Drug Profile

The drugs in this profile are selective serotonin reuptake inhibitors (SSRIs). Except for fluvoxamine (LUVOX), they are all approved by the Food and Drug Administration (FDA) for major depressive disorder (MDD). Various SSRIs also are approved to treat other psychiatric disorders: obsessive-compulsive disorder, bulimia, panic disorder, social anxiety disorder and post-traumatic stress disorder. Although SSRIs may reduce the risk of suicide in depressed adult patients, particularly adults over age 65, there is evidence that fluoxetine (PROZAC, SARAFEM, SYMBYAX) and other antidepressants may actually increase suicide risk in children, teenagers and young adults aged 18 to 24.[2],[3] Only fluoxetine is approved for MDD in children. Fluoxetine, fluvoxamine and sertraline (ZOLOFT) are approved in children and adolescents for the treatment of obsessive-compulsive disorder.[4]

For patients who need an antidepressant drug, we recommend trying one of these SSRIs first, as these are the safest antidepressants. If symptoms do not improve sufficiently with use of an SSRI and remain severe, further treatment with other antidepressants is warranted.

Do not use paroxetine (BRISDELLE) for hot flashes

BRISDELLE contains a low dose (7.5 milligrams [mg]) of the SSRI paroxetine, the same active ingredient contained in PAXIL and PEXEVA. This low-dose version of paroxetine is FDA-approved for treatment of hot flashes associated with menopause.

In March 2013, Public Citizen's Health Research Group testified before an FDA advisory committee to warn about paroxetine's questionable benefits in women with hot flashes associated with menopause as well as the drug's previously well-established risks.[5] Also, some patients who took paroxetine to treat hot flashes in clinical trials and who had no history of prior mental illness developed suicidal thoughts and mood changes after starting the drug.[5] The advisory committee subsequently opposed approval of Brisdelle, but the FDA ultimately rejected this recommendation and, in June 2013, approved yet another drug with risks that clearly outweigh its benefits.

Other drugs containing paroxetine remain designated as Limited Use for treatment of depression and other psychiatric disorders.

Most depression can be treated without drugs

The time it takes an antidepressant to work can overlap with the time of spontaneous recovery — recovery that might occur without the use of medications — especially if the depression is situational (that is, if it is caused by a death or other external circumstances). Most people recover from depression with the help of friends, spiritual resources or activities such as exercise, work, reading, play, art interests and travel. If these measures do not work for you, try seeking help from mental health professionals, such as therapists or psychiatrists. Antidepressant drugs should be reserved for situations in which a patient suffering from major depression does not respond to psychotherapy alone.

Adverse effects

The most frequently reported adverse effects of SSRI antidepressants are nausea, anxiety, headache, sexual dysfunction and insomnia. These adverse effects, except for sexual dysfunction, tend to be worst at the start of treatment and improve over a few weeks. Akathisia — a condition characterized by symptoms of restlessness, constant pacing and purposeless movements of the feet and legs — also may occur. Dry mouth, sweating, diarrhea, tremor, loss of appetite and dizziness are also common adverse effects.

Serotonin syndrome

A potential danger when taking SSRIs or selective serotonin/norepinephrine reuptake inhibitors (SNRIs; for example, venlafaxine [EFFEXOR XR]) in combination with migraine headache drugs called triptans) is serotonin syndrome. Serotonin syndrome is a potentially life-threatening adverse drug reaction that happens when there is an excess of serotonin, a naturally occurring nerve transmitter in the brain. Excess serotonin is usually the result of taking two or more drugs that have an effect on serotonin — such as SSRIs. (Read more in the April 2008 Worst Pills, Best Pills News.)

