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Tricyclic (TCAs) and Heterocyclic Antidepressants For DepressionAn article about cyclic antidepressants: how they work, how to take them, and what side effects to expect.
Before Prozac, tricyclics were the first line of defense against encroaching depression, and had been ever since imipramine's release in 1958 under the brand name Tofranil. Today, tricyclics are a less popular choice than the new generation of antidepressants, but they're still an important weapon in the antidepressant arsenal for a subset of people who don't respond to anything else. This type of medication is used to help relieve the symptoms of major depression. Common Cyclic Antidepressants
Before tricyclics were developed, psychiatrists treating severely depressed clients had only two real choices: amphetamines or electroshock therapy. Imipramine was discovered by Swiss scientists searching for a successful schizophrenia treatment; it turned out that imipramine didn't do much for schizophrenia at all. What it did do very well was perk up depressed patients. With the discovery of imipramine, doctors finally had a drug that relieved a person's underlying depression. And when scientists realized how effective imipramine was -- about 70 percent of depressed patients responded to this drug -- they flocked to the laboratories in search of similar drugs based on imipramine's three-ring ("tricyclic") antihistaminic chemical structure. Before long, laboratories all over the country began churning out tricyclic clones, each one a little different from, but none any better than, imipramine itself. A later-developed drug in this class, maprotiline (Ludiomil), had four rings and was therefore called "tetracyclic." Taken together, the tricyclics and tetracyclics are known as "heterocyclics" or "cyclics." But while all these cyclics were effective, not one provided the perfect solution to depression for which scientists had been searching. How They WorkThe cyclic antidepressants work by beefing up the brain's supply of norepinephrine and serotonin levels -- chemicals that are abnormally low in depressed patients. This allows the flow of nerve impulses to return to normal. The cyclics do not act by stimulating the central nervous system or by blocking monoamine oxidase. The problem with cyclics is that they don't stop there. They go on to interfere with a range of other neurotransmitter systems and a variety of brain cell receptors, affecting nerve cell communication all over the brain in the process. And the more neurotransmitter systems and receptors you affect, the more side effects a patient will have. Who Responds to CyclicsSide effects notwithstanding, for some people the cyclics work better than any other drug available. "I've been taking imipramine for the past five years," says Carol, 47, a New Jersey teacher. "It was the first and only antidepressant I've ever taken. When I was depressed, I had a feeling of being lost. I was discontented with myself -- I felt 'blah' for a long time. I just don't feel that way anymore." The challenge, of course, is to figure out who will respond best to them. The important thing to understand is that some types of tri- and tetracyclics are riskier than others, and some people tolerate some types better. Just as scientists aren't sure exactly what causes depression, they're not sure exactly what cures it, either. Often, your doctor will choose an antidepressant drug for you based not on the cause of your depression as much as the symptoms you have, and how well you might be expected to tolerate certain side effects. Unfortunately, there's no simple test that can reveal which drug might work best for you. How well you react to any particular drug is often as much a surprise to your doctor as it is to you. That's why it may take some time before you and your doctor discover the perfect antidepressant "fit." The tricyclic nortriptyline (Pamelor), for example, may be useful in treating patients with depression following a stroke. Both trimipramine and imipramine work equally well at relieving depression in hospitalized patients. Because it has a sedative effect, the tetracyclic Ludiomil is useful in treating depression accompanied by anxiety or sleeping problems. Protriptyline is more likely to aggravate agitation and anxiety, but it's particularly good if you're withdrawn or lethargic and tired. On the other hand, it's likely to cause sleeping problems, especially when taken late in the day. (For this reason, protriptyline is a popular choice in the treatment of narcolepsy.) In the past, depressed patients were almost always started out on tricyclics. With the growing popularity of SSRIs, however, most patients are now given Prozac or Zoloft, and then moved to a tricyclic or tetracyclic if the depression doesn't respond to the first- or second-choice drugs. "When I became very depressed after experiencing some family problems, I tried Prozac," reports Gina, 52, a personnel manager in Arizona. "But after six months it hadn't affected my depression at all. So my doctor switched me to imipramine. Within a few weeks, I felt less prone to tears, less hopeless. It's not so much that I was suddenly pro-life. It's just that the negative outlook wasn't so stupefying." Sometimes, doctors may add Prozac or lithium to small doses of tri- or tetracyclics to boost the antidepressants' effectiveness. However, this can be risky; the com-bination has sometimes caused an increase in the blood level of the cyclic. Since cyclics already can be dangerous to the heart and can set off seizures, adding Prozac may increase this risk. Who Shouldn't Take CyclicsThe first job for your doctor is to decide whether you're one of the people who shouldn't take cyclic antidepressants. Obviously, your doctor won't prescribe them if you're allergic to this type of antidepressant. If you've taken an MAOI within the past two weeks, you'll want to wait two weeks before taking cyclics, since the combination of these two can cause serious side effects. If you have any kind of drinking problem, you should avoid cyclics, since alcohol can be toxic when mixed with these drugs.
