By Paul W. Andrews, Lyndsey Gott & J. Anderson Thomson, Jr.

Antidepressant medication is the most commonly prescribed treatment for people with depression. They are also commonly prescribed for other conditions, including bipolar depression, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain syndromes, substance abuse and anxiety and eating disorders. According to a 2011 report released by the US Centers for Disease Control and Prevention, about one out of every ten people (11%) over the age of 12 in the US is on antidepressant medications. Between 2005 and 2008, antidepressants were the third most common type of prescription drug taken by people of all ages, and they were the most frequently used medication by people between the ages of 18 and 44. In other words, millions of people are prescribed antidepressants and are affected by them each year.

The conventional wisdom is that antidepressant medications are effective and safe. However, the scientific literature shows that the conventional wisdom is flawed. While all prescription medications have side effects, antidepressant medications appear to do more harm than good as treatments for depression. We reviewed this evidence in a recent article published in the journal Frontiers in Psychology (freely available here).

The widespread use of antidepressants is a serious public health problem, and it raises a number of ethical and legal issues for prescribers (physicians, nurse practitioners). Here, we summarize some of the most important points that prescribers should ethically tell their patients before they prescribe antidepressant medications. We also discuss the ways that prescribers could be held legally liable for prescribing antidepressants. Finally, we implore practitioners to update the informed consent procedure for antidepressant medication to reflect current research and exercise greater caution in the prescription of antidepressants.

1. How antidepressant medication works

Most antidepressants are designed to alter mechanisms regulating serotonin, an evolutionarily ancient biochemical found throughout the brain and the rest of the body. In the brain, serotonin acts as a neurotransmitter—a chemical that controls the firing of neurons (brain cells that regulate how we think, feel, and behave). However, serotonin evolved to regulate many other important processes, including neuronal growth and death, digestion, muscle movement, development, blood clotting, and reproductive function.

Antidepressants are most commonly taken orally in pill form. After they enter the bloodstream, they travel throughout the body. Most antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), are intended to bind to a molecule in the brain called the serotonin transporter that regulates levels of serotonin. When they bind to the transporter, they prevent neurons from reabsorbing serotonin, which causes a buildup of serotonin outside of neurons. In other words, antidepressants alter the balance of serotonin in the brain, increasing the concentration outside of neurons. With long-term antidepressant use, the brain pushes back against these drugs and eventually restores the balance of serotonin outside of the neuron with a number of compensatory changes.

It is important to realize that the serotonin transporter is not only found in the brain—it is also found at all the major sites in the body where serotonin is produced and transported, including the gut and blood cells called platelets. Since antidepressants travel throughout the body and bind to the serotonin transporter wherever it is found, they can interfere with the important, diverse processes regulated by serotonin throughout the body. While physicians and their patients are typically only interested in the effects of antidepressants on mood, the harmful effects on other processes in the body (digestion, sexual function, abnormal bleeding, etc.) are perfectly expectable when you consider how these drugs work.

2. Antidepressants are only moderately effective during treatment and relapse is common

Since the brain pushes back against the effects of antidepressants, the ability of these drugs to reduce depressive symptoms is limited (see our article for a review). While there is some debate over precisely how much antidepressants reduce depressive symptoms in the first six to eight weeks of treatment, the consistent finding is that the effect is quite modest.

Many people who have suffered from depression report a substantial symptom-reducing benefit while taking antidepressants. The problem is that symptoms are also substantially reduced when people are given a placebo—a sugar pill that lacks the chemical properties of antidepressant medications. In fact, most of the improvement that takes place during antidepressant treatment (approximately 80%) also takes place with a placebo. Of course, antidepressants are slightly more effective than placebo in reducing symptoms, but this difference is relatively small, which is what we mean when we say that antidepressants have a “modest” ability to reduce depressive symptoms. The pushback of the brain increases over months of antidepressant treatment, and depressive symptoms commonly return (frequently resulting in full blown relapse). Often this compels practitioners to increase the dose or switch the patient to a more powerful drug. Prescribers fail to appreciate that the return of symptoms often occurs because the brain is pushing back against the effect of antidepressants.

