Clinical Context

Treatment-resistant depression (TRD) is generally defined as the failure to improve after trials of at least 2 antidepressant drugs from different classes, provided that the dosage was adequate and the treatment period was at least 4 weeks with each drug. The authors of the current study suggest that TRD can occur in approximately 30% of cases of depression. A previous study by Rizvi and colleagues focused on the prevalence of TRD in primary care practices in Canada and explored risk factors for TRD as well. The research was published in the July 2014 issue of the Canadian Journal of Psychiatry.^[1]

A total of 135 primary care physicians completed 1212 case reports on patients with depression. The prevalence of TRD was 21.7%. Patient sex and race/ethnicity did not affect the risk for TRD; however, patients with TRD were slightly older compared with patients without TRD, and patients who were unemployed or disabled also had higher rates of TRD.

Several comorbid illnesses also affected the risk for TRD. In particular, sleep disorders and chronic pain were associated with higher rates of TRD. Type 2 diabetes, cardiovascular disease, chronic obstructive pulmonary disease, and hepatitis also were associated with higher rates of TRD, but arthritis, asthma, cancer, chronic kidney disease, peripheral vascular disease, and osteoporosis were not.

Chronic health conditions contribute to TRD, and their associated treatment can as well. The current study by Mojtabai and colleagues evaluates how the use of medications with potential depressive symptom side effects (PDSS) affects the treatment of depression.

Study Synopsis and Perspective

Patients with TRD may be taking other medications with adverse effects (AEs) that interfere with antidepressant efficacy.

Investigators studied more than 800 patients who were taking antidepressants for major depressive disorder (MDD) and found that close to two-thirds were taking at least 1 nonpsychiatric medication with PDSS, more than 30% were taking 2 or more such medications, and 20% were taking at least 3 such medications.

These medications, which included antihypertensive medications and corticosteroids, among others, were associated with higher odds of moderate to severe depressive symptoms compared with medications without PDSS.

"When evaluating the reasons for inadequate response to treatment for depression, clinicians should consider whether their patient is also receiving a nonpsychiatric medication with a potential for depressive symptom side effects," study investigator Mark Olfson, MD, MPH, Elizabeth K. Dollard professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York, New York, told Medscape Medical News.

The study was published May 24 in The Journal of Clinical Psychiatry.^[2]

Previous Research Limited

"In earlier research, we found that people who were taking medications with a potential to cause depressive symptom side effects were at increased risk of depression, especially those adults who were taking more than one of these medications," said Olfson.

This finding led Olfson and his team to "wonder whether the risks of depressive symptoms associated with these medications extended to people who were being actively treated with antidepressants for depression."

To investigate, they turned to the National Health and Nutrition Examination Survey (NHANES): a nationally representative cross-sectional survey of the US general population.

The study was based on the 2013-2014, 2015-2016, and 2017-2018 waves and included 885 adults who reported using antidepressant medications for 6 weeks or longer for depression and whose depression could be ascertained.

Researchers identified prescription medications with PDSS through Micromedex, whose accuracy is "established" and primarily based on the FDA-labeled AEs.

The analysis did not include non-antidepressant psychiatric medications and medications for Alzheimer disease or substance use disorders.

Antidepressant-treated MDD was defined as taking an antidepressant for MDD for 6 or more weeks. Investigators ascertained depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9) with a score of less than 5 representing no/minimal depressive symptoms and a score of 10 or higher indicating moderate/severe symptoms.

Other variables included self-reported sex; age; race/ethnicity; income; education; health insurance; and common chronic medical conditions, such as hypertension, arthritis, lung disease, diabetes mellitus, thyroid disease, cancer, heart disease, liver disease, stroke, and congestive heart failure.

Recovery Interrupted

Of the patients in the study treated with antidepressants, most were female, aged 50 years or older, non-Hispanic White, and who had a college education (HR 70.7%, 62%, 81.7%, and 69.4%, respectively).

More than two-thirds (67.9%) of the participants with MDD used selective serotonin reuptake inhibitors (SSRIs). Most had been on the same antidepressant medication for a "long time," the authors reported, with 79.2% and 67.8% taking them for more than 1 year and more than 2 years, respectively.

Despite the large number of patients on antidepressants, only 43% scored in the no/minimal symptoms range, according to the PHQ-9, whereas 28.4% scored in the moderate/severe range.

Most patients (85%) took 1 or more medications for medical conditions, with the majority taking medications with PDSS.

Almost 75% were using 1 or more medications without PDSS, and 52% were using more than 1.

The number of medications with PDSS was significantly associated with lower odds for no/minimal depressive symptoms (adjusted odds ratio [aOR] 0.75 [95% CI: 0.64, 0.87]; P < .001) and higher odds for moderate/severe symptoms (aOR 1.14 [95% CI: 1, 1.29]; P = .044).

"The predicted probability of no/minimal symptoms in those taking 5 medications with PDSS was less than half the predicted probability in those taking no medications with PDSS (0.23 vs 0.52)," the authors reported.

Conversely, the predicted probability of moderate/severe symptoms was about 50% higher in individuals taking 5 vs 0 medications with PDSS (0.36 vs 0.24).

The researchers found no corresponding associations for medications without PDSS.

The results were even stronger when the researchers repeated their adjusted regression analyses to focus on the 10 individual medications most associated with the severity of depressive symptoms. These were omeprazole, gabapentin, meloxicam, tramadol, ranitidine, baclofen, oxycodone, tizanidine, propranolol, and morphine, with an aOR of 0.42 (95% CI: 0.3, 0.6) for no/minimal symptoms and 1.68 (1.24, 2.27) for moderate/severe symptoms.

"Many widely prescribed medications, from antihypertensives, such as atenolol and metoprolol to corticosteroids, such as dexamethasone and triamcinolone, are associated with depression side effects," said Olfson.

"These medications could interfere with recovery from depression. When available, consideration should be given to selecting a substitute with lower risk for depressive symptoms," he said.

Role in Treatment-Resistant Depression

Commenting for Medscape Medical News, Dima Qato, PharmD, MPH, PhD, Hygeia Centennial chair and associate professor, University of Southern California (USC) School of Pharmacy, said the study "is an important reminder that the use of medications with depressive symptoms side effects is increasingly common and may contribute to delays in responsiveness or worsen depressive symptoms among individuals being treated for depression."

Qato, who is also the director of the Program on Medicines and Public Health, USC School of Pharmacy, and was not involved with the study, recommended that clinicians "consider the role of medications with depression side effects when evaluating patients with treatment-resistant depression."

The study was not supported by any funding agency. Olfson and coauthors have disclosed no relevant financial relationships. Qato is a consultant for the Public Citizen Health Research Group.

Implications for the Healthcare Team

• A previous study by Rizvi and associates found that sleep disorders and chronic pain were particularly associated with higher rates of TRD. Type 2 diabetes, cardiovascular disease, chronic obstructive pulmonary disease, and hepatitis also were associated with higher rates of TRD, but arthritis, asthma, cancer, chronic kidney disease, peripheral vascular disease, and osteoporosis were not.
• The current study by Mojtabai finds that the concomitant use of drugs with PDSS with antidepressants used to treat depression results in worse symptom scores for depression, with progressively worse results with more drugs with PDSS added.
• The healthcare team should scan the medication list of adults with depression for medications with PDSS and then replace these drugs, if possible.

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