advertisement There are also some specific health problems that don't mix well with certain antidepressants. If you have a problem with your bone marrow function or any blood cell disorder or if you have seizures or an adrenalin-producing tumor, you'll want to stay away from clomipramine (Anafranil). If you have serious heart disease, you should avoid trimipramine (Surmontil). Ludiomil shouldn't be used if you have a seizure disorder, or if you've had a heart attack within the past six weeks. You should also avoid Ludiomil if you have glaucoma or if you're an alcoholic. Also, before giving Ludiomil, your doctor will want to know if you have an enlarged prostate, stomach or intestinal problems, overactive thyroid, asthma, seizure disorders, or liver disease. Complicating Medical ProblemsBefore taking cyclic antidepressants, be sure to tell your doctor if you have any of the following medical problems:
How to Use CyclicsIf your doctor is considering one of the cyclics to treat your depression, you may be asked to get a physical examination, an electrocardiogram (EKG), and routine blood tests first. These can help determine which type of drug will be safest for you to use. No matter which cyclic you take, you'll begin with a small dose, gradually increasing in strength until your depression begins to improve. If you're one of those people who responds well to cyclics, you'll probably notice your sleeping problems improving within the first several days. Some cyclics may work more quickly than others. A few people find that their depression disappears overnight -- they go to sleep feeling depressed and wake up in a completely different mood. Others find their symptoms gradually fade over a period of days. Don't get discouraged if you're not turning handsprings within moments of starting therapy. Some people find it takes as long as three or four weeks before they see improvement. Within a month, you'll probably notice that you're starting to be more interested in your surroundings, in other people and in activities that you once enjoyed. As the days pass, you should begin to feel better and better. "When I began taking imipramine, I thought it would be like taking an aspirin -- you pop it in and within an hour you feel different," says Carol. "It didn't happen that way. I began to feel gradual changes by the end of the second week, and by the third week there was quite a difference in my depression." If you don't respond to a cyclic, it may mean your dose isn't high enough. Your doctor may order blood tests to find out how much of the drug is actually circulating in your blood, especially if you're taking imipramine, desipramine, nortriptyline, or amitriptyline. If after increasing the dose you still feel depressed after four or five weeks, your doctor will probably switch you to a different drug. How Cyclics Are AdministeredThe usual adult dosage of protriptyline is 15 to 40 milligrams daily, divided into three or four doses. If necessary, doses may be increased up to 60 milligrams daily, but doses above this limit are not recommended. Any increases in amount should be given in the morning dose. Lower doses are recommended for adolescents and the elderly. Your doctor will probably begin with about 75 milligrams of trimipramine daily in divided doses, increasing to 150 milligrams per day. Doses over 200 milligrams daily aren't recommended. Because this drug is so sedating, you can take the entire dose at bedtime. Ludiomil may be taken in a single daily dose (usually at bedtime) or in divided daily doses. An initial dosage of 75 milligrams daily is usually effective. However, in some patients (such as the elderly, who tend to be oversensitive to antidepressants), an initial dose of 25 milligrams daily is recommended. Because Ludiomil doesn't break down rapidly in the body, the initial dose should be maintained for at least two weeks. It may then be increased by 25-milligram increments as tolerated. Most people find that a maximum level of 150 milligrams is enough to keep symptoms under control. A maximum of 225 milligrams daily may be needed. If you're taking Ludiomil for an extended period of time, your doctor may order blood cell counts and liver function studies and may monitor your blood pressure. An overdose of a cyclic antidepressant may cause hallucinations, drowsiness, enlarged pupils, respiratory failure, fever, irregular heartbeat, severe dizziness, severe muscle stiffness or weakness, restlessness or agitation, breathing problems, vomiting, convulsions, and coma. These drugs can be dangerous at fairly small amounts (10 to 15 times your normal dose) -- and even smaller amounts in children. If You Forget a DoseOne daily dose (bedtime)
More than one daily dose
