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Broadly speaking, there are three classes of antidepressant medications in use - - the tricyclics (or heterocyclics), the monoamine oxidase (MAO) inhibitors and the newer, so-called second-generation agents by and large developed in the 1980 's. While there is considerable overlap in their actions and uses, these diffe rent categories of antidepressants work by distinct mechanisms, have different s ide effect profiles, and may be favored for varying indications. For these reas ons, they will be discussed separately below.

The tricyclics began to see broad use in psychiatry in the early 1950's with the introduction of imipramine (Tofranil and others), still one of the most-used me dications in this group. Other tricyclics (see table 1) include amitriptyline ( Elavil, Endep), desipramine (Norpramin, Pertofrane), nortriptyline (Pamelor and Aventyl), trimipramine (Surmontil), protriptyline (Vivactil), and doxepin (Adapi n, Sinequan). Clomipramine (Anafranil) is a somewhat specialized tricyclic agen t only recently introduced into the United States and approved specifically for the treatment of obsessive-compulsive disorder, in contrast to the other members of this class which have a broader range of accepted uses. Tricyclics also app ear in fixed-dose combination with other agents (Etrafon, Triavil, Limbitrol) al though many psychiatrists frown on these preparations as not allowing enough ind ividual titration of the doses of the component medications.

For what are the tricyclics used? The tricyclics, while accepted first and foremost for the treatment of depressiv e conditions and primarily referred to as "antidepressants," are useful in a wid e range of disorders. Their effectiveness is agreed upon for major depressive e pisodes, some so-called atypical depression (see further discussion of this belo w under the monoamine oxidase inhibitors), panic disorder, social phobia, bulimi a, narcolepsy, attention deficit disorder (ADHD) with or without hyperactivity, migraine headache and various other chronic pain syndromes, enuresis in children , and obsessive-compulsive disorder. Depressive symptoms occurring in the conte xt of other major mental illnesses such as manic depressive disorder, schizophre nia and schizoaffective disorder, are also treated with tricyclics, with certain caveats discussed below. These medications are possibly useful as well for a broader range of depressive conditions not meeting strict criteria for major dep ressive episodes (such as so-called "dysthymia" or depressive neurosis; and even prolonged or pathological mourning), for agoraphobia without panic attacks, and for some of the symptoms (such as intrusive nightmares) in post-traumatic stres s disorder.

What will it feel like to be taking a tricyclic? It is a common supposition that taking an antidepressant produces some kind of " high." In fact, this is not the case; usually the recipient will not be aware a t all subjectively of being on a medicine except that one's depression, panic di sorder, etc. will be lessened in intensity or one's ability to function in the f ace of it (including in one's therapy) will be enhanced. Except for the side ef fects, a person who does not have a disorder treatable with an antidepressant wi ll not feel any different when taking one.

Often, the benefits will not be apparent except in retrospect over some time. I n other cases relief, especially from depressive symptoms, may be more dramatic; only in the sense of this dramatic relief do responders feel elated. Certainly , one does not "escape," ignore or become numb to one's problems or sadnesses th rough taking an antidepressant. Being aware of this in advance will often be of great assistance in the realistic appraisal with one's caregivers of whether it is advantageous to take an antidepressant medication. To know this will be a r elief to some and may well be disappointing to others!

Two corollaries of the above are that the antidepressants are not "addictive" an d that they have low abuse potential. Taking more than the prescribed dose of a tricyclic is not an attractive but rather a disagreeable experience. In additi on, patients do not describe craving or yearning for the experience of being on the medication after it is stopped. (Of course, it is possible to have a reboun d of depressive symptoms, especially if the medication is stopped prematurely. Furthermore, there is a "withdrawal" syndrome, with malaise, nausea and headache s, if the medication is stopped too abruptly, although this is not indicative of dependency.)

When a person benefits from a tricyclic in the treatment of depression, some of the discernable effects include sounder or more restful sleep, decreased dreamin g (particularly a decrease in troubling dreams), increased energy and ability to concentrate, and correction of appetite disturbance.

How do these medicines work? Over time, the tricyclics enhance the concentrations in certain regions of the C NS of two neurotransmitter chemicals, norepinephrine and serotonin, whose undera ctivity has been implicated in depression and other disorders. When these neuro transmitters, known as monoamines, have been secreted, they must then be inacti vated by a variety of mechanisms including reuptake into the secreting cells. T ricyclics impede this reuptake process so that the monoamines remain active long er after secretion, presumably affecting the preexisting underactivity which was responsible for the target symptoms. Some tricyclic side effects relate to the fact that these medications have similar effects on other neurotransmitters in the CNS, notably histamine and acetylcholine.

