ANTIDEPRESSANTS

Depression in older adults is now being recognized as a severe and widespread health problem. Despite the availability of newer and safer antidepressants, depression is often unrecognized and undertreated in this population. Currently, there are several classes of antidepressants available for treatment of depression. They could be classified as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the miscellaneous group.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) were the original antidepressants. MAOIs are very potent but more risky to use, particularly in older patients. MAOIs work by blocking the enzyme monoamine oxidase either reversibly or irreversibly. MAOIs that block the enzyme irreversibly are Iproniazid, Phenelzine, and Tranylcypromine. While taking these medications, patients have to avoid certain food products such as cheese (which contain higher levels of tyramine) as well as many over-the-counter cold medications. In combination with MAOIs these drug-food and drug-drug interactions may cause alarming increases in blood pressure and could be lethal. Since safer antidepressants are available now, these medications are seldom used.

Reversible inhibitors of monoamine oxidase, such as moclobemide and selegiline (only at lower doses) were introduced with the claim that they may not have the dangerous interactions like the irreversible MAOIs. Nonetheless, recent reports suggest that they should also be used very cautiously.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants (TCAs) work by increasing the availability of the neurotransmitters norephinephrine and serotonin in the synaptic space between nerve cells in the brain. Until recently this group of antidepressants was the "gold standard" in the treatment of late-life depression and is still used as a standard to compare newer antidepressants. This group includes medication such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotyline, nortriptyline, protriptyline, and trimipramine. Medications in this group have been shown to slow conduction of electrical impulses in the heart and could be lethal if a patient were to overdose with them. The TCAs also have anticholinergic side effects (dry mouth, blurred vision, constipation, urinary retention, etc.) to which older patients are very sensitive and thus are not currently used as first-line medication for late-life depression. Despite this, nortriptyline is the best studied antidepressant for acute and continuation treatment of depression in older patients. If nortriptyline is used, it is essential that plasma concentrations be monitored, since there is a proven blood level range at which it is effective and safe. It is also recommended that the electrocardiogram (ECG) be assessed prior to starting and during treatment.

Common side effects of the TCAs include dry mouth, urinary retention, confusion, constipation, blurred vision, dizziness (may lead to falls and fractures), and sedation.

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) act by increasing the concentration of serotonin available to nerve cells. Currently the most prescribed antidepressants in the world, this group includes of citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are safer and better tolerated than MAOIs and TCAs. There is still some lingering controversy as to whether they are as potent as the older antidepressants for very severe depression. The SSRIs are generally not lethal in overdose, which is a significant benefit in the elderly depressed patients who are at the highest risk for suicide. The common side effects of SSRIs include nausea, vomiting, diarrhea, headaches, anxiety, sexual problems, and sleeplessness. Usually the side effects are temporary in nature. In elderly people, fluoxetine has been reported to cause some weight loss, agitation, and also stays in the body for a long time. Also, it should be noted that fluvoxamine is not approved by the FDA (Food and Drug Administration) for the treatment of depression. Medications in this group are also known to interact with other drugs often causing a reduced metabolic breakdown. Of the available SSRIs, citalopram and sertraline have relatively lesser drug interactions and are well tolerated in older people. These medications are also associated with some unusual side effects predominantly in elderly people. One such side effect is the decrease in sodium in the blood (hyponatremia). The other is the report of higher incidence of Parkinson's disease—like movement problems in elderly people. There have been some recent reports of falls in elderly patients even with the use of SSRIs (which were previously thought not to increase the risk of falls in the elderly when compared to TCAs).

Miscellaneous

There are other antidepressants that do not belong to the previous categories mentioned and are grouped together here.

There is some data showing that the antidepressant buproprion is effective in late-life depression. It is thought to work by increasing the amount of dopamine available to the brain nerve cells and hence may be an attractive alternative medication. It has few interactions with other medications and fewer sexual side effects compared to the SSRIs but there is some concern for seizures at higher doses.

Nefazodone works somewhat like the SSRIs, but also has some other specific pathways through which it acts. Limited information is available at this time about the effectiveness of this medication in late-life depression. It can cause some very serious drug interactions.

Venlafaxine works by increasing both norepinephrine and serotonin, as do the TCAs. However, it is much more selective than the TCAs in affecting other nerve systems, which contribute to side effects. Nonetheless increases in blood pressure and nausea may be significant problems for some patients when using this medication.

Mirtazapine works at multiple sites in the brain to induce its antidepressant effect. There is information that it may help older patients, particularly those at risk of significant weight loss. Mirtazapine does increase appetite and also causes sedation, which may actually be helpful for some older people.