Dietary RestrictionsThere are some dietary cautions to keep in mind with specific cyclics. If you're taking the liquid version of doxepin (Adapin, Sinequan), don't mix it with grape juice or carbonated beverages, since these may reduce its effectiveness. Mix up this drug just before you take it. ToleranceWhile long-term treatment with antidepressants is controversial, more and more people are taking antidepressants for longer periods. Perhaps as a result, more and more of the antidepressants (even including some of the SSRIs, such as Prozac) are developing a reputation for decreasing effectiveness as treatment progresses. This is known as tolerance, and among the tricyclics, amoxapine in particular has been associated with this problem. Once you develop tolerance to an antidepressant, you'll need higher doses in order to keep your depression under control. Side EffectsOn the whole, cyclics are pretty safe and effective, falling somewhere between the MAOIs, which have many side effects, and SSRIs, which have very few. Even if you do run into some unpleasant side effects in the beginning, chances are they will become less of a problem as time goes by. If not, you can always switch to a drug with a different side-effect profile. Side effects with cyclics may include dry mouth, constipation, blurred vision, weight gain, increased heart rate, drowsiness, urinary retention, impotence, decreased blood pressure, and dizziness when standing up. Those with the highest probability for these side effects include amitriptyline, clomipramine, doxepin, imipramine and trimipramine. Desipramine has the lowest risk for these effects (see "Potential Side Effects with Cyclic Antidepressants" below). And patients taking high doses of cyclics often complain of memory problems and trouble in finding the right words. And like every other antidepressant, cyclics can trigger a mild manic high in some people. In a retrospective study published in the British Medical Journal of 3,065 patients with major depression, tricyclics worsened suicidal thinking slightly more than Prozac did (16.3 percent compared with 15.3 percent). Suicidal acts were reported as 0.3 percent for Prozac and 0.4 percent for tricyclics. About 15 percent of people may feel nauseated (compared with about 21 percent of people taking Prozac); headaches occur in about 20 percent of people taking either Prozac or tricyclics. Because some of these drugs are known for sedative effects that cause drowsiness, dizziness or decreased alertness, don't drive, fly an aircraft, operate dangerous machinery, or do anything requiring alertness until you learn how your medicine affects you. Following is a detailed explanation of the major cyclics' side effects: Dry mouth, blurred vision. As part of their action on many different brain systems, the cyclics act on histamine receptors, flicking on the body's "fight or flight" response, speeding up the heart, and shunting energy away from bodily functions, such as waste removal. The result: you get dry mouth, blurred vision, constipation, urinary problems. These side effects may be especially annoying if you're taking amitriptyline, clomipramine, doxepin, imipramine, or protriptyline. "When I was taking imipramine, I had to chew gum all the time if I wanted to talk," remembers Gail, 52. "And I had to be sure I ate a jar of prunes every day -- or else!" She notes that her dry mouth and constipation lasted for the entire two years she took imipramine. If you're particularly bothered with a dry mouth, you can try sucking on sugarless candy or gum. (A lack of saliva can lead to tooth decay, so try not to aggravate this situation with sugar.) Or ask your physician to prescribe a saliva-promoting drug like pilocarpine. Blood sugar levels. If you're a diabetic, you should be aware that cyclic antidepressants may affect your blood sugar levels. This means that you could notice your blood or urine test results are changing. If you have any questions, check with your doctor. Constipation. It's important to remember that constipation may be a symptom of your depression and not a side effect of a cyclic antidepressant. If it is a symptom of your depression, the problem should disappear as the cyclic takes effect. If it's clear you're constipated as a result of the drug, there are some dietary changes you can try. Begin by eating more fruits and vegetables, getting lots of fiber, and drinking plenty of fluids. If all other methods fail, your doctor can prescribe a stool softener or bulk agent. Finally, your doctor can switch you to an antidepressant that carries less of a risk for this type of side effect, such as Prozac or Zoloft or another of the newer antidepressants. Contact lenses. You may experience problems with your contact lenses if you take cyclics. Because these drugs can cause dry eyes, your lenses may get gummed up with deposits of thick secretions, making them