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Depression. Diagnosis, Treatment and FAQ.
July 16, 2009 |
Drug Therapy
Fifty years ago “talking therapy” was considered essential in the treatment of depression. Psychologists and psychiatrists saw lots of patients who suffered from mild to moderate depression. But during the 1970s biological psychiatry took off. The medical profession embraced the theory that depression was primarily caused by an imbalance of chemicals in the brain. Many health professionals adopted the belief that a depressed person only needed antidepressant medication to normalize brain biochemistry. All you had to do was “feed your head” the right chemicals and the depression would disappear.
During those heady days many patients were given tricyclic antidepressants to soothe their troubled psyches. Medications like amitriptyline (Elavil), desipramine (Norpramin, Pertofrane), doxepin (Adapin, Sinequan), imipramine (Janimine, Tofranil), and nortriptyline (Aventyl, Pamelor) were prescribed in huge numbers. Never mind that such drugs caused drowsiness, fatigue, constipation, dry mouth, dental problems, weight gain, blurred vision, urinary difficulties, dizziness, disturbed concentration, impaired memory, mental confusion, sexual dysfunction, and impotence.
Although these medications did help many people get out of the depths of despair, the side effects were sometimes as depressing as the depression itself. Imagine what it would be like to put on 30 or 40 pounds, feel mentally cloudy and constipated most of the time, and have no sex life. But insurance companies liked these medications. It seemed far more cost-effective to have an internist or a family practice doctor prescribe an antidepressant than to approve a lengthy series of counseling sessions with a psychologist or psychiatrist.
Then along came Prozac (fluoxetine). In 1987 when it was introduced, this antidepressant hardly made a splash. First-year sales were just barely respectable, but more than doubled in the second year. By the third year, Americans spent more on Prozac than on all other antidepressants combined. Everyone seemed to fall in love with Prozac—physicians, pharmacists, patients, and, most of all, the big payers (insurance companies and HMOs).
Prozac—a selective serotonin reuptake inhibitor, or SSRI—was so successful because it got great PR, and because it seemed to have fewer side effects than traditional tricyclic antidepressants. At least it was less likely to cause sedation, dizziness, constipation, or dry mouth. It also was more effective—or at least that was the impression among physicians and patients. There were never any data to support that belief, but that didn’t stop the media blitz. Prozac even made the cover of Newsweek and Time magazines. Once people decided it was the new wonder drug, other pharmaceutical manufacturers were desperate to get in the game. The race was on.
It wasn’t long before the wannabes started showing up, trying to claim a piece of the Prozac pie. Today the competitors include bupropion (Wellbutrin), citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), and venlafaxine (Effexor). Almost 190 million prescriptions are written for these antidepressants each year, with sales exceeding $12 billion.
Such coeds are being prescribed enthusiastically for a wide range of other health problems, too. The pharmaceutical industry has promoted some of these antidepressants for conditions such as obsessive-compulsive disorder, panic attacks, hot flashes, premenstrual distress, nervousness, and shyness (”social anxiety disorder”).
Almost from the beginning, though, these drugs have been controversial. In the original clinical trial for Prozac, 15 percent of patients in the study dropped out because they felt worse instead of better—a statistic that was not widely publicized. Anxiety, insomnia, restlessness, nausea, and tremors caused distress for some people. There also was a high incidence of sexual dysfunction with the SSRIs. But the real controversy has always swirled around whether Prozac and similar compounds could trigger thoughts of suicide or homicide in some people.
Antidepressants and Suicide
In 1988, we received a letter from a grieving physician. His daughter had been prescribed Prozac for an eating disorder; a month later she took her er life by hanging herself. This oph- thalmologist was convinced that Prozac had contributed to her tragic death. At the time, we discounted this story—which we now regret—and told him that depressed people sometimes take desperate action and may try to harm themselves when they start treatment. Later, he responded that his daughter had never been depressed, nor had she been acting like a person who planned to take her life.
