A Caution Regarding Conclusions Based on Population-Based Analysis: Consider the Clinical Confounders

Journal of Psychiatry Reform  Vol 11 # 7, May 2022


James A. Bourgeois, O.D., M.D.1,✉, Ana Hategan, M.D.2,iD

Author information:

1  Clinical Professor, CL Psychiatrist, Chair, Department of Psychiatry, Baylor Scott & White Health, Central Texas Division; College of Medicine, Texas A&M University Health Science Center, Temple, TX, USA.  [email protected]

2  Clinical Professor, Geriatric Psychiatrist, Department of Psychiatry and Behavioural Neurosciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. iD: https://orcid.org/0000-0003-0221-1154.


To the Editor:  A recent study by Almohammed et al. [1] concluded that antidepressants were not associated with improved quality of life; among depressed patients, those using antidepressants in the long run had no significantly improved health-related quality of life, compared to those who did not take antidepressants. Although the authors appreciated that their study was not able to separately analyze any subtypes or varying severities of depressive disorder, their conclusion was concerning in that it did not take into account many confounding variables.

Most concerning was that they grouped all depressive disorders together and made no mention of illness severity (e.g., melancholic, catatonic, psychotic, Ham-D scale score > 24) and impact of other medication interventions, adequacy of treatment compliance, adequate dosing, and other important clinical variables. Patients with mild symptoms such that they would not qualify for inclusion in medication efficacy studies, nonetheless in vivo, will often receive antidepressant therapy; due to their mild degree of illness, it is very difficult to discern clear benefit from treatment with statistical analysis. Altogether, the main point is the likely variable severity of depressive illness considered in their comparison groups. Previous literature has indicated that the magnitude of benefit of antidepressant use compared with placebo increases with severity of depressive symptoms, and may be minimal or nonexistent, on average, in those with mild/moderate symptoms [2]. Studies have shown that the high level of depressive symptom severity appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving antidepressant medication in clinical practice present with scores below these levels [2]. It is all about only analyzing patients who are “sick enough to show an improvement.”

Their research methodology only screens for 296.xx and 311 diagnostic codes, which, though inclusive of the majority of depressive disorders, crucially misses the highly likely psychiatric co-morbidity common in depressive disorders. A modest list of common co-morbid conditions includes anxiety, OCD, PTSD, substance use, personality, and neurocognitive disorders. Many patients have more than one co-morbid condition, which can severely impact response to antidepressants (not to mention other psychiatric interventions) and thus represents a likely controllable source of bias. Cases with multiple psychiatric co-morbidity are much less likely to respond to antidepressants as sole therapy with a robust improvement. Thus, what these authors are measuring is at best a qualitative variable. There is no doubt that many patients do not respond fully to “just medications” (e.g., STAR-D study [3]) but these are important methodological shortfalls.

Methodology such as that used in the study with large de-identified data sets and standardized outcomes measures are a useful approach to population-based studies. However, for the reasons cited above (plus perhaps several others), the authors are advised to be more “modest and measured” in their conclusions, perhaps calling for more granular analysis in future studies, incorporating some of the above considerations, plus others of presumed clinical and epidemiologic relevance. In addition, the proper DSM-5 term for (former) “depression” is “depressive disorders.”



  1. Almohammed OA, Alsalem AA, Almangour AA, et al. Antidepressants and health-related quality of life (HRQoL) for patients with depression: Analysis of the medical expenditure panel survey from the United States. PLoS One. 2022;17(4):e0265928. doi: 10.1371/journal.pone.0265928.
  2. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA. 2010;303(1):47-53. doi:10.1001/jama.2009.1943.
  3. Sinyor M, Schaffer A, Levitt A. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A review. Can J Psychiatry. 2010;55(3)126-135. doi:10.1177/070674371005500303.


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