Drug Comparisons

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.

Tricyclic antidepressants (TCAs) increase the effects of neurotransmitters by blocking their reuptake. Some of the TCAs limit the reuptake of all three major neurotransmitters, while others mostly block the reuptake of norepinephrine. In use since the 1960s, TCAs were the first-choice medications for treating depression for many years. Most of the newer antidepressants were tested against the TCAs before they received FDA approval. However, newer medicines for depression now focus on only one or two neurotransmitters. Therefore, some of the newer antidepressants are more targeted, so they have fewer side effects than the tricyclics.

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
Desipramine Tablets (Norpramin)
Doxepin Capsules ()
Amitriptyline Injection (Elavil Injection, Vanatrip Injection)
Trimipramine Capsules (Surmontil)
Clomipramine Capsules (Anafranil)
Amitriptyline ()
Amoxapine ()
Nortriptyline Oral Solution (Aventyl Oral Solution)
Protriptyline (Vivactil)
Imipramine Pamoate Capsules (Tofranil PM Capsules)
Imipramine Hydrochloride Tablets (Tofranil Tablets)
Nortriptyline (Aventyl, Pamelor)
Maprotiline ()

Summarizing the Evidence

Tricyclic Antidepressants in General

A review was done to compare the results of over 40 studies of selected tricyclic antidepressants (TCAs), certain selective serotonin reuptake inhibitors (SSRIs), and the serotonin norepinephrine reuptake inhibitor (SNRI) extended-release venlafaxine. In general, about 58% of the patients taking a TCA achieved at least a 50% reduction in the symptoms of depression. However, SSRIs relieved depression for about 61% of the patients taking them; extended-release venlafaxine helped about 74%.

A separate review of 11 different studies that compared side effects among over 400 patients taking a TCA (amitriptyline, clomipramine, or doxepin) with a similar number of SSRI-treated patients found that TCAs produced more dizziness, dry mouth, and fatigue while the SSRIs caused more nausea and vomiting.

Amitriptyline

• One analysis of published studies found that amitriptyline was as effective at treating depression as the other TCAs and certain SSRIs, but it caused more general side effects.
• No substantial differences in effectiveness or side effects were found by a study done in the 1970s to compare amitriptyline with the miscellaneous antidepressant, maprotiline. A second small (40 participants) study at about the same time seemed to show that amitriptyline?s effects might start slightly faster than mapritoline?s, but overall effectiveness was about the same.
• For 115 patients who participated in an 8-week long study of amitriptyline and venlafaxine (a serotonin norepinephrine reuptake inhibitor or SNRI), both drugs were comparable in effectiveness. More patients taking amitriptyline reported side effects, however.

Amoxapine

• While amoxapine and maprotiline (a miscellaneous antidepressant) were about equally effective in a small, 4-week long study of patients with moderate to severe depression, the effects of amoxapine started sooner.

Doxepin

• No significant differences in either effects or side effects were seen between doxepin and maprotiline, which is a miscellaneous antidepressant, during a study involving 95 patients with depression.
• When compared with the miscellaneous antidepressant, bupropion; doxepin showed approximately equal effectiveness for treating depression but better improvement of sleep disturbances. Doxepin was associated with more side effects, however, including constipation, dry mouth, fatigue, and weight gain.

Imipramine

• A 6-week study compared imipramine with placebo (inactive sugar pills) and the miscellaneous antidepressant, nefazodone. For 180 patients with major depression, both drugs relieved depression better than placebo, but nefazodone also helped with symptoms of anxiety and caused fewer side effects than imipramine. A slightly longer (8-week) study of 128 depressed patients found that nefazodone was effective for more patients than imipramine and that fewer nefazodone-treated patients stopped taking medication due to side effects.
• A larger study included 341 patients taking either imipramine or maprotiline (a miscellaneous antidepressant). While both drugs in that study showed about equal effectiveness for controlling depression, taking imipramine was associated with more side effects such as nausea and nervousness.

Nortriptyline

• In a 14-week long study of 235 patients with major depression that had not responded to previous treatment, nortriptyline was slightly more effective than the miscellaneous antidepressant, mirtazapine.
• Results from a year-long observational study of 51 elderly patients who had responded to treatment for depression showed that depression returned for fewer patients who were taking the monoamine oxidase inhibitor (MAOI), phenelzine, than for those who took either the TCA, nortriptyline, or placebo (inactive sugar pills).
• For 116 patients over the age of 65 years who took part in a 12-week long study, both nortriptyline and the selective serotonin reuptake inhibitor (SSRI), paroxetine, relieved depression about equally. More than twice as many nortriptyline-treated patients stopped taking medication due to side effects, though.

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.

• Adult patients taking amitriptyline tablets are usually maintained at 50 mg to 100 mg per day, with a usual range of 40 mg to 150 mg. The total dose may be taken at bedtime or it may be divided into two or three parts and taken during the day.
• The recommended total daily adult dose for amoxapine tablets is 200 mg to 300 mg divided into two three doses. As little as 100 mg per day may be effective for some patients, while others may need as much as 400 mg per day.
• Clomipramine capsules are generally started at 25 mg per day and then increased to a maximum of 250 mg per day, if needed. The usual effective dose for adults is 100 mg per day?divided into two or three doses that are taken after a meal or snack. Once an effective dose has been established, the entire dose may be taken at bedtime
• For desipramine tablets, the daily adult dose range is generally 100 mg to 200 mg, either as one dose at bedtime or divided into two or three smaller doses throughout the day.
• Adult patients who take doxepin capsules or oral solution usually begin with a daily dose of 75 mg, which can be increased to 150 mg. The entire amount may be taken at bedtime, or it can be divided into two or three doses
• Imipramine hydrochloride tablets and imipramine pamoate capsules typically are started at 75 mg per day and then adjusted to an effective maintenance dose between 50 mg and 150 mg per day for adult outpatients. For hospitalized adults, doses of imipramine may be as high as 300 mg per day.
• Nortriptyline capsules and oral solution are usually started at 25 mg three times a day. The total daily amount can be increased to 150 mg per day in three or four doses, if needed.
• Protriptyline tablets may be taken three times or four times daily to treat depression. The recommended total dose range for adults is 15 mg to 40 mg per day in three or four doses. If needed, doses can be adjusted to as much as 60 mg daily.
• The usual starting dose for trimipramine in adults is 75 mg, divided into smaller doses and taken throughout the day. Maintenance doses typically range from 50 mg to 150 mg per day. The total daily dosage is commonly taken as one dose at bedtime, but it may also be divided and taken throughout the day.

Generic Availability

All of the tricyclic antidepressants except protriptyline are 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.

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.

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Last Updated: March 2008
This content was created by members of the DrugDigest team of experts and is solely under DrugDigest's editorial control.

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.