Madeline Levin, MPH, Nicolas J. Jury, PhD, Kousha Mohseni, MS, Varuna Srinivasan, MBBS MPH, National Center for Health Research
Antidepressant medications are widely prescribed to try to decrease the symptoms of depression and to reduce the risk of suicide. However, the medications have risks that outweigh the benefits for more patients than you probably realize.
When a person’s depression starts to lift, he or she may feel less hopeless and helpless. That sounds like an improvement, but when people feel less helpless but still feel depressed, they may think about suicide as a way out, whereas before they were too immobilized to make a suicide plan. For that reason, a decrease in the symptoms of depression can increase the risk of suicidal thoughts or actions. That risk is well known by mental health specialists, and can occur regardless of the type of treatment that a patient is receiving, or even if the patient is feeling less depressed without any treatment.
However, reducing depression is not the only reason why antidepressants can increase the chances of a person committing suicide. As antidepressants became more commonly prescribed for anxiety and obsessive compulsive disorder, the reports of patients’ suicidal thoughts and actions became more worrisome to physicians and family members. If a depressed person on antidepressants is suicidal, that is not so surprising, but if someone who was not depressed and taking antidepressants for other reasons becomes suicidal, that raises questions about the safety of these medications. Researchers found evidence that individuals taking antidepressant medication may be at even higher risk of suicide than individuals whose depression is easing for other reasons. That controversy has not yet been completely resolved.
Antidepressants and Children
The additional risks of antidepressants first became clear in research on children, and in the fall of 2004, the FDA issued a warning that children and adolescents taking antidepressant medications might experience increased suicidal thoughts and behaviors. In June 2005, this warning was extended to include young adults up to age 25. That’s because studies showed that children and adolescents taking antidepressants were almost twice as likely to have suicidal thoughts or to attempt suicide, compared to patients taking a sugar pill. The FDA required antidepressant drug manufacturers to add a “black box” to the label warning about the increased risk for children. The warning also says that children and adolescents taking the types of antidepressant known as “serotonin reuptake inhibitors” (SSRIs) should be carefully watched for increased depression, suicidal thoughts or behaviors, or “unusual changes in behavior, such as sleeplessness, agitation, or withdrawal from normal social situations.” Placing a black box around a warning, similar to those for cigarettes, is the strongest type of warnings about risks that the FDA requires, and indicates FDA’s great concern.
Violent behavior is also a side effect of antidepressants. A 2015 Swedish study of their entire population ages 15 and older reported that 11,225 out of 856,493 (1.3%) teens and adults taking SSRIs were convicted of a violent crime compared to 40,384 out of 7.1 million individuals (0.6%) of the same age not taking SSRIs. The risk of being convicted of a violent crime was the highest among the youngest age group: 3.3% of SSRI patients between the ages of 15 and 24 years old were convicted of a violent crime. 77% of these convictions (2,169) were in males in that age group who were taking an SSRI. However, when comparing five of the most prescribed SSRIs (fluoxetine, citalopram, paroxetine, sertraline, and escitalopram), only sertraline (Zoloft) increased the risk of a violent crime conviction.
Since there is no evidence that some antidepressants are more dangerous than others for children, the FDA includes the same black box warning on all antidepressants given to children and adolescents. (See the list here)
Antidepressants and Adults
In 2010, researchers brought together data from several studies to see if antidepressants increased suicide risk in adults over 25 as well. They found no significant increase in risk of suicide for adults taking antidepressants. A 2011 study in the United Kingdom (UK), which included over 60,000 patients between the ages of 65 and 100, did not find a significant increase in suicide risk for adults over 65 who take antidepressants. However, the study also reported that mirtazapine and venlafaxine were the antidepressants that were much more likely to be taken by adults who attempted suicide or harmed themselves, or that died from other causes.
A different UK study published in 2015 that included more than 238,000 adults ages 20 to 64 years of age reported that patients reported that patients taking mirtazapine, venlafaxine, or trazodone were much more likely to commit suicide or attempt suicide/self-harm compared to patients taking a SSRI. In contrast, a study of almost 300,000 adults ages 18 and older who started taking antidepressants between 1997 and 2005 found no meaningful difference in risk for suicide when comparing the different types of antidepressants.