feel gritty, itchy, or painful. If this happens, your doctor may be able to prescribe a different antidepressant, reduce your dose, or prescribe artificial tears. Dizziness. Some tricyclics, especially amitriptyline, might make you dizzy when you stand up (this is called "orthostatic hypotension"). If you notice this, try standing up more slowly. In the morning, dangle your feet over the side of the bed for a few minutes before slowly standing up. If you have a serious problem with dizziness, your doctor may be able to adjust your dose or switch you to another cyclic. The tricyclics least likely to cause this problem are amoxapine and nortriptyline (Pamelor). Drowsiness. Sedation is a common side effect of many tricyclics and tetracyclics; three of the most sedating are doxepin, amitriptyline, and trimipramine. "I found the sleepiness to be fairly pleasant," Sally, 52, reports. "I was sleepy all the time, but it was a blissful sort of sleepiness. And since I'd been having trouble sleeping before I started taking imipramine, I didn't mind it so much." Neuroleptic malignant syndrome. If you use clomipra-mine too long, you run the small risk of developing a group of symptoms called "neuroleptic malignant syndrome," including fever, fast or irregular heartbeat, sweating, weakness, muscle stiffness, seizures, or loss of bladder control. Sexual problems. Most antidepressants affect sexual functioning in one way or another, and cyclics aren't any different. You may experience either an increase or a decrease in sexual interest. Men may experience problems with erection or ejaculation or suffer from impotence. Cyclics may trigger swollen testicles, or breast enlargement in men and women. If you experience significant problems with sexual functioning, your doctor may choose to switch you to a different antidepressant that doesn't cause these problems, such as Wellbutrin (bupropion). Sun sensitivity. If you take a cyclic antidepressant and you go out into the sun even briefly, you may end up with a rash, red or discolored skin, or a dreadful sunburn. Before going out in the sun, study the accompanying list of "Sunlight Precautions When Taking Cyclic Antidepressants" (see below). If you do get a severe reaction from the sun, consult your doctor. Sunlight Precautions When Taking Cyclic Antidepressants To prevent harmful skin reactions following exposure to sunlight, take the following precautions when you are taking cyclics:
Sweating. Doxepin may interfere with sweating, making it harder for your body to withstand heat. To avoid the risk of heat stroke, avoid saunas or extremely hot climates while taking this drug. Tardive dyskinesia. Amoxapine carries the risk of a group of unique side effects called "tardive dyskinesia" -- speech or swallowing problems, lip smacking or puckering, loss of balance, cheek puffing, rapid or wormlike tongue movements, shakiness or trembling, shuffling walk, slow movements, arm or leg stiffness, uncontrolled chewing movements, and uncontrolled movements of hands, arms, or legs. This tardive dyskinesia may be permanent. Potential Side Effects with Cyclic AntidepressantsCommon Side Effects
Infrequent Adverse Effects
Rare Adverse Effects
Side effects more common to people over age 60
Weight gain. Many of the tricyclics cause weight gain. While it begins with just a few pounds, long-term treatment can add more and more weight until people stop taking the antidepressant (one study found that 48 percent of people stopped taking tricyclics because of weight gain). While there aren't any specific restrictions on diet, you may want to guard against eating too much to avoid gaining too much weight. You can take clomipramine with meals or after eating to lessen stomach distress. If you're having a serious problem with weight gain, your doctor may want to consider one of the newer antidepressants (such as Wellbutrin, Paxil, Prozac, Zoloft, Desyrel, or Effexor), which don't usually cause weight gain. Drug InteractionsSome medicines should never be used with cyclics (see "Potential Drug Interactions with Cyclic Antidepressants" below), but other drug combinations are okay as long as your doctor monitors your condition closely. Of course you'll want to avoid alcohol, which can be toxic when combined with cyclics. Taking cocaine with cyclics may cause irregular heartbeat; smoking marijuana may make you too sleepy. Some experts also believe that tobacco may make cyclics less effective. There are also some specific interactions with a few of the cyclics. If you're taking desipramine, you should know that the effects of estrogen or birth-control pills may decrease the antidepressant's effectiveness. Lithium will decrease the effectiveness of imipramine; imipramine's effects will be strengthened by simultaneously taking Prozac, estrogens, Ritalin, or