3. The risk of relapse is increased after antidepressant medication has been discontinued

Another effect of the brain pushing back against antidepressants is that the pushback can cause a relapse when you stop taking the drug. This pushback effect is analogous to the action of a spring. Imagine a spring with one end attached to a wall. An antidepressant suppresses the symptoms of depression in a way that is similar to compressing the spring with your hand. When you stop taking the drug (like taking your hand off the spring from its compressed position), there is a surge in the symptoms of depression (like the overshoot of the spring before it returns to its resting position). The three month risk of relapse for people who took a placebo is about 21%. But the three month risk of relapse after you stop taking an SSRI is 43%—twice the risk. For stronger antidepressants, the three month risk is even higher.

4. Antidepressants have been found to cause neuronal damage and death in rodents, and they can cause involuntary, repetitive movements in humans

Antidepressants can kill neurons (see our article for a review). Many medical practitioners will be surprised by this fact because it is widely believed in the medical community that antidepressants promote the growth of new neurons. However, this belief is based on flawed evidence—a point that we address in detail in our article. One way antidepressants could kill neurons is by causing structural damage of the sort often found in Parkinson’s disease. This neurological damage might explain why some people taking antidepressant medication can develop Parkinsonian symptoms and tardive dyskinesia, which is characterized by involuntary and repetitive body movements. Many prescribers mistakenly think these syndromes only occur in patients taking antipsychotic medications.

5. Antidepressants may increase the risks of breast cancer, but may protect against brain cancers

Recent research indicates that antidepressants may increase the risk of cancer outside of the brain, such as breast cancer. However, the neuron-killing properties of antidepressants may make them potentially useful as treatments for brain cancers, and current research is testing this possibility.

6. Antidepressants may cause cognitive decline

Since neurons are required for proper brain functioning, the neuron-killing effects of antidepressants can be expected to have negative effects on cognition. In rodents, experiments have found that prolonged antidepressant use impairs the ability to learn a variety of tasks. Similar problems may exist in humans. Numerous studies have found that antidepressants impair driving performance, and they may increase the risk of car accidents. Recent research on older women also indicates that prolonged antidepressant use is associated with a 70% increase in the risk of mild cognitive impairment and an increase in the risk of probable dementia.

7. Antidepressants are associated with impaired gastrointestinal functioning

The action of antidepressants results in elevated levels of serotonin in the intestinal lining, which is associated with irritable bowel syndrome. Indeed, antidepressants have been found to cause the same symptoms as irritable bowel syndrome—pain, diarrhea, constipation, indigestion, bloating and headache. In a recent study, 14-23% of people taking antidepressants suffered these side effects.

8. Antidepressants cause sexual dysfunction and have adverse effects on sperm quality

Depression commonly causes problems in sexual functioning. However, many antidepressants make the problem worse, impairing sexual desire, arousal, and orgasm. The most widely studied and commonly prescribed antidepressants—Celexa, Effexor, Paxil, Prozac, and Zoloft—have been found to increase the risk of sexual dysfunction by six times or more. Evidence from case studies suggests that antidepressants may also interfere with attachment and romantic love. Some antidepressants have been found to negatively impact sperm structure, volume, and mobility.

9. Antidepressant use is associated with developmental problems

Antidepressant medication is frequently prescribed to pregnant and lactating mothers. Since SSRIs can pass through the placental barrier and maternal milk, they can affect fetal and neonatal development. Generally, if SSRIs are taken during pregnancy, there is an increased risk of preterm delivery and low birth weight. Exposure during the first trimester can increase the risk of congenital defects and developing an autism spectrum disorder, such as Asperger’s Syndrome. Third trimester SSRI exposure is associated with an increased risk of persistent pulmonary hypertension in the newborn (10% mortality rate) and medication withdrawal symptoms such as crying, irritability, and convulsions. Prenatal exposure to SSRIs is also associated with an increased risk of respiratory distress, which is the leading cause of death of premature infants.

