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Cited by 252Treatment of Major DepressionTryptophan and brain disordersSchizophrenia research and treatment

Cognitive remission: a novel objective for the treatment of major depression?

Open access
Bortolato, Beatrice, Miskowiak, Kamilla W., Köhler, Cristiano A., Maes, Michael, Fernandes, Brisa S., Berk, Michael, Carvalho, André F.·2016·BMC Medicine
DOI 10.1186/s12916-016-0560-3PMC PMC4724131
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Abstract

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

AI snapshot

Written from the paper’s full text.

TL;DR

This opinion/review argues that cognitive dysfunction is a frequent, persistent, and functionally impairing feature of major depressive disorder (MDD), and proposes “cognitive remission” as a novel treatment target. It reviews conventional antidepressants and candidate novel agents, concluding that evidence for direct procognitive effects remains limited, with vortioxetine having the strongest RCT support.

Key findings

  • Cognitive impairment in MDD spans attention, memory, psychomotor speed, and executive function; meta-analyses report small-to-moderate deficits, including effect sizes of 0.48 for psychomotor speed, 0.36 for attention, and 0.53 for visual learning/memory in first-episode MDD, and Cohen’s d from −0.34 to −0.65 in a CANTAB meta-analysis.
  • Only 30–40% of individuals with MDD reach symptomatic remission after adequate first-line antidepressant treatment, and approximately 20% of MDD patients show deficits of two standard deviations below the mean on two or more cognitive domains.
  • Conventional antidepressants may improve some cognitive domains, but a meta-analysis found small effects (standard mean difference 0.16 for psychomotor speed and 0.24 for delayed recall), and no single antidepressant has FDA approval for treating cognitive disturbances associated with MDD.
  • Vortioxetine showed significant procognitive effects in two multicenter RCTs with cognitive performance as the primary outcome, largely independent of mood improvement, though a meta-analysis found the overall effect size was small (0.34); lisdexamfetamine dimesylate improved executive dysfunction in an RCT of 143 adults, and erythropoietin improved verbal learning and memory in a preliminary RCT of 40 treatment-resistant MDD patients.

Methods

  • Design: opinion article/narrative review, not a systematic review or primary study.
  • Data: synthesizes clinical studies, meta-analyses, and RCTs on cognitive dysfunction in MDD and on standard antidepressants plus novel therapeutic targets, including a table of candidate agents.
  • Analysis: narrative synthesis of evidence for procognitive effects; no primary data collection, formal meta-analysis, or systematic search strategy is reported.

Limitations

  • The paper states that most antidepressant trials did not evaluate cognition as a primary outcome, lacked placebo control and proper statistical control for clinical severity, and were limited by heterogeneous demographic and clinical features, lack of gold-standard cognitive assessment tools, and confounding.
  • The paper also notes over-representation of elderly subjects, poor correlation between subjective and objective cognitive measures, and lack of consensus on screening for cognitive dysfunction and on which cognitive measures should be primary outcomes.
  • Evident from the text: as an opinion/narrative review, it does not systematically assess risk of bias or study quality, and many novel agents discussed have no published clinical trial data on cognition in MDD.

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

Integrity signals

Registry

Crossref · 10.1186/s12916-016-0560-3

Cites

198 of 198 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 252 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In a recent study, patients with cognitive impairment at baseline had substantially greater chances of achieving a clinically meaningful cognitive improvement in response to erythropoietin treatment compared with patients with normal baseline cognition.

    “Indeed, in a recent study, we demonstrated that patients with cognitive impairment at baseline had substantially greater chances of achieving a clinically meaningful cognitive improvement in response to EPO treatment compared with patients with normal baseline cognition (Miskowiak et al., unpublished observations).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Cognitive deficits may impede functional recovery, including workforce performance, in patients with major depressive disorder.

    “Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30(6):515–27. source

      Not checked in the free run.

    • cites [15] Buist-Bouwman MA, Ormel J, de Graaf R, de Jonge P, van Sonderen E, Alonso J, et al. ESEMeD/MHEDEA 2000 investigators. Mediators of the association between depression and role functioning. Acta Psychiatr Scand. 2008;118(6):451–8. source

      Not checked in the free run.

    • cites [16] Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006;145(1):39–48. source

      Not checked in the free run.

  • Premisecitation

    Impairments in executive function and attention may persist after affective symptoms are fully mitigated.

    “Impairments in executive function and attention may persist after the affective symptoms are fully mitigated [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–40. source

      Not checked in the free run.

  • Interpretationreasoning

    The management of cognitive dysfunction remains an unmet need in the treatment of major depressive disorder.

    “The management of cognitive dysfunction remains an unmet need in the treatment of MDD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Individuals with major depressive disorder exhibit clinically significant cognitive impairment across multiple domains.

    “A significant body of evidence shows that individuals with MDD exhibit clinically significant cognitive impairment across multiple domains.”
    Quote in the paperSubstantial claim
  • May combine two claims. 61
  • Classified as probably not a substantial claim. 27
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation

    Cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase.

    “Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–40. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cognitive dysfunction in major depressive disorder encompasses several domains, including executive function, verbal memory, and attention.

    “Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry. 2001;178:200–6. source

      Not checked in the free run.

    • cites [8] Douglas KM, Porter RJ. Longitudinal assessment of neuropsychological function in major depression. Aust N Z J Psychiatry. 2009;43(12):1105–17. source

      Not checked in the free run.

    • cites [9] Reppermund S, Ising M, Lucae S, Zihl J. Cognitive impairment in unipolar depression is persistent and non-specific: further evidence for the final common pathway disorder hypothesis. Psychol Med. 2009;39(4):603–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive symptoms are acknowledged clinical manifestations of major depressive disorder, with fatigue, sleepiness, and executive dysfunction among the most frequently reported residual manifestations.

    “Cognitive symptoms are acknowledged clinical manifestations of MDD, with fatigue, sleepiness, and executive dysfunction being among the most frequently reported residual manifestations of MDD [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Stahl SM, Grady MM. Differences in mechanism of action between current and future antidepressants. J Clin Psychiatry. 2003;64 Suppl 13:13–7.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Several novel agents may be repurposed as cognitive enhancers for major depressive disorder treatment.

    “Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of 13 studies in 644 symptomatic patients with first-episode depression versus 570 healthy controls showed significant impairments in psychomotor speed, attention, and most aspects of executive function, with small to moderate effect sizes.

