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Antidepressants

Antidepressants

Definition

An antidepressant is a medication used primarily in the treatment of depression. Depression can occur if some of the chemicals called neurotransmitters in the brain are not functioning effectively. There are three specific chemicals that can affect a person's mood: serotonin, norepinephrine, or dopamine. Antidepressants affect one or more of these chemicals in different ways to help stabilize the chemical imbalance often seen in depression. Antidepressant drugs are not happy pills, and they are not a panacea. They are prescription-only drugs that come with risks as well as benefits and should only be taken under a doctor's supervision. Because children and adolescents experience depression just as adults do, they are sometimes prescribed antidepressants by their physician.

Description

Antidepressants are medicines used to help people who have depression. Antidepressant medications may be indicated for those children and adolescents with bipolar depression, psychotic depression, depression with severe symptoms that prevent effective psychotherapy or counseling, and depression that does not respond to psychotherapy. However, given the psychosocial dynamics that often coexist with depression, antidepressants are usually insufficient as the only treatment for children who have the disorder. Psychotherapy is often recommended as an adjunct treatment along with the prescribed antidepressant. The use of antidepressants among children has been growing steadily since the late 1980s.

All antidepressant medications have a slow onset of action, typically three to five weeks. Although side effects may be observed as early as the first dose, significant therapeutic improvement is always delayed. Most antidepressants are believed to work by slowing the removal of certain chemicals from the brain. These chemicals are called neurotransmitters, which are needed for normal brain function. Antidepressants help people with depression by making these natural chemicals more available to the brain. There are many different kinds of antidepressants, including the ones listed below.

Monoamine oxidase (MAO) inhibitors

MAO inhibitors work by blocking the action of a chemical substance known as monoamine oxidase in the nervous system. Studies done in animals suggest that MAO inhibitors may slow growth in children. Little information on the use of MAO inhibitors in children under 16 years old was available as of 2004.

Tricyclics

Tricyclics have been used to treat depression for a long time. They include amitriptyline, desipramine, imipramine, nortriptyline, and trimipramine. Tricyclic anti-depressants work by shoring up the brain's supply of norepinephrine and serotonin, chemicals that are abnormally low in depressed patients. This effect allows the flow of nerve impulses to return to normal. The tricyclics do not act by stimulating the central nervous system or by blocking monoamine oxidase.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are a group of antidepressants that includes drugs such as citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and escitalopram (Lexapro). In the early 2000s SSRIs have replaced tricyclic antidepressants as the drugs of choice in the treatment of depressive disorders, primarily because of their improved tolerability and safety if taken in overdose. These medicines tend to have fewer side effects than the tricyclics.

Others

There are several antidepressants available as of 2004 that, because they are not chemically structured like the other types of antidepressants, are grouped into the category "other" or miscellaneous. Bupropion (Wellbutrin), mirtazapine (Remeron), and venlafaxine (Effexor) are among those in this category.

General use

SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are considered an improvement over older antidepressants because they are better tolerated and are safer if taken in an overdose. The prescription of SSRIs has risen dramatically in the past several years in children and adolescents age 10 to 19. Some research points out that this increase has coincided with a significant decrease in suicide rates in this age group, but it is unknown if SSRIs are directly responsible for this improvement. As of 2004, fluoxetine (Prozac) was the only SSRI that the Food and Drug Administration (FDA) has approved for the treatment of children's depression. Fluoxetine (Prozac), sertraline (Zoloft), and fluvoxamine (Luvox) are approved by the FDA for the treatment of obsessive-compulsive disorder because studies have shown they are safe and effective medicines for adolescents with this disorder. An early 2000s study showed that citalopram (Celexa) significantly reduced symptoms of major depression in children and adolescents. Sertraline (Zoloft) was also found in studies to be effective with youths, slightly more so for adolescents than younger children. Physicians may frequently prescribe many of the SSRI antidepressants besides fluoxetine (Prozac) for children to treat depression, even though they have not been approved for this use by the FDA. This is called "off-label" use. Off-label refers to the use by doctors of FDA-approved drugs for purposes other than those approved by the agency.

Tricyclics

Tricyclic antidepressants (TCAs) are primarily used to treat depression in adults. The most commonly used ones are nortriptyline (Pamelor), desipramine (Elavil), and imipramine (Tofranil). They function similarly and have similar risks and side effects. They are not as effective in treating depression in children who have not reached puberty, and for these children should only be used as a second line agent. There is marginal evidence to support the use of tricyclics in the treatment of depression in adolescents, but the effect is likely to be moderate. Although they are actually not very effective as antidepressants with children, they can be quite helpful for a variety of other problems, including attention deficit disorder, enuresis (bed-wetting ), and obsessive-compulsive disorder. The American Academy of Child and Adolescent Psychiatry (AACAP) does not recommend TCAs as a first-line treatment for youths requiring medicine for depressive disorders. However, the AACAP acknowledges that some young people with depression may respond better to TCAs than to other antidepressants.

MAO inhibitors

Studies on MAO inhibitors have only been performed on adult patients, and there is as of 2004 no specific information comparing the use of MAO inhibitors in children with use in other age groups. However, animal studies have shown that these medicines may slow growth in young children and are therefore not generally recommended for use in children. Parents should be sure to speak with the doctor regarding whether the use of these medicines is appropriate before giving a monoamine oxidase inhibitor to their child.

Others

Bupropion (Wellbutrin) seems to be a better antidepressant for children than the tricyclic antidepressants. Again, as of 2004 bupropion has not been approved for this use by the FDA. It has also proven to be an effective treatment for children diagnosed with attention deficit disorder. The manufacturer of venlafaxine (Effexor) has issued a statement that the drug is not effective in treating depression in children and teenagers and is recommending that venlafaxine (Effexor) not be used in pediatric patients. Early 2000s studies have found increased reports of thinking about suicide and self-harm, among children and teens taking venlafaxine (Effexor). Mirtazapine (Remeron) must be used with caution in children with depression. Studies have shown occurrences of children thinking about suicide or attempting suicide in clinical trials for this medicine.

Precautions

In 2004, the FDA issued a health advisory recommending close observation for worsening depression in both adults and children treated with certain antidepressants. The FDA requested that a warning of a possible association between the use of SSRIs and suicidal behavior be inserted in the labeling of these medications. Studies have found no direct link between these antidepressants and worsening depression or increased suicide in children. In fact, no suicide has been reported among the more than 4,100 people studied who take SSRIs. However, the FDA continues to study this issue. Some believe the increased risk of suicide is not related to the SSRIs themselves, but a phenomenon seen when the symptoms of depression first begin to improve. This phenomenon occurs when the depressed person starts to gain more energy but is not yet fully relieved of the depressive symptoms. The drugs under review include bupropion (Wellbutrin), citalopram (Celexa), fluoxetine (Prozac), mirtazapine (Remeron), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), escitalopram (Lexapro) and venlafaxine (Effexor). It should be again noted that the only drug that has received approval for use in children with major depressive disorder is fluoxetine (Prozac). Several of these drugs, including sertraline (Zoloft) and fluoxetine (Prozac) are approved for the treatment of obsessive-compulsive disorder in pediatric patients. The drug escitalopram (Lexapro) does not appear to help depressed children and adolescents, according to one clinical study.

Side effects

MAO inhibitors

MAO inhibitors have largely been supplanted in therapy because of their high risk of significant side effects, most notably severe, possibly fatal high blood pressure, if foods or alcoholic beverages containing tyramine are consumed. Other side effects include dizziness, fainting, headache, tremors, muscle twitching, confusion, memory impairment, anxiety, agitation, insomnia, weakness, drowsiness, chills, blurred vision, and heart palpitations. Treatment with MAO inhibitors should never be halted abruptly, and should not be stopped without first consulting a physician.

Tricyclics

Although TCAs have been shown to be effective in many clinical situations, their use is associated with potentially serious side effects. The most important of these is the potential for an irregular heartbeat, which can at times (though rarely) be fatal. The vast majority of TCA-related deaths happen when an overdose is taken. Physician will likely monitor blood levels, as well as perform echocardiograms to monitor heart functioning. Other side effects include dry mouth, constipation, difficulty urinating, blurred vision, sedation, weight gain, central nervous system and cardiovascular toxicity, delirium, and risk of suicide by overdose. The risk of side effects can be reduced with careful prescribing practices.

SSRIs

Several side effects are possible with SSRIs. Special care should be paid in the first few weeks of taking the prescribed drug. Should nervousness, agitation, irritability, mood instability, or sleeplessness emerge or worsen during treatment with SSRIs, parents should obtain a prompt evaluation by their doctor. Some of the side effects that can be caused by SSRIs include dry mouth, nausea, nervousness, insomnia, and headache. Those taking fluoxetine (Prozac) might also have a feeling of being unable to sit still. Children already on any of the SSRIs should remain on the drug if it has been helpful, but they should also be carefully monitored by a physician for evidence of side effects. Once begun, treatment with these medications should not be abruptly stopped, because the child may experience further agitation and restlessness. Families should not discontinue treatment without consulting their physician.

Others

Bupropion (Wellbutrin) has several side effects, including drowsiness, lightheadedness, headache, constipation, dry mouth, nausea, and vomiting. Occasionally patients may experience tiredness, muscle twitching, weight loss, blurred vision, and trouble sleeping. The main side effect is appetite suppression. In some children this may also lead to hypoglycemia (low blood sugar). It is recommended that children on Wellbutrin should eat mid-morning, mid-afternoon, and bedtime snacks in addition to the usual three meals in a manner similar to that of diabetics. The main risk of Wellbutrin is that it increases the likelihood of seizures, though the incidence is rare. Some of these seizures may be related to hypoglycemia and so may be prevented by sticking to the diet as described above. The drug should not be used when there is a past history of seizures or a family history of epilepsy.