In 1990 an article appeared in the American Journal of Psychiatry describing a half-dozen patients who developed “intense violent suicidal preoccupation after 2 to 7 weeks of fluoxetine treatment.” This report stirred up quite a lot of concern, but many psychiatrists downplayed the connection. When we asked the drug company and the FDA about this report, we were told that depressed people sometimes commit suicide and that the drug was not to blame.
Over the last 18 years we have heard of many other instances in which people became preoccupied with harming themselves or others after starting on an antidepressant. A man taking Zoloft awoke in the middle of the night with a strong urge to kill himself. A woman reported wild thoughts on Prozac about ramming her car into other cars and getting a gun to kill an irritating co-worker. Another woman told us that she experienced an overwhelming urge to open her car door and jump-out of the vehicle while it was going at 50 miles an hour down the highway.
My son Mike was prescribed Paxil for depression while he was a graduate teaching assistant at New Mexico State University. Around day 13 he slipped into a mood that I had never seen before. He never came out of it. Four days later he shot himself in the temple with a rifle. He had taken Paxil for 17 days.
I hold the FDA and GlaxoSmithKline (maker of Paxil) responsible for my son’s suicide. No one should ever have to look at a son or daughter’s tombstone!
Whenever we discussed our concerns with psychiatrists, drug companies, or FDA officials, we were told that such events were purely coincidental. Our federal watchdog insisted that the medicines could not have been responsible for such tragic outcomes. But when British drug regulators began warning physicians that SSRI-type medications might trigger suicidal thoughts, agitation, and self-injury in young patients, the whole ball of yarn began to come unraveled.
Eventually, an FDA staffer, Andrew Mosholder, MD, MPH, was given the task of analyzing 22 studies. His conclusion: “Short-term pediatric trials of antidepressant drugs demonstrate an increased rate of suicidal events with active drug compared to placebo.” He also said that there is not adequate information to tell if antidepressants other than Prozac are effective for children.
FDA JULY 1, 2005, PUBLIC HEALTH ADVISORY
• Adults being treated with antidepressant medicines, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal thinking or behavior.
• Close observation of adults may be especially important when antidepressant medications are started for the first time or when doses for the specific drugs prescribed have been changed.
• Adults whose symptoms worsen while being treated with antidepressants, including an increase in suicidal thinking or behavior, should be evaluated by their health-care professional.
The idea that drugs designed to fight depression and prevent suicide could potentially make things worse for some kids seemed to shock FDA officials to the core. Initially, Dr. Mosholder was muzzled. Eventually, though, the data convinced even the FDA hardliners. Belatedly, the agency issued warnings about suicidal thinking and antidepressants. These cautions came far too late to prevent many terrible tragedies over nearly 2 decades. As difficult as it has been for psychiatrists and FDA officials to contemplate, people taking SSRI-type antidepressants are sometimes preoccupied with thoughts of suicide or homicide. Harvard psychiatrist Joseph Glenmullen,’ MD, has criticized the makers of SSRI-type antidepressants for delaying adequate warnings.”‘ The maker of Effexor XR added “homicidal ideation” to its label years after the drug was introduced. The company considers this a very rare adverse event and does not believe the drug can be causally linked to actual homicides. But there have been a number of high-profile violent events associated with antidepressants. Causal or not, this controversy continues to simmer. The entire SSRI-suicide story strikes us as mishandled. Just as with the Vioxx (rofecoxib) scandal, it has seemed to us that FDA officials have been more intent on protecting the pharmaceutical companies’ profits than the public health. To add even more confusion to this already sordid affair, the reputation these drugs have enjoyed as being highly effective against depression is now suspect. Remember that placebo-controlled trials are the gold standard that everyone is supposed to adhere to. Drug companies are required to show that their expensive antidepressants are significantly superior to a placebo. But an “analysis of 96 antidepressant trials between 1979 and 1996 showed that in 52 percent of them, the effect of the antidepressant could not be distinguished from that of placebo. In other words, “more than half of all recent clinical trials of commonly used antidepressants failed to show statistical superiority for the drug over placebo.”
That, dear reader, is almost beyond belief. It suggests that either placebos—sugar pills—are amazingly effective in relieving depression or that current antidepressants are not all that impressive.