birth-control pills. In addition, this drug may mask poisoning by organophosphorous-type insecticides. Ludiomil may increase the effect of anticoagulants and may decrease the effect of guanethidine. Increased sedation may result by combining Ludiomil and anticholinergics or central-nervous-system depressants. The affects of Ludiomil may be increased if taken with cimetidine, thiazide, or Prozac, and may be decreased if taken with clonidine. Toxic symptoms may follow a combination of Ludiomil with methylphenidate. Finally, Ludiomil combined with levodopa may increase blood pressure. The effects of clomipramine may be increased if taken with Prozac, Haldol, some diuretics, and Tagamet. If taken with Dilantin, chloral hydrate, or lithium, its effects may be decreased. The effects of desipramine may be increased if taken with phenothiazine and decreased if taken with chloral hydrate, estrogen, lithium, or birth-control pills. Imipramine's effects may be increased by taking it simultaneously with Tagamet, Prozac, or Ritalin. Its effects may be decreased by taking chloral hydrate or lithium at the same time. Nortriptyline increases the effects of dicumarol and the drug's effects may be increased if taken with Tagamet or quinidine. Potential Drug Interactions with Cyclic Antidepressants
Pregnancy and Breast-feedingIf you're pregnant and seriously depressed, you and your doctor will have to weigh the risks of your untreated depression against possible damage to your fetus. While one study published in the January 1997 issue of The New England Journal of Medicine concluded that Prozac was safe to use during pregnancy, more research is needed. Theoretically, all cyclics can pass into breast milk; therefore, you may want to discuss the wisdom of breast-feeding with your doctor if you are going to take cyclics after giving birth. The only specific negative information about tricyclics and breast-feeding infants is that doxepine may cause drowsiness in nursing babies. Cyclics and ChildrenImipramine is the most widely studied antidepressant when it comes to treating children. Because it's also one of the least toxic, it's the antidepressant most likely to be prescribed for youngsters. When a child is taking imipra-mine, his blood pressure, pulse, and heart rhythm should be monitored, since there's a greater risk of heart problems in youngsters between 6 and 12 than there is in adults. Despite extensive studies with children, no one knows whether this drug is safe for youngsters under age 6. Imipramine is usually started at low doses (usually 25 milligrams daily) and increased by increments of 25 milligrams every few days until the depression begins to fade. Doses should always be given by an adult, since overdoses in children have been reported. Overdoses of tricyclics are particularly serious in children, who are unusually sensitive to these drugs. Doses should not exceed 2.5 milligrams per kilogram per day in children. Because children are especially sensitive to all cyclics, they are at greater risk for side effects, especially nervousness, sleeping problems, fatigue, and mild stomach irritation. Check with your doctor if your child has any of these symptoms. Cyclics and the ElderlyIf you're over age 60 and take cyclics, don't be surprised if you experience one or more of these symptoms: confusion, dizziness, drowsiness, dry mouth, shakiness, fainting, constipation, urinary problems, headache, insomnia, and vision problems. Call your physician immediately if you experience any of these symptoms after you stop taking the drugs. Cyclics and Obssessive-Compulsive DisorderAntidepressants are sometimes used for other disorders besides depression, including obsessive-compulsive disorder, panic disorder, and (in the case of imipramine) bed-wetting. People with OCD become obsessed with certain thoughts and are bogged down with repetitive activities like washing themselves or rechecking doors and windows. The standard treatment for this disorder, which affects about 5 million Americans, is the tricyclic clomipramine, although in 1994 the FDA approved the SSRIs Prozac and Luvox as OCD treatments as well. Because clomipramine must sometimes be taken in high doses (200 to 300 milligrams daily) to be effective against OCD, severe side effects are common. This is why more and more physicians are turning to Prozac, which produces only very mild side effects with this group. Source: "Copyright © 1997 by the RGA Publishing Group. From Making the Prozac Decision: A Guide to Antidepressants, by arrangement with RGA Publishing, Inc." top ~ next ~ send page to a friend HealthyPlace.com Depression Center Links home ~ site map ~ causes ~ types ~ people ~ living with treatments ~ self-help ~ support ~ suicide ~ related issues |
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