Skirmish or Siege?

Is depression primarily a recurring disease? Can you ever really be cured?

By Christina Frank, published March 1, 1999 - last reviewed on June 9, 2016

Depression is a chronic illness with recurring episodes. So should we deploy antidepressants battle by battle, or order them in for the long war?

When Sheila Singleton, 45, filled her first prescription for an antidepressant, she assumed it would also be her last. "I thought OK, when the pills work and get myself straightened out, I'll go back to taking nothing but my vitamins," she says. Seventeen years later, Singleton still pops a pill every day. During the brief intervals when she's gone off medication, or when the ones she was on stopped working, the depression returned with a vengeance.

Among the newer antidepressants, options range from SSRIs (selective serotonin reuptake inhibitors) such as Prozac, Paxil, and Zoloft, to those—Wellbutrin and Effexor, for example—that target different or combined neurotransmitters. Most satisfied patients claim they provide highly effective relief with few side effects.

But there is one notorious downside: roughly 70% of SSRI users are plagued by sexual difficulty. "It's a big problem," acknowledges Donald Klein, M.D., professor of psychiatry at Columbia University and director of research at the New York State Psychiatric Institute. "There are no hard data on how many people actually discontinue treatment due to the sexual side effects; it largely depends on how they are handled by the specific doctor. Zoloft, for example, is short-acting and can be stopped for a couple of days, restoring sexual function for that period. Adding Wellbutrin to an SSRI is another way to restore libido. But not all doctors may try these adjustments; they may just say that's the price you have to pay."

Another fly in the psychiatric salve is that that these drugs have been officially approved only for short-term use—six to 12 months—yet are routinely prescribed for indefinite periods, in order to prevent future depressive episodes. It's not that the drugs are contraindicated for long-term use, it's just been impossible to conduct long-term studies. Americans move or drop out.

"So you have this disparity between the length of time for which the medications are approved and the length of time you might have to take them in order to have a good interval without depression," says Peter D. Kramer, M.D. "No one has really bridged that gap and figured out just what is appropriate for long-term treatment. It does seem that recurrences are prevented. On the other hand, do the medications lose their effectiveness? Are there long-term side effects? These are just not known."

What is known is that although many individual depressive episodes can be temporarily "fixed" by antidepressants, the drugs are not curative, no more than insulin cures diabetes or anti-hypertensives cure high blood pressure. The demon almost always returns at some point.

"We're increasingly recognizing something our European colleagues, who've been able to do longitudinal studies on depression, have known for some time: That major depression is predominantly a recurrent illness," says Fred Goodwin, M.D., professor of psychiatry at George Washington University, former director of the National Institute of Mental Health, and host of "The Infinite Mind" on National Public Radio. "Eighty percent of people who have had one episode will eventually have another one, one year or many years down the road."

So why not just stop the medication after one episode is cured and wait until the next one hits before resuming treatment? Kramer points to a phenomenon known as kindling: the more episodes you have, the worse they get—and the less stress it takes to trigger them. Anecdotal evidence also suggests that going on and off medications may increase the dose needed next time to achieve the same benefit as last time. In the long run, stopping and starting doesn't reduce overall drug exposure.

Untreated, some depressive episodes eventually resolve themselves, on average, says Goodwin, in less than a year, though there is considerable variation from person to person. What antidepressants do is speed recovery by eliminating symptoms and enhancing motivation and energy.

Klein points out that of 100 depressed patients given any antidepressant, only 66 will show improvement. However, half of these positive responses are a placebo effect. Thus, only a third of patients are truly responding to the specific drug.

In Klein's estimation, the vast majority of sufferers—85% to 90%—can find substantial relief with one or a combination of drugs within six to eight weeks, assuming they faithfully follow the prescribed drug regimen ("total compliance" in medical jargon). Most people with depression, he says, can find relief with the first or second antidepressant they try. Only about 10% to 15% of patients, unipolar and bipolar, are truly resistant to treatment.