The symptoms of serotonin syndrome include the following:

• Restlessness
• Hallucinations
• Loss of coordination
• Fast heartbeat
• Increased body temperature
• Rapid changes in blood pressure
• Overactive reflexes
• Diarrhea
• Coma
• Nausea
• Vomiting[6]

Neuroleptic malignant syndrome

In 2009, the FDA updated the product label of antidepressants to warn of the occurrence of neuroleptic malignant syndrome (NMS) resulting from the use of SSRIs and SNRIs alone or with subsequent use of serotonergic drugs (such as triptans), drugs that decrease the metabolism of serotonin, or antipsychotics or other dopamine antagonists.[7]

Symptoms and signs of NMS can include hyperthermia (extremely high body temperature); heavy sweating; fast heart rate; fast respiratory rate; rapidly fluctuating blood pressure; impaired consciousness; tremor; and rigid, stiff muscles. (Read more in the December 2010 Worst Pills, Best Pills News.)

Abnormal bleeding

The product labels for SSRIs and SNRIs include a precaution that these drugs may increase the risk of bleeding. Combined use of SSRIs or SNRIs and aspirin, nonsteroidal anti-inflammatory drugs, warfarin (COUMADIN, JANTOVEN) or other anticoagulants may increase this risk. (Read more in the March 2012 Worst Pills, Best Pills News.)

A study published in 2009 in the Clinical Gastroenterology and Hepatology journal found that current, recent (last used within 90 days) and past (last used more than 90 days ago) users of SSRIs were at an increased risk of serious gastrointestinal bleeding compared with those who did not use SSRIs.[8] (Read more in the April 2010 Worst Pills, Best Pills News.)

Further, research published in 2011 in the Canadian Medical Association Journal found that patients prescribed an SSRI antidepressant (such as fluoxetine or paroxetine) in addition to aspirin or with aspirin plus clopidogrel (PLAVIX) after a heart attack were at a significantly increased risk of bleeding compared with patients who were prescribed aspirin, clopidogrel or both.[9]

Low blood sodium

SSRIs and SNRIs also have been associated with cases of clinically significant hyponatremia (low blood sodium). Elderly patients may be at greatest risk of this condition.

Symptoms of hyponatremia include the following:

• Headache
• Difficulty concentrating
• Memory impairment
• Confusion
• Weakness
• Unsteadiness, which may lead to falls

Symptoms associated with more severe or acute cases of hyponatremia have included the following:

• Hallucination
• Syncope (fainting)
• Seizure
• Coma
• Respiratory arrest
• Death[10]

QT prolongation

In August 2011, the FDA issued an advisory that citalopram (CELEXA), when used at a dosage of 40 mg a day, could cause abnormal changes in the electrical activity of the heart. The agency advised against using citalopram at a dosage greater than 40 mg per day. Changes in the electrical activity of the heart (prolongation of the QT interval) can lead to an abnormal heart rhythm (including torsades de pointes), which can be fatal. The advisory also stated that studies did not show a benefit in the treatment of depression with dosages greater than 40 mg per day.[11]

In December 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom also issued a warning on QT prolongation associated with the dose of citalopram and escitalopram (LEXAPRO). The MHRA warning included the following recommendation:

For citalopram, new restrictions on the maximum daily doses now apply: 40 mg for adults, 20 mg for patients older than 65 years and 20 mg for those with hepatic impairment. For escitalopram, the maximum daily dose for patients older than 65 years is now reduced to 10 mg/day; other doses remain unchanged.[12]

In 2011 in Australia[13] and 2012 in Canada, similar regulatory advisories were issued on the dose-dependent QT prolongation associated with citalopram and on the recommended dosing changes.