Interactions

MAO inhibitors

MAO inhibitors have many dietary restrictions, and people taking them need to follow the dietary guidelines and physician's instructions very carefully. A rapid, potentially fatal increase in blood pressure can occur if foods or alcoholic beverages containing tyramine are ingested by a person already taking MAO inhibitors. Foods containing tyramine include sour cream; parmesan, mozzarella, cheddar and other cheeses; beef or chicken liver; cured meats; game meat; caviar; dried fish; bananas; avocados; raisins; soy sauce; fava beans; and caffeine-containing products like colas, coffee and tea, and chocolate. Beverages to be avoided include beer, red wine, other alcoholic beverages, non-alcoholic and reduced alcohol beer, and red wine products.

SSRIs

SSRIs should not be used with any drug that increases serotonin concentrations, including MAO inhibitors, tramadol, sibutramine, meperidine, sumatriptan, lithium, St. John's wort, ginkgo biloba, and some anti-psychotic agents. A "serotonin syndrome" may occur, where mental status changes and where agitation, sweating, shivering, tremors, diarrhea, and uncoordination, and fever may develop. This syndrome may be life-threatening. SSRIs interact with a number of other drugs that act on the central nervous system. Care should be used in combining SSRIs with major or minor tranquilizers or with anti-epileptic agents such as phenytoin (Dilantin) or carbamazepine (Tegretol).

Tricyclics

Tricylic antidepressants should not be taken with the gastric acid inhibitor cimetidine (Tagamet), since this increases the blood levels of the tricyclic compound. TCAs have many interactions, and specialized references should be consulted. Specifically, it is best to avoid other drugs with anticholinergic effects. Tricyclics should not be taken with the antibiotics grepafloxacin and sprafloxacin, since the combination may cause serious heart arrythmias.

Others

Alcohol, phenothiazines, and benzodiazepines may all increase the likelihood of seizures if consumed with bupropion (Wellbutrin).

KEY TERMS

Monoamine oxidase (MAO) inhibitors A type of antidepressant that works by blocking the action of a chemical substance known as monoamine oxidase in the nervous system.

Selective serotonin reuptake inhibitors (SSRIs) A class of antidepressants that work by blocking the reabsorption of serotonin in the brain, thus raising the levels of serotonin. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil).

Tricyclic antidepressant A class of antidepressants, named for their three-ring structure, that increase the levels of serotonin and other brain chemicals. They are used to treat depression and anxiety disorders, but have more side effects than the newer class of antidepressants called selective serotonin reuptake inhibitors (SSRIs).

Parental concerns

Major depression in children and adolescents is a serious condition that should be treated in a way that includes careful follow-up and monitoring. If the physician determines that medication is indicated, parents should ensure their child continues to receive ongoing assessment. Selection of an antidepressant for their child is done on an individual basis, as drugs may work differently for different people. What is effective for some may not be effective for others. If one antidepressant is ineffective, then there is probably another one that can be tried. All potentially effective treatments can be associated with side effects. A careful weighing of risks and benefits, with appropriate follow-up to help reduce risks, is the best that can be recommended.

See also Depression.

Resources

BOOKS

Mondimore, Francis Mark. Adolescent Depression. Baltimore, MD: Johns Hopkins University Press, 2002.

PERIODICALS

Ables, Adrienne Z., and Otis L. Baughman III. "Antidepressants: Update on New Agents and Indications." American Family Physician 67, no. 3 (February 1, 2003): 54754.

ORGANIZATIONS

National Alliance for the Mentally Ill. Colonial Place Three, 2107 Wilson Blvd., Suite 300, Arlington, VA 222013042. Web site: <www.nami.org>.

National Mental Health Association. 2001 N. Beauregard Street, 12th Floor, Alexandria, Virginia 22311. Web site: <www.nmha.org>.

WEB SITES

National Institute of Mental Health. Available online at <www.nimh.nih.gov/> (accessed October 16, 2004).

National Mental Health Association. Available online at <www.mentalhealth.org> (accessed October 16, 2004).

Deanna M. Swartout-Corbeil, RN

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Antidepressants

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 diseaselike 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): 4857.

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): 11551166.

Glassman, A. H., and Roose, S. P. "Risks of Antidepressants in the Elderly: Tricyclic Antidepressants and Arrhythmia-Revising Risks." Gerontology 40 (1994): 1520.

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): 11861190.

Leo, R. J. "Movement Disorders Associated with the Serotonin Selective Reuptake Inhibitors." Journal of Clinical Psychiatry 57 (1996): 449454.

Newhouse, P. A. "Use of Selective Serotonin Reuptake Inhibitors in Geriatric Depression." Journal of Clinical Psychiatry 57 (1996): 1222.

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): 2739.

Richelson, E. "Synaptic Effects of Antidepressants." Journal of Clinical Psychopharmacology 16 (1996): 19.

Schneider, L. S. "Pharmacological Considerations in the Treatment of Late-Life Depression." American Journal of Geriatric Psychiatry 4 (1996): 5165.

Solai, L. K.; Mulsant, B. H.; and Pollock, B. G. "Update on the Treatment of Late-Life Depression." In The Psychiatric Clinics of North AmericaAnnual of Drug Therapy. Edited by David L. Dunner and J. F. Rosenbaum. Philadelphia: W. B. Saunders Co., 1999: Pages 7392.

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): 875882.

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Antidepressants

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.

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antidepressant

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.

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Antidepressant

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

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antidepressant

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.

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antidepressant

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

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Antidepressant

Antidepressant

Antidepressants are a diverse group of drugs used to treat symptoms of depression. The term "depression" describes several psychiatric disorders in which a person has abnormal moods. Everyone has moods—silly, happy, angry, sad. Most people, no matter what mood they happen to be in, are able to follow their daily routines and meet obligations at school, at work, and with their families. Sometimes a person has moods, often of anger or sadness, that are extremely powerful. Often these moods, not the person, determine behavior. Very strong moods can prevent a person from completing work or lead to clashes with others. When this happens regularly, the moods are considered abnormal.

Antidepressants can also be useful for treating anxiety, panic disorders, and chronic pain. They are not helpful for short-term depressed moods that are part of everyday life or for the normal period of grief that follows loss of a loved one. Antidepressants include tricyclics (such as Tofranil and Aventyl), monoamine oxidase inhibitors (Nardil, Marplan), lithium (Eskalith, Lithonate), nontricyclics, and selective serotonin-reuptake inhibitors (Prozac, Paxil, Zoloft).

see also Alcohol Treatment: Medications; Personality Disorder.

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Antidepressants

Antidepressants

Definition

Description

Recommended dosage

Precautions

Side effects

Interactions

Resources

Definition

Antidepressants are medications that are used primarily to treat depression. Antidepressant drugs are also sometimes used to treat other psychological disorders, such as anxiety disorders and eating disorders. Because they are thought to increase the effectiveness of some pain medications, they are sometimes used in the treatment of migraine-type headaches. They are also used as a component of smoking cessation programs, and in the treatment of fibromyalgia and some types of sleep disorders.

Description

Antidepressant drugs can be used to treat depression and other disorders. A person with depression has symptoms that last for at least two weeks. These symptoms can include feelings of sadness, emptiness, guilt, or worthlessness, loss of interest in previously pleasurable activities, changes in eating and sleeping patterns, fatigue, lethargy or agitation, difficulty concentrating, and suicidal thoughts. Antidepressant drugs are not the only treatment for depression; psychotherapy and other treatments are also independently effective in alleviating depression. Antidepressant drugs, if prescribed, are often used in combination with these other treatments.

The type of antidepressant medication prescribed depends on the particular array of symptoms a patient displays or reports. There are several different types of antidepressant drugs. All of them work by altering the level or activity of neurotransmitters in the brain. Neurotransmitters are chemicals that are released by neurons, or nerve cells. They attach to other neurons and activate them in various ways. Although antidepressant drugs affect communication between neurons within hours after these drugs are ingested, symptoms of depression usually improve only after a few weeks of taking the medication. Some people notice improvement in symptoms after only two weeks, but many people notice a benefit only after six to eight weeks of using the medication. The reason for this delayed effect of antidepressants is not entirely clear. One theory is related to the finding that the changes in neurotransmitter activity caused by antidepressants increase the release of other chemicals, called neurotrophins, in the brain. In the normal brain, neurotrophins help neurons to grow and connect to other neurons. People with depression sometimes have shrinkage of neurons in parts of the brain. When more neurotrophins are present, neurons in these areas of the brain can grow.

The main classes of antidepressant drugs are tricyclics, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants. A patient who does not improve with one type of antidepressant drug may sometimes be helped by another type of antidepressant, because different drugs work in different ways.

Tricyclic antidepressants

The first class of drugs used to treat depression, from the 1960s through the 1980s, was that of tricyclic antidepressants. Tricyclic antidepressants work by preventing neurons from reabsorbing the neurotransmitters serotonin, dopamine, and norepinephrine, after they are released. This means that the neurotransmitters are able to remain in the gaps between neurons for a longer period of time, thus continuing to activate the neurons that receive them. Tricyclic anti-depressants can have side effects because they can prevent nerve cells from functioning normally, and because they can prevent additional neurotransmitters from working effectively. For example, they block the activity of histamine, a neurotransmitter that is involved in keeping people alert and awake. They also block the activity of acetylcholine, a neurotransmitter that is involved in many automatic bodily activities. Tricyclic antidepressants include imipramine (trade name Tofranil), amitriptyline (trade names Elavil, Endep), clomipramine (trade name Anafranil), doxepin (trade names Sinequan, Adapin), desipramine (trade name Norpramin), nortriptyline (trade name Pamelor), protriptyline (trade name Vivactil), and trimipramine (trade name Surmontil).

MAOIs

The monoamine oxidase inhibitors are drugs that prevent neurotransmitters such as dopamine, serotonin and norepinephrine from being broken down into inactive chemicals. This means that, when MAOIs are used, more of these neurotransmitters are available to send messages in the brain. MAOIs can have potentially serious side effects because they also prevent the amino acid tyramine from being broken down. Tyramine is a chemical that the body needs, and it is found in foods like aged cheese, smoked and pickled meats and fish, and raisins. If tyramine that is ingested cannot be broken down, it can accumulate in the body, causing increased blood pressure and possibly strokes. The MAOIs include isocarboxazid (trade name Mar-plan), phenelzine (trade name Nardil), and tranylcypromine (trade name Parnate).