Methylphenidate is not considered an antidepressant but is sometimes used for older depressed people who are significantly withdrawn and lack motivation. Therefore it may be particularly useful in older depressed people undergoing rehabilitation. Limited data is available for its effect in depression.

St. John's Wort, a popular herbal remedy for mild to moderate depression, has not yet been thoroughly evaluated in older adults. However, St. John's Wort has recently been found to cause important drug interactions for many medications commonly used in the elderly, such as digoxin.

LalithKumar K. Solai Bruce G. Pollock

See also Depression; Electroconvulsive Therapy; Interpersonal Therapy; Problem Solving Therapy.

BIBLIOGRAPHY

Dunner, D. L. "Therapeutic Consideration in Treating Depression in the Elderly." Journal of Clinical Psychiatry 55 (1994): 48–57.

Georgotas, A.; Mccue, R. E.; Hapworth, W.; Friedman, E.; Kim, M.; Welkowitz, J.; Chang, I.; and Cooper, T. B. "Comparative Efficacy and Safety of MAOIs Versus TCAs in Treating Depression in the Elderly." Biological Psychiatry 21 (1986): 1155–1166.

Glassman, A. H., and Roose, S. P. "Risks of Antidepressants in the Elderly: Tricyclic Antidepressants and Arrhythmia-Revising Risks." Gerontology 40 (1994): 15–20.

Lebowitz, B. D.; Pearson, J. L.; Schneider, L. S.; Reynoldsiii, C. F.; Alexopoulos, G. S.; Bruce, M. L.; Conwell, Y.; Katz, I. R.; Meyers, B. S.; Morrison, M. F.; Mossey, J.; Niederehe, G.; and Parmelee, P. "Diagnosis and Treatment of Depression in Late Life: Consensus Statement Update." Journal of the American Medical Association 278 (1997): 1186–1190.

Leo, R. J. "Movement Disorders Associated with the Serotonin Selective Reuptake Inhibitors." Journal of Clinical Psychiatry 57 (1996): 449–454.

Newhouse, P. A. "Use of Selective Serotonin Reuptake Inhibitors in Geriatric Depression." Journal of Clinical Psychiatry 57 (1996): 12–22.

Reynoldsiii, C. F.; Frank, E.; Perel, J. M.; Mazumdar, S.; and Kupfer, D. J. "Maintenance Therapies for Late-Life Recurrent Major Depression: Research and Review Circa." International Psychogeriatrics 7 (1995): 27–39.

Richelson, E. "Synaptic Effects of Antidepressants." Journal of Clinical Psychopharmacology 16 (1996): 1–9.

Schneider, L. S. "Pharmacological Considerations in the Treatment of Late-Life Depression." American Journal of Geriatric Psychiatry 4 (1996): 51–65.

Solai, L. K.; Mulsant, B. H.; and Pollock, B. G. "Update on the Treatment of Late-Life Depression." In The Psychiatric Clinics of North America—Annual of Drug Therapy. Edited by David L. Dunner and J. F. Rosenbaum. Philadelphia: W. B. Saunders Co., 1999: Pages 73–92.

Thapa, P. B.; Gideon, P.; Cost, T. W.; Milam, A. B.; and Ray, W. A. "Antidepressants and the Risk of Falls among Nursing Home Residents." New England Journal of Medicine 339 (1998): 875–882.

Antidepressants

Medications used to treat depression.

The two most common types of antidepressants are tricyclic antidepressants (TCAs) and selective serotonin re-uptake inhibitors (SSRIs). Examples of TCAs include nortriptyline (also known by the brand name Pamelor), imipramine (Tofranil), and desipramine (Norpramin). Examples of SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). Clinical studies have shown that some people benefit from these medications.

Tricyclic antidepressants (TCAs)

Before using TCAs, it is necessary to have a medical history and examination of the patient, including an electrocardiogram (EKG). Not everyone develops side effects when taking TCAs, but the most common side effects include: dry mouth, impaired ability to focus vision at close range, constipation, urinary hesitation, dizziness, weight gain, and sedation. TCAs may produce minor cardiovascular changes such as orthostatic hypotension (low blood pressure when the person stands up, often causing light-headedness), hypertension, rapid heart beat, and minor changes in the electrical activity of the heart, which may show in the electrocardiogram (EKG). Most of these side effects can be minimized by slowly adjusting the dose of the drug.

