Washington Center For Psychiatry

Special to The Washington Post

Tuesday , June 20, 2000

By Alen J. Salerian, MD

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