Depression can occur if some of the neurotransmitters (chemicals that carry messages between nerve cells) in the brain are not functioning effectively. Released by one part of nerve cells, the neurotransmitters float across the synapse (the space between nerve cells) to stick on specific places known as receptors on other cells. Occupying the receptors activates the second nerve cell to release additional neurotransmitters that keep the message going along the nervous system. Once they have delivered their messages, neurotransmitters are either broken down by enzymes or taken back into the nerves in a process known as reuptake.

The three main neurotransmitters involved in depression are dopamine, norepinephrine, and serotonin (also known as 5-HT). In Canada, Europe, and other areas of the world, norepinephrine is known as noradrenaline. When brain levels of one or more neurotransmitter are low or unbalanced, depression and other conditions can result. Generally, antidepressant drugs work by increasing the production or decreasing the breakdown of one or more neurotransmitter.

Several antidepressants currently on the U.S. market have unique properties. They are not chemically structured like any other class of antidepressant and they do not work in the same ways that other types of antidepressants do. Although they are all included in the general "Miscellaneous Antidepressants" category, most of the drugs in this group also differ from the others in structure and activity. Each of the miscellaneous antidepressants affects one or more neurotransmitter in different ways to help steady the chemical imbalance often seen in depression. Often, a miscellaneous antidepressant is added to therapy with another type of antidepressant when one drug does not relieve depression adequately.

Currently, no strong evidence firmly recommends any individual antidepressant or even any of the antidepressant classes for every situation. Not all patients will respond to the same antidepressant and an individual?s response may change over time. Often, a different antidepressant in the same class will be effective, but sometimes a change to a different type of antidepressant is needed. Patients with resistant or recurring depression may need to take two or more antidepressants from different classes at the same time. The choice of an antidepressant depends on multiple factors that include:

• the type of depression being treated
• the doctor's experience
• any other medical conditions the patient may have
• other medications the patient takes
• the patient?s response to previous therapy
• the patient?s prescription formulary

Drugs in this Class
Bupropion (Wellbutrin)
Trazodone Tablets ()
Nefazodone ()
Lithium Carbonate Extended-Release Tablets (Lithobid Extended-Release Tablets)
Lithium Carbonate Tablets ()
Mirtazapine Oral Disintegrating Tablets (Remeron Soltabs ODT Tablets)
Bupropion Extended-Release 12-Hour (Depression/Mood Disorders) (Budeprion SR, Bupropion SR, Bupropion Sustained-Release, Extended-Release 12-Hour (Depression/Mood Disorders), Wellbutrin SR, Wellbutrin SR Extended-Release )
Bupropion Extended-Release 24-Hour (Depression/Mood Disorders) (Budeprion XL, Wellbutrin XL)

Summarizing the Evidence

Comparative studies between miscellaneous antidepressants are limited, but a few have been published.

• A study comparing bupropion to trazodone for 124 patients with moderate-to-severe depression found that patients taking trazodone began to feel better faster. By the end of the 7-week study, though, effectiveness of the two drugs was about the same. Bupropion was associated with side effects such as anxiety and slight weight loss, while trazodone caused more sleepiness and weight gain.
• General results from several studies show that mirtazapine may cause patients to gain more weight than trazodone, venlafaxine (a selective serotonin and norepinephrine reuptake inhibitor or SNRI), or selective serotonin reuptake inhibitors (SSRIs). In clinical trials and general use, mirtazapine has also been associated with arthralgia (pain in the joints) more frequently than most other antidepressants.

Miscellaneous antidepressants have also been compared to other types of antidepressants in many studies:

Bupropion

• Combined results from six studies that included over 1,300 patients with major depression showed that bupropion generally improved sleep problems associated with depression better than selective serotonin reuptake inhibitors (SSRIs).
• In one study of patients with bipolar disorder, bupropion caused less inappropriately excessive happiness than venlafaxine (a drug in the selective serotonin and norepinephrine reuptake inhibitor or SNRI class of antidepressants). Formerly known as manic-depressive illness, bipolar disorder is a condition that involves drastic mood swings from extreme sadness to exaggerated feelings of happiness.
• In a 13-week long, double-blind, controlled study, depressed patients taking either bupropion or the tricyclic antidepressant (TCA), doxepin, had similar relief from their symptoms. Doxepin relieved insomnia better than bupropion, but it also caused more side effects, including constipation, dry mouth, fatigue, and weight gain.

