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Cited by 136Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesPsychotherapy Techniques and Applications

Antidepressant side effects and their impact on treatment outcome in people with major depressive disorder: an iSPOT-D report

Open access
Braund, Taylor A., Tillman, Gabriel, Palmer, Donna M., Gordon, Evian, Rush, A. John, Harris, Anthony W. F.·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01533-1PMC PMC8338944
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Abstract

Side effects to antidepressant medications are common and can impact the prognosis of successful treatment outcome in people with major depressive disorder (MDD). However, few studies have investigated the severity of side effects over the course of treatment and their association with treatment outcome. Here we assessed the severity of side effects and the impact of treatment type and anxiety symptoms over the course of treatment, as well as whether side effects were associated with treatment outcome. Participants were N = 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic MDD. Participants were randomised to receive escitalopram, sertraline, or venlafaxine-extended release with equal probability and reassessed at 8 weeks regarding Hamilton Rating Scale Depression (HRSD 17 ) and Quick Inventory of Depressive Symptomatology (QIDS-SR 16 ) remission and response. Severity of side effects were assessed using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale and assessed at day 4 and weeks 2, 4, 6, and 8. Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6. Treatment type and anxiety symptoms did not impact the severity of side effects. A greater burden—but not frequency or intensity—of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment. Together, this work provides an informative mapping of the progression of side effects throughout the treatment course and their association with treatment outcome. Importantly, the burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely. iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849.

AI snapshot

Written from the paper’s full text.

TL;DR

In N = 1008 adults with major depressive disorder randomized to escitalopram, sertraline, or venlafaxine-XR, side-effect frequency, intensity, and burden peaked at week 2; frequency and intensity then declined up to week 6, while burden did not decline after week 4. Greater side-effect burden predicted poorer treatment outcome, including as early as day 4, whereas treatment type and anxiety symptoms did not affect side-effect severity.

Key findings

  • Side effects were greatest at week 2. Frequency and intensity gradually decreased up to week 6, but burden did not decrease after week 4 and endured throughout treatment; mean FIBSER burden was 0.56 (SD 1.11) at day 4, 0.88 (SD 1.25) at week 2, 0.90 (SD 1.20) at week 4, 0.81 (SD 1.18) at week 6, and 0.85 (SD 1.20) at week 8.
  • Treatment type, DASS42 anxiety, HRSD17 anxiety/somatization, and presence of anxious depression did not improve model fit for side-effect severity (e.g., treatment type p = 0.162 for frequency, p = 0.091 for intensity, p = 0.149 for burden; anxiety predictors all p > 0.05). There were also no differences in maximum frequency, intensity, or burden between anxious and non-anxious depression.
  • Greater burden of side effects was associated with poorer QIDS-SR16 remission and response at every timepoint except week 4 QIDS-SR16 response; at day 4, QIDS-SR16 remission OR = 0.69 (95% CI 0.51–0.92, p = 0.016) and response OR = 0.70 (95% CI 0.53–0.91, p = 0.010). For HRSD17, greater burden at week 2 was associated with poorer remission (OR = 0.76, 95% CI 0.60–0.95, p = 0.015), and greater intensity at week 6 was associated with poorer remission (OR = 0.68, 95% CI 0.50–0.93, p = 0.015).
  • Adverse events occurred in 473/1008 participants (46.9%); 1016 adverse events were reported, of which 804 (79.1%) were related to antidepressant treatment. Adverse events were not associated with HRSD17 or QIDS-SR16 remission and response (all p > 0.05).

Methods

  • Phase-IV, multi-site, international, randomized, open-label trial; N = 1008 adults aged 18–65 with current single-episode or recurrent, nonpsychotic MDD diagnosed by MINI-Plus per DSM-IV, requiring HRSD17 > 16 at entry. Participants were randomized with equal probability to escitalopram, sertraline, or venlafaxine-extended release; data were collected between December 1, 2008 and September 30, 2013.
  • Side-effect severity was measured with the self-reported FIBSER at day 4 and weeks 2, 4, 6, and 8. Depression severity was assessed with HRSD17 and QIDS-SR16; remission was HRSD17 ≤ 7 or QIDS-SR16 ≤ 5, and response was ≥50% decrease from baseline.
  • Hierarchical linear mixed-effect models tested timepoint, treatment type, anxiety measures, and anxious depression against side-effect scores, with subject as a random effect and covariates age, sex, baseline QIDS-SR16, dosage at study outcome, and age of MDD onset; model comparison used AIC/BIC. Pearson correlations and logistic regression models, adjusted for the same covariates, tested associations between side effects and treatment outcome.

