June 25, 2020

Medications May Contribute to Suicide Risk

by Meghan Bellamy 

“The good physician treats the disease; the great physician treats the patient who has the disease.”  – Sir William Osler

It’s already the final week of June! Summer crept up on us due to safer-at-home orders across the globe, and your body might be feeling it. From fresh-cut grass to blooming trees and gardens, the summer season can aggravate physical sensitivities and allergies. This year, just as summer surprised us when it showed up, it also brought a change in available medicines for those sensitivities: a popular allergy medication, montelukast (Singulair®), has now been black boxed by the FDA for suicide risk.

On March 4, 2020 the FDA announced a black box warning for the allergy and asthma medication montelukast, originally known as Singulair®. After reviewing reports regarding mood, mental health changes, and completed suicides correlated to the prescription, the FDA strengthened their previous warnings with a black box label. Their recommendations to physicians were to use montelukast only after other safer alternatives had proven ineffective, in light of the potential risks of the drug. The FDA highlighted that the black box decision was made because safer medications are available, and, despite earlier warnings, both doctors and patients seemed ill informed of the risks.  Many patients reported changes in mood and/or thoughts when the medication was started, and, while some experienced resolution when the medication was stopped, others reported continuing mental health distress.  

The FDA’s Black Box Label and other Common Medications

It’s important to understand that a “black box” warning, according to the FDA, “appears on a prescription drug’s label and is designed to call attention to serious or life threatening risks.” A black box warning is not intended to scare patients away from certain drugs, but to spark a conversation between the provider and patient regarding risk/benefit, features of concern (e.g. rash or fever), and when and how to ask questions, seek guidance, or alter or stop treatment. Medications can be black boxed for suicide risk, but are more commonly singled out for effects such as liver damage, birth defects, and respiratory or cardiovascular events.

The primary class of medications with a black box warning for suicide risk is anti-depressants, primarily SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), used to treat depression, anxiety and pain. These are familiar names such as Prozac®, Zoloft®, and Lexapro®. The FDA issued a black box warning in 2004 for antidepressants, specifically for adolescents and children, as studies showed increasing suicidal thoughts and behaviors in youth. Risk is elevated when starting the medication and increasing dosage. Additional findings led to the extension of the warning to young adults in 2006.

This black box has been controversial in the years since it was issued because it is difficult to interpret whether patients are experiencing suicidal thought patterns due to their medication or the depression itself. Clinicians voiced frustration that an important tool for treating depression (and perhaps thereby reducing suicide) had been taken from them as the black box typically reduces prescriptions, but a review paper earlier this year concluded that the duty to warn was warranted and should continue. Given the challenges with depression medications and youth, some experts counsel expert guidance from a psychiatrist who understands these unique risks, rather than a primary doctor. 

Antidepressants can be challenging to administer, since their effects are slow and the body needs time to adjust–which means stopping them abruptly, missing several doses, or using them inconsistently could result in withdrawal-like physical symptoms such as diarrhea, vomiting, headache, and insomnia. A notable change since the FDA issued this warning is that providers are starting at lower doses and moving more slowly with dose increases in order to better assess how the patient tolerates the medication.

While the black box warning is directed to those under the age of 25, challenges in adjustment to these widely-used medications are not isolated to children and young adults. It may be that certain individuals, regardless of age, may be particularly vulnerable for as yet unknown reasons. In 2010, a 57-year old attorney died by suicide five days after starting the medication paroxetine (Paxil®), an SSRI. His wife believes the restlessness, agitation, and anxiety brought on by his new SSRI was responsible.

Another common medication that carries a black box warning is isotretinoin, more commonly known as Accutane® or Roaccutane®. Accutane® is used to treat severe acne, and its black box pertains to observable, physical birth defects, with additional warnings for depression, suicidal thoughts and behavior, psychosis, and violent behavior. Those undergoing treatment with Accutane® are counseled and monitored very closely with the iPledge program, and women are regularly pregnancy tested. While safety during treatment is carefully considered when it comes to reproductive health, this approach is not applied in the same intensity to the user’s mental health and there is controversy surrounding the necessity of these warnings. Although many have voiced concerns about the dangers of this medication, a common rationale from the drug’s supporters is that the nature of the condition (severe acne) drove the patient to depression or suicide, rather than the drug. Unlike the observable physical birth defects, determining the medication’s contribution to suicide is more challenging in these circumstances.