Bupropion Sustained-Release

• Bupropion sustained release was comparably effective to sertraline (a selective serotonin reuptake inhibitor or SSRI) and both drugs worked better than placebo (inactive sugar pills) for 360 patients with moderate-to-severe major depression. During treatment, which lasted 8 weeks or less, patients taking bupropion reported less sexual dysfunction.

Lithium

• In an analysis of numerous studies and case reports, researchers found that taking lithium for at least 3 weeks in combination with another antidepressant increased antidepressant effects.

Maprotiline

• At the time that maprotiline was being developed (the 1970s), tricyclic antidepressants (TCAs) were the standard of treatment for depression, so most of clinical trials for maprotiline compared it to a TCA. Overall, maprotiline?s effects, time of onset, and side effects were comparable to the TCAs.
• When maprotiline was compared to a selective serotonin reuptake inhibitor or SSRI, (citalopram) for a small group of severely depressed inpatients, both drugs relieved depression in about half the patients taking them. In general, though, maprotiline caused different side effects (such as constipation and dry mouth) than citalopram (which included drowsiness, headache, and sweating).

• Among nearly 300 patients with severe depression who were treated for 12 weeks with either mirtazapine or fluoxetine (an antidepressant in the selective serotonin reuptake inhibitor?SSRI?class), both drugs appeared comparable in effectiveness. Patients taking mirtazapine reported better sleep, however. In general, patients taking mirtazapine gained weight while those taking fluoxetine lost weight during the study. Another very small study of patients with major depression found no difference in effectiveness or tolerability between mirtazapine and fluoxetine during a 6-week treatment period. Results from a separate but similar study showed slightly better response for mirtazapine than fluoxetine after three weeks of therapy.
• Mirtazapine also began to work faster than paroxetine, a selective serotonin reuptake inhibitor (SSRI); and fewer patients had side effects that caused them to stop treatment with mirtazapine during one 24-week long study of elderly patients with major depression.
• In a study that lasted for more than a year, patients taking mirtazapine or a selective serotonin reuptake inhibitor (SSRI) generally experienced less serious negative effects on driving skills?such as attention, reaction time, and vision?than those taking another group of antidepressants, tricyclics or TCAs.
• In a study of patients whose depression had not responded to treatment with at least two other antidepressants, mirtazapine and the tricyclic antidepressant (TCA), nortriptyline, were both slightly effective with about 13% of patients responding to mirtazapine and about 17% to nortriptyline.
• An analysis of studies that compared mirtazapine with selected tricyclic antidepressants (TCAs) or certain selective serotonin reuptake inhibitor antidepressants (SSRIs), found that all the drugs had approximately equal effectiveness. Generally, mirtazapine started to work more quickly than SSRIs, caused fewer side effects than TCAs, and helped to relieve anxiety and insomnia better than either other type of antidepressant.

Nefazodone

• Nefazodone has been compared to the tricyclic antidepressant (TCA), imipramine, in several studies. For the most part, the effectiveness of both drugs for depression is about the same. However, patients taking nefazodone generally reported earlier effects, relief of anxiety associated with depression, and fewer side effects than those taking imipramine.
• When nefazodone was compared to a selective serotonin reuptake inhibitor (SSRI), paroxetine, both drugs produced similar results and side effects. The 6-month long study included108 depressed patients.

Trazodone

• In trials that were conducted in the 1980s, trazodone generally was comparable in effectiveness with the tricyclic antidepressants (TCAs) for treating depression. Trazodone may have started to work more quickly and it may have relieved anxiety for more of the patients taking it than the TCAs did.
• Several short, small studies included 320 elderly patients who took one of the tricyclic antidepressants (TCAs), a selective serotonin reuptake inhibitor (SSRI), or trazodone. While all the drugs relieved depression about equally well, trazodone also helped to control anxiety and insomnia for more patients than either of the other antidepressant types.
• In one 6-week-long study comparing trazodone and venlafaxine (a selective serotonin and norepinephrine reuptake inhibitor or SNRI) in 115 patients, both drugs were about equally effective, but trazodone may have reached full effectiveness faster. A longer (one year) study of trazodone versus venlafaxine also showed that both drugs treated depression about equally. In that study, patients taking trazodone had less insomnia, but venlafaxine was better at relieving problems with thinking and memory.

