Authors: Andrew Solomon
“It’s like putting a grain of sand in an oyster,” Steven Hyman says of antidepressant medication, “and it turns into a pearl. It’s in the
adaptations
to altered neurotransmitters that slowly, over many weeks, the therapeutic effect occurs.” Elliot Valenstein, at the University of Michigan, adds, “Antidepressants are pharmacologically specific, but not behaviorally specific. The chemistry of products is ever more specific, but God knows what’s really happening in the brain.” William Potter, who was running the psychopharmacological side of the NIMH through the seventies and eighties and has now gone to Eli Lilly to work on the development of new drugs, explains it this way: “There are multiple mechanisms that produce antidepressant effects; drugs with acutely different spectrums of biochemical activity actually have very similar effects. They converge in ways you would never have expected. You can get pretty much the same antidepressant effects through the serotonin or norepinephrine systems, and in some people, through dopamine. It’s not simple; it’s like a weather system. You do something somewhere that changes wind speeds or humidity, and you get a completely different kind of weather, but how which change will affect what, even the best meteorologists can’t be sure.” Does it matter that most antidepressants suppress REM sleep, or is that an irrelevant side effect? Is it important that antidepressants usually lower brain temperature, which, in depression, tends to go up at night? It has become clear that all the neurotransmitters interact and that each influences the others.
Animal models are imperfect, but useful information can be gained from animal studies. Monkeys separated from their mothers in infancy grow up psychotic; their brains become physiologically different and they develop much lower serotonin levels than do monkeys raised with their mothers. Repeated maternal separations in a range of animals give them excessive levels of cortisol. Prozac will reverse these effects. Put the dominant male from one colony of marsupials into another grouping in which he is not dominant, and he will go through weight loss, lowered sexual performance, disrupted sleep, and all the other characteristic symptoms of major depression. Raise his serotonin levels and he may well have a total remission of these symptoms. Animals with low serotonin
tend to brutalize other animals; they take unnecessary and irrational risks and are confrontational without reason. Animal models of external factors and serotonin levels are extremely revealing. A monkey who rises through the dominance structure of his peer group will show higher levels of serotonin when his rank increases—and high serotonin is associated with lower levels of aggression or suicide. If such monkeys are isolated so that they do not have group status, their serotonin will fall by as much as 50 percent. On selective serotonin reuptake inhibitors (SSRIs), they become less aggressive and less prone to self-destructive activity.
Four classes of antidepressant medication are currently available. The most popular are the SSRIs, which bring about higher brain levels of serotonin. Prozac, Luvox, Paxil, Zoloft, and Celexa are all SSRIs. There are also two older kinds of antidepressants. The tricyclics, named for their chemical structure, affect serotonin and dopamine. Elavil, Anafranil, Norpramin, Tofranil, and Pamelor are all tricyclics. The monoamine oxidase inhibitors (MAOIs) inhibit the breakdown of serotonin, dopamine, and norepinephrine. Nardil and Parnate are both MAOIs. Another category, atypical antidepressants, includes drugs that operate on multiple neurotransmitter systems. Asendin, Wellbutrin, Serzone, and Effexor are all atypical antidepressants.
The choice of which medication to use is usually based, at least initially, on side effects. It is hoped that we will eventually find a way to test for responsiveness to specific drugs, but so far we are completely unable to do so. “There is little scientific basis for choosing a particular antidepressant for a particular patient, with a few exceptions,” Richard A. Friedman of Cornell’s Payne-Whitney Hospital says. “Prior response to a given drug is a good predictor of future response to the same drug. And if you have a special subtype of depression, atypical depression, where you overeat and oversleep, you’ll do better on an MAOI than on a tricyclic, though most clinicians use the newer drugs in these patients anyway. Aside from that—you choose a drug that appears to have a low side-effect profile as the first line of action. You can decide on a more activating drug such as Wellbutrin for someone who is very withdrawn, or a deactivating drug for someone who is agitated, but beyond that—it’s just trial and error with the individual patient. The labeling will tell you that one drug has more frequency of certain side effects than another, but in my clinical experience there really isn’t much difference within a particular class in overall levels of side effect from drug to drug. The differences in response at the individual level, however, may be very pronounced.” The great current popularity of the SSRIs—the Prozac
revolution—is due not to superior efficacy but to their low side-effect profile and their safety. It’s almost impossible to commit suicide with these drugs, and this is an important consideration in treating depressed people, who may, as they recover, become self-destructive. “Prozac is a very forgiving drug,” says one scientist at Eli Lilly. Decreased side effects mean not only that people will more readily take the drug, but also that they will comply with their regimens better. It’s the same as the principle that if your toothpaste tastes good, maybe you’ll brush longer.