In July 2013, the FDA issued an advisory that the agency received reports of QT interval prolongation and life-threatening abnormal heart rhythms, including torsades de pointes, in patients treated with fluoxetine.[14]

In 2016, Prescrire International published an article reporting that citalopram and escitalopram were associated with more cardiac adverse effects than other SSRI drugs.[15]

In September 2023, The Lancet published an article showing that escitalopram and citalopram may be associated with an increased risk of irregular heartbeat in older adults who are already taking the recommended dose of the drug.[16]

Sperm abnormalities

In 2015, Prescrire International published an article summarizing data from three studies showing that men taking SSRI drugs had decreased sperm counts and other changes in sperm that may affect fertility.[17]

Antidepressants and pregnancy

On Aug. 9, 2004, Health Canada, a regulatory body similar to the FDA, issued a public advisory warning to Canadians that newborns may be adversely affected when their mothers take SSRIs and other newer antidepressants during the third trimester of pregnancy. Health Canada reported that some newborns whose mothers took these drugs during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. The symptoms reported include feeding and breathing difficulties, seizures, muscle rigidity, jitteriness and constant crying. In most cases, the mothers took a newer antidepressant during the third trimester of pregnancy.[18]

The labeling for paroxetine includes findings from an epidemiological study suggesting that exposure to the drug in the first trimester of pregnancy may be associated with an increased risk of cardiac birth defects.[19]

An article published in Prescrire International in February 2011 presented information from the European Medicines Agency indicating that fluoxetine and other SSRIs may cause cardiac birth defects during pregnancy. The agency had reported in 2010 that there was an increase in the risk of cardiac malformations in newborns whose mothers used fluoxetine during the first trimester of pregnancy. The authors of the article stated:

In practice, all [SSRIs] should be considered to carry a potential risk of congenital cardiac malformations. This is yet another reason to carefully weigh the potential benefits and risks of prescribing SSRIs to pregnant women or to women who may become pregnant.

In July 2006, the FDA notified health care professionals and consumers that there may be additional, though rare, risks associated with taking SSRI medications during pregnancy. This FDA notification cited a study focused on newborn babies with persistent pulmonary hypertension of the newborn (PPHN), a serious and life-threatening lung condition that occurs soon after birth.[20] Babies with PPHN have high pressure in the blood vessels in their lungs and are not able to get enough oxygen into their bloodstream. However, the agency backtracked on this warning in another announcement issued in December 2011. In the new announcement, the FDA stated that since the 2006 study, additional studies have presented conflicting information, meaning a link between SSRI use and PPHN could not be confirmed.[13]

In 2015, the American Journal of Obstetrics and Gynecology published an article warning that infants born to mothers who used sertraline during the first trimester of pregnancy had an increased risk of cardiac birth defects and an increased risk of craniosynostosis (a skull birth defect that prevents the brain from growing normally). The study also showed that skull and muscle defects were associated with exposure to other drugs in the SSRI drug group.[21]

In 2016, the British Journal of Clinical Pharmacology published a meta-analysis of data from 23 studies showing that paroxetine use during the first trimester of pregnancy was associated with an increased risk of major birth defects of the heart.[22]

In 2020, JAMA Psychiatry published an article showing that SSRI drug use during early pregnancy may be associated with a small increased risk of birth defects.[23]

Comparing SSRIs with older tricyclic antidepressants

Multiple meta-analyses of available data on SSRIs have failed to show superior effectiveness compared with tricyclic antidepressants, an older class of drugs approved for the same purpose. In fact, when the results of 64 randomized, controlled trials were pooled, researchers found no clear benefit for the newer SSRI drugs over older antidepressants.

The adverse effects of new and old antidepressants are different, (except for withdrawal symptoms, which are common to both groups). SSRIs are less likely than tricyclic drugs to have anticholinergic effects (for example, double or blurry vision, constipation, urinary retention, decreased sweating and hyperthermia) or to cause sedation and heart rhythm disturbances. On the other hand, SSRIs commonly affect the gastrointestinal tract, especially causing nausea and diarrhea, and also may cause sexual dysfunction, insomnia, agitation, drug-induced Parkinsonism and withdrawal effects.

Patients are simply trading off one group of adverse effects for another when deciding between SSRIs and tricyclic antidepressants.[24] In terms of adverse effects, large-scale meta-analyses combining data from multiple clinical trials found that patients taking SSRIs were just as likely to discontinue the drugs as those taking tricyclic antidepressants.[25] (Drug discontinuation rates can be used to compare adverse reactions between drugs.)