Limitations

  • Stated in the paper: findings are limited to the antidepressants used in the study; specific side effects were not assessed and side effects could not be matched with their corresponding severity; allowed non-psychotropic medications may have been misinterpreted as study-treatment side effects; and DSM-IV criteria were used, so the DSM-5 anxious distress specifier was not assessed.
  • Evident from the text: the trial was open-label with no placebo arm and participants knew which medication they were taking, so expectancy effects on side-effect reporting cannot be ruled out. Also, both FIBSER and QIDS-SR16 are self-reported, which the paper notes may help explain why burden associations were found for QIDS-SR16 but not clinician-rated HRSD17.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41398-021-01533-1

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The association between greater burden of side effects and poorer treatment outcome was present as early as 4 days post-treatment.

    “A greater burden—but not frequency or intensity—of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment.”
    Quote in the paperSubstantial claim
  • Findingown data

    Only frequency and intensity of side effects gradually decreased up to week 6.

    “Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Missing data are missing at random.
  • Findingown data

    Greater burden of side effects was associated with poorer treatment outcome.

    “A greater burden—but not frequency or intensity—of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment.”
    Quote in the paperSubstantial claim
  • Findingown data

    Anxiety symptoms did not impact the severity of side effects.

    “Treatment type and anxiety symptoms did not impact the severity of side effects.”
    • Also stated in: § Frequency, intensity, and burden of side effects · plain
      “However, including treatment type, DASS42 anxiety, HRSD17 anxiety/somatization, or the presence of anxious depression did not improve the model’s fit to the data (for significant covariates, see Supplementary Material).”
    • Also stated in: § Frequency, intensity, and burden of side effects · plain
      “However, there were no differences in the maximum frequency, intensity, or burden of side effects in people with HRSD or syndromal anxious depression compared to non-anxious depression (see Supplementary Table 5).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Missing data are missing at random.
  • Findingown data

    Treatment type did not impact the severity of side effects.

    “Treatment type and anxiety symptoms did not impact the severity of side effects.”
    • Also stated in: § Frequency, intensity, and burden of side effects · plain
      “However, including treatment type, DASS42 anxiety, HRSD17 anxiety/somatization, or the presence of anxious depression did not improve the model’s fit to the data (for significant covariates, see Supplementary Material).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Missing data are missing at random.
  • May combine two claims. 13
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Findingown data

    Burden of side effects, but not frequency or intensity, was associated with poorer treatment outcome, as early as 4 days post-treatment in the iSPOT-D sample.

    “Finally, burden of side effects—but not frequency or intensity of side effects—were associated with poorer treatment outcome and as early as 4 days post-treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Burden of side effects did not decrease after 4 weeks of treatment and endured throughout the course of antidepressant treatment in the iSPOT-D sample.

    “However, burden of side effects did not decrease after 4 weeks of treatment and endured throughout the course of antidepressant treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Frequency and intensity of side effects at week 2 were greater compared to weeks 6 and 8, but not week 4.

    “Frequency and intensity of side effects at week 2 were greater compared to weeks 6 (both p = 0.002) and 8 (p = 0.012 and 0.009, respectively), but not week 4.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Missing data are missing at random.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    People with anxious depression were found to have a greater maximum frequency, intensity, and burden of side effects compared to people with non-anxious depression in the STAR*D trial.

    “For example, people with anxious depression were found to have a greater maximum frequency, intensity, and burden of side effects compared to people with non-anxious depression in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342–51. https://doi.org/10.1176/appi.ajp.2007.06111868 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anxious depression is present in approximately half of the MDD population.

    “Anxious depression is present in approximately half of the MDD population and is commonly defined either syndromally (i.e., co-occurring MDD and anxiety disorder diagnoses) or using 17-item Hamilton Rating Scale Depression (HRSD17) criteria (i.e., MDD diagnosis and an HRSD17 anxiety/somatisation factor score of ≥7 [9–11]).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Ionescu DF, Niciu MJ, Henter ID, Zarate CA. Defining anxious depression: a review of the literature. CNS Spectr. 2013;18:252–60. https://doi.org/10.1017/S1092852913000114 source

      Not checked in the free run.

