• Highlights
• Introduction
• Causes
• Risk Factors
• Complications of Depression
• Diagnosis
• Treatment
• Antidepressants and Drug Treatment Guidelines
• Psychotherapy
• Other Treatments
• Lifestyle Changes
• Resources
• References

Depression

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of depression.

Alternative Names

Seasonal affective disorder

Antidepressants and Drug Treatment Guidelines

Major Classes of Antidepressants and General Treatment Guidelines

Major classes of antidepressants include:

• Selective serotonin-reuptake inhibitors (SSRIs). These have become the standard antidepressants. They target the brain chemical (neurotransmitter) serotonin. They are effective and have very moderate side effects. Some may be beneficial in treating anxiety and certain subtypes of depressive disorders unresponsive to previous drugs, including premenstrual dysphoric disorder and seasonal affective disorder, atypical depression, and recurrent brief depression.
• "Designer antidepressants." These drugs target neurotransmitters other than or in addition to serotonin, such as norepinephrine. Many are being proving to be effective in patients who do not respond to standard antidepressants or in specific patients, such as smokers who want to quit or patients with chronic pain.
• Tricyclic antidepressants (TCAs). These drugs are effective but can have severe adverse effects, particularly in older people.
• Monoamine oxidase inhibitors (MAOIs). These drugs include newer selective MAOIs. MAOIs are the most effective antidepressants for atypical depression, but have some severe side effects and require restrictive dietary rules.
• St. John's wort and other herbal remedies are included in the Lifestyle section of this report.

A great deal of leeway exists in choosing an appropriate antidepressant. Overall, they seem to be equally effective, although cost, individual responses, and side effects vary widely.

Approach and Duration of Initial Treatment. The guidelines for the duration of an initial antidepressant regimen is as follows:

• Patients should start at a low dose, which is increased over a period of 5 - 10 days.
• Patients should see their doctor every 1- 2 weeks until substantial improvement occurs. It may take 4 - 8 weeks before a patient experiences the effects of any antidepressant.
• Side effects usually diminish within 1 - 4 weeks. (Exceptions may be weight gain and sexual dysfunction.)
• If no improvement occurs, an alternative drug may be tried. More than 80% of patients respond to some antidepressant, although specific drugs are helpful for only about half of patients. This suggests that if one medication fails, another has a good chance of being helpful. However, according to important results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trials, the fewer drug treatment strategies required, the better a patient’s chances of recovering completely from depression. Patients who become symptom-free have the best chance for complete recovery compared to patients whose symptoms merely improve.
• In general, patients should continue taking antidepressants for at least 6 months after symptom relief to help prevent relapse. (Patients who improve within 2 weeks of taking medications may not require lengthy treatment.)

Treating Recurrence. Recurrence of depression is very common. About a third of patients will relapse after a first episode within a year of ending treatment, and more than half will experience a recurring bout of depression at some point during their lives. Among those at highest risk for early relapse and who may require ongoing antidepressants are:

• Patients with at least two episodes of major depression or major depression that lasts for 2 years or longer before initial treatment.
• Patients who continue to have low-level depression for 7 months after starting antidepressant treatments.

In one study, 41% of patients relapsed after they stopped treatment compared to only 18% who had continued their antidepressants. Patients, then, may need maintenance therapy. Experts disagree, however, on the optimal length or the appropriate dosage of maintenance therapy. Some patients may need to stay on antidepressants for 1 - 2 years -- or even indefinitely. Some experts recommend withdrawing from medication after a year. (This should be gradual, over 2 - 3 months.) If depression recurs, the patient should go back on the antidepressants.

There is no risk for addiction with current antidepressants, and many of the common antidepressants, including most standard SSRIs, have been proven safe when taken for a number of years.

Common Side Effects of Most Antidepressants. No matter how well a drug treats depression, the ability of the patient to tolerate its side effects strongly influences his or her compliance with therapy. Lack of compliance is probably the major barrier to success. Side effects can be avoided or moderated if any regimen is started at low doses and built up over time. Although specific side effects are discussed under individual drugs, there are a few that are common to many of them:

• Sexual dysfunction is a common side effect of nearly all the standard antidepressants and some of the newer drugs. These side effects can be particularly distressing for patients on maintenance treatment who otherwise feel well. Some of the newer antidepressants, such as bupropion, may be effective alternatives without as high a risk for this problem. Sildenafil (Viagra), used for erectile dysfunction in men, may help reverse sexual dysfunction from antidepressants in both men and women. It does not heighten sexual interest, however.
• An increased risk of oral health problems caused by dry mouth is associated with long-term use of most antidepressants. The risks appear to be highest with some of the new designer antidepressants, with the use of multiple drugs, and with the presence of oral infections. Patients can increase salivation by chewing gum, taking vitamin C tablets, using saliva substitutes, and rinsing the mouth frequently.
• Virtually all antidepressants have complicated interactions with other drugs; some are very serious. A few are mentioned in the individual drug discussions below, but many are not, and patients should inform the doctor of any drugs they are taking, including over-the-counter medications.
• Nearly all antidepressants are metabolized in the liver, so anyone with liver abnormalities should use them with caution.
• Abrupt withdrawal from many antidepressants can produce severe side effects; no antidepressant should be stopped abruptly without consultation with a doctor.

Suicide Risk and Antidepressant Medications

In recent years, there has been concern that SSRI antidepressants may increase the risk for suicidal behavior. Of particular concern is a greater risk for suicide in young people taking these medications. While depression is itself associated with suicide, and antidepressant medication may revitalize suicidal attempts in patients who were too despondent before treatment to make the effort, evidence suggests that in some cases the medication itself can cause suicidal behavior. One specific SSRI, paroxetine (Paxil), has been definitely linked with suicidal behavioral risk in adults ages 18 - 30. In May 2006, the drug’s manufacturer warned doctors that all patients, and particularly young adults, should be carefully monitored during paroxetine therapy.

The U.S. Food and Drug Administration (FDA) has been conducting in-depth research on suicide risk and antidepressant medications. In October 2004, after careful review of scientific evidence, the FDA issued a public health advisory instructing drug manufacturers to include a "black box" warning explaining the association between antidepressant use and increased risk for suicidality (suicidal thoughts and behavior) in children and adolescents. In December 2006, the FDA announced plans to update the labels of antidepressant medications to include additional warnings about the risk of suicidal thoughts and behavior in young adults (ages 18 - 25).

The FDA based its recommendations for children and adolescents on a review of 24 clinical trials of nine antidepressant drugs. These trials enrolled over 4,400 pediatric patients and tested the safety and efficacy of SSRIs as well as other classes of antidepressants. The data suggested a greater risk for suicidality within the first few months of treatment. The average risk was minimal. Children and adolescents treated with these drugs had a 4% risk for suicidality compared with 2% for patients who received placebo. No patients in these studies actually committed suicide.

Based on these findings, the FDA recommends that caregivers monitor children being treated with antidepressants for sudden behavioral changes, and immediately notify their doctor if such changes occur. These behavioral signs include:

• Agitation
• Irritability
• Anxiety
• Panic attacks
• Insomnia
• Aggressiveness
• Impulsivity
• Hyperactivity in actions and speech
• Worsening of depression
• Increased thoughts of suicide

The FDA’s guidelines for medication usage recommend that patients see their doctor regularly after initiating drug treatment. The recommended schedule is:

• Once per week for 4 weeks (1st month)
• Every 2 weeks for the next month (2nd month)
• At the end of week 12 following the start of drug treatment (3rd month)
• More frequently if changes in mood or behavior occur
• Patients should also be closely monitored if their drug dosage is changed.

Research continues on antidepressant medications’ suicide risk for adults. It appears that drug-related suicide risk may be age-dependent with the risk decreasing as people age. At this time, the FDA recommends that adults who receive antidepressants follow the standard warnings included with antidepressant medications. Adults should be observed for increased depression or suicidality during the first few months of treatment or following a change in medication dosage. Patients should immediately contact their doctor if depression symptoms worsen or if suicidal thoughts or behavior increase.

Selective Serotonin-Reuptake Inhibitors

Selective serotonin-reuptake inhibitors (SSRIs) are now the first-line treatment of major depression. They work by increasing levels of serotonin in the brain. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Asimia, Seroxat), fluvoxamine (Luvox), citalopram (Celexa, Cipramil), and escitalopram (Lexapro, Cipralex). There are no significant differences among SSRI brands in effectiveness for treating major depressive disorder, although individual drugs may have different side effects or benefits for specific patients. At this time, fluoxetine is the only one of these drugs to be approved for children over age 7 and adolescents.

Because they act specifically on serotonin, SSRIs have fewer side effects than older antidepressants, which have more widespread effects in the body.