During treatment with TCAs, patients should be monitored by a physician trained in the management of these medications. It is recommended that he or she perform regular blood pressure, heart rate, and EKG monitoring. TCAs may interact with other medications the patient is taking, so it is important to consult a doctor before doing so. Finally, the TCAs should not be stopped abruptly, as this may induce mild withdrawal side effects (malaise, chills, stomachache, flu-like symptoms). Though they are safe if carefully monitored and taken as prescribed, TCAs can be lethal if taken in overdose.

Selective serotonin re-uptake inhibitors (SSRIs)

The reports that SSRIs are effective in treating adults with major depressive disorder (MDD), together with the findings that SSRIs have a relatively benign side effect profile, low lethality after an overdose, and once-a-day administration, have encouraged the use of SSRIs.

Several studies have reported 70-90% response rate to fluoxetine or sertraline for the treatment of adolescents with major depressive disorder, but the results of these studies are not conclusive because they have methodological limitations. A recent, large, well-performed investigation showed that fluoxetine was more effective for the treatment of depressed children and adolescents than a placebo. Despite the significant response to fluoxetine, many patients had only partial improvement.

Overall, the SSRIs have similar effectiveness and side effects as TCAs. The most common side effects include nausea, stomachache, diarrhea, headaches, mild tremors, sweating, sleep disturbance, sedation, restlessness, lack of appetite, decreased weight, vivid dreams , and sexual dysfunction (inability to have an orgasm or delayed ejaculation). Most of these side effects are temporary and may be diminished by reducing the dose or discontinuing the medication. There are no specific laboratory tests required before administering SSRIs. These drugs do have potentially harmful interactions with several commonly prescribed drugs; therefore, all physicians should be informed if someone is taking an SSRI.

Patients who do not respond to treatment

The most common reasons for failure of treatment are inadequate medication dosage or length of medication trial, lack of compliance with treatment, exposure to chronic or severe life events that require different modalities of therapy, existence of other psychiatric disorders (e.g., substance abuse, anxiety disorder), and misdiagnosis. In adults with resistant depression , several types of combinations of medications and ECT (electroconvulsive therapy ) have been found to be useful.

antidepressant any of a wide range of drugs used to treat psychic depression . They are given to elevate mood, counter suicidal thoughts, and increase the effectiveness of psychotherapy . Before the introduction of such drugs in the late 1950s, most patients with major depression had no recourse but hospitalization; only 45% improved after one year. In contrast, 80%–90% of such patients can expect significant relief from depression with one of the medications now prescribed.

Antidepressants act on the flow of the neurotransmitters epinephrine , serotonin , and norepinephrine across neural synapses . Common antidepressants include monamine oxidase inhibitors (MAOIs) such as isocarboxazid (Marplan), tricyclics such as imipramine (Tofranil) and amitriptyline (Elavil), and the newer selective serotonin reuptake inhibitors (SSRIs) as fluoxetine (Prozac) and sertraline HCL (Zoloft). Venlafaxine (Effexor) inhibits both serotonin and norepinephrine reuptake.

The choice of antidepressant often has more to do with its side effects (variously sedation, constipation, hypotension, tachycardia, weight gain, sexual dysfunction) than efficacy, as they are generally regarded to be equally effective. The newer drugs, especially SSRIs, are tolerated better and are currently by far the most widely prescribed, but SSRIs also appear to be less effective in children and teenagers and may cause some of them to become suicidal.

ANTIDEPRESSANT

Antidepressants are a diverse group of drugs that demonstrate a capacity to produce improvement in the symptoms of clinical depression, and they are used to treat the abnormal mood states that characterize depressive illnesses. The word depression is used commonly to describe a state of sadness; but health professionals use the term in a more restricted or defined manner to describe several psychiatric disorders characterized by abnormal moods. One of these is bipolar disorder, in which periods of depression (marked by dejection, lack of energy, inactivity, and sadness) alternate with periods of manic behavior (marked by abnormally high energy levels and increased activity). Another is major depression, which is often a recurring problem characterized by severe and prolonged periods of depression without the manic swing. A third is dysthymia, a chronic mood state characterized by depression and irritability, which was once referred to as depressive neurosis. The signs and symptoms of depressive mood disorders may occur as part of other medical and psychiatric disorders (i.e., following stroke); as a result of endocrine disorders; or as a consequence of excessive drug use. Often these abnormal mood states may not meet established criteria for one of the major psychiatric mood disorders, but they may nevertheless respond to one of the antidepressant drugs.

Antidepressants can also be useful in a number of medical and psychiatric disorders where depression is not the major feature. For example, some categories of antidepressants can be used to treat anxiety and panic disorders, and they are often useful as adjunctive medications for chronic pain. Antidepressant drugs are not generally helpful for short-term depressed moods that are part of everyday life or for the normal period of grief that follows the loss of a loved one.