    • cites [10] Braund TA, Palmer DM, Williams LM, Harris AW. Characterising anxiety in major depressive disorder and its use in predicting antidepressant treatment outcome: an iSPOT-D report. Aust NZ J Psychiatry. 2019. https://doi.org/10.1177/0004867419835933. source

      Not checked in the free run.

    • cites [11] Gaspersz R, Nawijn L, Lamers F, Penninx B. Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome. Curr Opin Psychiatry. 2018;31:17–25. https://doi.org/10.1097/YCO.0000000000000376 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    No differences in frequency of side effects between people with syndromal and non-syndromal anxious depression were found by Gaspersz et al.

    “However, these associations are not found in all definitions of anxious depression, with Gaspersz et al. [14]. finding no differences in the frequency of side effects between people with syndromal and non-syndromal anxious depression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Gaspersz R, Lamers F, Kent JM, Beekman A, Smit JH, van Hemert AM, et al. Anxious distress predicts subsequent treatment outcome and side effects in depressed patients starting antidepressant treatment. J Psychiatr Res. 2017;84:41–8. https://doi.org/10.1016/j.jpsychires.2016.09.018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The QIDS-SR16 has shown good internal consistency (α = 0.86), as well as convergent and discriminant validity.

    “The QIDS-SR16 has also shown good internal consistency (α = 0.86), as well as convergent and discriminant validity [20, 23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573–83. https://doi.org/10.1016/s0006-3223(02)01866-8 source

      Not checked in the free run.

    • cites [23] Cameron IM, Crawford JR, Cardy AH, du Toit SW, Lawton K, Hay S, et al. Psychometric properties of the Quick Inventory of Depressive Symptomatology (QIDS-SR) in UK primary care. J Psychiatr Res. 2013;47:592–8. https://doi.org/10.1016/j.jpsychires.2013.01.019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacological treatments for people with major depressive disorder (MDD) and anxiety disorders.

    “Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacological treatments for people with major depressive disorder (MDD) [1] and anxiety disorders [2].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Malhi GS, Mann JJ. Depression. Lancet. 2018;392:2299–312. https://doi.org/10.1016/S0140-6736(18)31948-2 source

      Not checked in the free run.

    • cites [2] Craske MG, Stein MB. Anxiety. Lancet. 2016;388:3048–59. https://doi.org/10.1016/S0140-6736(16)30381-6 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some but not all studies suggest that anxious depression increases the severity of side effects.

    “Some, but not all studies suggest that anxious depression increases the severity of side effects (for a review, see Ionescu et al. [8]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ionescu et al. [8] Ionescu DF, Niciu MJ, Richards EM, Zarate CA, Jr. Pharmacologic treatment of dimensional anxious depression: a review. Prim Care Companion CNS Disord. 2014. https://doi.org/10.4088/PCC.13r01621. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Participants were diagnosed on the MINI-Plus according to DSM-IV criteria.

    “Participants were diagnosed on the Mini-International Neuropsychiatric Interview—Plus (MINI-Plus) [17] according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria [18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22–33.

      Not checked in the free run.

    • cites [18] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Vol. 4. Washington, DC: American Psychiatric Association; 1994.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Frequency, intensity, and burden of side effects are impacted by antidepressant treatment type, anxiety symptoms, and the presence of anxious depression.

    “Previous studies suggest that frequency, intensity, and burden of side effects are impacted by antidepressant treatment type, anxiety symptoms, and the presence of anxious depression (for a review, see Ionescu et al. [8]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ionescu et al. [8] Ionescu DF, Niciu MJ, Richards EM, Zarate CA, Jr. Pharmacologic treatment of dimensional anxious depression: a review. Prim Care Companion CNS Disord. 2014. https://doi.org/10.4088/PCC.13r01621. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Forty-two participants dropped out due to safety, tolerability, or efficacy reasons.

    “Forty-two participants dropped out due to safety, tolerability, or efficacy reasons (see Supplementary Table 3 for distribution of last recorded FIBSER scores).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Post hoc t tests were corrected for multiple comparisons using the Bonferroni-Holm method.

    “Post hoc t tests were performed using estimated marginal means and corrected for using the Bonferroni–Holm [31] method.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65–70.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The HRSD17 has shown good internal consistency (α = 79) and test-retest reliability (r = 0.87) in a recent meta-analysis.