What side effects can I expect if I take a tricyclic? While there are individual differences among the agents in terms of degree, they produce quite similar and troubling side effects (see tables 2 and 3). With ma ny tricyclics, the most troublesome effect with ongoing use is sedation. They a re often administered at bedtime so that this effect is bearable, but it may per sist into the following day.

Commonly, they cause enduring anticholinergic effects including dry mouth or eye s (of concern particularly in patients with dental problems and contact lenses, respectively); a peculiar taste in the mouth; and dilation of the pupils with re sultant sensitivity to bright light. Disturbances in visual accommodation (the rapid adjustment in focus necessary when the gaze is shifted from near to far or vice versa) can cause blurry vision. Constipation or urinary hesitancy are com mon. These effects can occasionally be quite serious or exacerbate underlying p roblems or tendencies in the affected organ system, occasionally precipitating c onditions requiring immediate medical attention such as acute glaucoma, paralyti c ileus of the bowel or acute urinary retention.

Weight gain is a common complaint of which patients should be made aware at the outset so that they can anticipate controlling their intake. It seems that the weight gain comes from a mechanism distinct from the mere correction of the appe tite suppression that often coincides with depression. In men, erectile dysfunc tion or, more rarely, difficulty achieving an ejaculation may be important and u nderreported barriers to compliance with the tricyclics.

At the outset of treatment, people taking these medications often are restless o r anxious, may be tremulous or feverish, may report increased perspiration or ni ght sweats, can experience difficulty falling asleep or restless disturbed sleep , and may report some clouded thinking or interference with their concentration. These symptoms are usually transitory although they may be so uncomfortable th at they cause the patient to discontinue the drug during the first few days or w eeks of treatment. At about the point where the therapeutic benefits of the med ication begin to be apparent several weeks into the course of treatment, this cl ass of adverse reactions has usually resolved or become tolerable.

Cardiovascular effects are also associated with these medications. Orthostatic hypotension, i.e. dizziness upon arising or otherwise rapidly changing posture, is common. A rapid heartbeat is often reported, sometimes with palpitations. T he medications can have deleterious effects on an unhealthy heart, e.g. causing EKG (electrocardiogram) changes or arrhythmias (disturbances in cardiac rhythm o r conduction); or, rarely, worsening or precipitating angina or heart failure or precipitating a myocardial infarction (heart attack). These cardiac effects m ay eliminate the tricyclics from consideration for some patients, although with close ongoing monitoring they may often be employed to good effect. A thorough evaluation of their safety in the presence of reported history of cardiac diseas e, especially a cardiac conduction defect, is always warranted and may involve a referral for a consultation with a cardiologist. In all patients from middle a dulthood, it is prudent to obtain an EKG prior to treatment and with dosage incr eases beyond a certain extent.

It is the cardiac effects which make the tricyclics so dangerous in overdose. T aken at one time, a one- to two-week supply can cause serious, potentially letha l, cardiac complications. Tricyclic antidepressants are now the leading cause o f death by drug overdose in the United States. It is ironic that such effective medications for conditions which often involve serious suicidal intent have such potential lethality.

The tricyclics can occasionally cause seizures in patients with a history of hea d injury, especially those with a preexisting seizure history. In these cases, collaboration of care between your psychiatrist and a neurologist is often warra nted. As with all medications to which one has not previously been exposed, the possibility of an allergic reaction should be borne in mind. Once allergy to o ne of these medications has been established, it must be avoided by that individ ual. Certain of these medications are very closely related and there may be cro ss-sensitivity among imipramine, clomipramine, desipramine and trimipramine; or among amitriptyline and its derivatives nortriptyline and protriptyline.

As with other antidepressants, the tricyclics can cause a swing from the depress ed to the manic state when given to a depressed patient with manic-depressive il lness. In someone whose manic-depressive illness has not been recognized, it ca n declare itself in just such a fashion when the individual presents for treatme nt of a depressive episode. There is some debate about whether the antidepressa nts can precipitate mania in someone who would not otherwise have a manic component to their affective disease.

