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Comparing Antidepressants

Comparing Antidepressants


Selective Serotonin Reuptake Inhibitors

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.


Currently the most prescribed type of antidepressants in the U.S., selective serotonin reuptake inhibitors (SSRIs) primarily affect serotonin levels, Serotonin may influence mood more than the other neurotransmitters do. Abnormally low levels of serotonin not only play a role in depression, they also contribute to other conditions such as eating disorders, obsessive-compulsive disorder, panic disorder, and social anxiety disorder. By blocking the body?s reabsorption of serotonin and possibly increasing serotonin release, SSRIs keep more serotonin in the brain.


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


Escitalopram (Lexapro)
Fluoxetine Oral Solution (Prozac Oral Solution)
Fluvoxamine (Luvox)
Fluoxetine tablets or capsules (Prozac)
Paroxetine Oral Suspension (Paxil Suspension)
Citalopram (Celexa)
Sertraline (Zoloft)
Citalopram Oral Solution (Celexa Solution)
Sertraline Oral Solution (Zoloft Oral Solution)
Paroxetine (Paxil, Paxil CR, Pexeva)


Summarizing the Evidence


Because different SSRIs may work differently for different individuals, however; depressed individuals who have not responded to a particular SSRI or who have had side effects from it, may be tried on a different SSRI. For example, in one study, most patients who stopped taking fluoxetine because of side effects, were able to take sertraline .In another study, many of the patients with major depressive disorder that did not respond well to sertraline were successfully treated with fluoxetine. Researchers estimate that up to one-quarter of individuals who begin an SSRI will change to another antidepressant before treatment is successful.


Deciding which SSRI to use first generally depends on the doctor's experience, the specific type of depression being treated, the patient?s response to previous therapy, other medical conditions the patient may have, other medications the patient takes, and the patient?s prescription formulary.


SSRIs in General

  • In a study that lasted for more than a year, patients taking an SSRI or mirtazapine (a miscellaneous antidepressant) generally experienced less serious negative effects on driving skills?such as attention, reaction time, and vision?than those taking another group of antidepressants, tricyclics (TCAs).
  • An analysis of studies that compared certain SSRIs with the miscellaneous antidepressant, mirtazapine, or with selected tricyclic antidepressants (TCAs), found that all the drugs had approximately equal effectiveness. Generally, however, mirtazapine started to work more quickly than SSRIs and helped to relieve anxiety and insomnia better than either other type of antidepressant. Both mirtazapine and SSRIs caused fewer side effects than TCAs,
  • Several short, small studies included a total of 320 elderly patients who took an SSRI, one of the tricyclic antidepressants (TCAs), or the miscellaneous antidepressant, 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.
  • Two studies conducted in the early 2000s compared four SSRIs?citalopram, fluoxetine, paroxetine, and sertraline?with placebo (inactive sugar pills) and the selective norepinephrine and serotonin reuptake inhibitor (SNRI), extended-release venlafaxine. Long-term response rates for depression were similar for all patients that took one of the antidepressants, but those taking extended-release venlafaxine generally began to feel better faster. A separate analysis of over 40 studies that involved about 4,000 patients found that extended-release venlafaxine produced a higher success rate than other types of antidepressants. Success was defined as an improvement of 50% or more in the rating scales used to measure depression. In the analysis, 73.7% of patients taking extended-release venlafaxine were considered to be successful, as compared with 61.1% of those taking an SSRI and 57.9% taking a tricyclic antidepressant (TCA).
  • A review of published studies found SSRI response rates (improvements of 50% or more in depression rating scores) ranged between 53% and 64% as compared to 43% to 70% for tricyclic antidepressants (TCAs). Side effects were generally milder and less frequent with SSRIs, however.


  • Researchers compared the published results of 11 studies of citalopram versus placebo (inactive sugar pills), 11 studies of citalopram versus tricyclic or miscellaneous antidepressants, and four studies of citalopram versus other SSRIs. They concluded that citalopram is more effective than placebo and similar in effectiveness to other types of antidepressants, including other SSRIs.
  • A study involving a very small group of severely depressed, hospitalized patients compared citalopram to a miscellaneous antidepressant (maprotiline). Both drugs relieved depression in about half the patients taking them. Citalopram caused side effects such as drowsiness, headache, and sweating; while maprotiline was associated with side effects such as constipation and dry mouth.
  • Citalopram was compared to amitriptyline (a tricyclic antidepressant) for a group of patients over the age of 64 years. After 8 weeks of treatment, symptoms of major depression had improved for at least half of patients taking each drug. More than twice as many patients taking citalopram reported having nausea, but patients taking amitriptyline had many more side effects, including constipation and drowsiness.


  • A modified version of citalopram, escitalopram is the newest SSRI to be approved in the United States.
  • In a study that compared escitalopram with the miscellaneous antidepressant, extended-release venlafaxine, for nearly 200 patients with major depression, both drugs were about equally effective. Only 4 percent of the patients taking escitalopram stopped because of side effects, though, as compared to 16 percent of the patients taking extended-release venlafaxine. An analysis of 10 studies that compared either escitalopram or extended-release venlafaxine with placebo (inactive sugar pills) concluded that the effectiveness of the two drugs was about equal.
  • When compared with duloxetine?a serotonin norepinephrine reuptake inhibitor (SNRI), escitalopram showed approximately equal effectiveness but had less risk of side effects. The 8-week long study involved 278 patients with major depression. A much longer (8 month) study found that 75% of the patients taking escitalopram and 70% of those taking duloxetine experienced relief of major depression. Generally, side effects of citalopram (including diarrhea and weight loss) occurred after several weeks of treatment while side effects of duloxetine (such as dry mouth and nausea) tended to begin soon after treatment started.
  • In an 8-week study comparing escitalopram to sertraline, no substantial differences were found in effectiveness or side effects among 212 patients with major depression.


