From the Editor

“Many may be surprised to learn that their medications, despite having nothing to do with mood or anxiety or any other condition normally associated with depression, can increase their risk of experiencing depressive symptoms, and may lead to a depression diagnosis.”

JAMA Psychiatry papers rarely make international news. A new paper by the University of Illinois’ Dima Mazen Qato (who is quoted above) and her co-authors has, however. In looking at prescribed drugs like proton pump inhibitors, they find that many are linked to depressive symptoms. One online news report began with the headline: “37% of US Adults Are Using Common Meds They Don’t Realise Could Cause Depression: It’s even worse if you use several medications together.”

It’s a big study with a big result. For the record, a couple of patients have already brought up the findings with me.

statin_2819148bMany small pills, one big problem?

What to think and how should it affect patient care? In this week’s Reading, we consider the paper.


“Prevalence of Prescription Medications With Depression as a Potential Adverse Effect Among Adults in the United States”

Dima Mazen Qato, Katharine Ozenberger, Mark Olfson

JAMA Psychiatry, 12 June 2018

Prescription medications are widely and increasingly used in the United States, with approximately 15% of adults estimated to have been using 5 or more concurrent prescription medications in 2011 and 2012. Alongside evidence that adverse drug events from prescription medications are often implicated in emergency department visits and hospitalizations, there is gaining recognition that many commonly used prescription medications, including hormonal contraceptives and β-blockers, are associated with an increased risk of depression.

In the years 2009 through 2012, depression was estimated to affect more than 5% of US adultsand in 2011 and 2012, an estimated 28.7% of adults with depressive symptoms were undiagnosed or untreated. Despite progress in understanding risk factors for depression, including among adults with comorbid medical disorders,there is only limited information about the use of medications that have the potential for depression as an adverse effect. Several studies have investigated associations between medication classes and depression. The strength of evidence for depression as an adverse effect varies across medication classes. For example, depression has been consistently associated with interferon α treatment of hepatitis C with mild to moderate depression developing in 45% to 60% of treated patients and moderate to severe depression developing in 15% to 40%. By contrast, evidence linking β-blockers to depression and suicide is less consistent.

The current study extends prior research by using nationally representative survey data to consider a broad spectrum of medications that have a potential for depression as an adverse effect and examine their associations with concurrent depression.

1_1Dima Mazen Qato

So begins a paper by Qatoet al.

Here’s what they did:

  • The authors drew data from the National Health and Nutrition Examination Survey; NHANES is a nationally representative cross-sectional survey of the US population.
  • They used the five most recent NHANES 2-year cycles (from 2005 to 2014), and also used the PHQ-9 scale (defining scores of 10 or higher as depression) and prescription medication data from interviews. For the adverse effects of medications (depression, depressive disorder, suicide suicidal thoughts, suicidal ideation, suicidal behavior), the authors used the Micromedex (which is based on US FDA labelling of adverse effects).
  • The analysis also considered other variables, including demographics and health.
  • Statistical analyses were done, including: “Multivariable logistic regression was used to model associations between use of medications that have depression as an adverse effect and depression.”

Here’s what they found:

  • The study included 26,192 adults, and 7.6% reported depression.
  • 2% of adults used a prescription medication in the prior 30 days that had depression as a potential side effect. Demographically, these adults tended to be older (65 and older), widowed, and had a higher number of chronic conditions.
  • The number of medications with potential adverse effects increased from 35.0% to 38.4% over the study years. See figure below.
  • “The estimated prevalence of depression increased from 6.9% for patients taking 1 to 15.3% for patients taking 3 or more medications that have depression and a potential adverse effect vs 4.7% for patients not using such medications…”
  • “It was estimated that 7.9% of adults used antihypertensive agents associated with depression as a potential adverse effect (metoprolol and atenolol). Use of proton pump inhibitors and histamine H2 antagonists that are associated with depression as a potential adverse effect increased from 5.4% in 2005 and 2006 to 9.5% in 2013 and 2014…”


In this cross-sectional survey study, reported use of prescription medications that have depression as adverse effects was common. Use of multiple prescription medications with these potential effects was associated with greater likelihood of concurrent depression. These findings persisted in analyses restricted to adults with hypertension and after excluding users of any psychotropic medications. The results suggest that physicians should consider discussing these associations with their patients who are prescribed medications that have depression as a potential adverse effect.


A few thoughts:

  1. This is an interesting study.
  1. The paper tapped a large database and was published in a big journal (and included an impressive co-author, Mark Olfson).
  1. Our interpretation of the paper ultimately comes down to our thoughts on the list of medications associated with depression and suicidal symptoms. The authors write: “Adults in the United States reported use of more than 200 medications that have been associated with depression or suicidal symptoms as adverse effects. With the exception of antidepressants, the only drug class with a black-box warning for suicidal risk,the most commonly used medications that have depression as a potential adverse effect were antihypertensives, proton pump inhibitors, analgesics, and hormonal contraceptives.” But is the list too inclusive? In part because of the medicolegal environment of the United States, drug companies tend to list many adverse effects for their medications. To be clear: the authors drew on established work; that said, the list of medications is long. It includes prednisone (good) but also ranitidine and ibuprofen (maybe not so good).
  1. And a question: are the authors finding causation or correlation? The authors mention in the limitations section: “because NHANES is cross-sectional in design, medication use and depressive symptoms cannot be temporally ordered, therefore precluding causal inference.”
  1. To steal a line from Samuel Johnson: what is new in this study is not good, and what is good is not new. What’s good is the observation that some medications are linked to depressive and suicidal symptoms – but then every psychiatry textbook would note this already. What’s new is the implication that a large percentage of people with depression may be taking everyday medications linked to depression – except that the paper can’t distinguish between causation and correlation.
  1. What to tell patients if asked about this paper? I’ve said the following: While there are some problems with the study, it’s always important to consider side effects when starting a new drug, and to work with your family doctor to ensure that medications started by different providers at different points are helpful and don’t interfere with those you may already be taking.


Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.