    “Accordingly, a meta-analysis of 13 studies in 644 symptomatic patients with first-episode depression versus 570 healthy controls showed significant impairments in psychomotor speed, attention, and most aspects of executive function (i.e. attentional switching, verbal fluency, cognitive flexibility), with small to moderate effect sizes [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA. A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord. 2012;140(2):113–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many patients with major depressive disorder do not reach premorbid levels of psychosocial functioning, such that a significant proportion present residual symptoms.

    “Only a subset of individuals with MDD (30–40 %) reach symptomatic remission after adequate treatment with a first-line antidepressant, and many patients do not reach premorbid levels of psychosocial functioning, such that a significant proportion of patients present residual symptoms.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Stotland NL. Recovery from depression. Psychiatr Clin North Am. 2012;35(1):37–49. source

      Not checked in the free run.

    • cites [11] Carvalho AF, Miskowiak KK, Hyphantis TN, Kohler CA, Alves GS, Bortolato B, et al. Cognitive dysfunction in depression - pathophysiology and novel targets. CNS Neurol Disord Drug Targets. 2014;13(10):1819–35. source

      Not checked in the free run.

    • cites [12] Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32(5):415–28. source

      Not checked in the free run.

    • Rests on an assumption: Only 30–40% of individuals with major depressive disorder reach symptomatic remission after adequate treatment with a first-line antidepressant.

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

    Premisecitation

    Major depressive disorder is a prevalent and disabling condition with a high frequency of non-recovery and recurrence, leading to substantial mortality and morbidity.

    “Major depressive disorder (MDD) is a prevalent and disabling condition with a high frequency of non-recovery and recurrence, leading to substantial mortality and morbidity [1–3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Ann Rev Public Health. 2013;34:119–38. source

      Not checked in the free run.

    • cites [2] Stotland NL. Recovery from depression. Psychiatr Clin North Am. 2012;35(1):37–49. source

      Not checked in the free run.

    • cites [3] Alonso J, Vilagut G, Adroher ND, Chatterji S, He Y, Andrade LH, et al. Disability mediates the impact of common conditions on perceived health. PLoS One. 2013;8(6), e65858. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with the greatest objective cognitive dysfunction do not necessarily experience the most pronounced cognitive problems, and vice versa.

    “Notably, however, subjective and objective neuropsychological measures of cognition are not closely related [31, 32], indicating that patients with the greatest objective cognitive dysfunction do not necessarily experience the most pronounced cognitive problems, and vice versa.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Demant KM, Vinberg M, Kessing LV, Miskowiak KW. Assessment of subjective and objective cognitive function in bipolar disorder: correlations, predictors and the relation to psychosocial function. Psychiatry Res. 2015;229(1–2):565–71. source

      Not checked in the free run.

    • cites [32] Svendsen AM, Kessing LV, Munkholm K, Vinberg M, Miskowiak KW. Is there an association between subjective and objective measures of cognitive function in patients with affective disorders? Nordic J Psychiat. 2012;66(4):248–53. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive dysfunction in depression is not simply an epiphenomenon of mood symptoms but is a core and persisting phenomenon.

    “Cognitive dysfunction in depression does not appear to be simply an epiphenomenon of mood symptoms (e.g. fatigue) but instead is a core and persisting phenomenon [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Hammar A, Sorensen L, Ardal G, Oedegaard KJ, Kroken R, Roness A, et al. Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm. Scand J Psychol. 2010;51(4):304–8.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 13 studies on adults with a first major depressive episode reported significant impairment in psychomotor speed (effect size 0.48), attention (effect size 0.36), and visual learning and memory (effect size 0.53) compared with healthy controls.

    “For example, a meta-analysis of 13 studies on adults with a first MDE reported significant impairment in psychomotor speed (effect size 0.48), attention (effect size 0.36), and visual learning and memory (effect size 0.53) compared with healthy controls [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA. A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord. 2012;140(2):113–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A systematic review of 11 studies involving 500 adult patients in remission from major depressive disorder documented persistent deficits in sustained and selective attention, memory, and executive function, but heterogeneity prevented estimation of precise effect sizes.

    “For example, a systematic review of 11 studies involving 500 adult patients in remission from MDD documented persistent deficits in sustained and selective attention, memory, and executive function. However, the heterogeneity across studies did not allow for the estimation of precise effect sizes [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Hasselbalch BJ, Knorr U, Kessing LV. Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord. 2011;134(1–3):20–31. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cognitive impairment may represent a risk biomarker that may antedate illness onset, a trait marker present in remitted patients, a marker of progression showing greater severity with illness progression, and a state or acuity marker of major depressive disorder.

    “Taken together, using the classification proposed by Davis et al. [44], these studies suggest that cognitive impairment may represent a risk biomarker that may even antedate illness onset, a trait marker present in remitted patients, a marker of progression showing greater severity with illness progression, and a state or acuity marker of MDD, with more marked effects on acutely ill individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Davis J, Maes M, Andreazza A, McGrath JJ, Tye SJ, Berk M. Towards a classification of biomarkers of neuropsychiatric disease: from encompass to compass. Mol Psychiatry. 2015;20(2):152–3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 24 studies using the Cambridge Neuropsychological Test Automated Battery showed significant impairments in executive functions, attention, and memory in the symptomatic phases of major depressive disorder, with Cohen's d effect sizes ranging from −0.34 to −0.65.

    “For instance, a meta-analysis of 24 studies in which all participants had been assessed with the same comprehensive neuropsychological battery (Cambridge Neuropsychological Test Automated Battery) showed significant impairments in executive functions, attention, and memory in the symptomatic phases of MDD (Cohen’s d effect sizes ranging from −0.34 to −0.65) [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–40. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Objective cognitive impairment is a consistent, replicable, non-specific, and clinically significant feature of major depressive disorder and many major psychiatric disorders.

    “Notwithstanding these limitations, separate meta-analyses provide compelling evidence that (objective) cognitive impairment is a consistent, replicable, non-specific, and clinically significant feature of MDD – and, for that matter, many major psychiatric disorders [10, 14, 33–35].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029–40. source

      Not checked in the free run.

    • cites [14] McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30(6):515–27. source

      Not checked in the free run.