This paper reviews studies of psychiatric data associated with both acne and isotretinoin, concluding there is no distinct evidence of cause, but also enough evidence for the provider to monitor and address mental health concerns. Recent unpublished data claims that Accutane® shows a decreased risk of depression on a population basis–but does that absolve it of a role in suicidal thoughts and behaviors? Depression is not essential to suicide, and in fact, other mechanisms may be more related to the risks of this drug. News reports from the BBC indicate that this question might not yet be answered in the minds of patients who have had challenging experiences, and the controversy appears to be ongoing.

What happens, however, when a risky medication isn’t black boxed for suicide?

As it turns out, there are numerous common medications that list suicidal thoughts or behaviors as a possible side effect, but most are not black boxed. Why is that? Well, for a medication to be black boxed there have to be enough reported events with evident correlation to a drug for the FDA to even consider reviewing it for a boxed warning. Since a black box is the last step before removal from the market, evidence is gathered, reviewed, and considered over time-often years.

It is a common misconception that adverse mental health reactions are correlated only to drugs intended to treat a neurological or psychological condition. According to a JAMA study published in 2018, more than one third of adults in the US are using at least one of the 100 medications that list depression as an adverse effect, with almost a quarter on one of the 103 medicines listing a risk of suicidal symptoms. These numbers are nothing short of astounding, and the 203 drugs identified aren’t obscure. They include antibiotics, pain killers, hormonal birth control, respiratory agents, beta blockers for blood pressure management, anticonvulsants, and GI medications, in addition to therapeutics for a variety of neurological and psychiatric conditions. To see the list of medications, follow this link and scroll to eBox1.

With possible side effect warnings of mood changes, suicidal symptoms, and depression, the researchers found those who were taking these medications had higher rates of depression. The more medications patients were taking, the higher their rates of depression, with some taking as many as three medications on these lists. Put simply, at a bare minimum, 25% of the American population has an increased risk of depression and suicidality due to the medications they are taking.

When considering and treating mental health and/or suicidal thoughts or actions, these numbers and the individual patients they represent, should be given a second look. Improving clinical and consumer awareness of how medication affects mental wellbeing could do more than just improve the lives of patients-it could potentially save them.

There is much that we do not know about the mechanisms of disease states, medications, or biological contributors to suicidal behavior, but research is unfolding and it is important to follow the clues and the data even as the field continues to make discoveries. As mentioned earlier, it isn’t only psychiatric medications that can cause mental health issues. Following a growing interest in the bidirectional association between depression and cardiovascular disease, a study of blood pressure medications and suicide looked at those who had died within 100 days of being prescribed either an ARB or an ACE inhibitor, with notable differences in suicide risk between these two medications. While further research is needed, the lead investigator noted that even with insufficient proof, preference should be given to choosing a less-risky ACE inhibitor, particularly in those with a history of sleep disorders and mental health concerns.

As the JAMA Study mentioned earlier highlights, more than one-third of Americans are taking “at least” one medication that lists depression as an adverse effect. What happens when they are using more than one? Polypharmacy, or the use of multiple medications, raises the risk for pharmaceutically-related adverse events, including suicidality. For example, patients over the age of 65 are at high-risk of polypharmacy, simply due to more physical ailments as the body ages. That same population, despite representing just 12% of the population, also makes up 18% of all suicide deaths. According to the CDC, the rate of suicide in men is highest in those over the age of 75. 

Although the elderly represents a high-risk population, adverse events caused by polypharmacy are a risk for any patient taking three or more medications—not all of which need to be prescription. Suicide rates are higher in many chronic diseases, many of which are complex and require multiple interventions. In those with diabetes or renal disease, clearance issues can allow toxic blood levels to build.

