Antidepressants

views updated

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).