Candidates for SSRIs. SSRIs appear to help people with the following conditions:

• Mild to moderately severe major depression
• Seasonal affective disorder
• Dysthymia
• Severe premenstrual syndrome and premenstrual dysphoric disorder (PMDD) -- a repackaged form of fluoxetine (Sarafem) is the first SSRI specifically FDA-approved for PMDD. Other SSRIs and newer antidepressants are also proving to be effective.
• Anxiety disorders.
• Bulimia
• Impulsive and aggressive behaviors in psychiatric patients and in people with no mental health problems

Duration of Effectiveness and Use. SSRIs take, on average, 2 - 4 weeks to be effective in most adults. They may take even longer, up to 12 weeks, in the elderly and in those with dysthymia. By 14 weeks, depression should be in remission in everyone who responds to the drugs. Unfortunately, recurrence is common once the drugs are stopped. Studies indicate that the standard SSRIs are generally safe, although it is still unclear which patients would most benefit from on-going medication. Some experts recommend withdrawing from medication after a year. If depression recurs, then the patients should go back on the antidepressants.

Side Effects of SSRIs. Side effects may include:

• Nausea and gastrointestinal (GI) symptoms usually wear off over time.
• Agitation, insomnia, mild tremor, and impulsivity occur in 10 - 20% of people who take SSRIs. These symptoms may be particularly problematic in patients who also suffer from anxiety, sleeplessness, or both.
• Drowsiness affects about 20% of SSRI-treated patients. Newer SSRIs, such as escitalopram (Lexapro), may have fewer of these adverse effects.
• Dry mouth is common and can increase the risk for cavities and mouth sores.
• Patients may lack motivation, feel tired, be confused, and experience mental dullness.
• Headache and flu-like symptoms may occur.
• Heart palpitations and chest pain may occur.
• Weight gain varies depending on the SSRI. For example, in one study patients who took paroxetine (Paxil) experienced five times the weight gain as those who took citalopram (Celexa). Patients should be encouraged to maintain a low-calorie diet and to exercise. They should be aware that some of the weight-loss medications, notably sibutramine (Meridia), can have serious interactions with SSRIs.
• Sexual side effects include delayed or loss of orgasm and low sexual drive. They are a well-known side effect of SSRIs. Taking a supervised drug "holiday" on the weekend may improve sexual function during that time. Some of the newer SSRIs or designer antidepressants may cause less severe impairment of sexual function.
• Paroxetine (Paxil) may cause birth defects if taken during the first 3 months of pregnancy. Most reported defects have been heart-related. The most common heart abnormalities are ventricular septal defects, which are holes in the muscular wall that separate the main pumping chambers of the heart. Venlafaxine (Effexor) has also been associated with birth defects. Recent research suggests that SSRIs may also cause complications. However, due to high risk for relapse, pregnant women who are being treated for major depression should not stop taking antidepressants without first talking to their doctors. [For more information on antidepressant treatment guidelines during pregnancy, see Depression in Women in Causes section.]

Drug Interactions. SSRIs can interact with other antidepressants such as tricyclics and, in particular, monoamine oxidase inhibitors (MAOIs). SSRIs should never be taken in combination with an MAOI or within 2 weeks after discontinuing MAOI treatment. Other serious interactions have occurred with meperidine (Demerol) and illegal substances (such as LSD, cocaine, or ecstasy). People who take SSRIs may drink alcohol in moderation, although the combination may compound any drowsiness experienced with SSRIs, and some SSRIs increase the effects of alcohol.

Withdrawal Symptoms. Cognitive problems, sleep disturbances, increase in depressive symptoms, and electric shock-like symptoms have been known to occur with sudden discontinuation of SSRIs. The symptoms are more likely to occur with antidepressants with shorter half-lives as compared with fluoxetine, which has a long half-life. Reducing the dose of the antidepressant before stopping it is recommended.

Designer Antidepressants

These newer antidepressants target other neurotransmitters, such as norepinephrine or dopamine, alone or in addition to serotonin. In general, the advantages of the new designer antidepressants are:

• They may be more tolerable than the older tricyclic compounds and even some SSRIs, although long-term side effects are not fully known in this group.
• Most of these drugs have fewer adverse effects than SSRIs on sexual function, and some people have even reported enhanced sexuality with some of them.
• They may be more effective than SSRIs for severely depressed patients.
• Some of these drugs are helpful for additional problems -- such as insomnia, fibromyalgia and similar chronic pain syndromes, or smoking -- that may affect people with depression.

They do share some side effects, including dizziness and dry mouth, with other antidepressants. Comparison studies are needed, however, to determine if any of these drugs are superior to standard SSRIs in treating different stages or aspects of depression.

Dual Inhibitors. Dual inhibitors act directly on two neurotransmitters -- norepinephrine and serotonin. On the basis of a review of the literature, in 2002 an expert panel concluded that simultaneous targeting of both serotonin and norepinephrine was currently the optimal approach for patients who failed standard antidepressant therapies.

