Concomitant Med Use May Explain Poor Antidepressant Response

Patients with "treatment-resistant depression" may be taking other medications with side effects that interfere with antidepressant efficacy.

Investigators studied over 800 patients who were taking antidepressants for major depressive disorder (MDD) and found that close to two thirds were taking at least one nonpsychiatric medication with potential depressive symptom side effects (PDSS), more than 30% were taking two or more such medications, and 20% at least three 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 City, told Medscape Medical News.

The study was published online May 24 in The Journal of Clinical Psychiatry.

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 for depression, and whose depression could be ascertained.

Prescription medications with PDSS were identified through Micromedex, whose accuracy is "established" and primarily based on the US Food and Drug Administration's (FDA) labeled side effects.

Nonantidepressant psychiatric medications and medications for Alzheimer's disease or substance use disorders were not included in the analysis.

Antidepressant-treated MDD was defined as taking an antidepressant for MDD for ≥ 6 weeks. Depressive symptoms were ascertained using the Patient Health Questionnaire-9 (PHQ-9) with a score of < 5 representing no/minimal depressive symptoms and a score of ≥ 10 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, ≥ 50 years, non-Hispanic white, and with a college education (70.55, 62.0%, 81.7%, and 69.4%, respectively).

Selective serotonin reuptake inhibitors (SSRIs) were used by 67.9% of participants with MDD. Most had been on the same antidepressant medication for a "long time," the authors report with 79.2% and 67.8% taking them for > 1 year and > 2 years, respectively.

Despite the large number of patients on antidepressants, only 43.0% scored in the no/minimal symptoms range, based on the PHQ-9, while 28.4% scored in the moderate/severe range.

Most patients (85%) took ≥ 1 medication for medical conditions, with the majority medications with PDSS:

Number of Medications With PDSS	Percent of Patients Using Them
≥ 1	66.7%
≥ 2	37.3%
≥ 3	21.6%
≥ 4	10.7%
≥ 5	4.9%

Almost 75% were using ≥ 1 medication without PDSS, and about 50% were using > 1.

The number of medications with PDSS was significantly associated with lower odds of no/minimal depressive symptoms (AOR, 0.75 [95% CI, 0.64 - 0.87]; P < .001) and higher odds of moderate/severe symptoms (AOR, 1.14 [1.004 - 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 report.

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

No corresponding associations were found 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 [0.30 - 0.60] 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 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.

J Clin Psychiatry. Published online May 24, 2023. Abstract

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as "Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom" (the memoir of two brave Afghan sisters who told her their story).

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