    • cites [33] Wagner S, Doering B, Helmreich I, Lieb K, Tadic A. A meta-analysis of executive dysfunctions in unipolar major depressive disorder without psychotic symptoms and their changes during antidepressant treatment. Acta Psychiatr Scand. 2012;125(4):281–92. source

      Not checked in the free run.

    • cites [34] Snyder HR. Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol Bull. 2013;139(1):81–132. source

      Not checked in the free run.

    • cites [35] McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord. 2009;119(1–3):1–8. source

      Not checked in the free run.

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

    Premisecitation

    Workplace impairment may contribute to more than 60% of the major depressive disorder-related economic burden.

    “Importantly, it has been suggested that workplace impairment may contribute to more than 60 % of the MDD-related economic burden [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465–75. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The lack of gold-standard tools to assess cognition in major depressive disorder and the variety of neuropsychological tests employed hinder clear comparisons between studies.

    “In addition, the lack of gold-standard tools to assess cognition in MDD and the variety of neuropsychological tests employed in different investigations hinder clear comparisons between studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Path analysis showed that better cognitive performance was determined not only by decreases in depression severity but also by enhancements of verbal learning and memory performance.

    “Path analysis showed that better cognitive performance was determined not only by decreases in depression severity but also by enhancements of verbal learning and memory performance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Greer TL, Sunderajan P, Grannemann BD, Kurian BT, Trivedi MH. Does duloxetine improve cognitive function independently of its antidepressant effect in patients with major depressive disorder and subjective reports of cognitive dysfunction? Depress Res Treat. 2014;2014:627863.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect sizes derived from the meta-analysis of standard antidepressants on cognition were small, with standard mean difference 0.16 for psychomotor speed and 0.24 for delayed recall.

    “However, the evidence base remains limited, and the effect sizes derived from this meta-analysis were small in magnitude (standard mean difference was 0.16 for psychomotor speed and 0.24 for delayed recall, respectively).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol. 2015. [Epub ahead of print] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conventional antidepressants are generally associated with a beneficial effect on cognitive impairment in individuals with major depressive disorder, which may be mediated at least in part by improvement in affective symptoms.

    “Nevertheless, conventional antidepressants are generally associated with a beneficial effect on cognitive impairment in individuals with MDD, which may be mediated at least in part by improvement in affective symptoms.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A cross-sectional naturalistic study reported a superior effect of bupropion over selective serotonin reuptake inhibitors or venlafaxine on cognitive function.

    “Moreover, no significant between-group differences were observed in this study, in contrast to data obtained from a cross-sectional naturalistic study that reported a superior effect of bupropion over SSRIs or venlafaxine on cognitive function [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22.

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  • Classified as probably not a substantial claim.

    Premisecitation

    Some authors have advocated for the achievement of 'cognitive remission' as an appropriate, novel aim for major depressive disorder treatment.

    “Since cognitive dysfunction is one of the residual symptoms of MDD that most strongly impairs quality of life and since accumulating evidence suggests that persistent cognitive impairment prevents full recovery even following the resolution of depressive episodes, some authors have advocated for the achievement of ‘cognitive remission’ as an appropriate, novel aim for MDD treatment [57, 58].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] McIntyre RS. Using measurement strategies to identify and monitor residual symptoms. J Clin Psychiatry. 2013;74 Suppl 2:14–8. source

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    • cites [58] Trivedi MH, Greer TL. Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord. 2014;152–154:19–27. source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The concept of remission provides only a vague theoretical definition that may be influenced by the psychometric limitations of available instruments.

    “However, the concept of remission provides only a vague theoretical definition that may be influenced by the psychometric limitations of available instruments [52, 53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Ostergaard SD, Bech P, Miskowiak KW. Fewer study participants needed to demonstrate superior antidepressant efficacy when using the Hamilton melancholia subscale (HAM-D) as outcome measure. J Affect Disord. 2016;190:842–5. source

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    • cites [53] Fountoulakis KN, Moller HJ. Antidepressant drugs and the response in the placebo group: the real problem lies in our understanding of the issue. J Psychopharmacol. 2012;26(5):744–50. source

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  • May combine two claims.

    Premisecitation

    Sertraline, citalopram, or paroxetine administration were not associated with significant changes in cognitive performance in a cohort of elderly patients with major depression, whereas a beneficial effect was observed in patients with minor depression.

    “On the other hand, other findings indicated that sertraline, citalopram, or paroxetine administration, were not associated with significant changes in cognitive performance in a cohort of elderly patients with major depression, whereas a beneficial effect was observed in patients with minor depression, regardless of changes in the severity of depressive symptoms and concomitant benzodiazepine or p”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Han L, McCusker J, Cole M, Capek R, Abrahamowicz M. Antidepressant use and cognitive functioning in older medical patients with major or minor depression: a prospective cohort study with database linkage. J Clin Psychopharmacol. 2011;31(4):429–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a cross-sectional naturalistic study, the selective serotonin reuptake inhibitor group performed significantly worse than healthy controls in tests of psychomotor and processing speed and cognitive flexibility, the venlafaxine group performed worse than controls in measures of processing speed, and the bupropion group did not differ from healthy controls in any cognitive measure.

    “However, whereas in this study the SSRI group (n = 27) performed significantly worse than healthy controls in tests of psychomotor and processing speed and cognitive flexibility, and the venlafaxine group performed worse than controls in measures of processing speed, the bupropion group (n = 27) did not differ from healthy controls in any cognitive measure; this aspect limits the generalizability”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Remission does not equate to recovery.

    “Furthermore, remission does not equate to recovery.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Executive deficits in the elderly were found to correlate with increased residual symptomatology, higher recurrence rates, and worse response to antidepressant medication.

    “In particular, executive deficits in the elderly were found to correlate with increased residual symptomatology, higher recurrence rates, and worse response to antidepressant medication [77, 78].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Alexopoulos GS, Reynolds 3rd CF, Bruce ML, Katz IR, Raue PJ, Mulsant BH, et al. PROSPECT Group. Reducing suicidal ideation and depression in older primary care patients: 24-month outcomes of the PROSPECT study. Am J Psychiatry. 2009;166(8):882–90. source

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    • cites [78] Potter GG, Kittinger JD, Wagner HR, Steffens DC, Krishnan KR. Prefrontal neuropsychological predictors of treatment remission in late-life depression. Neuropsychopharmacol. 2004;29(12):2266–71. source

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  • May combine two claims.