Do not use antidepressants to treat dementia

In 2011, the medical journal Lancet published an article on the results of a study conducted to evaluate the effects of sertraline and mirtazapine (REMERON) on depression in patients with dementia. Randomized, multicenter, double-blind and placebo-controlled, the study demonstrated that in depressed patients with dementia, use of these antidepressant drugs did not show a benefit over the use of a placebo.[26] Based on the adverse effects of these medications and their lack of benefit for this use, antidepressants should not be used to treat dementia.

Do not use antidepressants to prevent depression following a stroke.

In 2021, Journal of the American Medical Association Neurology published a study showing that fluoxetine use after a stroke did not prevent the symptoms of depression. The study also showed that using fluoxetine after a stroke increases the risk of bone fractures.[27]

Other regulatory actions surrounding SSRIs

1991: Public Citizen's Health Research Group petitioned the FDA to require a warning in the product label for fluoxetine. The proposed warning would inform doctors that a small minority of persons taking the drug have experienced intense, violent or suicidal thoughts; agitation; and impulsivity after starting treatment with the drug.

2004: In October, the FDA required manufacturers to add a boxed warning to the product label of all antidepressants that contained information on adverse effects such as suicidal thoughts, agitation and impulsivity in children and adolescents.4 A black-box warning is the strongest type of warning that the FDA can require.

The FDA also required that a Medication Guide be given to patients receiving this drug. The FDA-approved guides advise patients of the risks of taking the drugs and of precautions that can be taken. The guides specifically tell patients not to take these drugs for mild depression or anxiety or as a sleeping pill. (Find FDA-approved Medication Guides for SSRIs here.)

2005: In March, the FDA amended the product label of fluvoxamine to include warnings about its use together with tizanidine (ZANAFLEX; a Limited Use drug used for spasticity) and alosetron (LOTRONEX, a Do Not Use drug used to treat irritable bowel syndrome). Fluvoxamine can increase the amounts of each of these drugs in the bloodstream to dangerous levels.[3]

2006: In July, the FDA notified health care professionals and consumers that there may be additional, though rare, risks associated with taking SSRI medications during pregnancy, noted above.

Also in July, the FDA issued a public health advisory warning consumers about the possibility of life-threatening reactions — such as changes in blood pressure or hallucinations — that may be caused by the interaction of triptans and certain antidepressants. As mentioned previously, taking SSRIs or SNRIs with triptans can cause serotonin syndrome.

2007: The FDA announced in May that it would require new boxed warnings concerning the increased risk of suicidal thoughts and behavior in young adults ages 18 to 24 years during the first one to two months of treatment with antidepressants. The agency required the new warnings to be printed on the product labels for all antidepressants sold in the United States. The warnings amended an existing boxed warning for children and adolescents.[28]

2009: The FDA approved changes to the product labels of SSRIs and SNRIs describing the risk of developing potentially life-threatening serotonin syndrome or NMS-like reactions. These reactions have been reported with SNRIs and SSRIs alone, but the risk is greatest when these drugs are combined with serotonergic drugs (including triptans), drugs that impair metabolism of serotonin (including MAO [monoamine oxidase] inhibitors), or antipsychotics or other dopamine antagonists.[7]

2017: The FDA updated the drug product label of sertraline (ZOLOFT) to state that the drug should be used with caution in patients with risk factors for QT prolongation.[29]

2020: The Medicines and Healthcare products Regulatory Agency (an agency in the United Kingdom similar to the FDA) issued an advisory that SSRI drugs may be associated with a small increased risk of bleeding in women following childbirth when the drugs are used during the month before delivery.[30]

2023: The FDA updated the drug product label of SSRIs to warn that when these drugs are used in the month before delivery there is an increased risk of bleeding after giving birth.[31]