• Venlafaxine (Effexor) is similar to Prozac in effectiveness and tolerability for most patients. It has a faster action, however. As with the SSRIs, venlafaxine impairs sexual function. The drug can increase blood pressure and heart rate and should be used with caution in patients with high blood pressure or heart disease. It can also cause uterine and vaginal bleeding unrelated to menstruation. Venlafaxine should not be taken during the last trimester of pregnancy as it can cause complications in newborn infants. Some patients report severe withdrawal symptoms, including dizziness and nausea and there are also reports that the drug is associated with a higher rate of overdose than SSRIs. In 2006, the drug’s manufacturer warned of this increased overdose risk and advised doctors to prescribe their patients only small amounts of venlafaxine pills.
• Duloxetine (Cymbalta) also acts on both serotonin and norepinephrine. The drug was granted FDA approval in the summer of 2004 for treatment of major depressive disorder and is one of the newest antidepressants on the market. Side effects are generally mild and include dry mouth, nausea, and sleepiness. Patients with narrow-angle glaucoma or patients with liver or kidney diseases should not take duloxetine. Because duloxetine can cause liver damage, patients who drink large quantities of alcoholic beverages should not take it. Signs of liver damage include itching, dark urine, yellowing of skin and eyes (jaundice), and fatigue. Patients should immediately contact their doctor if they experience these symptoms.

Other Antidepressants with Effects on Multiple Neurotransmitters.

• Bupropion (Wellbutrin, Zyban) affects the reuptake of serotonin, norepinephrine, and dopamine -- a third important neurotransmitter. In addition to depression, bupropion is also approved for smoking cessation and for treating seasonal affective disorder (SAD). Bupropion causes less sexual dysfunction than SSRIs. About 25% of patients experience initial weight loss. Side effects include restlessness, agitation, sleeplessness, headache, rashes, stomach problems, and in rare cases, menstrual irregularities (rare), hallucinations and bizarre thinking. High doses can be toxic and may cause dangerous heart arrhythmias. Seizures have also been reported, usually in patients with eating disorders (anorexia or bulimia) or those with risk factors for seizures.
• Nefazodone (Serzone) is more rapidly effective and has fewer distressing side effects, including sexual dysfunction and sleep disorders, than SSRIs. Its safety for pregnant women is unknown. Nefazodone has been linked with increased risk for liver failure. Patients should consult their doctor concerning the relative risks and benefits of taking this nefazodone. The drug was withdrawn from the Canadian market in 2003 due to its risk for liver failure, but is still available in the United States.
• Mirtazapine (Remeron) is a unique antidepressant known as a 5-HT2 blocker. It may indirectly enhance the affects of both serotonin and norepinephrine. Compared to some common SSRIs, studies indicate it works more rapidly and has stronger early actions against anxiety in patients who suffer both disorders. It also improves sleep. Patients may be able to safely switch directly from an SSRI to mirtazapine without having to do through a withdrawal period. It has a lower incidence of sexual dysfunction than many other antidepressants. However, it may elevate cholesterol and triglyceride levels slightly. It also causes blurred vision and may cause slight weight gain.

Selective Noradrenaline Reuptake Inhibitor. Reboxetine (Edronax, Vestra) is at least equal to fluoxetine in reducing depression and improving social functioning, but it has many side effects including insomnia. Reboxetine is available in many countries, but not the United States.

Tricyclic Antidepressants

Before the introduction of SSRIs, tricyclics were the standard treatment for depression.

Tricyclics are sometimes grouped into two categories:

• Tertiary amines include amitriptyline (Elavil, Endep) and imipramine (Tofranil).
• Secondary amines include desipramine (Norpramin) and nortriptyline (Pamelor, Aventyl). Secondary amines may have fewer side effects, including drowsiness, than tertiary amines, but they are as toxic in high amounts.

Less commonly used tricyclics include doxepin (Sinequan), amoxapine (Asendin), maprotiline (Ludiomill), protriptyline (Vivactil), trimipramine (Surmontil), mianserin (Bolvidon), and dothiepin (Prothiaden).

Tricyclics are as effective for treating depression but they have many side effects. They may offer benefits for many people with dysthymia, who generally do not respond to SSRIs.

Side Effects of Tricyclics. Side effects are common with these medications. In fact, in an analysis of studies, more tricyclic users discontinued their drugs due to side effects than did SSRI or MAOI users. Those most often reported include:

• Dry mouth
• Constipation
• Blurred vision
• Sexual dysfunction
• Weight gain
• Difficulty urinating
• Drowsiness
• Dizziness -- blood pressure may drop suddenly when sitting up or standing.