Some people experience upset stomach with the SSRIs, and there have been occasional reports of headaches, of feeling strung out, of insomnia, and of somnolence. Their major side effect, however, is their undermining of sexuality. “When I was on Prozac,” Brian D’Amato, a depressive friend said to me, “Jennifer Lopez could have appeared at my bedside in a sarong and I’d have asked her whether she could help me with filing.” The tricyclics and MAOIs also have negative sexual side effects; because those drugs, while they dominated the market until the late 1980s, tend to be used only for more severe depression, beside which sexual side effects seem insignificant, their diminishing of erotic pleasure has not been discussed so much and so broadly as that of the SSRIs has been. In studies at the time Prozac was launched, a limited number of patients reported that Prozac was having negative sexual effects. In subsequent studies, when patients were specifically asked about sexual problems, an overwhelming number of them reported difficulties. Anita Clayton, of the University of Virginia, divides sexual experience into four phases: desire, arousal, orgasm, and resolution. Antidepressants affect all four. Desire is compromised by decreased libido. Arousal is diminished by inhibited sexual excitement, diminished genital sensation, impotence, or lack of vaginal lubrication. Orgasm is delayed; some people become totally anorgasmic. Confusingly, these effects can be irregular: one day everything goes fine, and the next day there’s crippling impotence, and you can’t tell which way it’s going to be until you’re in the act itself. Resolution is of course rather undermined when there has been no desire or arousal or orgasm.
The sexual side effects are often brushed aside as insignificant compared to a severe depression, and by that standard they are insignificant. Nonetheless, they are unacceptable. One patient I interviewed said that he could not have an orgasm in intercourse at all and described the complicated process of going off medication for long enough to impregnate his wife. “If I didn’t know how awful the consequences of being off medication might be,” he said, “I’d have stayed off it. Oh, my sexual self—it was so nice to have it back for a few days. I wonder whether I’ll ever have an orgasm with my wife again.” When you’re first recovering from a depressive
episode, when you’ve got other things on your mind, sexual deficiency is not so bothersome, but then to get over unbearable pain at the cost of erotic pleasure—well, it sure struck me as a bum deal. It is also a motivation for noncompliance, which is probably the single biggest problem in the treatment of depression. Less than 25 percent of patients who take antidepressants continue the treatment for six months, and a large proportion of those who stop do so because of sexual and sleep-related side effects.
Once the sexual effects set in, sexual anxiety ensues, so that erotic encounters may become disturbing moments of failure; people afflicted with this burden may develop a psychological aversion to sexual interaction, which makes the symptoms worse. Most men who have impotence problems suffer from depression; lifting the impotence may be sufficient to reverse the depression. It is both important and difficult, as Clayton has observed, to tease out the sexual problems that are characteristic of the underlying psychology that may have made a person depressed; the sexual problems that are a result of the depression (99 percent of people with acute major depression report sexual dysfunction); and the sexual problems that are the result of antidepressant therapy. Clayton stresses the need for nonintrusive but rigorous scanning of patients for sexual problems.