10. Antidepressant use is associated with an increased risk of abnormal bleeding and stroke

Serotonin is crucial to platelet function and promotes blood clotting, which is important when one has a bleeding injury. Patients taking SSRIs and other antidepressants are more likely to have abnormal bleeding problems (for a review see our article). They are more likely to have a hemorrhagic stroke (caused by a ruptured blood vessel in the brain) and be hospitalized for an upper gastrointestinal bleed. The bleeding risks are likely to increase when SSRIs are taken with other medications that reduce clotting, such as aspirin, ibuprofen, or Coumadin

11. Antidepressants are associated with an increased risk of death in older people

Depression itself is associated with an increased risk of death in older people—primarily due to cardiovascular problems. However, antidepressants make the problem worse. Five recent studies have shown that antidepressant use is associated with an increased risk of death in older people (50 years and older), over and above the risk associated with depression. Four of the studies were published in reputable medical journals—The British Journal of Psychiatry, Archives of Internal Medicine, Plos One, and the British Medical Journal—by different research groups. The fifth study was presented this year at the American Thoracic Society conference in San Francisco.

In these studies, the estimated risk of death was substantial. For instance, in the Women’s Health Initiative study, antidepressant drugs were estimated to cause about five deaths out of a 1000 people over a year’s time. This is the same study that previously identified the dangers of hormonal replacement therapy for postmenopausal women. In the study published in the British Medical Journal, antidepressants were estimated to cause 10 to 44 deaths out of a 1000 people over a year, depending on the type of antidepressant. In comparison, the painkiller Vioxx was taken off the market in the face of evidence that it caused 7 cardiac events out of 1000 people over a year. Since cardiac events are not necessarily fatal, the number of deaths estimated to be caused by antidepressants is arguably of much greater concern.

An important caveat is that these studies were not placebo-controlled experiments in which depressed participants were randomly assigned to placebo or antidepressant treatment. For this reason, one potential problem is that perhaps the people who were taking antidepressants were more likely to die because they had more severe depression. However, the paper published in the British Medical Journal was able to rule out that possibility because they controlled for the pre-medication level of depressive symptoms. In other words, even among people who had similar levels of depression without medication, the subsequent use of antidepressant medications was associated with a higher risk of death.

These studies were limited to older men and women. But many people start taking antidepressants in adolescence or young adulthood. Moreover, since the risk of a relapse is often increased when one attempts to go off an antidepressant (see point 3 above), people may remain on medication for years or decades. Unfortunately, we have no idea how the cumulative impact of taking antidepressants for such a long time affects the expected lifespan. In principle, long-term antidepressant use could shave off years of life.

It is commonly argued that antidepressants are needed to prevent depressed patients from committing suicide. Yet there is a well-known controversy over whether antidepressants promote suicidal behavior. Consequently, it is not possible to reach any firm conclusions about how antidepressants affect the risk of suicidal behavior. However, most deaths attributed to antidepressants are not suicides. In other words, antidepressants appear to increase the risk of death regardless of their effects on suicidal behavior. We suggest that antidepressants increase the risk of death by degrading the overall functioning of the body. This is suggested by the fact that antidepressants have adverse effects on every major process in the body regulated by serotonin.

12. Antidepressants have many negative effects on older people

Most of the research on the adverse health effects of antidepressants has been conducted on older patients. Consequently, our conclusions are strongest for this age group. In addition to cognitive decline, stroke and death, antidepressant use in older people is associated with an increased risk of falling and bone fracture. Older people taking SSRIs are also at an increased risk of developing hyponatremia (low sodium in the blood plasma). This condition is characterized by nausea, headache, lethargy, muscle cramps and disorientation. In severe cases, hyponatremia can cause seizures, coma, respiratory arrest and death.

The fact that most research has been conducted on older people does not mean that antidepressants do not have harmful effects on the young. As previously discussed, antidepressants can have harmful effects on development. Moreover, many people start taking these drugs when they are young and remain on them for years or decades. In principle, the negative effects of these drugs could be substantial over such long periods of time.

Altogether, the evidence leads us to conclude that antidepressants generally do more harm than good as treatments for depression. On the benefit side, the drugs have a limited ability to reduce symptoms. On the cost side, there is a significant and unappreciated list of negative health effects because these drugs affect all the processes regulated by serotonin throughout the body. While the negative effects are unintended by the physician and the patient, they are perfectly expectable once you understand how these drugs work. Taken together, the evidence suggests that these drugs degrade the overall functioning of the body. It is difficult to argue that a drug that increases the risk of death is generally helping people.