  • Fluoxetine was the first SSRI to be developed. In general, it may take longer to become effective than other SSRIs. Additionally, when analyzed together, the results from several studies seem to show that fluoxetine may cause more central nervous system (CNS) side effects (such as anxiety, insomnia, and restlessness) and more gastrointestinal (GI) side effects (such as nausea) than other SSRIs.
  • Several studies have compared fluoxetine with the miscellaneous antidepressant, mirtazapine. In 1998, the results of a 6-week long study of 133 patients with major depression were reported. In the study, both fluoxetine and mirtazapine appeared about equally effective until the fourth week, when mirtazapine took an advantage. At the end of another 6-week study of 36 patients with major depression, both antidepressants were approximately equal in effects and side effects. A larger (292 patient) study that lasted for 8 weeks confirmed that both fluoxetine and mirtazapine are about equally effective. In the larger study, however, more participants taking mirtazapine reported gaining small amounts of weight (about 4 pounds to 8 pounds). In another study, nearly 300 patients with severe depression were treated for 12 weeks with either fluoxetine or mirtazapine. Both drugs appeared comparable in effectiveness. Patients taking mirtazapine reported better sleep, however. In general, patients taking fluoxetine lost weight and those taking mirtazapine gained weight during the study.
  • A small (173-participant) short (8-week) study was conducted to compare fluoxetine with duloxetine (a selective norepinephrine and serotonin reuptake inhibitor or SNRI), and placebo (inactive sugar pills). Both antidepressants were more effective than placebo, but a slightly higher percentage of patients responded to duloxetine than fluoxetine (64% and 52%, respectively).


·      Twenty-four weeks of treatment for approximately 250 older patients (age 65 and over) found that paroxetine averaged 40 days to reach full effectiveness?about 2 weeks longer than the miscellaneous antidepressant, mirtazapine. Additionally, during the first 8 weeks, more individuals in the paroxetine group stopped taking the drug due to side effects.

·      When paroxetine was compared to another miscellaneous antidepressant, nefazodone, in a 6-month long study that included 108 depressed patients, both drugs produced similar results and side effects. At the end of a separate 6-week study comparing the effects of paroxetine and nefazodone, some patients continued taking the drug they had started. After another 12 weeks, both drugs showed comparable effects and side effects.

·      No substantial differences in effectiveness were discovered between paroxetine and nortriptyline (a tricyclic antidepressant or TCA) in a 6-week long comparison among 80 senior patients with major depression.


·      Sertraline was as effective as sustained-release bupropion (a miscellaneous antidepressant) and both drugs worked better than placebo (inactive sugar pills) for 360 patients with moderate or severe depression in one study. However, during treatment, which lasted 8 weeks or less, patients taking sustained-release bupropion reported fewer sexual problems than those taking sertraline.

·      Sertraline and the tricyclic antidepressant (TCA) nortriptyline were compared in a 12-week long study of individuals over 59 years of age. All the study participants had major depression. In this study, sertraline may have improved memory, thinking, and general well-being better than nortriptyline, but the antidepressant effects of the two drugs were about equal.


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.

·      All of the SSRIs come as tablets or capsules and most of them have liquid forms for individuals who have difficulty swallowing.

·      For treating depression, citalopram, escitalopram, fluoxetine, paroxetine, and sertraline usually are taken once daily. Typical daily dose ranges for adults are:

o     Citalopram tablets and oral solution?20 mg to 40 mg

o     Escitalopram tablets?10 mg to 20 mg

o     Fluoxetine capsules, tablets, and oral solution?20 mg to 80 mg

o     Paroxetine tablet and oral suspension?20 mg to 50 mg

o     Sertraline tablets and oral solution concentrate?50 mg to 200 mg

·      Paroxetine also has a once-daily, controlled-release form (Paxil CR) that releases paroxetine over 4 hours or longer, possibly resulting in steadier blood levels of the drug than regular paroxetine. The recommended starting dose of 25 mg per day may be increased to as much as 62.5 mg per day, if necessary. Paxil CR tablets should not be broken or crushed.

·      Prozac Weekly is a brand-only, 90-mg, delayed-release form of fluoxetine that is taken only once a week.


Generic Availability

·      Citalopram, fluoxetine, paroxetine, and sertraline are all available generically. Generic medications may be a less expensive but comparably effective treatment option.

·      Because Paxil CR and Prozac Weekly are available only as brands, they may be more expensive treatment options than the generic SSRIs.


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 ask your healthcare professional/doctor.

Side Effects

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.


In general, SSRIs are considered safer than tricyclic antidepressants because extremely high doses are needed before serious side effects begin to occur. Taking enough of an SSRI to cause death from toxicity is unlikely.

Results from a 5-year follow-up of 5,000 individuals over the age of 50 associated taking an SSRI on a daily basis with an increased risk of breaking a bone.


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. SSRIs in general and fluoxetine in particular may be associated with more treatment-related sexual dysfunction than other kinds of antidepressants.


Fluvoxamine is an SSRI that is not FDA-approved for the treatment of depression in the U.S. However, it is approved for treating obsessive-compulsive disorder (a type of anxiety that causes persistent worries and leads to repetitive behavior) and it has been used successfully as an antidepressant in Europe for many years. Available only in generic form, it may be associated more often with annoying side effects (mainly nausea and vomiting) than the other SSRIs are.




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