SSRIs

The selective serotonin reuptake inhibitors are drugs that work by preventing neurons from reabsorbing serotonin after it is released, so that the effect of serotonin on adjoining neurons is prolonged. The SSRIs include citalopram (trade name Celexa), escitalopram (trade name Lexapro), fluoxetine (trade name Prozac), fluvoxamine (trade name Luvox), paroxetine (trade name Paxil ), and sertraline (trade name Zoloft).

Atypical antidepressants

The atypical antidepressants are a miscellaneous collection of drugs. One of these drugs, bupropion (trade name Wellbutrin), prevents dopamine, and to some extent, norepinephrine, from being reabsorbed by neurons, so that these neurotransmitters are able to have a more prolonged effect. Another drug, venlafaxine (trade name Effexor), prevents serotonin, and to a smaller extent, norepinephrine and dopamine, from being reabsorbed. Other atypical antidepressants include mirtazapine (trade name Remeron), trazodone (trade name Desyrel) and duloxetine (trade name Cymbalta).

Recommended dosage

The dosage of antidepressants depends on the particular drug being prescribed, and other factors such as the age of the patient, the patient’s body chemistry, and the patient’s body weight. Patients are usually started on a low dose to minimize side effects, and the dose is gradually increased over time to a level that is therapeutic. Newer antidepressants, however, may be started at the therapeutic dosage level.

Precautions

In 2005, the U.S. Food and Drug Administration warned that SSRI drugs may increase suicidal thoughts in children and adolescents. It urged health-care practitioners and families of patients to carefully monitor people, of any age, who take these drugs. The National Institutes of Health is currently carrying out research to study the nature of the association between suicidal thoughts and antidepressant drugs. Canadian researchers at McGill University also found that adults over age 50 who take SSRIs are at double the risk of bone fractures.

Antidepressants can precipitate mania in people who are susceptible to bipolar disorder. Therefore, a health-care practitioner typically takes a detailed history of a patient before prescribing antidepressants. Various medical problems may affect the effectiveness or risks of antidepressants. These include, but are not limited to, angina, headaches, epilepsy, recent heart attacks or stroke, kidney disease, and diabetes. Some antidepressants may affect a fetus, therefore pregnant women should inform their doctors about their condition before antidepressants are prescribed. Patients taking tricyclic antidepressants should carefully adhere to the dietary restrictions provided by their doctor, in order to avoid potentially serious side effects. Patients who stop taking antidepressants may experience withdrawal symptoms if the drugs are abruptly discontinued.

KEY TERMS

Anxiety disorder —A type of psychological disorder characterized by unrealistic, irrational fear or intense anxiety.

Eating disorder —A type of psychological disorder characterized by disturbances in eating patterns, extreme concern about weight gain and unhealthy efforts to control weight.

Sleeping disorders —Disorders in which people experience disturbances of sleep.

Fibromyalgia —A condition in which a person experiences chronic pain in the muscles and soft tissues around joints.

Mania —A state in which a person experiences intense excitement and euphoria.

Stroke —A temporary loss of normal blood flow to an area of the brain, caused by blockage or rupture of a blood vessel.

Side effects

People who take antidepressants may experience side effects. Different people experience different side effects. Such side effects may include dry mouth, constipation, nausea, bladder problems, sexual problems, blurred vision, dizziness, daytime drowsiness, insomnia, increased heart rate, headache, nervousness, and agitation. The newer antidepressants are thought to have fewer and less troublesome side effects than the tricyclic antidepressants and the MAOIs.

Interactions

Antidepressants may result in dangerous side effects if taken in combination with other medications. There can also be dangerous side effects if different types of antidepressants are combined with each other. Patients should inform their doctor about all other medications and herbal supplements they are taking before antidepressant drugs are prescribed. Alcohol or other recreational drugs may decrease the effectiveness of antidepressants. Antidepressants may increase the intoxicating effect of alcohol.

Resources

BOOKS

American Psychiatric Association. Diagnostical and Statistical Manual of Mental Disorders, 4th edition, Text revision. Washington, D.C.:American Psychiatric Association, 2000.

Diamond, Ronald, J. Instant Psychopharmacology. 2nd edition. New York: W.W. Norton and Company, 2002.

Dunbar, Katherine Read, ed. Antidepressants. Farmington Hills, MI: Greenhaven Press, 2006.

Kalat, James W. Biological Psychology. 9th edition. Belmont, CA: Thomson Wadsworth, 2007.

OTHER

“New NIMH Research Strives to Understand How Anti-depressants May Be Associated with Suicidal Thoughts and Actions.” National Institutes of Health. 2006. <http://www.nih.gov/news/pr/nov2006/nimh-13.htm> (January 12, 2006).

“Medications.” National Institutes of Mental Health. 2002. <http://www.nimh.nih.gov/publicat/medicate.cfm> (January 12, 2006).

“Drug Information: Antidepressants, Monoamine Oxidase (MAO) Inhibitor (Systemic).” Medline Plus. 2005. <http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202054.html> (January 2006).

“Drug Information: Antidepressants, Tricyclic (Systemic).” Medline Plus. 2005. <http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202055.html> (January 2006).

“Daily Use of Antidepressants Associated with Increased Risk of Fracture in Older Adults” Newswise. <http://www.newswise.com/articles/view/526667/> (January 2007).

Ruvanee Pietersz Vilhauer, Ph.D.

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Antidepressants

ANTIDEPRESSANTS

OFFICIAL NAMES: Amitriptyline (Elavil), amoxapine (Asendin), bupropion (Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), fluoxetine (Prozac), imipramine (Norfranil, Tofranil), isocarboxazid (Marplan), maprotiline (Ludiomil), mirtazapine (Remeron), nefazodone (Serzone), nortriptyline (Aventyl, Pamelor), paroxetine (Paxil), phenelzine (Nardil), protriptyline (Vivactil), sertraline (Zoloft), thioridazine (Mellaril), tranylcypromine (Parnate), trazodone (Desyrel), trimipramine (Surmontil), venlafaxine (Effexor); the herb St. John's wort (Hypericum perforatum) is sold over-the-counter without prescription

STREET NAMES: Happy pills

DRUG CLASSIFICATIONS: Not scheduled, psychotherapeutic drugs


OVERVIEW

Depression is an illness that affects the body, moods, and thoughts. It affects how people eat, sleep, take care of themselves, and how they think of themselves. It is an illness that requires medical assistance. It may originate with a stressful situation, a medication, or another illness.

Scientists were looking for drugs to treat different medical problems when their observations almost accidentally led them to the study of depression and its treatment. Many scientists continued in this new direction to the discovery of the current three classifications of antidepressant drugs used today: monamine oxidase inhibitors (MAOIs), tricyclic drugs (TCAs), and selective serotonin reuptake inhibitors (SSRIs).

One such accident occurred in the 1950s, when scientists searching for a tuberculosis treatment observed that the drug iproniazid caused mood elevation. Since there were few treatments for depression, the findings were exciting.

Reserpine, a drug used for the treatment of high blood pressure, was known to have the side effect of depression. Upon studying this effect, scientists observed that this drug caused a depletion of the amine neurotransmitters serotonin and norepinephrine. Neurotransmitters transmit "information" from one nerve to another across a "synapse." The neurotransmitters are than reabsorbed by the first nerve in the process called reuptake.

The depletion of the neurotransmitters—as observed with reserpine—came under study as the possible cause of depression and became known as the "amine hypothesis of depression." The drug iproniazid reversed some of these negative side effects, confirming the usefulness of drugs in the treatment of depression.

When used with psychiatric patients, iproniazid showed mood elevation and heralded the first class of antidepressants—the monoamine oxidase inhibitors (MAOIs)—into psychiatric practice.

Names associated in these discoveries include Roland Kuhn and John Cade. While looking for a treatment for depression, Kuhn worked with thorazine, the newly found drug effective with schizophrenia. He progressed to find the second classification of antidepressants, the tricyclic drug (TCA) imipramine, a close chemical relative of thorazine.

In the 1950s Marsilid (the brand name of iproniazid) and Tofranil (imipramine) were manufactured and sold as antidepressant drugs.

When studying manic patients, who have a form of depression with periods of abnormal excitability and excessive activity, Australian psychiatrist John Cade found that lithium had a controlling effect on the patient's mania. He used lithium as a solvent when he attempted to inject the urine of manic patients into guinea pigs and found it made the urine less toxic. It was this finding that sparked his interest in lithium. In 1948 he injected lithium into ten patients and observed that lithium controlled their mania.

As a result of these findings, the emphasis in the study of depression from the 1950s to the present has centered on the study of the brain and the chemical actions occurring there. Research emphasis in the 1980s moved to serotonin, a neurotransmitter in the brain. Through the 1990s into the 2000s, the newer and third classification of antidepressants became the serotonin reuptake inhibitors (SSRIs). Prozac is among this group of drugs. They interfere with the reabsorption of serotonin in the brain and have fewer side effects than the earlier classes of antidepressant drugs.

Extensive media coverage in the 1990s made the public aware of Prozac and greatly increased the demand for the drug. Some people got the impression that it had no side effects, helped in weight loss, and was a sort of "happy pill" that everyone should take. But neither this nor the other SSRI drugs improve mood or make healthy people high or happier if they are not clinically (observed symptoms) depressed.

Knowledge of these drugs has increased the public's demand for them at times of personal or societal tragedies and crises. In 1999, as many as 135 million prescriptions for antidepressants were filled in the United States.

As far back in history as the Greek physicians Hippocrates, Pliny, and Galen, through to present time, the herb St. John's wort has been used for its antidepressant effect. It is believed to influence the neurotransmitters in the brain. Although some research has shown it to be effective in cases of mild to moderate depression, many questions remain as to its safety and effectiveness.