Another overview of many clinical trials concludes that the latter is the case. It goes even further and suggests that “recent meta-analyses show selective serotonin reuptake inhibitors have no clinically meaningful advantage over placebo…. Antidepressants have not been convincingly shown to affect the long-term outcome of depression or suicide rates.” Of course, this kind of analysis relies on the statistical manipulation and combining of many smaller studies. As compelling as the conclusions may be, they do not substitute for really big, well-conducted trials.
The largest and most definitive study of depression and antidepressant medications was a $35 million project, funded by the National Institutes of Health, called the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial. This was no drug company whitewash. This was your tax money at work. What made this research so valuable was that the investigators looked at actual recovery from depression (”remission”), not just some symptom improvement. Recovery is, after all, what depressed patients really care about. The antidepressants used in the STAR*D trial were bupropion SR (Wellbutrin SR), citalopram (Celexa), sertraline (Zoloft), and venlafaxine XR (Effexor XR). When the long-awaited results were published in the New England Journal of Medicine (March 2006), they were surprisingly disappointing. About one-fourth of the patients achieved real remission, regardless of the type of antidepressant that was taken. What makes this so discouraging is that these patients got optimal treatment. They received intense evaluation and a level of care not usually available to the average patient. If the depressed folks in this study had been treated in a more typical manner, “the remission rate probably would have been significantly lower—perhaps even in the single digits.”That’s abysmal. If there is any good news that came out of the STAR*D research, it is that when a different antidepressant medication was substituted after initial treatment failure, about one in three patients finally did achieve remission. What this means is that antidepressants actually do what they are supposed to do (cure depression) about half the time. Depending upon your perspective, that means the glass is either half full or half empty.
We are happy to learn that 50 percent of the patients in this trial got better. But even under these ideal conditions, half did not, regardless of the type of medicine used. That means that an awful lot of people are suffering drug side effects without benefit. And since there were no placebo controls in STAR*D, we have no idea how many folks might have improved if they had received sugar pills instead of drugs. So how can you determine which antidepressant is best for you? In truth, it is extremely difficult for physicians and patients to make clear decisions about safety and effectiveness when it comes to these medications. Despite all the hype from the drug companies, it is hard to prove that one type of antidepressant is better than another one.
Newer drugs like Cymbalta affect both serotonin and another neurotransmitter called norepinephrine (hence their name serotonin/norepinephrine reuptake inhibitors, or SNRIs). This dual action is supposed to make such drugs more effective. It has certainly driven up the cost. A single Cymbalta pill can cost between $3 and $4. A Wall Street Journal review reported that when Cymbalta was compared head-tohead with venlafaxine (Effexor), an older drug in this class, “Cymbalta wasn’t significantly different from Effexor in treating depression.”
The bottom line is that there are no “best choices” when it comes to these kinds of antidepressants. All these drugs are roughly similar in effectiveness, and all have the potential to cause serious adverse reactions for some people. Anyone who experiences anxiety, agitation, irritability, and especially thoughts of violence toward himself or others should contact a health professional immediately!
Watch Out for Withdrawal!
There is one other complication associated with these antidepressants that is rarely discussed. Sudden discontinuation of drugs like Effexor, Paxil, Serzone, and Zoloft may cause unexpected symptoms. We have heard from many patients that they experienced dizziness, nausea, insomnia, headaches, nervousness, sweating, shakiness (like a bad hangover), weakness, visual disturbances, and an inability to concentrate. One reader called the problem “Paxil Head,” like having your head stuck in a blender.
I take Zoloft, and have tried to stop taking it several times. Each time I stop I experience a-very strange thing. Doctors, nurses, and pharmacists dismiss me like I’m a nut case, but I swear this is true. I get electrical shocklike sensations in my head and become extremely dizzy. I absolutely know this is associated with not taking Zoloft. Not 2 hours after I resume taking it again the symptoms, which are overwhelming, disappear completely. I would like to get off of this drug but have no idea how to do so, especially when I cannot function without it and no one recognizes I’m having any trouble. They just think I’m crazy.
