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  • Writer's pictureChristy Callahan, PMHNP-BC, NP

Can Some Medications Make Depression More Difficult to Treat?

The vast majority of individuals undergoing treatment for major depressive disorder continue to report lingering depressive symptoms even after a six-week treatment period. Around 30 percent of these individuals are labeled as treatment resistant. Could nonpsychiatric medications, known to have side effects linked to depressive symptoms, play a role in this treatment resistance? Ramin Mojtabai, Masoumeh Amin-Esmaeili, Stanislav Spivak, and Mark Olfson have recently conducted a study published in the Journal of Clinical Psychiatry to explore this very question.

The team of researchers made use of data from the National Health and Nutrition Examination Survey (NHANES), a biennial survey that captures insights from a cross-section of the general U.S. population. The survey entails computerized interviews conducted within the participants' households. Mojtabai and his colleagues focused their analysis on the data collected from over 18,000 adults aged 18 and above who participated in the survey during the periods of 2013-2014, 2015-2016, and 2017-2018.

From this sample, they identified a group of 885 individuals who had reported using antidepressant medications to alleviate depression for a minimum of six weeks. The severity of their depressive symptoms had been evaluated using the Patient Health Questionnaire-9 (PHQ-9), a tool that gauges the nine symptom criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, for major depressive disorder over the preceding two weeks. Alongside this, NHANES interviewers recorded all medications self-reported by the participants and cross-checked the list by verifying medication packaging. Previous research had established a roster of nonpsychiatric medications with the potential to induce depressive symptoms.

Remarkably, nearly two-thirds of the individuals who were on antidepressants were concurrently taking one or more medications that carried potential side effects of depressive symptoms. Over a third of them were using two or more of these medications, while more than 20 percent were taking three or more, and the figures decreased progressively, with around 10 percent taking four or more, and nearly 5 percent taking five or more such medications.

The researchers, Mojtabai and his team, proceeded to delve into the correlation between the number of medications individuals were using, which had possible depressive symptom side effects, and the severity of their depressive symptoms, as indicated by their PHQ-9 scores. Their findings illuminated a significant pattern: the higher the count of these medications, the greater the proportion of individuals experiencing moderate to severe depressive symptoms, and conversely, the lower the proportion of those exhibiting minimal or no depressive symptoms. Their statistical analyses, adjusted to account for socio-economic factors like education and family income, as well as concurrent medical conditions, revealed that individuals who were taking five or more medications with potential depressive symptom side effects were 50 percent more likely to be moderately or severely depressed, and had less than half the likelihood of experiencing minimal or no depressive symptoms, compared to those not using such medications. The relationship between the number of medications and depressive symptoms was linear in nature - the more medications taken, the more pronounced the effects. Conversely, no such patterns emerged with medications that did not carry the potential for depressive symptom side effects.

Omeprazole (commonly known as generic Prilosec), a proton pump inhibitor often prescribed for gastric reflux, emerged as the most prevalent medication among the individuals in this study, having an adverse impact on their depressive symptoms. Notably, the analysis of individual medications unveiled a significant connection between omeprazole and heightened depressive symptoms, alongside other medicines such as ranitidine (a histamine-2 blocker utilized as an antacid), baclofen and tizanidine (two distinct muscle relaxants), and propranolol (a medication for blood pressure and heart conditions). Additionally, five other medications exhibited noteworthy effects, encompassing various pain relievers, including a range of opiates, meloxicam (a nonsteroidal anti-inflammatory drug), and gabapentin.

The interplay between states of pain and depressive symptoms is extensively documented, albeit not comprehensively understood. The researchers acknowledged the complexity of distinguishing the impacts on depressive symptoms caused by medical conditions linked to pain and the drugs employed for pain management.

Might it be plausible that by reducing the number of drugs containing potential side effects for depressive symptoms, there could be an enhancement in the outcomes of depression treatment? While the findings of this study do establish a correlation between the quantity of such drugs ingested and the persistence of depressive symptoms, it's important to note that this connection doesn't necessarily imply a direct causal relationship between these drugs and reduced responsiveness to antidepressant treatments. Nonetheless, the prudent reduction of the utilization of certain aforementioned medications could be a consideration for both medical practitioners and patients, even though this needs to be done with safety as a paramount concern.


Mojtabai, R., Amin-Esmaeili, M., Spivak, S., & Olfson, M. (2023). Use of non-psychiatric medications with potential depressive symptom side effects and level of depressive symptoms in major depressive disorder. J Clin Psychiatry. 84(4):22m14705.

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