    “The HRSD17 has shown good internal consistency (α = 79) and test–retest reliability (r = 0.87) in a recent meta-analysis [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Trajković G, Starčević V, Latas M, Leštarević M, Ille T, Bukumirić Z, et al. Reliability of the Hamilton Rating Scale for Depression: a meta-analysis over a period of 49 years. Psychiatry Res. 2011;189:1–9. https://doi.org/10.1016/j.psychres.2010.12.007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    SSRIs and SNRIs are associated with a range of side effects, including loss of appetite, weight loss, drowsiness, dizziness, fatigue, headaches, increased suicidal thoughts, nausea/vomiting, sexual dysfunction, and increased risk of cardiovascular and cerebrovascular events.

    “However, SSRIs and SNRIs are associated with a range of side effects, including loss of appetite, weight loss, drowsiness, dizziness, fatigue, headaches, increased suicidal thoughts, nausea/vomiting, sexual dysfunction, and increased risk of cardiovascular and cerebrovascular events [3–5].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS, et al. Addressing the side effects of contemporary antidepressant drugs: a comprehensive review. Chonnam Med J. 2018;54:101–12. https://doi.org/10.4068/cmj.2018.54.2.101 source

      Not checked in the free run.

    • cites [4] Moret C, Isaac M, Briley M. Problems associated with long-term treatment with selective serotonin reuptake inhibitors. J. Psychopharmacol. 2009;23:967–74. https://doi.org/10.1177/0269881108093582 source

      Not checked in the free run.

    • cites [5] Jakobsen JC, Katakam KK, Schou A, Hellmuth SG, Stallknecht SE, Leth-Møller K, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis. BMC Psychiatry. 2017;7:58. https://doi.org/10.1186/s12888-016-1173-2 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The iSPOT-D trial was designed with no placebo arm and participants were aware of the medication they were taking.

    “The iSPOT-D trial was designed with no placebo arm and participants were aware of the medication that they were taking to best match real-world practice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The iSPOT-D trial was registered on ClinicalTrials.gov with registration number NCT00693849.

    “iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All participants were either antidepressant medication naive or washed out.

    “All participants were either antidepressant medication naive or washed out.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Syndromal anxious depression did not predict severity of side effects (Gaspersz et al.).

    “Gaspersz et al. [14]. found that syndromal anxious depression did not predict severity of side effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Gaspersz R, Lamers F, Kent JM, Beekman A, Smit JH, van Hemert AM, et al. Anxious distress predicts subsequent treatment outcome and side effects in depressed patients starting antidepressant treatment. J Psychiatr Res. 2017;84:41–8. https://doi.org/10.1016/j.jpsychires.2016.09.018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Participants provided written informed consent after receiving a complete description of the study.

    “Participants provided written informed consent after receiving a complete description of the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The DSM-5 anxious distress specifier definition was not assessed because participants were diagnosed with DSM-IV criteria.

    “because participants were diagnosed with DSM-IV criteria, the DSM-5 anxious distress specifier definition was not assessed [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Gaspersz R, Nawijn L, Lamers F, Penninx B. Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome. Curr Opin Psychiatry. 2018;31:17–25. https://doi.org/10.1097/YCO.0000000000000376 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Non-psychotropic medications allowed by the protocol may have been misinterpreted for study treatment side effects and could impact the findings.

    “While the FIBSER specifically targets side effects due to antidepressant medication, other protocol allowed non-psychotropic medications may have been misinterpreted for study treatment side effects and could impact the findings.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by institutional or ethical review boards at each site, and its protocols followed International Conference on Harmonization and Good Clinical Practice principles, the U.S. Food and Drug Administration Code of Federal Regulations, and country-specific guidelines.

    “The study was approved by institutional or ethical review boards at each site, and its protocols followed International Conference on Harmonization and Good Clinical Practice principles, the U.S. Food and Drug Administration Code of Federal Regulations, and country-specific guidelines (see Supplementary Table 1 for individual iSPOT-D study management sites and investigators).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The difference between the current findings and previous studies on anxious depression and side effects may be attributable to differences in clinical severity of samples or lack of covariate controls.

    “Given that we found no differences in either the maximum reported side effects or frequency, intensity, and burden of side effects across timepoints between people with anxious and non-anxious depression, our difference in findings may be attributable to either a difference in the clinical severity of samples or lack of covariate controls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The enduring perceived burden of side effects is a commonly reported issue that contributes to issues related to treatment adherence and efficacy.