What is so sad about this particular problem is that no one really knows how common withdrawal symptoms are. There are, as far as we can tell, few good guidelines for helping people overcome this complication. So we do not know how long people will experience dizziness, shocklike sensations, or nausea after they stop a drug like Zoloft. Drug companies are not particularly interested in developing protocols for discontinuing SSRI/SNRI-type medications, since they would then need to admit they have a problem on their hands. That means that patients and physicians are on their own. Gradual tapering over several weeks may be necessary. We have heard from some doctors that they switch patients over to fluoxetine and then taper it very slowly. That’s because Prozac lingers in the body and may be less likely to trigger withdrawal symptoms.
Fluoxetine (Prozac)
Fluoxetine is a stand-in for all SSRI-type drugs. Although there are subtle variations between medications in this class, there are more similarities than differences.
Side effects: Headache, nausea, dizziness, diarrhea, nervousness, anxiety, and insomnia are relatively common and may affect up to one-fourth of the patients who take SSRI-type medications. Some people may experience drowsiness or dizziness. Delayed ejaculation, inability to achieve orgasm, and decreased sexual desire are common complications of this entire class of drugs. Less frequent problems may include decreased appetite, indigestion, sweating, mania, dry mouth, heart palpitations, tremor, chills, constipation, blurred vision, memory problems, confusion, rash, and joint pains. Blood sugar control or thyroid function may be altered. Seizures, while uncommon, have been reported in roughly 0.1 to 0.2 percent of patients, an incidence comparable to that seen with older antidepressants. Any thoughts of suicide or violence must be reported to a physician immediately).
Downside: SSRI-type medications like Prozac can interact with many other drugs. Make sure your physician and pharmacist double-check to verify that any other medicine, herb, or dietary supplement you take is safe with your antidepressant.
Cost: Approximately $130 to $140 for a month’s supply of Prozac. Generic fluoxetine costs $16 to $20 for the same amount.
Despite all the controversy, we still think Prozac is worthy of consideration, especially since it is less likely to precipitate withdrawal symptoms when discontinued. And we are not convinced that other SSRI/SNRIs are more effective. Many people benefit dramatically from this or another SSRI or SNRI. Prozac is now available generically as fluoxetine, so the cost factor is less problematic. We’re not convinced, though, that all generic fluoxetine is created equal.
Bupropion (Wellbutrin)
This antidepressant is less likely to interfere with sexuality and may even be helpful for people who have experienced diminished libido. It is also available generically, so there is a cost savings. People tend to feel energized rather than sluggish when taking bupropion.
Side effects: Common complaints include insomnia, dry mouth, anxiety or agitation, headache, nausea, and dizziness. Less common adverse reactions that we are aware of include mania, seizures, irregular heart rhythms, skin rash, hallucinations, paranoia, high blood pressure, and migraine.
Downside: Bupropion can interact with many other medications. Make sure your physician and pharmacist double-check to verify that any other medicine, herb, or dietary supplement you take is safe with your antidepressant. Any thoughts of suicide or violence must be reported to a physician immediately!
Cost: Approximately $130 to $150 for a month’s supply of brand-name Wellbutrin SR; generic bupropion SR runs roughly $60 to $70 for a similar amount.
efit more from one antidepressant than another, this is mostly a process of trial and error. It may take 4 to 6 weeks to begin to see improvement, so it is important to give each medication a fair trial. If no success is achieved after a few drugs in the same class are tried, then it may be time to move on to another category.
Bupropion (Wellbutrin) may offer certain advantages over other SSRI-type drugs. For one thing, it is far less likely to interfere with sexuality. Some have even reported that it restores libido.
Some people do benefit from old-fashioned tricyclic-type antidepressants such as desipramine, imipramine, and nortriptyline. For people who become agitated or anxious on an SSRI/SNRI or find that bupropion keeps them wide awake, tricyclics may offer an acceptable alternative.
There is also a completely different kind of antidepressant that comes as a skin patch (Emsam). We will discuss it at the end of this chapter.