Many substances are said to help contravene the sexual side effects of antidepressants: serotonin antagonists such as cyproheptadine and granisetron; alpha-2 antagonists such as yohimbine and trazodone; cholinergic agonists such as bethanechol; dopamine-enhancing drugs such as bupropion, amantadine, and bromocriptine; autoreceptor agonists such as buspirone and pindolol; stimulants such as amphetamine, methylphenidate, and ephedrine; and herbals such as ginkgo biloba and L-arginine. Taking brief holidays—usually about three days—from drugs achieves occasional positive results. Sometimes switching drugs helps improve libido. None of these have been proved to work particularly well; but they do have some effect, varying from person to person. One woman whose story is told in this book had an alarming experience when she was put on a constellation of these drugs including Dexedrine: she was having such acute libido overflow that she found it physically uncomfortable to sit through routine meetings in her office. Things got to the point that, contrary to her usual habit, she was having sex with strangers in elevators. “I could come three times between the eighth and fourteenth floors,” she told me. “I stopped wearing underwear because it took too long to get it off. The guys thought they were doing something amazing—it was pretty uncomfortable for me, but I feel I really helped some male egos. But it just couldn’t go on. I’m basically a highly
repressed WASP. I’m not so young. I really wasn’t up for all this.” Some minor readjustments brought her back to a manageable level of sexual excitation. Unfortunately, the same drugs used on another patient I knew failed to do anything at all for her—“I couldn’t have an orgasm if I got stuck in an elevator for four hours with the young Montgomery Clift,” she sadly reported back to me.
Testosterone injections, administered to raise the level of free testosterone in the body, can have some useful effect, but they are difficult to administer and control and their effects are not entirely clear. The brightest ray of hope is Viagra. Because of its psychological and physical effects, it seems to affect three of Clayton’s stages; it falls short only in that it does not stimulate libido. It may as a secondary step help to restore confidence in one’s ability to interact sexually, and this helps one to relax, which in turn helps libido. It is to be hoped that dopamine boosters currently in development may take care of that, since dopamine appears to be strongly implicated in libido. Taken regularly, Viagra will also restore men’s nighttime erections, which are often eliminated by antidepressants. This in turn has a positive effect on libido. It has been proposed that men who are on antidepressants should take Viagra every night as a therapeutic agent, even if they are not having sex each time they take it. It can in effect be a quick and effective antidepressant; high levels of sexual function lift mood like almost nothing else. The research of both Andrew Nierenberg of Harvard and Julia Warnock of the University of Oklahoma indicates that Viagra, while it is not officially approved for women, seems to have good effects on their sexual drive and may facilitate orgasm. This is in part because it helps the clitoris to enlarge with blood flow. Hormone therapies are also useful in women with sexual dysfunction. Keeping up levels of estrogen improves mood, and sudden declines in estrogen levels can be devastating. The 80 percent drop in estrogen that women experience during menopause has pronounced mood effects. Women with low levels of estrogen develop all kinds of complaints, and Warnock stresses that the estrogen levels need to be normalized before Viagra can have any useful effect. Though it is important not to raise testosterone levels too high in women, lest they become hairy and aggressive, testosterone is a necessary hormone for female libido, and it too needs to be kept at appropriate levels.
The tricyclic antidepressants work on several neurotransmitter systems, including acetylcholine, serotonin, norepinephrine, and dopamine. The tricyclics are particularly useful in severe or delusional depression. The acetylcholine inhibition carries a number of unpleasant side effects, including dry mouth and eyes and constipation. Tricyclics
can also be somewhat sedating. Use of the tricyclics in people with bipolar illness can precipitate mania, so considerable care must be taken in prescribing them. The SSRIs and bupropion can also trigger mania, but are less likely to do so.
The MAOIs are particularly useful when depression carries acute physical symptoms such as pain, decreased energy, and interrupted sleep. These drugs block the enzyme that breaks down adrenaline and serotonin, thus increasing the level of these substances. MAOIs are excellent drugs but have many side effects. Patients taking them have to avoid a range of foodstuffs with which they have troubling interactions. They can also affect bodily function. One patient I interviewed got total urinary retention from MAOIs: “I pretty much needed to go to the hospital whenever I had to pee, which was not convenient.”
The atypical antidepressants are just that: atypical. Each has its own novel mode of action. Effexor affects both serotonin and norepinephrine. Wellbutrin acts on dopamine and norepinephrine. Asendin and Serzone work on all the systems. It is popular at the moment to try for so-called clean drugs, drugs that have highly specific effects. Clean drugs are not necessarily more effective than dirty ones; specificity may to some degree be connected to the control of side effects, but it seems that the more things you muck around with in the human brain, the more effective the treatment is likely to be for depression. Clean drugs are developed by the pharmaceutical companies, which are enthusiastic about the tidiness of chemical sophistication; but such drugs are not particularly distinguished for therapeutic purposes.