New categories of antidepressants are being continuously developed and tested. There are now at least five categories in use. These include tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, lithium, nontricyclic antidepressants, and serotonin-reuptake inhibitors (SSRIs). The chemical structures of some of these are shown below.

The tricyclic antidepressants, which have been used for many years in the treatment of depression, include such compounds as imipramine (Tofranil), nortriptyline (Aventyl), and desipramine (Norpramin). In addition to being used to treat depression, imipramine is sometimes used to treat alcoholism and cocaine withdrawal. Desipramine is also sometimes used to treat depression associated with cocaine withdrawal. In terms of dosage, most of the tricyclics can be given in a single dose at bedtime. The tricyclics as a group, however, have two major drawbacks. First, the patient must take a specific tricyclic for a period of 2 to 4 weeks before signs of clinical effectiveness occur. Second, the tricyclics have a relatively narrow margin of safety, which means that it is easier for a depressed patient to take an overdose. As a rule, physicians are cautious about prescribing tricyclic antidepressants if the patient appears to be at risk for suicide.

The monoamine oxidase (MAO) inhibitors are generally used as second-line drugs for depressed patients who do not respond to tricyclics, because they require certain dietary restrictions (patients are not allowed liver, aged meats, most cheeses, red wine, soy sauce, etc.) The MAO inhibitors are, however, first-choice drugs for treatment of panic disorder and of depression in the elderly. They include phenelzine sulfate (Nardil), isocarboxazid (Marplan), and tranylcypromine sulfate (Parnate). These antidepressants may be given in either the morning or the evening, depending on their effect on the patient's sleep.

Although lithium (Eskalith, Lithonate) is useful in treating manic states and in preventing depression in bipolar disorders, it is not generally used for other types of depression. Lithium may have serious side effects and may be toxic at high dosages. Exposure to lithium in early pregnancy is associated with an increased frequency of birth defects, and the long-term use of lithium damages kidney function. It also seems to have no significant value in treating cocaine dependence or alcoholism.

The serotonin reuptake inhibitors (SSRIs) are the newest category of antidepressant medications. They have become the most widely used drugs for depression; fluoxetine (Prozac) has been the best-selling antidepressant since the mid-1990s. Other SSRIs include paroxetine (Paxil) and sertraline (Zoloft). A fourth drug, bupropion (Wellbutrin), is not an SSRI but is often grouped with them because it is a newer antidepressant. The SSRIs have several advantages: They can often nip mild depression "in the bud" before it develops into a major depressive episode. They can also be used to treat bulimia, obesity, and obsessive-compulsive disorder as well as depression. Since insomnia is a common side effect of SSRIs, they are usually given as a single dose in the morning. The SSRIs also have several disadvantages, including a long response time (patients may need to wait 4 weeks to see any improvement); the same failure rate as the older tricyclics (20-40percent of patients); side effects that include sexual dysfunction; and high cost ($2-3 per tablet).

When a patient does not respond to a specific antidepressant after a trial of 2 to 4 weeks, the physician may prescribe another medication. If the new drug is from the same group as the first antidepressant, the physician can rapidly decrease the dosage of the first drug while increasing the dosage of the second. If, however, the new antidepressant is from a different category, a "washout time" must be allowed in order to prevent drug interactions. A washout period of 2 to 3 weeks is necessary when the patient is switched from an MAO inhibitor to a tricyclic; a period of 4 to 5 weeks is necessary when switching from an SSRI to an MAO inhibitor.

BIBLIOGRAPHY

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders, 4th ed. (DSM-IV). Washington, DC.

Baldessarini, R. J. (1991). Drugs and the treatment of psychiatric disorders. In: A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Eisendrath, S. J. (1998). Psychiatric Disorders. In L. M. Tierney et al. (Eds.), Current Medical Diagnosis & Treatment, 37th ed. Stamford, CT: Appleton & Lange.

George R. Uhl

Valina Dawson

Revised by Rebecca J. Frey

antidepressant (anti-di-press-ănt) n. a drug that alleviates the symptoms of depression. A widely prescribed group are the tricyclic antidepressants (TCAs), such as doxepin and imipramine. Side-effects include dry mouth, blurred vision, and difficulty in urination. See also MAO inhibitor, SNRI, SSRI.

an·ti·de·pres·sant / ˌantēdəˈpresnt; ˌantī-/ • adj. (chiefly of a drug) used to alleviate depression. • n. an antidepressant drug.