It is hard to make sense of these contradictory different findings for adults. However, since antidepressants like venlafaxine and mirtazapine are usually tried only when SSRIs are not effective, the people who take them may have depression that is more difficult to treat with medication. Therefore, the lack of success in treating depression with different medications may be the reason why those patients are more likely to try to kill themselves.
There is growing evidence that many antidepressants and anti-psychotics can cause ‘akathisia’. Akathisia is a type of body restlessness and an urgent need to keep moving. Sometimes misdiagnosed as restless leg syndrome, akathisia has in some cases caused suicide, perhaps because the person feels out of control. Forms of akathisia include pacing back and forth, rocking uncontrollably while sitting in a chair, shuffling the feet while walking, crossing and uncrossing legs, general irritability and agitation. More information about akathisia can be found here.
In summary, whether an antidepressant increases or lowers the risk of suicide seems to be somewhat unpredictable but may be influenced by the type of antidepressant being taken, the individual’s response to treatment, and the age of the person taking them. The different results for children and adults of different ages suggest that differences in metabolism may affect the safety of these medications. Studies have shown that genetic differences affect how well antidepressants work for different people and how well people are able to tolerate them.[7,8] Unfortunately, studies comparing the effectiveness of different antidepressants do not have enough participants from racial and ethnic minorities to draw conclusions about which drugs work best for which groups of people.
Antidepressants and Blood Clots
In addition to possibly increasing the risk of suicide, antidepressants can cause other serious problems. Research shows that antidepressants and depression can be a cause of venous thromboembolism (VTE), which is a blood clot that forms in a vein, typically when a person has been sitting or lying down for extended periods of time. There are two types of VTE: 1) deep vein thrombosis (DVT), a blood clot that is usually in the leg, and 2) pulmonary embolism (PE), a clot in the lungs that can instantly cause death. While the most common causes of VTE are hospitalization, surgery, and prolonged bed rest, researchers have found a link between antidepressants and VTE. A study published in 2018 that reviewed eight research articles found an association between depression, antidepressants, and VTE. They reported an increased risk of VTE for those who took tricyclic antidepressants (such as Norpramin, Tofranil, Pamelor, etc.), SSRIs (such as Lexapro, Prozac, Zoloft, etc.), and others.
The research hasn’t determined whether depression or antidepressants are the true cause of VTE. Researchers are studying the relation between depression and VTE as well as antidepressants and the risk of VTE but since so many people who are depressed take antidepressants, it is difficult to determine whether it is the depression or the drugs that are causing VTE.
A 2015 study of more than 2.2 million infants born in Denmark, Finland, Iceland, Norway and Sweden, 36,000 of which were exposed to an SSRI during pregnancy, reported that SSRIs decreased the risk of heart defects and did not affect neurological defects. In contrast, a previous study conducted by the U.S. Centers for Disease Control and Prevention (CDC) reported that Paxil (paroxetine) and Prozac (fluoxetine) taken by pregnant women increase the risks for heart and neurological defects in newborn babies. That study included more than 27,000 mothers of infants who had taken an SSRI starting one month prior to pregnancy, and through the third month of pregnancy. Women who took Paxil were 2.5 to 3.5 times more likely to have a newborn with a heart or neurological defect. Those women taking Prozac were 1.9 to 2.0 times more likely to have a newborn with a heart or neurological defect.
Risks vs. Benefits
Antidepressants have been widely prescribed for anxiety and other psychological problems in addition to depression, and it is important to weigh the likely benefits against the known risks. Whether for children or adults, antidepressants have other risks in addition to the possible risk of suicide. Common side effects include nausea, anxiety, restlessness, decreased sex drive, dizziness, weight gain or loss, tremors, sweating, sleepiness, fatigue, dry mouth, diarrhea, constipation, and headaches. More worrisome effects include increased hostility, anger and aggression, insomnia, and feeling of panic. All individuals taking antidepressants should be carefully watched for changes in behavior or suicidal thoughts, especially if it is the person’s first time taking antidepressants. If you notice these behaviors in yourself, a friend, or a family member, it is important to contact a doctor immediately.