There may be conditions other than depression where antidepressants are generally beneficial (e.g., as treatments for brain tumors and facilitating recovery after a stroke), but further research in these areas is needed (see our article).

Ethical and Legal Issues

Physicians and other medical practitioners have an ethical obligation to avoid causing greater harm to their patients. The Latin phrase primum non nocere (“first, do no harm”) that all medical students are taught means that it may be better to do nothing than to risk causing a greater harm to a patient. Although all prescription medications have adverse side effects that can cause harm, practitioners have an ethical obligation to not prescribe medications that do more harm than good. The evidence we have reviewed suggests practitioners should exercise much greater caution in the prescription of antidepressants and to reconsider their use as a first line of treatment for depression. Additionally, we suggest that physicians and other medical practitioners should consider their potential legal liability.

Legal liability for prescribing antidepressants

Medical practitioners can be sued for prescribing antidepressant medications if doing so violates their state’s standard of care laws. In most states, the standard of care is what a “reasonably prudent” practitioner in the same or similar field would do. The standard of practice is not defined by what the majority of physicians do because it is possible for an entire field to be negligent. Since studies on the health risks associated with antidepressant use (e.g., stroke, death) have been published in well-respected medical journals, medical practitioners could possibly be vulnerable to malpractice lawsuits. For instance, it seems likely that a reasonably prudent physician should be aware of the medical literature and avoid prescribing medications that could increase the risk of stroke and death.

Prescribers can also be held liable for not discussing information about medical risks so that patients can give informed consent for medical treatments and procedures. Prescribers have a duty to discuss the benefits and risks of any recommended treatment. Consequently, medical practitioners should discuss with their patients that antidepressant medication is only modestly more effective than placebo and could increase the risk of neurological damage, attentional impairments, gastrointestinal problems, sexual difficulties, abnormal bleeding, cognitive impairment, dementia, stroke, death, and the risk of relapse after discontinuation.

Antidepressants must cause harm to create liability

A medical malpractice lawsuit can only succeed if the antidepressant caused harm to the patient. It is important to realize that the antidepressant does not need to be the only cause of the harm—it only needs to contribute to or exacerbate the harm.

As we have argued, antidepressants play a causal role in many adverse health outcomes because they disrupt serotonin, which regulates so many important processes throughout the body. This may make it particularly difficult for a medical practitioner to defend against a medical malpractice suit from a patient who experiences any of a number of adverse health effects while taking an antidepressant. For instance, if a patient has a stroke while taking an antidepressant, the evidence that antidepressants increase the risk of stroke suggests that the antidepressant may have contributed to the patient’s stroke, even if it was not the only cause.

Conclusion

The evidence now indicates that antidepressants are less effective and more toxic than commonly believed. From ethical, health, and legal perspectives, it seems prudent for individual practitioners and professional medical organizations to revise informed consent guidelines and reconsider the status of antidepressants in standards of care for many diagnoses and as the front line treatment for depression. With older people, for instance, the current data suggest informed consent must include a discussion of the increased risk of hemorrhagic stroke and even early death.

We suspect that if prescribers realized they were placing themselves at legal risk for failing to discuss the adverse health effects of antidepressants with their patients, not only would they be more likely to discuss such information, they would be less likely to recommend these drugs in the first place.

Paul W. Andrews is an assistant professor in the Department of Psychology, Neuroscience & Behaviour at McMaster University in Canada. He has a PhD in Biology from the University of New Mexico and a law degree from the University of Illinois at Urbana-Champaign. His work on the evolution of depression with J. Anderson Thomson, Jr. has been featured in the New York Times Sunday Magazine and Scientific American Mind.

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Lyndsey Gott is an undergraduate student in the Honours Psychology, Neuroscience & Behaviour program at McMaster University.

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J. Anderson Thomson, Jr. is associate faculty at the Institute of Law, Psychiatry & Public Policy at the University of Virginia. He is also a staff psychiatrist at the University of Virginia Student Health Services. He received his MD from the University of Virginia in 1974 and has been a full-time practicing outpatient psychiatrist for over 35 years.