Biological Mechanisms and Features

While we tend to think of suicide as associated with depression, hopelessness, and burdensomeness, the features of anxiety, agitation, and impulsivity are gaining increasing attention as greater risks of suicide attempts and deaths. Surprisingly, for some it may be biological side effects of medications, and how the brain and emotions respond, that can make a patient vulnerable to mental health changes and suicidality.

Where there is still much that we need to learn, there are biological conditions and side effects that can be correlated with adverse psychological effects of medications. For some drugs, patients are known to be at highest risk for both physical and psychological adverse reactions in the early days of treatment or when changing dosage. For other drugs, risk of harm is related to dose, duration, or combination with other medications, drugs, or alcohol.

Some commonly listed side effects of medications that may, in turn, influence mental health and suicidal behaviors:

  • Hyperarousal: Agitation, Restlessness, Mania: In this article on sunshine and suicide, Dr. Emily Deans, an Evolutionary Psychiatrist, cites mania as an unusual and dramatic effect of antidepressants–whether they be medications or natural, like sunshine.  She describes mania in bipolar disorder as feeling “extremely euphoric or agitated, impulsive, often reckless, and doesn’t need sleep” and notes that those without bipolar disorder can also become “acutely agitated, irritable and anxious.” Anxiety, agitation, and impulsivity are factors associated with suicidal actions.
  • Gut Function and Microbiome Changes: Fascinating and evolving research indicates an important bi-directional communication network between the gut and the brain, generally mediated by the vagus nerve that connects them. The vagus nerve also plays a role in immune function, as well as the autonomic nervous system that balances our fight or flight (stress!) and rest and digest responses. While antibiotic effects on the gut are well recognized, many other medications, including antidepressants, can have adverse effects on the microbiome and GI function, including symptoms that mimic IBS (Irritable Bowel Syndrome) and IBD (Irritable Bowel Disease). Increasingly, researchers are paying attention to the role of the gut in psychiatric function. Many of us are surprised to learn that the majority of serotonin production occurs in the gut, which is sometimes called the second brain.
  • Nutrient Status: Medications can alter metabolism, be metabolized differently due to genetics or kidney and liver issues that slow clearance, or change how the body processes nutrients, thereby leading to imbalances and deficiencies in mental health essentials such as B6, B12, folate and Vitamin D.
  • Serotonin Syndrome: Serotonin syndrome is a dangerous condition associated with SSRIs, benzodiazepines, and other drugs that alter the levels of serotonin in the brain–and the gut. It isdefined by the accumulation of too much serotonin in the nervous system and can occur with other prescription medications, some illegal drugs, and even dietary supplements, often occurring when multiple medications that raise serotonin levels are combined. Some of the symptoms include increased heart rate, restlessness, agitation, sweating, and confusion. With a rapid onset, it can be life threatening and require immediate hospitalization.

However, serotonin syndrome can also occur in milder forms that go undiagnosed or treated as anxiety–often, with additional antidepressants that might increase serotonin levels further. Depression and anxiety often co-occur, and a study in mice showed that serotonin can trigger a fear response and may point to the mechanism explaining extreme reactions of some patients to SSRIs.

  • Akathisia: We know that the first days of taking an SSRI is when a patient is most vulnerable to suicide, and akathisia may be one mechanism involved in that pattern.  A drug-induced restlessness, akathisia can manifest as an adverse reaction to a drug, as well as a withdrawal symptom. Akathisia comes from the Greek “not to sit” and is a torturous mental and physical condition related to mania and often misdiagnosed as anxiety or restless leg syndrome. Whereas mania is generally known as a mental restlessness, akathisia often manifests with both physical and psychological agitation.

A 1991 paper linked SSRIs to akathisia (and akathisia to suicide) when three patients who had survived violent suicide attempts within days of starting or increasing SSRI treatment were re-exposed to fluoxetine. After trying the drug again under close surveillance, all three reported feeling agitated and suicidal again. One reported, “This is exactly what happened the last time I was on fluoxetine, and I feel like jumping off a cliff again.” Another stated that she “had tried to kill herself because of these anxiety symptoms. It was not so much the depression.”