Dosing and Administration

Note: Drug treatment for depression is highly individualized. Although many patients respond to recommended dose ranges; some can be treated with lower doses and others need higher doses. In general, treatment starts with a low dose, which is increased at specific intervals only if depression is not relieved. The maximum effectiveness of any antidepressant may take several weeks to develop and more than one antidepressant may be tried before the patient responds to treatment. Once an effective drug and dose are found, the patient is likely to continue therapy for 6 months or longer. When treatment is stopped, the dose of the antidepressant must be decreased slowly over several weeks or months.

• Bupropion tablets may be taken three times a day or four times a day. Bupropion should be started as 100 mg twice a day and then increased to 100 mg three times a day if depression does not respond after at least 3 days. The maximum recommended dose for adults is 450 mg per day in doses of 150 mg or less.
• Bupropion extended release is taken once daily?typically as one 300 mg tablet in the morning.
• Bupropion sustained-release tablets usually are taken twice a day. Dosing typically begins with one 150 mg tablet in the morning, and then increases to 300 mg per day in two doses at least 8 hours apart, if needed. No more than 400 mg per day is recommended.
• Lithium capsules may be taken three times a day or four times a day. Response is measured by blood levels of lithium, so typical doses are difficult to estimate.
• Lithium extended-release tablets generally are taken twice a day at total doses of 900 mg to 1,200 mg per day. If higher doses are needed, the larger part of the total dose usually is taken in the evening.
• Maprotiline tablets may be taken once daily or twice daily. Usually doses begin at 75 mg and increase by 25 mg every 2 weeks until depression is relieved or a maximum of 150 mg is reached.
• Mirtazapine tablets and mirtazapine orally disintegrating tablets are taken once a day in the evening or at bedtime. The typical adult dose range is 15 mg to 45 mg daily.
• Nefazodone tablets are taken twice a day at total usual doses of 300 mg to 600 mg.
• Trazodone tablets may be taken twice a day or three times a day after a meal or snack. The recommended total starting dose is 150 mg per day adjusted by 50 mg every 3 days or 4 days to a daily maximum of 400 mg.

Generic Availability

All of the miscellaneous antidepressants are available in generic formulations, but certain strengths or dosage forms may still be brand-only. Check with your doctor or pharmacist to see if your medication may be available generically. Generic medications may be a less expensive but comparably effective treatment option.

Drug Interactions

Some interactions between medications can be more severe than others. The best way for you to avoid harmful interactions is to tell your doctor and/or pharmacist what medications you are currently taking, including any over-the-counter products, vitamins, and herbals. For specific information on how the drugs interact and the severity of the interaction, please use our Drug Interactions Checker.

Side Effects

To view specific side effect information, please use our Side Effect Checker.

Additional Information

• In the last few years, some study results and case reports suggested that taking antidepressants was linked with an increase in suicides, attempted suicides, and thinking about suicide; especially for children, teens, and young adults. Generally, the risk is higher in first month or so and then appears to decrease as the body adjusts to the medication. Depressed individuals may be more likely to attempt or commit suicide whether or not they are taking antidepressants. Nevertheless, in 2004, the FDA required the manufacturers of all antidepressants to include on their labels the following safety warning:

  Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

• Typically, lithium is used to control bipolar disorder (formerly known as manic-depressive illness), a condition that involves extreme mood swings from depression to exaggerated feelings of happiness.
• In a group of 312 depressed women who took antidepressants while pregnant, 19% of the women taking mirtazapine had miscarriages compared to 17% taking other types of antidepressants and 11% taking no drugs. Using mirtazapine was also associated with more premature births.
• Sexual dysfunction includes the loss of interest in having sex, the failure to complete sexual relations or the inability to feel pleasure from having sex. Interference with normal sexual functioning is often associated with depression and it appears to increase as depression becomes more severe. Many antidepressants interfere with sexual performance, as well. When the rate of sexual problems associated with taking three separate antidepressants was compared in one large study, 24% of patients taking mirtazapine reported sexual dysfunction as compared to 8% of the individuals who took nefazodone. In another study that lasted for 12 weeks, bupropion extended-release tablets reportedly caused less sexual dysfunction than extended-release venlafaxine (a selective serotonin norepinephrine receptor inhibitor or SNRI), among 350 sexually active adults. Other reports also suggest that bupropion may have a lower incidence of sexual side effects in relation to other kinds of antidepressant medications. Lithium, however, may cause or worsen sexual problems among patients who take it for bipolar disorder.

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Last Updated: March 2008

Note: The above information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist, or other healthcare professional. It should not be construed to indicate that the use of the product is safe, appropriate, or effective for you. Consult your healthcare professional before taking any medication.

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