In Germany, St. John's wort is approved for use in depression and anxiety. It is the most common antidepressant used and is usually sold by prescription. However, in the United States it is sold only as an herb and without prescription. It is frequently used by people with self-diagnosed depression. Preparations of St. John's wort will vary in potency according to manufacturer. Although extensive studies have been conducted on the usefulness of St John's wort, the evidence has not been conclusive. More recent studies raise even more questions about its effectiveness.

By the end of 2002 the National Institutes of Health (NIH) will make their large study of the herb available. This should clear up the confusions concerning its effectiveness.

CHEMICAL/ORGANIC COMPOSITION

The antidepressants available in the United States are classified by either their chemical structure (e.g., the tricyclics, TCAs) or their actions on neurotransmitters (e.g., SSRIs and MAOIs) or simply as "other"(e.g., Wellbutrin). In the future, the classification of the antidepressants may become more confusing as new drugs are developed that are neither TCAs, SSRIs, or MAOIs.

A variety of substances (and more are being found each day) with differing chemical structures have antidepressant abilities. However, no group is known to be more effective than the others.

The tricyclic antidepressants have a three-ring nucleus and are norepinephrine and serotonin reuptake inhibitors. They have been used for decades. Trade names included in this group of drugs as of 2002 are: Etrafon, Limbitrol, Norpramin, Sinequan, Surmontil, and Vivactil.

The heterocyclic antidepressants were introduced between 1980 and 1996. They consist of an intertwined circular structure called benzene rings. Included among these are amoxapine and maprotiline, which have a similar structure to the tricyclics. Trazodone and bupropion are in this group but do not have this similar structure. These drugs do not have stronger potency than the earlier drugs. Newer drugs introduced since the 1990s include venlafaxine and mirtazapine.

The older generation of drugs are less desirable than the new selective serotonin reuptake inhibitors, because they have many actions in the body other than their antidepressant effect. Prozac (fluoxetine hydrochloride) is among this group. Other trade names in this group are Celexa, Paxil, and Zoloft.

The herb St. John's wort (Hypericum perforatum) has a number of constituent parts, including hyperforin, which is currently being studied as the responsible constituent for the antidepressant action. The herb contains at least ten compounds that can have an unpredictable effect on the consumer.

INGESTION METHODS

The prescription antidepressants are taken orally, once a day, either in capsules, tablets, oral suspensions, or solutions. In early 2002, a once-a-week dose in capsule and liquid forms became available for Prozac and some other antidepressants.

The leaves and tops of St. John's wort are taken as a tea, or as an olive oil extract taken internally or applied externally.

THERAPEUTIC USE

The antidepressants are used to relieve the symptoms of depression, which may include feelings of sadness, helplessness, loss of interest in usual activities, insomnia, loss of energy, problems concentrating, weight loss or gain, and decreased desire to socialize or communicate with others.

The three most common types of depression are major depression, dysthymia, and bipolar disorder. Major depression, which may occur once but usually occurs several times in a person's life, will interfere with the ability to work, eat, sleep, study, and take pleasure in formerly enjoyed activities. Dysthymia is less severe than major depression but will interfere with feeling good and functioning well. Bipolar disorder (formerly called manic-depression) can be more serious than the other forms of depression. In this illness the person's mood swings from symptoms of depression to extreme excitement with over-activity and feelings of elation. This type of depression can progress to serious mental illness if not treated.

Depression is twice as common in women than men and may occur with premenstrual syndrome or after childbirth as postpartum depression. Studies have not found any negative effects on the unborn child when the mother takes an antidepressant during the pregnancy, but this is a serious question that needs to be discussed with the physician. Antidepressants are very effective in the treatment of postpartum depression, but because they are secreted in the mother's milk, the option of breastfeeding is another essential area for discussion and decision. Usually, women are recommended to avoid drug use during pregnancy, including the use of St. John's wort.

Although less common than in women, about three to four million men have depression, and their rate of suicide is four times that of women. Men's symptoms of depression may be anger and irritability and be masked by alcohol and drug use.

In addition to the treatment of depression, the Food and Drug Administration (FDA) has approved the (on-label) use of the antidepressants for treatment of panic disorders, obsessive-compulsive disorders, bulimia nervosa, social phobia, and generalized anxiety disorder. And although not the treatment of choice, the tricyclics are sometimes used for enuresis—bed wetting.

A physician may prescribe an antidepressant for an off-label use. These are a variety of problems not specifically mentioned on the drug label. Among these are pain, anxiety, attention deficit hyperactivity disorder, post traumatic stress disorder, premenstrual exaggerated feelings of depression, social phobia, and obsessive-compulsive-related disorders such as compulsive hair pulling, compulsive gambling, compulsive buying, sexual addictions, and kleptomania (compulsive stealing).

Studies show that the SSRIs may help alcoholics reduce the amount of alcohol they consume and also increase the number of days they can abstain from alcohol. Patients with anorexia nervosa may also be helped by antidepressants. No other treatment has been approved by the FDA for this eating disorder, but the antidepressants are helping patients maintain their weight and avoid relapse.

Because each patient will respond differently to the various antidepressants, the physician may try several—or even combine them—in the search for the most effective treatment for a particular patient.

Although the tricyclic and MAOI antidepressants cause an immediate pharmacologic action (drug reaction in the body), their clinical action (observable reaction) is delayed. This delay can last weeks or even months. This makes it difficult to use these antidepressants to treat severe depression when an immediate response is desired. The more severe cases of depression and other psychiatric and emotional problems may require other treatments in addition to the drug therapy.

The antidepressants have been found effective in post-stroke patients when a positive attitude is needed for recovery. Treating post-stroke depression improves the chances of the patient regaining mental acuity.

USAGE TRENDS

An increasing demand for antidepressants is resulting from increased media coverage on television and in magazines. Also, antidepressants are frequently prescribed by physicians for patients they diagnose as having difficulty handling some personal problem or crisis. The 135 million prescriptions sold in 1999 is an indication of the popularity of these drugs, especially Prozac. Awareness of the availability of the drugs has also resulted in large numbers of people seeking the drugs at times of tragedy and crisis (as evidenced by the increased demand after the September 11, 2001 attack).

In addition to the demand for antidepressants as discussed above, their use has increased as their effectiveness and relative safety in the treatment of depression and other problems have been shown.

Some people will refuse antidepressants when their doctors offer to prescribe them, because they fear that taking the drug is an admission of a serious disease or problem. The very nature of depression may also leave the patient without hope of relief and discourage them from seeking help or accepting the antidepressants.

Falsely believing that a herb is safer than a prescribed drug, many people either take St. John's wort in place of, or in addition to, their prescription antidepressants. These are dangerous practices because of the serious side effects of the combinations and the serious consequences that may result when someone stops taking their antidepressant without the guidance of a physician.

Scope and severity

With an addiction, larger doses of the drug must be consumed to achieve the original high or "buzz." This build-up of tolerance does not occur with antidepressants. In those cases where an increase in drug dose is required, usually it is because the illness is no longer responding to the original dose. Another criteria of addiction not met by antidepressants is that they do not cause an artificial high but only help those depressed to reach a normal level of functioning.

Some patients may have to take the drug long-term to control their illness, and in some cases the illness will return after the medication is discontinued. However, the antidepressants have not been found to be addicting themselves. Actually, they may be useful in the treatment of patients undergoing treatment of addiction who are also depressed. Research shows that these patients may need specific antidepressants considering their state of addiction and depression.

The antidepressant therapy should not be stopped abruptly, but tapered off. The symptoms some may experience when stopping abruptly is not withdrawal as witnessed with addictions, but just the need of the body to adjust without the effect of the antidepressants on the neurotransmitters of the brain.

The inability of the antidepressants to make healthy people "high" prevents an illegal market for these drugs from developing.

Age, ethnic, and gender trends

Women are more prone to depression than men. They also differ in their reaction to SSRI and tetracycline antidepressants. It is interesting to note that women less than 44 years of age respond more effectively to the SSRIs than do women older than 44.

All age groups from children to the elderly that suffer from depression respond well to the antidepressants. Also, those elderly individuals with some loss of cognitive ability have shown some improvement in their skills, although the antidepressants do not return them to their former intellectual ability.

MENTAL EFFECTS

The antidepressants have not been found to effect judgment and thinking as some psychoactive drugs may. The antidepressants will relieve the symptoms of depression and those of the other psychological problems as mentioned above. The antidepressants will make it possible for people with depression to resume a normal life, such as returning to work and school. They will help people get over their feelings of worthlessness and assist them in social functioning.

The misuse of antidepressants may occur when patients diagnose themselves for depression, and their request for a prescription is honored by their physician. In such cases a placebo (sugar pill) might be just as effective. This person is not addicted to the drug, but may be overly concerned with his or her own personal health.

PHYSIOLOGICAL EFFECTS

The physiological action of antidepressants is not fully understood. However, they are thought to influence the metabolism, reuptake, or selective receptor antagonism of the neurotransmitters serotonin and norepinephrine. The MAOIs cause an increase of the neurotransmitters norepinephrine, serotonin, and dopamine in the brain by inhibiting their breakdown. The SSRIs prevent the reabsorbtion of serotonin, one of the 50-odd neurotransmitters in the brain.

Studies show little difference in the effects of the various antidepressants, but some individual patients appear to do better on one drug than another. In the search for the most effective drug for a particular patient, the physician may try various antidepressant drugs or even try some in combination.

Antidepressants do not cause addiction, which is usually evident by the build-up of tolerance (needing increasing amounts of a drug to achieve the initial effect). Withdrawal symptoms do not occur when the drug is discontinued. However, gradually decreasing the dosage will give the brain a chance to take over or function on its own without the drug, and help avoid some physiological symptoms such as the flu, headache, or nausea that sometimes occur. This gradual cutting back on the amount of drug can assist the physician in prescribing if the patient's symptoms return.

Harmful side effects

Patients are cautioned not to operate machinery until they know how the drug affects them personally (although antidepressants are not known to cause impairment in this way). Side effects can include agitation, insomnia or drowsiness, and thirst. Serious side effects are not expected with these drugs.