It is also important to be aware of the side effects of other drugs that are sometimes used for depression. For example, Seroquel (quetiapine) and Abilify (aripiprazole) are widely prescribed medications that were approved by FDA for schizophrenia and for psychosis from the manic stage of bipolar disorder (also called manic depression). In a controversial decision, the FDA then approved them for use in depression–-but only for patients who are taking other antidepressants at the same time and for whom antidepressant medication alone was ineffective. These antipsychotic drugs sometimes help with anxiety and sleeping problems because they can have a sedative effect, but that also makes them dangerous for patients to drive or use machinery. Since insomnia and anxiety are symptoms of depression, these drugs may be beneficial for those symptoms, but not necessarily for improving patients’ depressed mood. In addition to the questionable benefits, these drugs have serious side effects, such as dramatic weight gain (and potentially diabetes) and “sudden cardiac death.”
Other popular antidepressants have other risks. Cymbalta (duloxetine) is a serotonin norepinephrine re-uptake inhibitor (SNRI) that has been linked to liver failure. Zoloft (sertraline, an SSRI) is associated with higher rates of diarrhea than other antidepressants, and Effexor (venlafaxine), another SNRI, in addition to the above mentioned increase in suicide, is more likely to increase blood pressure, heart rate, and cause nausea, and in one study was linked to gastrointestinal bleeding.[11,12]
A study that included over 370,000 women reported that non-depressed women taking SSRIs are more than 50% more likely to have a bone fracture than non-depressed women who are not taking them. Another study published in 2012 that included results from thirteen other studies, reported that men and women who take SSRIs are 1.7 times more likely to develop a bone fracture.
In addition, it is not safe to combine most antidepressants with certain drugs or alcohol. One study found that healthy, depressed women using SSRI’s and tricyclic antidepressants are three times more likely to suffer from sudden cardiac death (SCD) than healthy, depressed women not taking antidepressants. It is not clear, though, from the study whether these women suffered from more severe depression (which is a risk for heart disease) and therefore were more likely to take antidepressants or whether they died because the antidepressants caused changes in their heart rhythms.
Antidepressants can negatively interact with many other drugs, including over-the-counter drugs such as cold medicines and pain killers.
So, although antidepressants may improve your mood, do not forget that taking them means subjecting yourself to many potential side effects, including some serious risks.
Are there effective treatments for depression that are not so risky? A type of therapy called cognitive behavioral therapy has been found to be very effective. It trains the patient to think about their shortcomings or problems in a different way, helping them to focus less on the helpless and hopeless feelings of depression and more on what they are doing well.
All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.
- National Institute of Mental Health (2010). Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers. Retrieved from http://www.nimh.nih.gov/health/topics/child-and-adolescent-mental-health/antidepressant-medications-for-children-and-adolescents-information-for-parents-and-caregivers.shtml.
- UNITED STATES ex rel. GREG THORPE, ET AL. (Consolidated) Plaintiffs, v. GLAXOSMITHKLINE PLC, and GLAXOSMITHKLINE LLC, Defendants.
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- Binder, EB; Owens, MJ; Liu, W; Deveau, TC; Rush, AJ; Trivedi, MH; Fava, M; et. al.; Association of polymorphisms in genes regulating the corticotrophin-releasing factor system with antidepressant treatment response; Archives of General Psychiatry, 2010, 67 (4) pp. 369-79.
- Tsai, MH; Lin, KM; Hsiao, MC; Shen, WW; Lu, ML; Tang, HS; Fang, CK; et.al(2010). Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response; Pharmacogenomics, 11(4) pp. 537-46.
- Furu K, Kieler H, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ. 2015 Apr 17;350:h1798. doi: 10.1136/bmj.h1798.
- Reefhuis Jennita, Devine Owen, Friedman Jan M, Louik Carol, Honein Margaret A. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports (2015) British Medical Journal. 351:h3190.
- Abajo FJ & Garcia-Rodrigues LA (2008). Risk of Upper Gastrointestinal Tract Bleeding Associated with Selection Serotonin Reuptake Inhibitors and Venlafaxine Therapy. Archives of General Psychiatry, 65(7): 795-803.
- Agency for Healthcare Research and Quality; Comparitive Effectiveness of Second-Generation Antidepressants in the Pharmacologid Treatment of Adult Depression: Executive Summary; 2007 Retrieved from www.ahrq.orgon August 25, 2010.
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- American Heart Association. What is Venous Thromboembolism (VTE)? Heart.org. Reviewed March 1, 2017. Accessed October 11, 2018.
- Kunutsor, S.K., Seidu, S., Khunti, K. (2018): Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence, Annals of Medicine: 1-9. DOI: 10.1080/07853890.2018.1500703
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