    “The enduring perceived burden of side effects is a commonly reported issue that contributes to the myriad of issues related to treatment adherence and efficacy [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci. 2012;9:41–6.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HRSD17 is a multidimensional construct measuring both anxiety and depression, while QIDS-SR16 is a unidimensional construct measuring depression alone.

    “Furthermore, while the HRSD17 is a multidimensional construct measuring both anxiety and depression, the QIDS-SR16 is a unidimensional construct measuring depression alone [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] McClintock SM, Haley C, Bernstein IH. Psychometric considerations of depression symptom rating scales. Neuropsychiatry. 2011;1:611–23. https://doi.org/10.2217/Npy.11.59 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All psychotropic medications (except sleep aids and anxiolytics) were discontinued and washed out prior to baseline assessments.

    “All psychotropic medications (except sleep aids and anxiolytics) were discontinued and washed out prior to baseline assessments.”
    Quote in the paperSubstantial claim
27 of 27

  • The paper relies on this without support.

    Missing data are missing at random.

    “Mixed effect models are well suited to the data as they retain participants with missing data and allow for the post hoc tests.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Such a lifestyle intervention is devoid of side effects of pharmacotherapy.

    “such a lifestyle intervention is further devoid of side effects of pharmacotherapy [107].”

    From Personalized machine learning guided intervention for optimizing lifestyle behaviors in depression: a pilot study (2026) · cites this paper as [107]

    The Introduction (page unavailable) states that antidepressants are associated with a range of side effects, supporting the pharmacotherapy part of the claim. The Methods’ Study overview (page unavailable) describes a medication trial with no lifestyle-intervention arm, so the paper does not establish that the lifestyle intervention is devoid of those side effects. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Patients may discontinue chronic treatment due to lack of rapid and consistent treatment benefits, treatment-related adverse events, and expectations of treatment that are misaligned with the treatment goals of HCPs.

    “Patients may discontinue chronic treatment due to lack of rapid and consistent treatment benefits, 37 treatmentrelated adverse events (AEs), [37][38][39][40] and expectations of treatment that are misaligned with the treatment goals of HCPs.41,42”

    From Digital health technologies and major depressive disorder (2023) · cites this paper as [41]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The abstract rules out an intensity association reported in the results

    Major

    The abstract says intensity was not associated with poorer treatment outcome, but the results report that greater intensity at week 6 was associated with poorer HRSD17 remission.

  • HRSD17 burden association is later said not to exist

    Major

    The results report that greater burden at week 2 was associated with poorer HRSD17 remission. The discussion instead says burden associations were found only for QIDS-SR16, not HRSD17.

  • Week-2 intensity is associated with better, not poorer, QIDS-SR16 remission

    Major

    The reported week-2 QIDS-SR16 remission odds ratio for intensity is 1.36, with a 95% confidence interval above 1 and p = 0.022. Greater intensity is therefore associated with higher odds of remission, contrary to the stated direction.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Vol. 4. Washington, DC: American Psychiatric Association; 1994.
  2. Cleary P, Guy W. Factor analysis of the Hamilton Depression Scale. Drugs Exp Clin Res. 1977;1:115–20.

Cited by

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Related

Authors
Braund, T. A., Tillman, G., Palmer, D. M., Gordon, E., Rush, A. J., & Harris, A. W. F.
Affiliations
  • The University of Sydney (AU)
  • Federation University (AU)
  • Westmead Institute for Medical Research (AU)
  • National University of Singapore (SG)
Corresponding author
Braund, Taylor A.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-08-04
Volume
11
Issue
1
Pages
417-417
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01533-1
PMC
PMC8338944
OpenAlex
W3191823183
Semantic Scholar
178e60eb49964e9bf6468c466a9b1a8826a82c8a
Cited by
135
References
39
Citations by year
2026: 32 · 2025: 39 · 2024: 32 · 2023: 21 · 2022: 11
FWCI
9.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion, cc-by)
  • FedUni ResearchOnline (Federation University Australia) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
Keywords
antidepressant side effects, major depressive disorder, treatment outcomes, escitalopram, sertraline, venlafaxine, selective serotonin reuptake inhibitors, anxiety symptoms
MeSH terms
Adult, Antidepressive Agents, Major Depressive Disorder, Humans, Citalopram, Treatment Outcome, Sertraline

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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