Because of their selective action on serotonin, the manufacturer of SSRIs claim there are fewer side effects from this class of drug than those of the tricyclics and MAOIs. These other drugs affect many neurotransmitters in the brain and therefore result in many side effects. However, the SSRIs can cause stomach upset, insomnia, and anxiety.

For the most part, antidepressants are considered safe. However, they may interact with other drugs taken by the patient—and the physician prescribing one of these drugs must take this into consideration. Additionally, some medical problems already under treatment may increase in severity in the presence of an antidepressant.

Patients suffering from bipolar disorder whose high periods exhibit anger, paranoia, or irritability may exhibit these symptoms when taking Prozac if they have not been first stabilized with another medication such as lithium.

The adverse effects of antidepressants will vary by drug and may include some or several of the following: insomnia, tremor, gastrointestinal symptoms, rashes, sexual dysfunction, anxiety, dizziness, dry mouth, sweating, sleepiness, blurred vision, constipation, aggravation of psychosis, weight gain, increased appetite, arrhythmias (disturbed rhythm of the heartbeat), hypertension or postural hypotension, nausea, and, with high doses, seizures.

It is unusual for the MAOIs to have a toxic effect. However, when it does occur the symptoms are severe and include dulled consciousness, seizures, shock, and hyperthermia (elevated temperature). Although some reactions with SSRIs—and even some fatalities—have occurred with overdoses, they are extremely rare. A reaction may be due to the combining of the SSRIs with other drugs.

Side effects of St. John's wort include headache, gastrointestinal discomfort, sun sensitivity, and dry mouth. Some of the effects of combining the herb with other drugs are very serious. For example, St. John's wort lessens the effectiveness of HIV drugs, as well as some drugs that are essential after a transplant operation and heart drugs (such as digoxin). It is essential that anyone desiring to take the herb consult with their doctor.

Overdoses of the antidepressants can result in death. However, the effects of overdosing will vary according to which drug is taken.

Long-term health effects

Long-term health effects from antidepressants include the increased risk of deliberate self-harm (DSH), which may occur more with the SRRIs than the tricyclic antidepressants. The self-harm may occur by overdosing with the prescribed drug, but is more frequently by other means.

Long-term use of the SSRIs has been found to increase the risk of gastrointestinal (GI) bleeding, especially in the elderly and in those who have previously experienced bleeding. In addition, although preliminary studies showed a decreased risk of heart attack for those using SSRIs, an increased risk for arrhythmias (irregular heart beats) and heart attacks has been observed in those taking the tricyclics. These older tricyclic antidepressants may disrupt the heartbeat, possibly resulting in death. Therefore, it is essential that physicians test patients prior to and during treatment with tricyclics.

Tricyclics may also pose a threat to vision by causing dry eyes, blurred vision, and even vision loss when narrow-angle glaucoma is present. Also, tricyclics may result in dry mouth that can lead to dental cavities, reduced urine output, and constipation. Although not fully understood, weight gain is also an effect. Whether a result of the drug or of the illness, sexual drive is decreased.

MAOIs frequently are not the first choice when an antidepressant is needed. This is because their side effects include sedation, dizziness, insomnia, sexual dysfunction, rapid heartbeat, constipation, and agitation. Severe sudden elevation of blood pressure, especially when the patient eats aged meats and cheeses, or takes some over-the-counter cold medications, poses a serious threat of a stroke or other symptoms including headache, vomiting, and palpitations.

Studies of the long term-health effects of St. John's wort are in progress. Avoidance of the herb by pregnant and lactating women is strongly recommended.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

Anyone prescribed an antidepressant should not take other medications without consulting with a physician. This warning of possible negative effects can also occur with over-the-counter-drugs that patients take themselves. A prescription for an antidepressant should include a list of foods to avoid, because some antidepressants can have dangerous reactions with foods.

Alcohol's ability to impair motor operation and driving skills will be increased if combined with an antidepressant. A few drinks taken by a person who has an antidepressant in their system is like having many more drinks.

The symptoms of jitters, insomnia, tremors, and agitation are common in those consuming caffeine and in those with depression or the other illnesses for which these drugs are prescribed. Combining caffeine with antidepressants may exaggerate the symptoms and make it difficult for the physician to arrive at an accurate diagnosis or evaluate the drug's effectiveness.

The reactions of recreational drugs with antidepressants are unpredictable and possibly very dangerous. The illness being treated with the antidepressants may also react negatively to recreational drugs.

In February, 2002, the Food and Drug Administration issued a Public Health Advisory warning physicians of the dangers of patients taking St. John's wort (as well as other herbs) in combination with prescription drugs. For one thing, the effects of combining St. John's wort with other drugs is practically impossible to predict. This is because people take varying amounts of the herb, and the potency of the herb's active compounds also varies from brand to brand.

To help avoid problems, it is important that the patient take the prescribed dosage. Physicians will have difficulty measuring the effectiveness of a drug when the prescription is not followed accurately.

TREATMENT AND REHABILITATION

Since antidepressants are not addictive, there is no need for treatment when the drugs are discontinued. However, when the drug is abruptly stopped, some users may experience discomfort—such as irritability, depressed mood, anxiety, and sleep disturbance—but these are not as severe as those of drugs that cause addiction. An ideal way of discontinuing the antidepressants is the "step-down method," a gradual lowering of the dose until the patient is weaned off the drug. This way, the physician can observe whether the patient's symptoms of depression return.

PERSONAL AND SOCIAL CONSEQUENCES

If depression has interfered with happiness or success, its treatment can have many positive consequences and result in a fuller and happier social life. Treatment may be long term, and may require psychotherapy in addition to the antidepressant drugs.

LEGAL CONSEQUENCES

Antidepressants are only available by prescription, and since individuals do not achieve a high with these drugs (as may occur with the drugs of abuse), there is not likely to be an illegal market for them.

RESOURCES

Books

Appleton, William S. Prozac and the New Antidepressants. New York: Plume, 2000.

Ernst, Edzard, Julia Rand, and Clare Stevinson. "Complementary Therapies for Depression," In Alternative Medicine, An Objective Assessment. Washington, DC: JAMA and Archives Journals,2000.

Foster, Steven, and Varro E. Tyler. Tyler's Honest Herbal. New York: Haworth Herbal Press, 2000.

Katzung, Bertrum G. Basic and Clinical Pharmacology. New York: Lange Medical Books/McGraw-Hill, 2001.

Morrison, Andrew L. The Antidepressant Sourcebook. New York: Broadway Books, 1999.

O'Hara, Mary Ann, et al. "A Review of 12 Commonly Used Medicinal Herbs." Alternative Medicine, An Objective Assessment. Washington, DC: JAMA and Archives Journal, 2000.

Physicians Desk Reference. 56th ed. Montvale, NJ: Medical Economics, 2002.

Schlaadt, Ricahrd G. Drugs, Society, & Behavior. New York: Dushkin Publishing Group, Inc., 1992.

Wong, Albert H. C., Michael Smith, and Heather Boon. "Herbal Remedies in Psychiatric Practice," In Alternative Medicine, An Objective Assessment. Washington, DC: JAMA and Archives Journals, 2000.

Periodicals

"Another Look at St. John's Wort and Depression." University of California, Berkley, Wellness Letter 17, no. 11 (August 2001).

The New England Journal of Medicine. "Post-Stroke Depression Impedes Recovery." Health News September 2000.

"9/11/01 Post-Traumatic Stress Disorder." Harvard Health Letter 27, no. 1 (November 2001).

Schuster, Mark A., et al. "A National Survey of Stress Reactions after the September 11, 2001, Terrorist Attacks." The New England Journal of Medicine 345, no. 20 (November 15, 2001).

Other

Headline News. "New Yorkers are Increasingly Turning to Sedation." September 8, 2001. <http://www.drugawareness.org>.

National Center for Complementary and Alternative Medicine. <www.nccam.nih.gov>.

National Institute of Mental Health. Depression. May 31, 2002. <http://www.nimh.nih.gov>.

Louise Catherine Chut, PhD, MPH

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Antidepressants

Antidepressants


What Kind of Drug Is It?

Antidepressant drugs are used to relieve the symptoms of depression and anxiety. Depression is a mood disorder that causes people to have feelings of overwhelming and lasting hopelessness, sadness, despair, and self-blame. The condition can also bring on changes in sleeping and eating habits, a loss of pleasure, feelings of apathy, and even suicidal thoughts. Anxiety is a disorder that causes feelings of being extremely overwhelmed, restless, fearful, and worried. Symptoms of anxiety include loss of sleep, dizziness, sweating, and shaking, among others.

Antidepressants play an important role in the treatment of depression and anxiety. They help to rebalance brain chemistry so the symptoms of depression and anxiety are alleviated. A large number of people take antidepressants. Richard Jerome, writing in People, reported that "133 million prescriptions for antidepressants were written in 2002" in the United States alone.

Overview

Depression is a condition that affects the way people feel, think, and act. "Ten to 20 percent of adults in the United States experience depression at some point in their lifetime," noted Adrienne Z. Ables and Otis L. Baughman III in an article for the journal American Family Physician.

Official Drug Name: Amitriptyline (ammuh-TRIP-tuh-leen; Elavil), bupropion (byoo-PROH-pee-on; Wellbutrin), citalopram (sye-TAL-oh-pram; Celexa), clomipramine (kloh-MIPP-ruh-meen; Anafranil), escitalopram (EE-sye-TAL-ohpram; Lexapro), fluoxetine (flu-AKS-uhteen; Prozac), imipramine (ih-MIPP-ruhmeen; Tofranil), mirtazapine (murr-TAZ-uh-peen; Remeron), paroxetine (purr-OKS-uh-teen; Paxil), phenelzine (FENN-uhl-zeen; Nardil), sertraline (SURR-truhleen; Zoloft), venlafaxine (venn-luh-FAKS-een; Effexor). The twelve drugs listed here are a sampling of the various types of antidepressants in use as of 2005.