The elderly are particularly susceptible to the range of side effects noted above. They often require treatment on lower dosages of these medications for comfort and safety; fortunately, such lower doses can also be therapeutic for them. The tricyclics should be used in pregnancy, as the Physician's Desk Reference puts it, "only if the clinical condition clearly justifies potential risk to the fetus." A woman taking these medications should not nurse an infant, as the medi- cation may be excreted in the breast milk.

With what other medications that I may be taking will the tricyclics interact?

You should always inform any physicians involved in prescribing for you of what medications you are already taking. Your primary care doctor, any specialists, surgeons and dentists involved in your care should be aware of the fact that you are taking a tricyclic; your prescribing psychiatrist should know all the other medications you take.

The effects of anticholinergic and sympathomimetic medications (employed in anae sthesia, treatment of gastrointestinal disturbances and certain ophthalmological conditions, allergy and cold remedies) may be additive with the side effects of the tricyclics described above. Certain blood pressure medications may interact with them as well, or their effectiveness may be inhibited by the presence of the tricyclic. Cimetidine (Tagamet), ranitidine (Zantac) and other similar medi cations used in peptic ulcer disease may raise the tricyclic levels in your body and thus increase the frequency and severity of adverse reactions. If you are receiving thyroid supplements for hypothyroidism, tricyclics may make you more sensitive to their adverse effects, especially on the heart and circulatory syste m, and should be more closely monitored.

The tricyclics amplify the CNS depressant effects of alcohol and other sedatives (tranquilizers and sleeping medications), so these medications should be used cautiously by someone receiving a tricyclic. You may find a reduced tolerance for excess caffeine while taking these medications. Except for the cold remedies noted above, no difficulty is presented by combining the tricyclics with any over-the-counter remedies, vitamin and other food supplements, or foods.

What are the preliminaries to starting on a tricyclic? A thorough medical screening including bloodwork is required to be sure that a m edical illness is not being mistaken for the psychiatric diagnosis. It is cruci al as well to determine whether you have the types of cardiac conduction disease which would make the use of a tricyclic dangerous. These can be detected with an EKG, which should be a routine precursor to beginning on a tricyclic for pati ents over 40 years of age or anyone with a history of heart disease. When doubt s about the safety of these drugs arise, a cardiology consultation is prudent.

Other medical conditions which can make the use of the tricyclics dangerous, suc h as narrow-angle glaucoma, should be ruled out in preliminary history, examinat ion and if necessary consultation.

How will my doctor choose among the various tricyclics? None of the antidepressants has been proven more effective or more rapidly-actin g than another, although this is a marketing claim that is often made for variou s ones. The grounds for choice among them is therefore largely based on their si de effect profile. There are two broad chemical classes of tricyclics. The tert iary amines (amitriptyline, imipramine, trimipramine and doxepin), which have pr oportionally more effect in boosting serotonin than norepinephrine, produce more sedation, anticholinergic effects and orthostatic hypotension. Amitriptyline an d doxepin are especially sedating. Secondary amines (nortriptyline, desipramine, and protriptyline) tend more toward enhancement of norepinephrine levels and he nce toward irritability, overstimulation and disturbance of sleep. The tertiary amines, thus, are more useful where depression is accompanied by sleep disturba nce, agitation and restlessness; whereas the secondary amines may be preferable where the depressed patient is fatigued, withdrawn, apathetic and inert. The p sychiatrist's initial evaluation, therefore, must go into extensive detail about the pattern of depressive symptoms you have experienced, to tailor the agent to the condition. An impression about which side effects you would best tolerate (or even benefit from) will enter into the physician's choice of tricyclic as we ll. Overall, desipramine and nortriptyline are perhaps the most benign in term s of patient tolerance, and are often the initial tricyclic of choice.

However, these are just the broadest guidelines, and treatment must be individua lized in terms of agent and dose in a trial-and-error fashion. Since there is r eason to believe that many of the tricyclic-responsive conditions have a heredit ary component, all other things being equal, starting on the same agent to which a genetically-related family member with the same disorder has responded favora bly in the past will usually be apt. You may wish to make inquiries about this within your family if you are under consideration for medication treatment. Of course, where you yourself have previously responded favorably and tolerably to a particular agent, it should generally be the drug of choice again.

