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

In the paper

“Finally, a meta-analysis of 27 studies investigating euthymic adult subjects with MDD showed that executive dysfunction (namely lower inhibitory control) could persist after improvement of depressive symptoms [39].”

What the sources say

• Supported

  The Abstract states that the meta-analysis included 27 studies of euthymic adults with MDD and concludes that poor response inhibition is likely to persist. The Cognitive domains section also reports significantly poorer Stroop interference performance in euthymic MDD patients than in healthy controls, supporting the inhibitory-control finding. (LLM, conf=0.94)

  cites [39] Bora E, Harrison BJ, Yucel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med. 2013;43(10):2017–26. source

In the paper

“In adults with late-life MDD (n = 177), greater pretreatment verbal memory was associated with better treatment response [75].”

What the sources say

• Partly supported

  The Methods (Participants) state that participants were aged 60 or older and met criteria for major depressive disorder. The Results report that better baseline verbal-memory performance was associated with stronger treatment response, but 177 was the baseline sample; only 103 patients had the one-year follow-up used to assess response. Thus the cited n=177 overstates the sample for that association. (LLM, conf=0.88)

  cites [75] Story TJ, Potter GG, Attix DK, Welsh-Bohmer KA, Steffens DC. Neurocognitive correlates of response to treatment in late-life depression. Am J Geriatr Psychiatry. 2008;16(9):752–9. sourceExperimental — accuracy not yet measured

In the paper

“Insulin resistance and adiposity have been associated with poor cognitive performance on tasks of attention, memory, and processing speed even in non-diabetic population-based samples of middle-aged individuals [112].”

What the sources say

• Partly supported

  The Results (page unavailable) report that adiposity was associated with poorer processing-speed performance in the non-diabetic, middle-aged sample. They also state that no metabolic markers were associated with poor performance on the word-list learning or word-fluency tests, and that the association between insulin resistance and Stroop performance was not significant after adjustment for adiposity. The claim therefore overstates the cognitive domains affected and omits an important qualification on insulin resistance. (LLM, conf=0.91)

  cites [112] Sanz CM, Ruidavets JB, Bongard V, Marquie JC, Hanaire H, Ferrieres J, et al. Relationship between markers of insulin resistance, markers of adiposity, HbA1c, and cognitive functions in a middle-aged population-based sample: the MONA LISA study. Diabetes Care. 2013;36(6):1512–21. sourceExperimental — accuracy not yet measured

In the paper

“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).”

In the paper

“Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD.”

What the sources say

• 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 [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 yetcites [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

In the paper

“Impairments in executive function and attention may persist after the affective symptoms are fully mitigated [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

“The management of cognitive dysfunction remains an unmet need in the treatment of MDD.”

In the paper

“A significant body of evidence shows that individuals with MDD exhibit clinically significant cognitive impairment across multiple domains.”

In the paper

“In addition, a significant proportion of patients with MDD do not recover baseline levels of psychosocial functioning even when they meet the conventional definition of remission (e.g. a score ≤7 on the Hamilton Depression Rating Scale (HDRS)) [2, 11, 12], suggesting that non-affective dimensions and domains are critical determinants of functional outcome.”

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

“Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD.”

What the sources say

• Not checked yetcites [97] Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacol. 2014;39(6):1399–408. source

In the paper

“Furthermore, some pilot studies show that cognitive deficits in MDD patients may predict non-response to treatment with selective serotonin reuptake inhibitors (SSRIs) or dual serotonergic-noradrenergic reuptake inhibitors (SNRIs), indicating that poor performance in selected cognitive domains may define a patient subgroup that requires complex or additional treatment [21–23].”

What the sources say

• Not checked yetcites [21] Dunkin JJ, Leuchter AF, Cook IA, Kasl-Godley JE, Abrams M, Rosenberg-Thompson S. Executive dysfunction predicts nonresponse to fluoxetine in major depression. J Affect Disord. 2000;60(1):13–23. source
• Not checked yetcites [22] Gorlyn M, Keilp JG, Grunebaum MF, Taylor BP, Oquendo MA, Bruder GE, et al. Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects. J Neural Transm (Vienna). 2008;115(8):1213–9. source
• Not checked yetcites [23] Herrera-Guzman I, Gudayol-Ferre E, Lira-Mandujano J, Herrera-Abarca J, Herrera-Guzman D, Montoya-Perez K, et al. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res. 2008;160(1):72–82. source

In the paper

“Altogether, these variables likely play a major role in producing the inconclusive findings reported in available studies [28].”