Also Known As: Happy pills

Drug Classifications: Not scheduled, psychotherapeutic drugs with "black box" warnings

Sometimes depressive episodes are sparked by an especially upsetting event in life such as the death of a loved one, the breakup of a relationship, a change in jobs, separation from friends or family, or a severe illness. Because depression seems to run in families, scientists are investigating possible biological causes for the condition. The authors of "Depression: Help Is at Hand," a publication of the Royal College of Psychiatrists (RCP), stated that people who have a parent who has become severely depressed "are about eight times more likely to become depressed" themselves. This may be due to an abnormality in the brain involving chemical messengers called neurotransmitters.

Depressed people often have a hard time tracing their sadness to a particular cause. Certain medicines and even some physical illnesses such as the flu can bring on depression, so it is extremely important for people to educate themselves about its signs, symptoms, and treatments.


Symptoms of depression include:

  • A long-lasting sad mood
  • A change in sleep patterns—either sleeping all the time or having difficulty getting enough sleep
  • A change in eating habits—some people eat more when they get depressed, others stop eating altogether and begin losing significant amounts of weight
  • A loss of interest in activities or hobbies that used to bring pleasure
  • Self-destructive thoughts or actions
  • Difficulty making decisions
  • A loss of confidence
  • Increased irritability
  • Problems with school or work
  • Problems with friends or family members
  • A feeling of hopelessness, as if things will never be any better.

Depression occurs in people of all ages, from small children to the elderly. "In contrast to the normal emotional experiences of sadness, loss, or passing mood states, depression is extreme and persistent and can interfere significantly with an individual's ability to function," stated the authors of the "Depression Research" page of the National Institute of Mental Health (NIMH) Web site.

A study sponsored by the World Health Organization and the World Bank is cited in "Depression Research." The study noted that major depression was found "to be the leading cause of disability in the United States and worldwide." Regardless of what triggers their depression, those who suffer from it require medical assistance. This assistance might include psychotherapy, medication, or a combination of both. Many depressed people from all age groups have responded well to treatment.

Anxiety, which is often associated with depression, can also be helped by medication. Severe anxiety can result in panic attacks. These attacks can make a person feel like he or she is dying. They cause rapid heartbeat, tightness in the chest, shaking, shortness of breath, and dizziness. Antidepressants can help a person focus on dealing with his or her fears before an attack occurs, and the drugs can alleviate the physical symptoms of an attack.

An Accidental Find

Chemists seem to have stumbled upon drugs with antidepressive effects while working on treatments for other medical problems. The very first antidepressants, iproniazid (sold under the brand name Marsilid) and imipramine (sold under the brand name Tofranil), were developed in the 1950s. Since then, great strides have been made in understanding how the human brain works. These strides contributed to the creation of the four main types of antidepressant drugs known as of 2005: 1) tricyclics, 2) monoamine oxidase inhibitors (MAOIs), 3) selective serotonin reuptake inhibitors (SSRIs), and 4) "others," including serotonin and norepinephrine reuptake inhibitors (SNRIs). All of these drugs get their names from the way they act on chemicals called neurotransmitters located in the human brain.

Depression Statistics


Doctors and research scientists continuously seek to learn more about depression. They have learned that:

  • Nearly 10 percent of the adult population in the United States suffers from a depressive illness. That is about 19 million Americans over the age of eighteen.
  • One in five children and adolescents in the United States suffers from some kind of emotional problem that affects his or her daily life.
  • As of 2004, doctors were writing about 11 million prescriptions for antidepressants to teenagers and children each year.
  • More women than men have been diagnosed with depression, but that does not necessarily mean that more women are depressed than men. Researchers suggest that women are just more likely to seek help than men.

Tricyclics and MAOIs were available years before the SSRIs came on the scene. Richard DeGrandpre, writing in Nation, stated that "SSRIs have not been clinically proven to be more effective" than the older tricyclics. The SSRIs gained a reputation for safety because they are generally less toxic, or harmful to the body, when taken in overdoses. In normal doses, however, both the new and the old classes of antidepressants have been shown to relieve the symptoms of depression in some patients. Because each patient will respond differently to the various antidepressants, physicians may try several different kinds—or even combine one with another—in the search for the most effective treatment for a particular patient.

The Ultimate Problem Solver?

The most popular antidepressants are the SSRIs. Prozac was the first SSRI approved for use in the treatment of depression. It became available in 1987, received extensive coverage in the media, and within a few years became a household name. Some people were under the impression that Prozac was the ultimate problem solver—a sort of "happy pill" that gave everyone who took it a more positive outlook on life. It had no reported side effects and was even thought to help in weight loss. What most people failed to realize, however, is that antidepressants have no psychological effects on people who don't suffer from depression. They only help depressed patients reach a normal level of functioning.

Still, the market for antidepressants grew wildly in the 1990s and early 2000s. According to The Pill Book, seven of the top fifty prescriptions written by U.S. doctors in 2003 were for antidepressants. Associated Press reporter Bruce Smith, as recorded on the ABC News Web site, noted that 32.7 million prescriptions for Zoloft, another SSRI, were written that year. This made Zoloft the most widely prescribed antidepressant in the United States.

Main types of antidepressants
Tricyclics (try-SICK-licks) MAOIs (monoamine oxidase inhibitors) SSRIs (selective serotonin reuptake inhibitors) Others, including SNRIs (serotonin and norepinephrine reuptake inhibitors)
source: Prepared by Barbara C. Bigelow for Thomson Gale, 2005.
amitriptyline (amm-uh-TRIP-tuh-leen; Elavil)mirtazapine (murr-TAZ-uh-peen; Remeron)citalopram (sye-TAL-oh-pram; Celexa)bupropion (byoo-PROH-pee-on; Wellbutrin)
clomipramine (kloh-MIPP-ruh-meen; Anafranil)phenelzine (FENN-uhlzeen; Nardil)escitalopram (EE-sye-TAL-oh-pram; Lexapro)venlafaxine (venn-luh-FAKS-een; Effexor)
imipramine (ih-MIPP-ruh-meen; Tofranil)fluoxetine (flu-AKS-uh-teen; Prozac)
paroxetine (purr-OKS-uh-teen; Paxil)
sertraline (SURR-truhleen; Zoloft)

What Is It Made Of?

A variety of substances have antidepressant actions. The anti-depressants available in the United States are classified in two main ways: 1) by their chemical structure, as in the case of tricyclics (three-ring structure), or 2) by their actions on neurotransmitters, as in the case of MAOIs, SSRIs, and SNRIs. Tricyclics work to increase the levels of the neurotransmitters norepinephrine and serotonin in the


brain. These neurotransmitters are usually at low levels in people who suffer from depression. The problem with tricyclics is that they can affect other neurotransmitters as well, causing a number of side effects. MAOIs stop the protein in the brain known as monoamine oxidase from breaking down serotonin, norepinephrine, and another neurotransmitter called dopamine after they deliver their messages to the brain. This leaves high levels of these chemicals in the brain and subsequently keeps depression at bay.

However, MAOIs also keep monoamine oxidase from destroying tyramine (found in various foods), which can cause fatal increases in blood pressure. SSRIs were specifically designed by scientists to stop the "reuptake," or reabsorption, of only serotonin in the brain, allowing levels of serotonin to build and remain high while not affecting the levels of other chemicals. They are the most prescribed forms of antidepressants because they usually have fewer side effects and interactions with other drugs. SNRIs focus on stopping the reuptake of serotonin and norepinephrine so that they both build and remain at a high level.

How Is It Taken?

Prescription antidepressants are taken orally, usually once a day, and usually in capsules or tablets. Some are available in liquid form for swallowing. It is very important that patients on antidepressants take their medications exactly as prescribed, even if the drugs do not seem to be working at first. In some cases, three to four weeks of antidepressant use may be needed before the effects of the drug can be observed.

The usual daily dose prescribed of an antidepressant can differ. For the SSRI Prozac, a patient is typically prescribed 20 to 40 milligrams per day. In higher doses, it has been used to treat obsessive-compulsive disorder (ocd) and the eating disorder bulimia. In 2002, Prozac became available in a once-a-week capsule-form that contains 90 milligrams of fluoxetine granules that are released over time. The effect of one of these capsules is equivalent to seven daily doses of 20 milligrams of Prozac.

Dosages of Zoloft, another SSRI, typically begin at 50 milligrams per day for adults and may be raised to 100 or 200 milligrams per day. When the SSRI Paxil is prescribed for depression, the initial dose is usually 20 milligrams per day. This dose may be increased to about 40 milligrams per day. Citalopram (Celexa) and escitalopram (Lexapro) are SSRIs that are gaining popularity for two reasons. First, their side effects are said to be minimal. Second, the risk of harmful interactions with other drugs is low. As of 2005, drug


researchers noted a definite increase in the number of prescriptions being written for these two particular antidepressants.

Are There Any Medical Reasons for Taking This Substance?

Antidepressants are used mainly to relieve the symptoms of depression, which include feelings of sadness, helplessness, and hopelessness. They may also be used to treat severe anxiety, panic attacks, post-raumatic stress disorder (ptsd), obsessive-compulsive disorders, eating disorders, chronic pain, severe premenstrual syndrome, and postpartum depression. Affecting more than one in ten new mothers, postpartum depression causes sadness, anxiety, irritability, tiredness, interrupted sleep, a loss of enjoyment or desire to do anything, and guilt over not being able to care properly for the baby.

Sometimes severely ill individuals become depressed. The symptoms of depression can have very negative effects on their recovery. stroke patients are especially vulnerable to depression. After-stroke, or post-stroke, effects can include a loss of voluntary movement (usually on one side of the body), a loss of sensation (especially in affected limbs), weakness, and difficulty speaking. The long process of rehabilitation for stroke patients is often hampered by depression. Antidepressants have proven very effective in post-stroke patients. A positive attitude is crucial to recovery and helps patients stick to their intensive and often exhausting physical therapy schedules. Treating post-stroke depression improves the chances of the stroke patient regaining both physical strength and mental sharpness.