Tricyclics can have serious, although rare, side effects:

• They tend to cause disturbances in heart rhythm, which can pose a danger for some patients with certain heart diseases. One study comparing nortriptyline with paroxetine, an SSRI, reported nine times more adverse cardiac events with the use of the tricyclic than with the SSRI.
• Also of concern are reports that tricyclics, particularly imipramine as well as mianserin and dothiepin, may increase the risk for a lung disease called idiopathic pulmonary fibrosis (IPF), which can cause lung inflammation and scarring. Initial symptoms are breathlessness and dry cough.
• Tricyclics can be fatal with an overdose.
• A 2000 study showed a small increased risk for non-Hodgkin's lymphoma associated with tricyclic use.
• Protriptyline can cause sun sensitivity. People who take this drug should take precautions against sunlight when they go outdoors.

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) block monoamine oxidase, an enzyme which has negative effects on many of the neurotransmitters that are important for well-being. MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate). Because these drugs can have very severe side effects, they are usually prescribed only when other types of antidepressants prove ineffective.

Newer MAOIs, such as selegiline (Eldepryl, Movergan), target only one form of the MAOI enzyme. They may cause fewer side effects than older MAOIs. In 2006, a skin patch form of selegiline (Emsam) was approved for treatment of major depressive disorder in adults.

Candidates for MAOIs. MAOIs may be effective for the following conditions:

• Atypical depression
• Eating disorders
• Post-traumatic stress disorder
• Borderline personality

Side Effects. MAOIs commonly cause the following side effects:

• Orthostatic hypotension (a sudden drop in blood pressure upon standing)
• Drowsiness or insomnia
• Dizziness
• Sexual dysfunction
• The most serious side effect is severe hypertension (high blood pressure), which can be brought on by eating certain foods having high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products.
• MAOIs can cause birth defects and should not be taken by pregnant women.
• Very dangerous side effects, such as serotonin syndrome, can occur from interactions with other antidepressants, including SSRIs. Serotonin syndrome is a potentially fatal condition that is caused by the interaction of serotonergic drugs. Symptoms include confusion, agitation, sweating and shivering, and muscle spasms. There should be at least a 2-week break between taking MAOIs and other antidepressants. MAOIs can have serious interactions with other drugs as well, including some common over-the-counter cough medications, psychostimulants (such as Ritalin), and decongestants.

Azapirones

Azapirones, including buspirone (BuSpar) and gepirone (Ariza, Variza), act on serotonin receptors called 5-HT(1A). Buspirone is primarily used to treat anxiety disorders, but they may have benefits for depression -- particularly gepirone in extended release formulations. Studies on gepirone indicate that it may help some people with major and atypical depression. Buspirone (BuSpar) has shown benefits in treating resistant depression when added to the SSRIs citalopram or fluoxetine. More research is needed to determine the role of these drugs in depression.

Augmentation Strategies

Augmentation strategies generally involve the use of drugs not typically thought of as antidepressants in combination with a standard antidepressant. Such strategies are being used for patients who fail standard therapies or who need to quickly speed up the response of the antidepressant. Augmentation therapies include:

• Mood stabilizers, such as lithium, carbamazepine, and divalproex sodium
• Newer antipsychotic drugs, such as risperidone
• Psychostimulants. Standard psychostimulants include dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). A newer psychostimulant, modafinil (Provigil, Alertec), is also showing promise for augmenting antidepressants. It may also pose less risk for abuse.
• Thyroid hormones. In one small study, high doses of thyroid hormone combined with an antidepressant had very mild side effects and were very effective in half of severely depressed treatment-resistant patients. Another study reported good results when thyroid hormone was followed by small doses of lithium.
• Beta-blockers. Pindolol (Visken), a beta-blocker normally used for heart disease, may help speed the response of antidepressants. In one study, after 10 days, nearly half the patients taking the combination were in remission compared to 25% of patients taking only paroxetine. In a study on fluoxetine, patients reached a sustained response within 19 days on the combination compared to 29 days with Prozac alone.

Investigational Drugs

Ketamine . Ketamine, an anesthetic drug, may be helpful for patients with severe treatment-resistant depression. In a small preliminary study, a single intravenous dose of ketamine helped patients quickly recover from depression within 2 hours, and some patients sustained benefits for up to a week. (Standard antidepressant drugs usually take about 8 weeks to have an effect.) Ketamine blocks the NMDA brain protein receptor, which is involved in glutamate regulation. Glutamate is a brain chemical that is thought to be involved in depression.

• Review Date: 12/21/2006
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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