What the sources say

• Not checked yetcites [28] Beblo T, Sinnamon G, Baune BT. Specifying the neuropsychology of affective disorders: clinical, demographic and neurobiological factors. Neuropsychol Rev. 2011;21(4):337–59. source

In the paper

“Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD.”

What the sources say

• Not checked yetcites [94] Madhoo M, Keefe RS, Roth RM, Sambunaris A, Wu J, Trivedi MH, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacol. 2014;39(6):1388–98. source

In the paper

“Notwithstanding the heterogeneity across individual studies, the most replicated findings indicate that cognitive impairment in MDD encompasses several domains, notably attention, memory, psychomotor speed, and executive function [7–9].”

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

“However, a significant proportion of MDD patients continue to experience significant cognitive impairment.”

What the sources say

• Not checked yetcites [17] Biringer E, Lundervold A, Stordal K, Mykletun A, Egeland J, Bottlender R, et al. Executive function improvement upon remission of recurrent unipolar depression. Eur Arch Psychiatry Clin Neurosci. 2005;255(6):373–80. source
• Not checked yetcites [18] Behnken A, Schoning S, Gerss J, Konrad C, de Jong-Meyer R, Zwanzger P, et al. Persistent non-verbal memory impairment in remitted major depression - caused by encoding deficits? J Affect Disord. 2010;122(1–2):144–8. source
• Not checked yetcites [19] Herrera-Guzman I, Gudayol-Ferre E, Herrera-Guzman D, Guardia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009;43(9):855–63. source
• 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

“However, a subpopulation of MDD patients (approximately 20 %) exhibited deficits of two standard deviations below the mean on two or more cognitive domains [6].”

What the sources say

• Not checked yetcites [6] Gualtieri CT, Morgan DW. The frequency of cognitive impairment in patients with anxiety, depression, and bipolar disorder: an unaccounted source of variance in clinical trials. J Clin Psychiatry. 2008;69(7):1122–30. source

In the paper

“Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD.”

In the paper

“Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement.”

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
• 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

“This finding is particularly important when considering that impairments in psychosocial functioning, notably decrements in work productivity, are key determinants of MDD-related societal costs [13].”

What the sources say

• Not checked yetcites [13] Ekman M, Granstrom O, Omerov S, Jacob J, Landen M. The societal cost of depression: evidence from 10,000 Swedish patients in psychiatric care. J Affect Disord. 2013;150(3):790–7. source

In the paper

“Several lines of evidence suggest that cognitive dysfunction is an important mediator of functioning, including workforce performance, in MDD [14–16].”

What the sources say

• 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 [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 yetcites [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

In the paper

“The most frequent findings include small to moderate deficits in attention [22], working memory [25], learning [10], processing speed [26], and executive functions [27].”

What the sources say

• Not checked yetcites [22] Gorlyn M, Keilp JG, Grunebaum MF, Taylor BP, Oquendo MA, Bruder GE, et al. Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects. J Neural Transm (Vienna). 2008;115(8):1213–9. source
• Not checked yetcites [25] Gupta M, Holshausen K, Best MW, Jokic R, Milev R, Bernard T, et al. Relationships among neurocognition, symptoms, and functioning in treatment-resistant depression. Arch Clin Neuropsychol. 2013;28(3):272–81. source
• 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

“Moreover, proper adjustment for confounding factors (e.g. depression severity or practice effects) is frequently lacking, which further complicates the analysis of available evidence [29].”

What the sources say

• Not checked yetcites [29] McClintock SM, Husain MM, Greer TL, Cullum CM. Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis. Neuropsychology. 2010;24(1):9–34. source

In the paper

“Data from The European Study of the Epidemiology of Mental Disorders, a cross-sectional survey including 21,425 adults from six European countries, reported that cognitive deficits and embarrassment (i.e. stigma) account for half of the association between a MDE and work loss [15].”

What the sources say

• Not checked yetcites [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

In the paper

“In keeping with the view that broad-based cognitive deficits are associated with MDD, the presence of significant deficits in executive functions and psychomotor speed in adults with MDD has been confirmed by a separate meta-analysis of 113 studies (Cohen’s d effect sizes ranging from −0.32 to −0.97) [34].”

