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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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
• Partly supported

  The Abstract reports that MDD is reliably associated with impaired performance on neuropsychological measures of executive function, and the Conclusions describe those impairments as significant. But the Objectives say the analysis was limited to MDD and did not determine whether the deficits are specific to MDD or shared across disorders. This source therefore does not establish the claim about many major psychiatric disorders. (LLM, conf=0.88)

  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. sourceExperimental — accuracy not yet measured
• Not checked yetcites [35] McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord. 2009;119(1–3):1–8. source

In the paper

“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.”

What the sources say

• Supported

  The Discussion says that neurocognitive tests, particularly those dependent on psychomotor speed, may differentially predict response to an SSRI or serotonergic dual therapy versus bupropion. The Methods specify that the serotonergic group included patients receiving the SNRI duloxetine; SNRI outcomes were pooled with other serotonergic treatments rather than assessed separately. (LLM, conf=0.90)

  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

In the paper

“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].”

What the sources say

• Supported

  The Methylation section describes SAMe as a methyl donor and says SAMe-dependent methylation is required for the synthesis and inactivation of several neurotransmitter monoamines. The Biological Importance of SAMe and Transsulfuration sections identify SAMe as a precursor to the transsulfuration pathway, which ultimately leads to glutathione synthesis. (LLM, conf=0.94)

  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

In the paper

“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.”

What the sources say

• Supported

  The Discussion reports an inverse relationship between cardiometabolic risk markers and cognitive performance in healthy subjects. It also says this finding highlights the potential of a preventive dietary approach to address both metabolic disorders and associated cognitive decline. The claim preserves that tentative framing. (LLM, conf=0.94)

  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

In the paper

“Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase.”

What the sources say

• Not checked yetcites [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

In the paper

“Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [4] Stahl SM, Grady MM. Differences in mechanism of action between current and future antidepressants. J Clin Psychiatry. 2003;64 Suppl 13:13–7.

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [2] Stotland NL. Recovery from depression. Psychiatr Clin North Am. 2012;35(1):37–49. source
• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [1] Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Ann Rev Public Health. 2013;34:119–38. source
• Not checked yetcites [2] Stotland NL. Recovery from depression. Psychiatr Clin North Am. 2012;35(1):37–49. source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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.

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Importantly, it has been suggested that workplace impairment may contribute to more than 60 % of the MDD-related economic burden [47].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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.

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [65] Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22.

In the paper

“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].”

What the sources say

• Not checked yetcites [57] McIntyre RS. Using measurement strategies to identify and monitor residual symptoms. J Clin Psychiatry. 2013;74 Suppl 2:14–8. source
• Not checked yetcites [58] Trivedi MH, Greer TL. Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord. 2014;152–154:19–27. source

In the paper

“However, the concept of remission provides only a vague theoretical definition that may be influenced by the psychometric limitations of available instruments [52, 53].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [65] Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22.

In the paper

“Furthermore, remission does not equate to recovery.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“However, some compounds under preliminary investigation show promising results with respect to their procognitive potential.”

In the paper

“Finally, psychotropic agents may have a similar effect on the immune system and, consequently, on cognitive performance [86, 87].”

What the sources say

• Not checked yetcites [86] McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009;33(3):355–66. source
• Not checked yetcites [87] Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25(2):181–213. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“Moreover, it exerts antioxidant properties by suppressing free radical generation and attenuates increases in lipid peroxidation [100]”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“modulates glutamate transmission reducing glutamate release and excitotoxicity, and may indirectly target the monoaminergic system [101].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [99] Dean OM, Data-Franco J, Giorlando F, Berk M. Minocycline: therapeutic potential in psychiatry. CNS Drugs. 2012;26(5):391–401. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Both vortioxetine and duloxetine were significantly superior to the placebo in reducing depressive symptoms assessed by MADRS.”

What the sources say

• Not checked yetcites [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

In the paper

“In addition, metformin improved memory performance (assessed by the Wechsler Memory Scale-Revised), which was significantly related to a decrease in depressive symptoms [122].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“ACE inhibitors have immune-modulating properties and suppress cytokine production (e.g. IL-1, TNF-α), likely through interference with NF-κB activation [123].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [131] Salazar MR. Alpha lipoic acid: a novel treatment for depression. Med Hypotheses. 2000;55(6):510–2. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“However, they both enrolled small samples, with that by Holtzheimer et al. [150] enrolling only elderly participants.”

What the sources say

• Not checked yetcites [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

In the paper

“Cognitive studies of NAC have produced inconsistent results, which may be linked to variations in study design [155].”

What the sources say

• Not checked yetcites [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

In the paper

“Curcumin is a pleiotropic agent that targets immune-inflammatory and oxidative and nitrosative stress pathways and promotes neuroprotection and improved neurogenesis [165, 166].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“However, few studies have investigated the effects of n-3 PUFAs on cognition, yielding inconclusive results to date.”

In the paper

“Acute curcumin administration improved performance on tasks that measured sustained attention and working memory, whereas chronic treatment also improved mood and fatigue [164].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [151] Elgamal S, MacQueen G. Galantamine as an adjunctive treatment in major depression. J Clin Psychopharmacol. 2008;28(3):357–9. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“However, no trial to date has evaluated the effects of statin members as cognitive enhancers for patients with MDD.”

In the paper

“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).”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“As an antioxidant, CoQ10 protects cells from the damaging effects of reactive oxygen species and reactive nitrogen species [177].”

What the sources say

• Not checked yetcites [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

In the paper

“Atorvastatin also promotes antidepressant-like effects and increases hippocampal BDNF levels in rodents [169].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

In the paper

“The data are preliminary across these agents and are promising for EPO, SAMe, insulin, NAC, and antidiabetic agents.”

In the paper

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

In the paper

“The group allocated to atorvastatin showed lower HDRS scores by the end of the trial; however, no participant achieved remission.”

What the sources say

• Not checked yetcites [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

In the paper

“CoQ10 displays antidepressant-like effects in chronically stressed rats, with a reduction in hippocampal oxidative/nitrosative DNA damage [181].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“at study completion, the latter showed significantly lower depressive symptoms, whereas differences in remission rates did not achieve statistical significance.”

What the sources say

• Not checked yetcites [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