Doxepin

fifteen years ago, Prozac launched a revolution. It rendered depression a disorder that was--finally--safely treatable. The torrent of prose hailing Prozac and its chemical kin eventually made the mental illness dinner-party discourse. Today, a much quieter revolution in treatment is taking place. It, too, has its origins in Prozac and its siblings, the selective serotonin reuptake inhibitors.

Fifteen years of experience with reasonably safe treatments has given the mental health world a new understanding of the disorder and its true course: It's no longer enough to merely treat depression; it's necessary to banish it.

Increasingly, the aim of treatment is not to make patients better but to make them completely well. In the absence of full remission from an episode of depression, the disorder tends to recur. What's more, studies now show that the longer patients remain sick, the harder it is for them to recover completely.

"It became very clear over the past several years that people who don't achieve full remission are at high risk for relapse and for doing poorly," says Jonathan Alpert, M.D., Ph.D., associate director of the depression research program at Massachusetts General Hospital in Boston. "Even if they don't have a full relapse, they don't do well in social and occupational function."

There is no magic bullet; evidence indicates that the available antidepressants are equally effective. All of the drugs get 70 percent of people better within six to ten weeks, according to David Dunner, M.D., director of the Center for Anxiety and Depression at the University of Washington. However, "better" does not necessarily mean symptom-free. "There isn't any difference among the drugs regarding that."

Where the drugs do differ, however, is in the side effects they create, especially in the long haul. Side effects have become a central consideration in the new approach to depression treatment.

Long-term treatment is also critical. Data indicate that individuals should be treated for at least nine months following their first acute episode. If they have chronic depression--an episode lasting two years or more--they need to be treated for two years after remission. "And if they have recurrent depression marked by multiple episodes, perhaps forever," notes Dunner.

However, the average duration of a prescription is about 100 days. "It's a serious problem," Dunner points out. "We're not treating people nearly long enough."

Nor is treatment aggressive enough, according to Alpert: "Really pushing for remission may mean using two antidepressants at once or pushing the close up higher than one would normally use."

Pick your pill

For many experts, the most sensible approach to selecting an antidepressant is to factor in the presence of associated or co-occurring conditions. Anxiety disorders, for example, commonly accompany depression. The selective serotonin reuptake inhibitors (SSRIs) have been well studied for the major anxiety disorders: panic, social phobia, generalized anxiety disorder and obsessive-compulsive disorder.

"For someone who has depression and social phobia, it's reasonable to use a medication whose effectiveness has been well documented for both disorders," reports Alpert. The data also suggest that SSRIs are "reasonable first choices" for those with eating disorders.

But antidepressants don't work if people don't take them. Patients have to be willing to put up with side effects that range from drowsiness to seizures. As true as that is for short-term treatment, it's even more the case with long-term treatment. "The issue is, what can we do to get these patients to stay on the drugs for the length of time the evidence now suggests is best?" explains Dunner.

In the long run, two side effects are especially bothersome: sexual dysfunction and weight gain. The SSRIs are strongly linked to sexual dysfunction in both sexes--diminished libido, erectile dysfunction and delayed, attenuated or absent orgasm. In one recent study, up to 70 percent of patients receiving the newer antidepressants reported sexual dysfunction when asked directly about it. That contradicts the 15 percent declared on product labels. Some of the atypical antidepressants--such as Wellbutrin (buproprion) and Remeron (mirtazapine)--do better at preserving sexual function.

In regard to weight gain, the SSRI antidepressants do not appear to be created equally. Paxil, for one, seems to cause more problems. One study, by Andrew Nierenberg, M.D., associate director at Massachusetts General's clinical depression and research program, showed that after six months, patients put on more weight with Paxil than with the other antidepressants. Evidence favors non-SSRIs for avoiding weight gain, particularly bupropion and Serzone (nefazodone). Nefazadone, however, bears a Food and Drug Administration warning that it can cause liver failure in rare instances.

Paxil also causes more sexual dysfunction, which leads many individuals to discontinue their regimen. Teresa* found that Paxil stanched her anxiety and depression after only two weeks. "I was calmer. My emotions weren't erupting," recalls the 55-year-old social worker. But the flip side was a sense of muted emotions and diminished sexual appetite. "The libido isn't just your sex drive, it's your passion for life," says Teresa. She plans to continue taking Paxil despite the side effects. "It did what I wanted it to do, which is take away the pain."

The bargaining table

Psychiatrists believe that side effects are a matter of negotiation. "Some of the most teary exchanges in my office have involved women who don't want to gain weight on a drug," confides John Herman, M.D., director of clinical services in psychiatry at Mass General. "The patients come in tearful because they're depressed; then they come in no longer depressed but distraught because they are way overweight."

"It's a stealth side effect," observes Jerrold Rosenbaum, M.D., chief of psychiatry at Massachusetts General. "It emerges subtly over time and surprises everybody."

Physicians must consider what is tolerable in exchange for a medication's primary effects and understand that the bar has been raised. "As the cookie lady Mrs. Fields once said, `Good enough is not good enough,'" says Dunner. "Just because a patient improves doesn't mean the treatment should be stopped."

Sometimes the problem lies with patients themselves. Often, they feel better and stop their medication, thinking it's no longer needed. "Although an individual patient might win, it's a mistake," observes Dunner. "The odds are against her."

At least as often, side effects interfere with long-term patient compliance. Therefore, clinicians must know how to manage the dosage or try to augment the antidepressant with another medication so the patient will stay on course. Psychostimulants such as Dexedrine, Ritalin and Adderall are widely used as antidepressant adjuncts, even though their primary indication is for attention deficit disorders or narcolepsy. Provigil, recently approved for the treatment of narcolepsy, is also used to boost the efficacy of antidepressants or reduce the drowsiness they cause. Thyroid hormones and natural remedies such as omega-3 fatty acids and SAM-e are also being explored.

Leading psychopharmacologists contend that antidepressant treatment can be delivered in a way that instills confidence in patients--enough to ride out early difficulties. "I try to emphasize the early side effects that might occur and how to manage them," reports Dunner. "So if a patient suffers from them, he doesn't say, `What is all this about?'"

It's also important for patients to know that taking one pill will not instantly make them better; in fact, the drugs are not likely to begin working for three to four weeks. Treatment will then progress in eight to twelve weeks.

Some 30 percent of depressed patients do not respond to the first drug they try. If there is no improvement after a patient uses a medication at an adequate dose and for an adequate duration of time, a switch is in order. A drug with a different mechanism of action may be preferred. The trial, though, isn't lost. The patient may have lost time, but valuable information has been gained.

"We're trying to get the patient over that last little hump," says Dunner. "Granted, we can improve most patients, but can we actually get them back to normal? I think we can do this with many more patients than we used to."

LEARN MORE ABOUT IT:

Night Falls Fast Kay Redfield Jamison (Vintage, 2000)

The Noonday Demon Andrew Solomon (Touchstone, 2002)

Depression and Bipolar Support Alliance: www.ndmda.org

Psychology Today: www.psychologytoday.com

American Psychological Association: www.apa.org

National Institute of Mental Health: www.nimh.nih.gov/publicat/medmenu.cfm

* Identifies have changed.

Hara Estroff Marano is the editor of Psychology Today's Blues Buster newsletter as well as editor at large of PT.

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