    Premisecitation

    A recent systematic review indicates that augmentation therapy may potentially improve cognitive performance after remission of a major depressive episode, but available evidence should be interpreted cautiously because of significant heterogeneity in study design and treatment duration.

    “Similarly, a recent systematic review indicates that although augmentation therapy may potentially improve cognitive performance after remission of a MDE, available evidence should be interpreted cautiously because of significant heterogeneity in study design and treatment duration across studies [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Keefe RS, McClintock SM, Roth RM, Doraiswamy PM, Tiger S, Madhoo M. Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(8):864–76. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In elderly subjects (age >65 years; n = 58) with major depressive disorder, executive dysfunction was associated with increased risk of relapse after 16-week therapy with nortriptyline, as well as higher recurrence rates after a 2-year placebo-controlled maintenance phase.

    “Conversely, in elderly subjects (age >65 years; n = 58) with MDD, executive dysfunction was associated with increased risk of relapse after 16-week therapy with nortriptyline, as well as higher recurrence rates after a 2-year placebo-controlled maintenance phase [76].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Alexopoulos GS, Meyers BS, Young RC, Kalayam B, Kakuma T, Gabrielle M, et al. Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry. 2000;57(3):285–90. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Despite the recent discovery of compounds with potential therapeutic use in major depressive disorder-related cognitive dysfunction, there are still few choices available.

    “Despite the recent discovery of compounds with potential therapeutic use in MDD-related cognitive dysfunction, there are still few choices available.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Certain neurocognitive tests, mostly those that depend on psychomotor speed, may serve as differential predictors of clinical response to a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor as opposed to bupropion.

    “Thus, the authors posit that certain neurocognitive tests, mostly those that depend on psychomotor speed, may serve as differential predictors of clinical response to an SSRI or to an SNRI as opposed to bupropion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Bruder GE, Alvarenga JE, Alschuler D, Abraham K, Keilp JG, Hellerstein DJ, et al. Neurocognitive predictors of antidepressant clinical response. J Affect Disord. 2014;166:108–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Poor pretreatment word fluency performance predicted non-response to selective serotonin reuptake inhibitors and longer choice reaction time on the Stroop Test predicted non-response to selective serotonin reuptake inhibitors or dual therapy.

    “Whereas poor pretreatment word fluency performance predicted non-response to SSRIs and longer choice reaction time on the Stroop Test predicted non-response to SSRIs or dual therapy, patients who responded to bupropion tended to show the opposite pattern of neurocognitive performance, exhibiting slower reaction time and poorer pretreatment word fluency performance compared with those of controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Bruder GE, Alvarenga JE, Alschuler D, Abraham K, Keilp JG, Hellerstein DJ, et al. Neurocognitive predictors of antidepressant clinical response. J Affect Disord. 2014;166:108–14. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Some compounds under preliminary investigation show promising results with respect to their procognitive potential.

    “However, some compounds under preliminary investigation show promising results with respect to their procognitive potential.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Psychotropic agents may have a similar effect on the immune system and, consequently, on cognitive performance.

    “Finally, psychotropic agents may have a similar effect on the immune system and, consequently, on cognitive performance [86, 87].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009;33(3):355–66. source

      Not checked in the free run.

    • cites [87] Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25(2):181–213. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Path analysis showed that more than one-half of the duloxetine effect on cognitive deficits was attributable to improvements in depressive symptoms, but the effect of vortioxetine on cognitive performance was largely independent of the alleviation of depressive symptoms.

    “Path analysis showed that, although more than one-half of the duloxetine effect on cognitive deficits was attributable to improvements in depressive symptoms, the effect of vortioxetine on cognitive performance was largely independent of the alleviation of depressive symptoms [92].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacol. 2015;40(8):2025–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Comorbid metabolic disturbances aggravate the burden of depressive illness, in part by sharing common risk factors and pathophysiological pathways, since impaired insulin signaling and insulin resistance play an important role in the pathogenesis of major depressive disorder.

    “Comorbid metabolic disturbances aggravate the burden of depressive illness, in part by sharing common risk factors and pathophysiological pathways, since impaired insulin signaling and insulin resistance have been documented to play an important role in the pathogenesis of MDD [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Stuart MJ, Baune BT. Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine co-morbidity. Neurosci Biobehav Rev. 2012;36(1):658–76. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Lisdexamfetamine dimesylate is a pharmacologically inactive pro-drug of D-amphetamine approved for Attention Deficit Hyperactivity Disorder treatment.

    “Lisdexamfetamine dimesylate (LDX) is a pharmacologically inactive pro-drug of D-amphetamine approved for Attention Deficit Hyperactivity Disorder treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Minocycline exerts antioxidant properties by suppressing free radical generation and attenuates increases in lipid peroxidation.

    “Moreover, it exerts antioxidant properties by suppressing free radical generation and attenuates increases in lipid peroxidation [100]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005;1044(1):8–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Path analyses showed that the vortioxetine effect on cognition was largely attributable to a direct effect of treatment on cognition because one-half to two-thirds of the procognitive effect could not be the result of the overall reduction in depression symptoms.

    “Path analyses showed that this effect was largely attributable to a direct effect of treatment on cognition because one-half to two-thirds of the procognitive effect could not be the result of the overall reduction in depression symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–67. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There is great research interest in the development or repurposing of various agents as cognitive enhancers for major depressive disorder.

    “There is also great research interest in the development or repurposing of various agents as cognitive enhancers for MDD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Erythropoietin crosses the blood-brain barrier and exerts antidepressant-like and neuroprotective effects enhancing hippocampus-dependent memory and neuroplasticity, partly via increased production of brain-derived neurotrophic factor.

    “EPO crosses the blood–brain barrier and exerts antidepressant-like and neuroprotective effects enhancing hippocampus-dependent memory and neuroplasticity, partly via increased production of brain-derived neurotrophic factor (BDNF) [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Miskowiak K, Vinberg M, Christensen EM, Kessing LV. Is there a difference in subjective experience of cognitive function in patients with unipolar disorder versus bipolar disorder? Nord J Psychiatry. 2012;66(6):389–95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preliminary randomized controlled trial of vortioxetine in non-demented subjects with recurrent major depressive disorder (n = 453), vortioxetine-treated individuals showed increased learning and memory performance and higher processing speed compared with a placebo group, and the effects were independent of the reduction in depression severity.

