serotonin, norepinephrine and dopamine affect the way the brain responds to life. Just as the three tenors sing best when they work together, the three neurotransmitters make the best mood music for the brain when they're balanced harmoniously. Which is largely why I believe that most depressions are curable - and that most patients are able, eventually, to hear the music. Alen J. Salerian, MD, is medical director of the Washington Psychiatric Center outpatient facility for the Psychiatric Institute of Washington. He has just completed a novel, "Red Zone," about abuses in psychiatric managed care. 2000 The Washington Post Company "http://www.washingtonpost.com/cgi-bin/gx.cgi/AppLogic+FTContentServer?pagename=wpni/print&articleid=A25065-200 0Jun20" janet paterson 53 now / 41 dx pd / 37 onset pd / 44 dx cd / 43 onset cd tel: 613 256 8340 url: "http://www.geocities.com/janet313/" email: "[log in to unmask]" smail: PO Box 171 Almonte Ontario K0A 1A0 Canada