Usage Trends

"I think the categorical belief is that depression is something you get over rather than something you take medication for," stated Dr. Zachary N. Stowe in an interview with Laurie Tarkan for the New York Times. Indeed, some "four out of five people with depression will get completely better without any help," noted the authors of "Depression: Help Is at Hand." Episodes of depression frequently last for eight months to a year before going away. For some depressed people, however, the symptoms hang on even longer.

September 11, 2001


Doctors reported that requests for antidepressants increased dramatically after the terrorist attacks of September 11, 2001, on American soil. Fear, depression, and anxiety were common among Americans after terrorists hijacked planes and flew them into the World Trade Center in New York City and the Pentagon in Washington, D.C.

Of the one in five people with depression that does not go away on its own, treatment is recommended. Without help, those people are twice as likely to fall into a pattern of repeated depressive episodes. A 2003 Time magazine article pointed to the potential seriousness of the condition. "Untreated depression has a lifetime suicide rate of 15 percent—with still more deaths caused by related behaviors like self-medicating with alcohol and drugs."

The Debate over SSRI Safety and Suicide Risks in Children and Teens

As more and more children and teens are diagnosed with depression, the effects of the drugs used to treat it must be evaluated in young people. Some experts worry that anti-depressants may act differently in people under the age of eighteen because their brains are not yet fully mature. "Our knowledge of antidepressant treatments in youth, though growing substantially, remains limited when compared with what we know about treatment of depression in adults," stated the authors of the NIMH article "Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers."

According to Christian Science Monitor correspondent Patrik Jonsson, two separate congressional hearings revealed that the U.S. Food and Drug Administration (FDA) had "known about problems with [antidepressant] drugs since 1996, but failed to take decisive action." These "problems" included higher rates of aggression and an increase in suicidal thinking among young patients being treated with antidepressants. By 2000, even more studies had emerged "showing a possible link between hallucinations and aggression in children and teens taking Zoloft, Paxil, and Prozac," reported "FindLaw" columnist Elaine Cassel on CNN.com. Despite these findings, in January of 2003 the FDA approved the use of Prozac in depressed children as young as seven years old. As of 2005, only ProzachasbeenapprovedtotreatdepressionandOCDinchildren. Zoloft, Luvox, and Anafranil are only approved for children for OCD. As of 2005, no other antidepressant is approved for use in children.

Defining Depression


Depression is hard to define, and not all doctors agree on whether it is a mood disorder or the more serious definition: a disease. In his 2005 book, Against Depression, Peter Kramer notes that his work presents "an insistent argument that depression is a disease." In fact, he calls depression one of the worst diseases to afflict humankind.

Dr. Peter R. Breggin sees the situation differently. In his 2001 work, The Antidepressant Fact Book, he states that "it is a mistake to view depressed feelings or even severely depressed feelings as a 'disease."' He continues: "Depression… is an emotional response to life. It is a feeling of unhappiness—a particular kind of unhappiness that involves helpless self-blame and guilt, a sense of not deserving happiness, and a loss of interest in life…. A human emotion or psychologi cal state—basically, a feeling—should not be considered a 'disease' simply because it becomes extreme."

Treatment for Adolescents with Depression Study (TADS):

To gain more information on the effects of antidepressants in young people, the NIMH spent $17 million on the Treatment for Adolescents with Depression Study (TADS), which was conducted between 2000 and 2003. More than 400 depressed adolescents were divided into groups that received varying forms of treatment. One group was treated with Prozac alone. Another group received a combination of Prozac and cognitive behavioral therapy (bt), a type of psychotherapy that stresses positive thinking. A third group received CBT without the Prozac. A fourth group received only a placebo.


The results of the study were released to the press by the NIMH in August of 2004. The participants were monitored for improvement in their depression and for trends in their suicidal thinking. The combination of medication and therapy proved the most effective in relieving the symptoms of depression. The data concerning suicidal thinking were more difficult to interpret.

The results of TADS revealed that 7 percent of adolescents receiving Prozac either attempted suicide or threatened to do so. Only 4 percent of participants in the placebo group had a suicide-related event. Still, the NIMH concluded that "it is extremely difficult to determine whether SSRI medications do or do not increase the risk of… suicide, especially since depression itself increases the risk for suicide." Experts believe that a larger study is needed to resolve unanswered questions.

Results Lead to "Black Box" Warnings

In 2004, the FDA examined information from more than twenty studies, including TADS, on antidepressants and adolescents. Together, the studies involved about 4,300 patients under the age of eighteen. Overall, the results mirrored the TADS findings. The rate of suicidal thinking or behavior was twice as high among adolescents taking SSRIs as it was in adolescents who were not. This prompted the FDA to announce in late 2004 that "black box" labeling of antidepressants would become mandatory. In "Antidepressant Medications for Children and Adolescents," the authors noted: "A black-box warning is the most serious type of warning in prescription drug labeling." Black box warnings for antidepressants state that the drugs may be linked with an increased risk of suicidal thinking or behavior. On its Web site, the FDA specifies the language to be used on the black box warnings. Part of the standard warning follows:

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [drug name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.

According to MSNBC.com, antidepressant use among children and teens has declined by about 10 percent since the information on suicide risks was released.

Testing New Drugs


The word placebo is Latin for "I shall please." Placebos, often called "sugar pills" or "dummy pills," are used in experiments that test the effectiveness of new drugs. Doctors give one group of patients regular doses of a placebo and one group of patients regular doses of the real drug that is being tested for a particular condition. Patients are not told what they have been taking until the testing period is over. After a few months, both groups are compared. A higher rate of improvement among patients in the test-drug group is good news for drug researchers. It indicates that the new drug is truly effective in treating the condition it was designed to treat.

Patients' conditions may improve for a time if they believe they are taking a medication that will relieve their symptoms. In the treatment of depression, an average of 35 percent of placebo-treated individuals will improve, compared with about 60 percent of SSRI-treated individuals.

Effects on the Body

Neurotransmitters, such as serotonin and norepinephrine, are chemical substances that transmit information from one nerve to another. By the middle of the twentieth century, researchers had found that depressed people seemed to have lower concentrations of neurotransmitters coating the nerve endings in their brains. Antidepressants help stop the reuptake of these chemical substances in the brain, creating a kind of bath of neurotransmitters like serotonin for the nerve endings to soak in. Raising the concentration of neurotransmitters in the brains of depressed individuals works to reduce the symptoms of their depression.

The actions of antidepressants on the brain are not fully understood, but scientists are learning more about them every day. Studies show little difference in the effectiveness of the various antidepressants, but some individual patients appear to do better on one drug than another. In the search for the most effective drug for a particular patient, a physician may prescribe various antidepressant drugs or even try some in combination.

General side effects of antidepressants can include stomach upset, agitation, anxiety, dizziness, insomnia, and a dry mouth (which usually increases a user's thirst). Since SSRIs were discovered, the older MAOIs are prescribed less often for the treatment of depression. Side effects of MAOIs can be severe and include a sudden elevation of blood pressure. Tricyclics may cause dryness of the mouth and eyes. A dry mouth can lead to the formation of dental cavities, and dry eyes can result in blurred vision. Use of tricyclics may also result in reduced urine output, constipation, and weight gain. Older patients are cautioned against tricyclic use because the drugs can disrupt the normal rhythm of the heartbeat. SNRIs should not be used by people with heart problems.

The Question of Addiction

Until the early 2000s, antidepressants were not believed to cause addiction in users. A traditional feature of addictive substances is the "high" or "buzz" they cause in users. "Antidepressants will not make you high," stated Andrew Weil and Winifred Rosen in From Chocolate to Morphine.

News from Around the Globe


Depression and anxiety are common problems throughout the world. Were you aware that:

  • The National Institute on Mental Health in England (NIMHE) reported that about 1 in every 100 deaths in the United Kingdom is a suicide.
  • Canada's labeling of SSRIs carries an additional warning of a potential increase in hostility, aggression, and "harm to others." A reference to harming others does not appear on the black box warnings of SSRIs in the United States, however.

Ables and Baughman mentioned in 2003 that some degree of withdrawal occurs with all antidepressants. This contradicts the belief that antidepressants are not addictive. The withdrawal symptoms, which are usually mild, begin about a week after the antidepressant medication is stopped. They include dizziness, nausea, headache, and flu-like symptoms, but agitation and even panic attacks may occur. Withdrawal symptoms usually end within three weeks for SSRIs. However, "withdrawal from paroxetine [SSRI Paxil]," explained Ables and Baughman, "was shown to cause more severe symptoms that may occur more quickly, even after the second missed dose."

Researchers in the United Kingdom noted similar findings. According to the Royal College of Psychiatrists, "up to a third of people who stop SSRIs and SNRIs have withdrawal symptoms. These include: stomach upsets, flu-like symptoms, anxiety, dizziness, vivid dreams at night, and sensations in the body that feel like electric shocks." These symptoms are more often associated with paroxetine (sold under the brand name Paxil in the United States and Seroxat in the United Kingdom) and venlafaxine (sold under the brand name Effexor in the United States and Efexor in the United Kingdom) than any other SSRIs and SNRIs. Research continues on the still-baffling question of addiction and withdrawal issues among antidepressant users.

Zoloft on Trial


Christopher Pittman threatened suicide and was hospitalized after his parents' final breakup in 2001. Pittman's mother had first left home when Pittman was just two years old. His parents' repeated attempts to get back together failed. After hearing that their relationship was really over, Pittman, then twelve years old, became desperate and ran away from his Florida home. After he was found, he spent a couple of weeks in a psychiatric hospital and was diagnosed with depression and defiant behavior. Doctors put him on Paxil, an SSRI, briefly. Days later he was prescribed Zoloft, a different SSRI. Zoloft was the most widely used antidepressant for both adults and teens in the United States at that time.