A study of 161 outpatients, reported in the Journal of the American Medical Association, demonstrated that long-term treatment with sertraline (Zoloft) prevents recurrence of chronic severe depression. In the study, conducted for 76 weeks, 50% (42) of 84 placebo-treated patients experienced recurrence of significant depressive symptoms, versus only 26% (20) of 77 patients given sertraline.

When determining who is a candidate for long-term drug therapy (lasting more than one year), doctors consider frequency of and length of time between episodes, severity of depressive symptoms, risk of suicide as well as family history of mood disorders. One of the most debated treatment dilemmas today is how to handle the persistent low-grade depression known as chronic dysthymia: does it merit long-term medication, or medication at all? Jesse Rosenthal, M.D., chief psychopharmacologist at Beth Israel Medical Center in New York City, suggests that the personal price paid by the chronically dysthymic can be as great as that paid by people with major depression, in terms of damaged relationships, poor work performance and overall low energy.

Still, it's not as simple as just putting everyone who is depressed on long-term drug therapy. Some patients will run into so-called "Poop-out"; the medications simply stop working after a while. There are no official data on the antidepressant poop-out rate, but experts estimate it at about 20%. According to Klein, poop-out is highly unlikely to occur before three or four months of treatment; after that, there is no saying whether or when it wilt. "Poop-out is not uncommon, but it's not the expectation" says Goodwin. "It is possible to keep taking these drugs indefinitely at the same dose and maintain the same level of relief."

Another unknown is what's behind poop-out—whether it is true pharmacologic failure or a worsening of the disease, a relapse that overrides medication. Other factors that can dent a medication's apparent effectiveness are aging (which tends to worsen or change depressive symptoms), substance abuse, a co-existing medical illness and noncompliance, a big problem.

Rajinder Judge, M.D., clinical research physician for Prozac at Eli Lilly, estimates that just 50% of patients actually take antidepressants properly. "They miss doses or just stop on their own," she says. It is not uncommon for patients to drop their medications after four months, although prevention of relapse is believed to warrant longer treatment. Some find the side effects too pesky. Others become overconfident because they feel so much better. "Once you recover," Judge explains, "you don't want to be reminded of those dark days and the only thing reminding you is this little pill."

Whatever the cause of poop-out, it can almost always be remedied by upping (or sometimes even reducing) the dose, or changing or adding medications. Whereas older medications—so-called tricyclic antidepressants and monoamine oxidase (MAO) inhibitors—can be dangerous at high doses, amounts of the SSRIs can be doubled and then doubled again without harm, according to Peter Kramer. "Sometimes the patient ends up on a more complicated regimen to get the same effect," he says. "Or sometimes it's a matter of taking a person off one drug and reintroducing it later. One way or another, it is mostly possible to get people back to where they were."

While Kramer is a proponent of antidepressants, he also expresses some skepticism, especially where dosing and long-term side effects are concerned. "My sense is that we're giving Prozac at too high a dose. Many people can do well with 10 mg, but 20 mg to 80 mg is common. Also, there's suspicion that the SSRIs may affect memory in the long run; it's hard to be sure because depression itself impairs memory."

And what role does good old-fashioned psychotherapy play these days? A mega-analysis of 595 patients with major depressive disorder, reported in the Archives of General Psychiatry, concluded that the best treatment plan involves a combination of psychotherapy and drug therapy.

But there are many kinds of therapy and not all are equally effective. Goodwin advocates a here-and-now approach of behavioral and cognitive techniques.

Furthermore, he says, even patients prescribed medication alone need psychological attention. Knowledgeable clinicians "can miss things like poor compliance, life stresses and substance abuse that can interfere with the medicine's working."

Depression, Donald Klein asserts, is among the most medically treatable illnesses. Accepting that short-term treatment may not be a possibility for most is perhaps the next hurdle to get over. "I now know that there is no cure," says Sheila Singleton. "I will have depression for the rest of my life and I'll take medication the rest of my life."