    “Procognitive effects were suggested by a preliminary RCT that investigated vortioxetine treatment in non-demented subjects with recurrent MDD (n = 453) [71]. Although these were secondary outcome measures, vortioxetine-treated individuals showed increased learning and memory performance (assessed by the Rey Auditory Verbal Learning Test; RAVLT) and higher processing speed (assessed by the Digit”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215–23. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Minocycline modulates glutamate transmission by reducing glutamate release and excitotoxicity, and may indirectly target the monoaminergic system.

    “modulates glutamate transmission reducing glutamate release and excitotoxicity, and may indirectly target the monoaminergic system [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Baptiste DC, Hartwick AT, Jollimore CA, Baldridge WH, Seigel GM, Kelly ME. An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. Mol Pharmacol. 2004;66(5):1113–22. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large double-blind 8-week-long randomized controlled trial found that vortioxetine (10 mg or 20 mg) significantly increased a composite index calculated from the Digit Symbol Substitution Test and the Rey Auditory Verbal Learning Test scores, as well as self-reported cognitive tests, in adults with recurrent, moderate-to-severe major depressive disorder.

    “Furthermore, a large double-blind 8-week-long RCT investigated the effects of vortioxetine (10 mg or 20 mg) on cognitive performance as the primary outcome measure in adults with recurrent, moderate-to-severe MDD [91]. The study showed that vortioxetine significantly increased a composite index calculated from the DSST and the RAVLT scores, as well as self-reported cognitive tests (i.e. Perceived”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–67. source

      Not checked in the free run.

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

    Premisecitation

    Vortioxetine may improve the cognitive symptoms of major depressive disorder through its effects on cognate serotoninergic receptors, which may modulate glutamatergic neurotransmission.

    “Furthermore, it has been postulated that vortioxetine may improve the cognitive symptoms of MDD through its effects on cognate serotoninergic receptors, which may modulate glutamatergic neurotransmission [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Pehrson AL, Sanchez C. Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction. CNS Spectr. 2014;19(2):121–33. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Minocycline promotes hippocampal neurogenesis and exerts anti-apoptotic and anti-inflammatory activities, reducing the expression of pro-inflammatory cytokines and up-regulating anti-inflammatory cytokines.

    “Minocycline promotes hippocampal neurogenesis and exerts anti-apoptotic and anti-inflammatory activities, reducing the expression of pro-inflammatory cytokines (e.g. IL-1β, IL-6, IL-2, TNF-α, INF-γ) and up-regulating anti-inflammatory cytokines (e.g. IL-10) [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Dean OM, Data-Franco J, Giorlando F, Berk M. Minocycline: therapeutic potential in psychiatry. CNS Drugs. 2012;26(5):391–401. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vortioxetine acts as an antagonist of the 5-HT3 and 5-HT7 serotonin receptors, a partial agonist of the 5-HT1B serotonin receptor, an agonist of the 5-HT1A receptor, and inhibits the serotonin transporter.

    “Vortioxetine (Lu AA21004) is an antidepressant that acts as an antagonist of the 5-HT3 and 5-HT7 serotonin receptors, partial agonist of the 5-HT1B serotonin receptor, agonist of the 5-HT1A receptor, and inhibits the serotonin transporter [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011;54(9):3206–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an 8-week duloxetine-referenced randomized controlled trial in individuals with moderate-to-severe major depressive episode who reported subjective cognitive dysfunction (n = 602), vortioxetine improved objective and subjective measures of cognitive function compared with placebo, whereas duloxetine was superior to placebo only with respect to subjective measures of cognitive function.

    “In accord with these findings, vortioxetine procognitive effects were confirmed as a primary outcome in another 8-week duloxetine-referenced RCT in individuals with moderate-to-severe MDE who reported subjective cognitive dysfunction (n = 602). Significant improvements in objective and subjective measures of cognitive function (i.e. Number of Correct Symbols in the DSST and the attention/con”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacol. 2015;40(8):2025–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In healthy volunteers, erythropoietin modulated neuronal activity in a frontoparietal network during working memory and improved executive function (verbal fluency) 1 week after a single high-dose administration of 40,000 IU.

    “In healthy volunteers, EPO modulated neuronal activity in a frontoparietal network during working memory and improved executive function (i.e. verbal fluency) 1 week after a single high-dose administration (40,000 IU) [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Miskowiak K, Inkster B, O'Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ. Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration. Exp Brain Res. 2008;184(3):313–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both vortioxetine and duloxetine were significantly superior to placebo in reducing depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale.

    “Both vortioxetine and duloxetine were significantly superior to the placebo in reducing depressive symptoms assessed by MADRS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacol. 2015;40(8):2025–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin improved memory performance, assessed by the Wechsler Memory Scale-Revised, which was significantly related to a decrease in depressive symptoms.

    “In addition, metformin improved memory performance (assessed by the Wechsler Memory Scale-Revised), which was significantly related to a decrease in depressive symptoms [122].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, et al. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exper Pharmacol Physiol. 2014;41(9):650–6. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims. The quote only partly states this claim.

    Premisecitation

    The antidepressant properties of pioglitazone appeared to be largely independent of insulin-sensitizing action and possibly mediated by anti-inflammatory and antioxidant actions, including inhibition of the nuclear factor kappa B cascade and cytokine production, as well as quinolinic acid-induced neurotoxicity.

    “Importantly, the authors of this study underscored that antidepressant properties appeared to be largely independent of insulin-sensitizing action and are possibly mediated by anti-inflammatory and antioxidant”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [118] Kashani L, Omidvar T, Farazmand B, Modabbernia A, Ramzanzadeh F, Tehraninejad ES, et al. Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinol. 2013;38(6):767–76. source

      Not checked in the free run.

    • cites [119] Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008;13:1813–26. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thiazolidinediones act as agonists of peroxisome proliferator-activated receptor gamma and exert neuroprotective effects, reducing oxidative stress and weakening the pro-inflammatory response, as well as promoting neuroplasticity via increased production of brain-derived neurotrophic factor.

    “Thiazolidinediones act as agonists of peroxisome proliferator-activated receptor gamma and have been demonstrated to exert neuroprotective effects, reducing oxidative stress and weakening the pro-inflammatory response, as well as promoting neuroplasticity via increased production of BDNF [116].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Menendez-Gutierrez MP, Roszer T, Ricote M. Biology and therapeutic applications of peroxisome proliferator- activated receptors. Curr Top Med Chem. 2012;12(6):548–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    n-3 polyunsaturated fatty acids reduce the inflammatory response, limiting the production of pro-inflammatory mediators by microglial cells following ischemic insults, and enhance glutathione-related antioxidant pathways.