How should the medication be taken? As with any medication, if your physician's instructions are unclear, you should ask for clarification. You and your prescribing doctor will individualize a treatment plan for you. However, some generalizations can be made. The medication will be started at a low dose to make sure you can tolerate it and to acclimatize your body to its effects. If you are in good health, the dose will be incre ased every two to four days as tolerated until it is in the therapeutic range. For the elderly or infirm, the interval between dosage increases is lengthened, generally to between seven and ten days as tolerated. Your doctor should do a t horough review with you of what side effects to anticipate. For example, knowin g of the risks of orthostatic hypotension may mean the difference between becoming faint on arising, falling and injuring yourself; and merely taking the care to move slowly when standing up.

During this period of acclimatization to the medicine, it is important for your psychiatrist to be available by phone or frequent follow-up appointment to check on your progress, answer questions about the effects you may be feeling, and reassure you. Your comfort with the medicine will be enhanced if you have a low threshold for contacting your doctor if you are puzzled or troubled by anything y ou are experiencing.

Generally, the medication is taken all at once at bedtime so that side effects will peak overnight and so that sedation will be less inconvenient. If necessary , the dose can be divided into two or more portions taken at different times of the day, where peak side effects after a single dose have been intolerable.

The recipient should not expect to respond at once after starting on an antidepr essant. A one- to three-week interval to therapeutic effect is the rule and a four- to six- week lag is conceivable. Unfortunately, there is no corresponding delay in the onset of adverse reactions, so it may even be useful to anticipate feeling worse on the medicine before you will feel better! Where bearable, it i s necessary to persist in the face of the discomfort of the side effects (some o f which will attenuate) and of the lack of quick symptom remission to give the m edicine a chance to be effective. Furthermore, responsiveness to a particular a gent or a particular dosage range is variable. While there are acknowledged "therapeutic dosage ranges" and some basis for individualizing choice of agent, an element of trial and error prevails and you and your doctor may have to make seve ral dosage increases or go on to a second or third medication before an effectiv e regimen is found.

It should be stressed that the tricyclics must be taken regularly and consistent ly to be beneficial. They cannot be used on an "as-needed" basis only on the da ys when you are feeling worst. The need to persevere with the medication during the two-to-four week lag time until it takes effect must be borne in mind.

What if I don't respond? Because it takes some time for a tricyclic at sufficient blood level to bring ab out the changes in the CNS that cause resolution of target symptoms, a patient m ust have a trial of adequate duration at effective dosage. Even if you are taki ng the recommended dose, poor absorption or rapid elimination of the medication from your system may necessitate a higher dose, especially if side effects are m inimal or being tolerated well. Occasionally, it will be useful to monitor the blood level of the medication, but the inaccuracy in measuring such miniscule co ncentrations limits the usefulness of the tests, and the range of effective bloo d levels has not been meaningfully defined for all the agents in this class. As mentioned above, when high doses of a tricyclic are employed, serial EKGs should be followed as well.

After an adequate but ineffective trial, you and your doctor will make a decisio n about switching to a different medication or attempting to potentiate your cur rent medication with agents such as lithium carbonate, thyroid hormone, or on oc casion the addition of a second antidepressant.

Will I have to take the medication for the rest of my life? On the basis of clinical experience and research, there is a consensus that pati ents with major depression can typically be taken off their antidepressant medic ation after six to eight months of clinical response without doing worse than pa tients who continue on the medication. In contrast, premature discontinuation a fter fewer months or after a less complete treatment response can often lead to a relapse. However, a patient who initially does well after discontinuing an an tidepressant may have a recurrence months or years later, as evidence suggests t hat up to 50% of patients who have had a single major depressive episode will ha ve subsequent episodes. The value of longer-term antidepressant maintenance to prevent recurrence, as opposed to episodic treatment of any relapses, is uncerta in.

Much less evidence bears on the proper length of a course of tricyclic therapy f or other conditions, either the attenuated (non-major) depressive syndromes or t ricyclic-responsive non-depressive syndromes such as panic disorder. Often, pat ients with panic disorder require open-ended treatment courses to avoid relapse, and medication-responsive chronic depression or dysthymia may also relapse if medication is not maintained. Attempts to discontinue medication should take pl ace in a measured way under regular ongoing followup with a sensitivity to the c hance that resumption of medication use will be merited.

As noted above, there is sometimes a withdrawal syndrome when tricyclic use is a bated abruptly. This consists mainly of headache, general malaise, and GI distress and can last several days. Over the weeks following discontinuation of an a ntidepressant, a patient may experience REM rebound, in which the frequency and intensity of his or her dreams is increased.

---eliot (Eliot Gelwan, Brookline MA USA),
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(Monday, 3 July 2000)