This intolerable sensation is an important and often-overlooked insight, and the opposite of what an observer might expect to see in a person whose ‘depression gets worse’ as a side effect. Akathisia provides a very different framework from the viewpoint that rationalizes suicide after antidepressant initiation as the outcome of a burst of energy provided to a previously-immobilized, hopeless, and depressed individual who finally gains the wherewithal to initiate suicidal action through this energy.

Awareness and Communication are Essential

The process of bringing a drug to market moves through many steps as the FDA looks to both safety and efficacy before approval. When a New Drug Application(NDA) is approved by the FDA, there is a strict post-market surveillance period in which manufacturers are required to report adverse events submitted by patients and providers through FAERS: The FDA Adverse Event Reporting System. More information on this system and how it functions can be found on this health analytic site promoting ‘pharmacovigilance.’

However, medications are rarely tested in combination with other prescription or over-the-counter medications, or in a range of patients with unique conditions, genetics, and characteristics. This article by a family physician outlines the FDA process and important considerations for prescribing physicians, and this PBS article highlights the importance of being a careful consumer.

The medical field has made incredible advances and we are lucky to have so many treatments available to us. Many of these medications bring considerable relief and healing, and it is essential that guidance for starting or stopping a drug is delivered by a doctor. However mental health considerations should not be sacrificed or overlooked when treating other ailments, and increasing awareness and attention on the part of physicians is warranted. In addition, many experts suggest that treatment of mood disorders and psychosis be done by trained psychiatrists.

As we have learned from these studies, pharmaceutical regimens should be considered when evaluating mental health changes. Communication and education between provider and patient are crucial, as risk evaluation is incredibly important before and during any treatment that might alter a patient’s mental state or health.

Experts suggest that when considering a medication, the consumer should review the ‘package insert’ and discuss risks with the prescribing physician to better understand vulnerability, as well as to reveal other medications and over the counter treatments that might need to be considered. Personal and family history of mood disorders should also be shared. Following dosing, timing, and titration directions is essential, as some medications can be disruptive when not taken as prescribed. Understanding side effects is also essential, as many of us skip over words we don’t know–such as akathisia–and might not connect this listed side effect of a medication to an unsettling desire to jump out of one’s skin. Warnings of increasing depression might not be sufficient or accurate, if agitation is what truly represents risk in a particular individual. While a reaction might be temporary, and even normal in the eyes of the physician, it just may be the trigger for someone who doesn’t know how else to escape an unsettling sense of terror. 

It is imperative that the provider and/or pharmacist educate the patient, and perhaps a support team or family member (especially with children and young adults), on risks and other considerations. For medications with these risks, experts recommend closely monitoring a patient in the “danger zone” periods and keeping track of additional medications and over the counter treatments. It is equally essential that the patient knows when and how to initiate contact with the provider or other supports if they should experience adverse events or effects.

In raising awareness of possible risks and complications of a variety of medications, the hope is that patients and their families will be more attuned to circumstances that require immediate attention, and thereby prevent suffering and suicide. Lastly, and perhaps most importantly, the art of medicine implies a strategic and delicate technique practiced to treat the whole patient, which simply cannot be done effectively without consideration of medication and mental health.


National Suicide Prevention Lifeline 1-800-273-8255
American Association of Poison Control Centers 1-800-222-1222


Meghan Bellamy is a freelance writer and MPH candidate at the Colorado School of Public Health studying Global Community and Behavioral Health. 


Reviewed 5/20 by Thomas L. Kurt, MD, MPH, Medical Toxicologist and Public Health Physician, FACPM, FACMT, FAACT, FCP, FACOEM, FACE Dr. Kurt has served on the Texas Medicaid/SCHIP Drug Utilization Review Board, as the Regional Medical Officer for the FDA’s Southwest Region and was the founding medical director of the North Texas Poison Center at UT Southwestern in Dallas.