    “Moreover, n-3 PUFAs reduce the inflammatory response, limiting the production of pro-inflammatory mediators by microglial cells following ischemic insults, and enhance glutathione-related antioxidant pathways [135, 136].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [135] Zhang W, Hu X, Yang W, Gao Y, Chen J. Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti-inflammatory actions. Stroke. 2010;41(10):2341–7. source

      Not checked in the free run.

    • cites [136] Smesny S, Milleit B, Schaefer MR, Hipler UC, Milleit C, Wiegand C, et al. Effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system in individuals at ultra-high risk of psychosis. Prostaglandins Leukot Essent Fatty Acids. 2015;101:15–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACE inhibitors have immune-modulating properties and suppress cytokine production, likely through interference with NF-kB activation.

    “ACE inhibitors have immune-modulating properties and suppress cytokine production (e.g. IL-1, TNF-α), likely through interference with NF-κB activation [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Andersson P, Cederholm T, Johansson AS, Palmblad J. Captopril-impaired production of tumor necrosis factor-alpha-induced interleukin-1beta in human monocytes is associated with altered intracellular distribution of nuclear factor-kappaB. J Lab Clin Med. 2002;140(2):103–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A pilot open-label trial involving adult outpatients with major depressive disorder (n = 23) with comorbid abdominal obesity or metabolic syndrome documented that adjunctive pioglitazone significantly improves depressive severity, with a concurrent reduction in insulin resistance and inflammatory markers.

    “A pilot, open-label trial involving adult outpatients with MDD (n = 23) with comorbid abdominal obesity (waist circumference >35 inches in women and >40 inches in men) or metabolic syndrome documented that adjunctive pioglitazone significantly improves depressive severity (assessed by the Inventory of Depressive Symptomatology), with a concurrent reduction in insulin resistance and inflammatory”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, et al. Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity. J Affect Disord. 2012;136(3):1164–73. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations in insulin signaling are associated with mitochondrial dysfunction and lead to activation of pro-inflammatory pathways, increased oxidative/nitrosative stress and glutamate excitotoxicity, resulting in neuroinflammation and neurodegeneration.

    “Alterations in insulin signaling are associated with mitochondrial dysfunction and lead to the activation of pro-inflammatory pathways, as well as increased oxidative/nitrosative stress and glutamate excitotoxicity, which result in neuroinflammation and neurodegeneration [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Spielman LJ, Little JP, Klegeris A. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J Neuroimmunol. 2014;273(1–2):8–21. source

      Not checked in the free run.

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

    Premisecitation

    SAMe is a major methyl donor required for the synthesis of several neurotransmitters and serves as a precursor molecule to the transsulfuration pathway, which leads to the synthesis of glutathione.

    “SAMe is a major methyl donor required for the synthesis of several neurotransmitters and serves as a precursor molecule to the transsulfuration pathway, which leads to the synthesis of glutathione [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Bottiglieri T. S-adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76(5):1151s–7s. source

      Not checked in the free run.

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

    Premisecitation

    It has been posited that alpha lipoic acid supplementation in major depressive disorder would result in antidepressant effects, possibly via increased insulin sensitization and a consequent increase in monoamine synthesis.

    “It has been posited that ALA supplementation in MDD would result in antidepressant effects, possibly via increased insulin sensitization and a consequent increase in monoamine synthesis [131].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Salazar MR. Alpha lipoic acid: a novel treatment for depression. Med Hypotheses. 2000;55(6):510–2. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An inverse relationship was observed between cardiometabolic risk factors and cognitive performance, suggesting that dietary prevention strategies may delay the onset of metabolic disorders and associated cognitive decline.

    “In addition, an inverse relationship was observed between cardiometabolic risk factors and cognitive performance, suggesting that dietary prevention strategies may delay the onset of metabolic disorders and associated cognitive decline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Nilsson A, Radeborg K, Salo I, Bjorck I. Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study. Nutrition J. 2012;11:99. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical evidence suggests that a diet enriched in n-3 polyunsaturated fatty acid (ethyl-eicosapentaenoic acid) may attenuate IL-1-induced memory impairment and block IL-1-induced increases in serum corticosterone concentration.

    “Preclinical evidence suggests that a diet enriched in n-3 PUFA (i.e. ethyl-eicosapentaenoic acid) may attenuate IL-1-induced memory impairment and block IL-1-induced increases in serum corticosterone concentration [134].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Song C, Phillips AG, Leonard BE, Horrobin DF. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. Mol Psychiatry. 2004;9(6):630–8. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Taken together, the results provide the rationale for investigating acetyl-L-carnitine's efficacy in the treatment of neurocognitive deficits in the context of major depressive disorder.

    “Taken together, these results provide the rationale for investigating ALC’s efficacy in the treatment of neurocognitive deficits in the context of MDD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Both galantamine RCTs enrolled small samples, with the trial by Holtzheimer et al. enrolling only elderly participants.

    “However, they both enrolled small samples, with that by Holtzheimer et al. [150] enrolling only elderly participants.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Holtzheimer 3rd PE, Meeks TW, Kelley ME, Mufti M, Young R, McWhorter K, et al. A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Inter J Geriatr Psychiat. 2008;23(6):625–31. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cognitive studies of N-acetylcysteine have produced inconsistent results, which may be linked to variations in study design.

    “Cognitive studies of NAC have produced inconsistent results, which may be linked to variations in study design [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Deepmala, Slattery J, Kumar N, Delhey L, Berk M, Dean O, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294–321. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Curcumin is a pleiotropic agent that targets immune-inflammatory and oxidative and nitrosative stress pathways and promotes neuroprotection and improved neurogenesis.

    “Curcumin is a pleiotropic agent that targets immune-inflammatory and oxidative and nitrosative stress pathways and promotes neuroprotection and improved neurogenesis [165, 166].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Pluta R, Bogucka-Kocka A, Ulamek-Koziol M, Furmaga-Jablonska W, Januszewski S, Brzozowska J, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015;53(2):89–99. source

      Not checked in the free run.

    • cites [166] Maes M, Fisar Z, Medina M, Scapagnini G, Nowak G, Berk M. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacol. 2012;20(3):127–50. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Few studies have investigated the effects of n-3 polyunsaturated fatty acids on cognition, yielding inconclusive results to date.