Pittman went to live with his father's parents in South Carolina later in 2001. He was there for only a matter of weeks, and life seemed to be going well for him. Then, one day that November, Pittman and his grandfather had a serious argument. They fought about some trouble that Pittman had caused on his school bus. Pittman was told that he might have to return to his father's home in Florida because of the incident. That night, the twelve-year-old boy shot his grandparents to death in their bed, set their home on fire, and drove away in their car with his dog. Pittman's lawyers argued that "the killings occurred for a reason beyond the boy's control—a reaction to the antidepressant Zoloft," noted Barry Meier in the New York Times. "Such defenses," Meier continued, have been used in the past but "have rarely succeeded."

Pittman's case did not go to trial until three years after the tragic incident. While in jail awaiting his trial, Pittman repeatedly claimed that he loved his grandparents. His own father even came to his defense, stating that the boy had always been especially


close to the couple. Pittman told police that on the night of the murders, he had heard voices urging him to kill his grandparents. Those voices in his head, claimed defense lawyers, were caused by the Zoloft, and possibly even the Paxil, he had been taking for depression.

The so-called "Zoloft defense" did not work for Christopher Pittman. On February 15, 2005, he was sentenced to thirty years in prison for the murders of his grandparents.

The Pittman case fueled the growing debate about the safety of antidepressants in children and teens. Between 2001 and 2004, the FDA stepped up its investigations into the effects of antidepressants on patients under the age of eighteen. In June of 2003, the FDA recommended against prescribing Paxil (the first medication prescribed by Pittman's doctors) for depression in children and adolescents.

Reactions with Other Drugs or Substances

Anyone prescribed an antidepressant should consult with a physician before taking any other drug, including over-the-counter medications. Patients taking MAOIs must avoid certain foods such as aged meats, cheeses, and pickles because they contain tyramine, which can cause harmful reactions when combined with MAOIs. These foods should not be consumed until well after a person stops taking the drug.

It is important to know that the effects of alcohol are greatly increased when combined with antidepressants. In addition, combining large amounts of caffeine with antidepressants may intensify the jitters and agitation that sometimes accompany depression.

The reactions of recreational drugs with antidepressants are unpredictable and possibly very dangerous. The symptoms of depression are often intensified by illicit drug use. To help avoid problems, it is important that patients taking antidepressants stick to their prescribed dosage and stay away from other drugs, unless prescribed by a physician. In addition, the effectiveness of a drug can only be measured when the prescription is followed accurately.

Treatment for Habitual Users

Antidepressants are not abused in the traditional sense. This means that they are not taken by users to get high. If antidepressant drug therapy is discontinued, it should be done under a doctor's care using the "stepdown method" in order to reduce the risk of side effects. This method involves gradually lowering the dose of the drug until the patient is weaned off it entirely.

Consequences

Depression and anxiety can interfere with a person's happiness, success, and relationships. The symptoms of depression and anxiety should not be ignored. About 80 percent of people with depression respond very positively to treatment, but that leaves a significant number—the other 20 percent—without help. Thus, an important goal of NIMH research is to advance the development of more effective treatments for depression, especially those "hard-to-treat" forms that don't respond well to currently available medications and/or counseling.

Major depression can occur just once in a person's lifetime, but it is usually recurring. Depressive episodes will interfere with the ability to work, eat, sleep, concentrate, and take pleasure in formerly enjoyed activities. Treatment for depression is often a long-term process, but it can help those with the condition lead fuller and happier lives.

Taking antidepressants for depression and/or anxiety does have consequences. They all have side effects, some dangerous, that need to be monitored. A number of people believe that taking drugs for depression and/or anxiety is not necessary. In fact, they claim, it can even be harmful. In 2005, actor Tom Cruise spoke out against the use of antidepressants, citing vitamins and exercise as better alternatives. However, others state that their lives have greatly improved since they started taking antidepressants.

Alternatives to Medicine


Antidepressants are believed to help relieve the symptoms of depression, but there are other things depressed people can do to feel better. Among these are:

  • Talking with trusted friends, family members, and counselors
  • Identifying and solving the problem that may have caused the depression in the first place
  • Getting regular exercise
  • Eating well
  • Staying away from alcohol and other depressants
  • Practicing relaxation techniques
  • Setting time aside for enjoyable activities or hobbies

The Law

Antidepressants are only available by prescription. It is illegal for people to take drugs that have not been prescribed for them. It is also illegal for patients to share prescribed drugs with other people. Since users of antidepressants do not achieve a high with these drugs (as may occur with the stimulant drugs amphetamines and other drugs of abuse), they are rarely abused. No market for the illegal sale of antidepressants has been reported.

For More Information

Books

Appleton, William S. Prozac and the New Antidepressants. New York: Plume, 2000.

Breggin, Peter R. The Antidepressant Fact Book. Cambridge, MA: Perseus, 2001.

Katzung, Bertrum G. Basic and Clinical Pharmacology. New York: Lange Medical Books/McGraw-Hill, 2001.

Kramer, Peter. Against Depression. New York: Viking, 2005.

Morrison, Andrew L. The Antidepressant Sourcebook. New York: Broadway Books, 1999.

Schull, Patricia Dwyer. Nursing Spectrum Drug Handbook. King of Prussia, PA: Nursing Spectrum, 2005.

Silverman, Harold M. The Pill Book, 11th ed. New York: Bantam, 2004.

Weil, Andrew, and Winifred Rosen. From Chocolate to Morphine. New York: Houghton Mifflin, 1993, rev. 2004.

Periodicals

Ables, Adrienne Z., and Otis L. Baughman III. "Antidepressants: Update on New Agents and Indications." American Family Physician (February 1, 2003): pp. 547-554.

Cheakalos, Christina. "A Big Letdown?" People (May 12, 2003): pp. 191-192.

DeGrandpre, Richard. "Trouble in Prozac Nation." Nation (January 5, 2004): pp. 6-7.

Dewan, Shaila, and Barry Meier. "Boy Who Took Antidepressants Is Convicted in Killings." New York Times (February 16, 2005).

Harris, Gardiner. "FDA Panel Urges Stronger Warning on Antidepressants." New York Times (September 15, 2004).

Jerome, Richard. "The Prozac Kids." People (July 28, 2003): pp. 46-49.

Jonsson, Patrik. "'Zoloft Defense' Tests Whether Pills Are Guilty." Christian Science Monitor (February 11, 2005).

"Medicating Young Minds." Time (November 3, 2003): p. 48.

Meier, Barry. "A Drug on Trial." New York Times (August 23, 2004).

"Post-Stroke Depression Impedes Recovery." New England Journal of Medicine Health News (September, 2000).

"Prescription for Suicide?" Time (February 9, 2004): pp. 59-60.

Schuster, Mark A. "A National Survey of Stress Reactions after the September 11, 2001, Terrorist Attacks." New England Journal of Medicine (November 15, 2001).

Shute, Nancy. "Teens, Drugs, and Sadness." U.S. News & World Report (August 30, 2004): pp. 36, 38.

Tarkan, Laurie. "Dealing with Depression and the Perils of Pregnancy." New York Times (January 13, 2004).

Web Sites

"Antidepressant Eases Late-Life Anxiety Disorders." Yahoo! News.http://news.yahoo.com (accessed January 5, 2005).

"Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers." National Institute of Mental Health.http://www.nimh.nih.gov/healthinformation/antidepressant_child.cfm (accessed June 30, 2005).

"Antidepressants." Royal College of Psychiatrists.http://www.rcpsych.ac.uk/info/factsheets/pfacanti.asp (accessed June 30, 2005).

Cassel, Elaine. "Did Zoloft Make Him Do It?" CNN.com, February 7, 2005. http://www.cnn.com/2005/LAW/02/07/cassel.pittman/index.html (accessed June 30, 2005).

"Changing Minds." Royal College of Psychiatrists.http://www.rcpsych.ac.uk/campaigns/cminds/depression.htm (accessed June 30, 2005).

"Class Suicidality Labeling Language for Antidepressants." U.S. Food and Drug Administration, Center for Drug Evaluation and Research.http://www.fda.gov/cder/drug/antidepressants/PI_template.pdf (accessed June 26, 2005).

Collins, Jeffrey. "Dad Cites Boy's Antidepressants in Deaths." ABC News, December 5, 2004. http://abcnews.go.com/Health/wireStory?id=303933&CMP=OTC-RSSFeeds0312 (accessed June 16, 2004).

"Combination Treatment Most Effective in Adolescents with Depression" (press release). National Institute of Mental Health.http://www.nimh.nih.gov/press/prtads.cfm (accessed June 16, 2005).

"Depression." National Institute of Mental Health.http://www.nimh.nih.gov/publicat/depression.cfm (accessed June 16, 2005).

"Depression: Help Is at Hand." Royal College of Psychiatrists.http://www.rcpsych.ac.uk/info/help/dep/index.asp (accessed June 30, 2005).

"Depression Research." National Institute of Mental Health.http://www.nimh.nih.gov/publicat/depresfact.cfm (accessed June 30, 2005).

"Fewer Kids Taking Antidepressants." MSNBC.com, February 1, 2005. http://www.msnbc.msn.com/id/6894036 (accessed June 16, 2005).

"NIMH Research on Treatment for Adolescents with Depression Study (TADS): Combination Treatment Most Effective in Adolescents with Depression." National Institute of Mental Health.http://www.nimh.nih.gov/healthinformation/tads.cfm (accessed June 16, 2005).

"ParentsMedGuide—The Use of Medication in Treating Childhood and Adolescent Depression: Information for Patients and Families." Parents-MedGuide.org.http://www.parentsmedguide.org/parentsmedguide.htm (accessed June 30, 2005).

Polk, Jim. "Doctor: Boy Not Responsible for Killing Grandparents." CNN.com, February 9, 2005. http://www.cnn.com/2005/LAW/02/08/zoloft.trial/index.html (accessed June 30, 2005).

Smith, Bruce. "Teen Gets 30 Years in Zoloft Murder Case." ABC News, February 15, 2005. http://abcnews.go.com/US/wireStory?id=502403 (accessed June 16, 2005).

See also: Herbal drugs

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