    “However, few studies have investigated the effects of n-3 PUFAs on cognition, yielding inconclusive results to date.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Acute curcumin administration improved performance on tasks that measured sustained attention and working memory, whereas chronic treatment also improved mood and fatigue.

    “Acute curcumin administration improved performance on tasks that measured sustained attention and working memory, whereas chronic treatment also improved mood and fatigue [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Cox KH, Pipingas A, Scholey AB. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol. 2015;29(5):642–51. source

      Not checked in the free run.

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

    Premisecitation

    Because of its modulatory effects on nicotinic receptors, galantamine may modulate other neurotransmitter systems, including monoamines, glutamate, and GABA.

    “Because of its modulatory effects on nicotinic receptors, it has been proposed that this drug may modulate other neurotransmitter systems, including monoamines, glutamate, and GABA [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current Neuropharmacol. 2013;11(3):315–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    N-acetylcysteine acts as a modulator of synaptic glutamate through the cysteine-glutamate exchanger, increases glutathione and oxidative defenses, enhances neurogenesis and mitochondrial function, decreases pro-inflammatory cytokines, and regulates apoptosis.

    “NAC acts as a modulator of synaptic glutamate through the cysteine-glutamate exchanger, increases glutathione and oxidative defenses, enhances neurogenesis and mitochondrial function, decreases pro-inflammatory cytokines, and regulates apoptosis [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830(8):4117–29. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two double-blind RCTs evaluated the effects of galantamine augmentation on neurocognitive function in major depressive disorder, and both failed to demonstrate beneficial effects on cognition.

    “Two double-blind, RCTs evaluated the effects of galantamine augmentation on neurocognitive function in MDD [150, 151], and both failed to demonstrate beneficial effects on cognition.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Holtzheimer 3rd PE, Meeks TW, Kelley ME, Mufti M, Young R, McWhorter K, et al. A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Inter J Geriatr Psychiat. 2008;23(6):625–31. source

      Not checked in the free run.

    • cites [151] Elgamal S, MacQueen G. Galantamine as an adjunctive treatment in major depression. J Clin Psychopharmacol. 2008;28(3):357–9. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The results of the above-reviewed studies of novel candidate treatments for cognitive dysfunction in major depressive disorder remain preliminary.

    “The results of the above-reviewed studies of novel candidate treatments for cognitive dysfunction in MDD remain preliminary.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Meta-analytic evidence suggests that statins induce mood-enhancing effects and decrease the risk of development of de novo depression in humans.

    “In addition, meta-analytic evidence suggests that statins induce mood-enhancing effects and decrease the risk of development of de novo depression in humans [170, 171].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [170] O'Neil A, Sanna L, Redlich C, Sanderson K, Jacka F, Williams LJ, et al. The impact of statins on psychological wellbeing: a systematic review and meta-analysis. BMC Med. 2012;10:154. source

      Not checked in the free run.

    • cites [171] Parsaik AK, Singh B, Murad MH, Singh K, Mascarenhas SS, Williams MD, et al. Statins use and risk of depression: a systematic review and meta-analysis. J Affect Disord. 2014;160:62–7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    No trial to date has evaluated the effects of statin members as cognitive enhancers for patients with major depressive disorder.

    “However, no trial to date has evaluated the effects of statin members as cognitive enhancers for patients with MDD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Another issue is the lack of guidelines on which cognition measures should be implemented as primary outcomes in cognition trials in major depressive disorder.

    “Another issue is the lack of guidelines on which cognition measures should be implemented as primary outcomes in these trials (i.e. single neuropsychological test measures or composite scores of tests assessing several cognitive domains).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Statins may decrease the activity of the enzyme indoleamine 2,3-dioxygenase, which is induced by IFN-gamma, leading to the cleavage of tryptophan, a precursor of serotonin and melatonin, as well as the production of neurotoxic tryptophan catabolites.

    “Furthermore, statins may decrease the activity of the enzyme indoleamine 2,3-dioxygenase [175], which is induced by IFN-γ, leading to the cleavage of the essential amino acid tryptophan, a precursor of serotonin and melatonin, as well as the production of neurotoxic tryptophan catabolites [176].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [175] Wirleitner B, Sperner-Unterweger B, Fuchs D. Statins to reduce risk of depression. J Am Coll Cardiol. 2004;43(6):1132. author reply 1132–1133. source

      Not checked in the free run.

    • cites [176] Reus GZ, Jansen K, Titus S, Carvalho AF, Gabbay V, Quevedo J. Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. J Psychiatr Res. 2015;68:316–28. source

      Not checked in the free run.

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

    Premisecitation

    As an antioxidant, coenzyme Q10 protects cells from the damaging effects of reactive oxygen species and reactive nitrogen species.

    “As an antioxidant, CoQ10 protects cells from the damaging effects of reactive oxygen species and reactive nitrogen species [177].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Morris G, Anderson G, Berk M, Maes M. Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol. 2013;48(3):883–903. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atorvastatin promotes antidepressant-like effects and increases hippocampal brain-derived neurotrophic factor levels in rodents.

    “Atorvastatin also promotes antidepressant-like effects and increases hippocampal BDNF levels in rodents [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Ludka FK, Zomkowski AD, Cunha MP, Dal-Cim T, Zeni AL, Rodrigues AL, et al. Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels. Eur Neuropsychopharmacol. 2013;23(5):400–12. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The lack of consensus regarding methodological issues in cognition trials in major depressive disorder is a substantial limitation that must be addressed to advance the field.

    “The lack of consensus regarding these methodological issues is a substantial limitation that must be addressed to advance the field.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Although inconsistent but positive effects of conventional treatments on cognitive impairment are observed, there is an absence of compelling evidence of a specific and direct effect with most antidepressants.

    “Although inconsistent but positive effects of conventional treatments on cognitive impairment are observed, there is an absence of compelling evidence of a specific and direct effect with most antidepressants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The data are preliminary across the novel therapeutic targets and are promising for erythropoietin, SAMe, insulin, N-acetylcysteine, and antidiabetic agents.

    “The data are preliminary across these agents and are promising for EPO, SAMe, insulin, NAC, and antidiabetic agents.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Among agents within a class of antidepressants, it is uncertain whether efficacy can be generalized to all members.

    “Among agents within a class of antidepressants, it is also uncertain whether efficacy can be generalized to all members.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In a 12-week RCT of participants with severe major depressive disorder under standard citalopram treatment (n = 60), the adjunctive atorvastatin group showed lower HDRS scores by the end of the trial, but no participant achieved remission.

    “The group allocated to atorvastatin showed lower HDRS scores by the end of the trial; however, no participant achieved remission.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Haghighi M, Khodakarami S, Jahangard L, Ahmadpanah M, Bajoghli H, Holsboer-Trachsler E, et al. In a randomized, double-blind clinical trial, adjuvant atorvastatin improved symptoms of depression and blood lipid values in patients suffering from severe major depressive disorder. J Psychiatr Res. 2014;58:109–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coenzyme Q10 displays antidepressant-like effects in chronically stressed rats, with a reduction in hippocampal oxidative/nitrosative DNA damage.

    “CoQ10 displays antidepressant-like effects in chronically stressed rats, with a reduction in hippocampal oxidative/nitrosative DNA damage [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Aboul-Fotouh S. Coenzyme Q10 displays antidepressant-like activity with reduction of hippocampal oxidative/nitrosative DNA damage in chronically stressed rats. Pharmacol Biochem Behav. 2013;104:105–12. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    One key issue is the lack of consensus on whether and how to screen for cognitive dysfunction in cognition trials in major depressive disorder.

    “One key issue is the lack of consensus on whether and how to screen for cognitive dysfunction in these trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a 6-week RCT of participants meeting criteria for major depressive disorder (n = 48), the fluoxetine plus simvastatin group showed significantly lower depressive symptoms, whereas differences in remission rates did not achieve statistical significance.

    “at study completion, the latter showed significantly lower depressive symptoms, whereas differences in remission rates did not achieve statistical significance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Gougol A, Zareh-Mohammadi N, Raheb S, Farokhnia M, Salimi S, Iranpour N, et al. Simvastatin as an adjuvant therapy to fluoxetine in patients with moderate to severe major depression: A double-blind placebo-controlled trial. J Psychopharmacol. 2015;29(5):575–81. source

      Not checked in the free run.

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  • The paper relies on this without support.

    Only 30–40% of individuals with major depressive disorder reach symptomatic remission after adequate treatment with a first-line antidepressant.

    “Only a subset of individuals with MDD (30–40 %) reach symptomatic remission after adequate treatment with a first-line antidepressant, and many patients do not reach premorbid levels of psychosocial functioning, such that a significant proportion of patients present residual symptoms.”

  • The authors state this as an assumption.

    The clinical magnitude of antidepressant effects on cognitive performance is small in non-elderly adult subjects with major depressive disorder.

    “Notwithstanding the paucity of data showing beneficial effects of antidepressants on cognitive performance in non-elderly adult subjects with MDD, converging evidence supports the assumption that the clinical magnitude of antidepressant effects is also small in this population.”

  • The paper relies on this without support.

    Insulin exerts anti-apoptotic activities and facilitates neuronal growth and differentiation by promoting synapse formation, thereby influencing learning and memory processes.

    “Insulin exerts anti-apoptotic activities and facilitates neuronal growth and differentiation by promoting synapse formation, thus influencing learning and memory processes.”

  • The paper relies on this without support.

    Insulin serves as a neuromodulator by enhancing serotonin synthesis and inhibiting the reuptake of norepinephrine by pre-synaptic neurons.

    “In addition, insulin serves as a neuromodulator by enhancing serotonin synthesis and inhibiting the reuptake of norepinephrine by pre-synaptic neurons.”

  • The paper relies on this without support.

    Scopolamine may modulate serotonin, neuropeptide Y, and the dopaminergic and glutamatergic systems.

    “In addition to its anticholinergic effect, scopolamine may modulate serotonin, neuropeptide Y, and the dopaminergic and glutamatergic systems.”

  • The paper relies on this without support.

    Simvastatin and atorvastatin inhibit inflammation by decreasing TNF-alpha and IL-1beta levels.

    “For example, simvastatin and atorvastatin inhibit inflammation by decreasing TNF-α and IL-1β levels.”

  • The paper relies on this without support.

    Simvastatin is neuroprotective in an animal model of ischemia, and this effect is associated with an increase in the activity of endothelial nitric oxide synthase.

    “Simvastatin was also shown to be neuroprotective in an animal model of ischemia; this effect was associated with an increase in the activity of endothelial nitric oxide synthase.”
7 of 7

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?

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.

  • Thiazolidinediones described as both PPAR-gamma antagonists and agonists

    Minor

    Table 1 calls thiazolidinediones PPAR-gamma antagonists, while the main text calls them agonists.

  • Omega-3 cognition trial contradicts table's claim of no trials

    Minor

    Table 1 states that no clinical trial has investigated omega-3 effects on cognition in MDD, but the main text describes an RCT measuring cognition in depressed patients.

2 of 2

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Authors
Bortolato, B., Miskowiak, K. W., Köhler, C. A., Maes, M., Fernandes, B. S., Berk, M., & Carvalho, A. F.
Affiliations
  • University of Padua (IT)
  • Copenhagen University Hospital (DK)
  • Universidade Federal do Ceará (BR)
  • Deakin University (AU)
  • Universidade Federal do Rio Grande do Sul (BR)
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-01-22
Volume
14
Issue
1
Pages
9-9
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-016-0560-3
PMC
PMC4724131
OpenAlex
W2264576686
Semantic Scholar
ff474a091e9300a6374d6b59c15f1e55ca7ac09b
Cited by
252
References
197
Citations by year
2026: 16 · 2025: 25 · 2024: 22 · 2023: 16 · 2022: 38 · 2021: 32 · 2020: 32 · 2019: 22 · 2018: 19 · 2017: 19 · 2016: 11
FWCI
2.72
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Health and Medical Research Council (1059660)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
major depressive disorder, cognitive impairment, antidepressants, vortioxetine, lisdexamfetamine dimesylate, erythropoietin, executive dysfunction, verbal memory, attention, nootropic drugs, drug repurposing, functional recovery
MeSH terms
Adult, Antidepressive Agents, Attention, Cognition, Cognition Disorders, Major Depressive Disorder, Depressive Disorder, Major, Humans, Memory, Remission Induction, Meta-Analysis as Topic, Nootropic Agents, Recovery of Function

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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 2026-10-10.

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

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