What the sources say

• Not checked yetcites [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

In the paper

“Furthermore, preliminary evidence suggests that cognitive impairment may even pre-date the onset of clinically significant depressive symptoms.”

What the sources say

• Not checked yetcites [26] Simons CJ, Jacobs N, Derom C, Thiery E, Jolles J, van Os J, et al. Cognition as predictor of current and follow-up depressive symptoms in the general population. Acta Psychiatr Scand. 2009;120(1):45–52. source
• Not checked yetcites [41] Airaksinen E, Wahlin A, Forsell Y, Larsson M. Low episodic memory performance as a premorbid marker of depression: evidence from a 3-year follow-up. Acta Psychiatr Scand. 2007;115(6):458–65. source

In the paper

“Current evidence supports a putative mediational role of cognitive dysfunction in psychosocial functioning, notably workforce productivity [45, 46].”

What the sources say

• Not checked yetcites [45] Adler DA, McLaughlin TJ, Rogers WH, Chang H, Lapitsky L, Lerner D. Job performance deficits due to depression. Am J Psychiatry. 2006;163(9):1569–76. source
• Not checked yetcites [46] Wang PS, Beck AL, Berglund P, McKenas DK, Pronk NP, Simon GE, et al. Effects of major depression on moment-in-time work performance. Am J Psychiatry. 2004;161(10):1885–91. source

In the paper

“Different population-based studies have suggested that poor performance in tests of episodic memory may predict the onset of depressive symptoms [26, 41].”

What the sources say

• Not checked yetcites [26] Simons CJ, Jacobs N, Derom C, Thiery E, Jolles J, van Os J, et al. Cognition as predictor of current and follow-up depressive symptoms in the general population. Acta Psychiatr Scand. 2009;120(1):45–52. source
• Not checked yetcites [41] Airaksinen E, Wahlin A, Forsell Y, Larsson M. Low episodic memory performance as a premorbid marker of depression: evidence from a 3-year follow-up. Acta Psychiatr Scand. 2007;115(6):458–65. source

In the paper

“In this same vein, Jaeger et al. [16] measured the neurocognitive performance of patients following hospitalization for an MDE and documented that more pronounced neurocognitive deficits at 6 months follow-up were associated with poorer functional outcome and greater disability.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, these analyses noted an effect of age as a correlate of poor cognitive performance in MDD, introducing disparate etiopathogenic mechanisms (e.g. vascular and neurodegenerative factors).”

What the sources say

• Not checked yetcites [39] Bora E, Harrison BJ, Yucel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med. 2013;43(10):2017–26. source

In the paper

“Moreover, the large-scale Vietnam Era Twin Study showed that, after adjustment for confounders, a lower score on a general cognitive measure was associated with increased risk of developing depressive symptoms [42].”

What the sources say

• Not checked yetcites [42] Franz CE, Lyons MJ, O'Brien R, Panizzon MS, Kim K, Bhat R, et al. A 35-year longitudinal assessment of cognition and midlife depression symptoms: the Vietnam Era Twin Study of Aging. Am J Geriatr Psychiatry. 2011;19(6):559–70. source

In the paper

“Consistent with these data, results from a study involving fully employed adults with MDD documented a significant interference of subjective cognitive deficits with workplace role-functioning, regardless of antidepressant therapy [48].”

What the sources say

• Not checked yetcites [48] Lawrence C, Roy A, Harikrishnan V, Yu S, Dabbous O. Association between severity of depression and self-perceived cognitive difficulties among full-time employees. Prim Care Companion CNS Disord. 2013;15:3.

In the paper

“In addition, cognitive impairment is a principal determinant of quality of life and function.”

In the paper

“In a subsequent study of individuals with unipolar depressive disorder in remission, Hasselbalch et al. [38] reported that the severity of cognitive impairment increases as a function of the cumulative duration of MDEs and, additionally, indicated that the occurrence of psychotic features is associated with worse cognitive performance.”

What the sources say

• Not checked yetcites [38] Hasselbalch BJ, Knorr U, Hasselbalch SG, Gade A, Kessing LV. The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder. Eur Psychiatry. 2013;28(6):349–55. source

In the paper

“In a subsequent study of individuals with unipolar depressive disorder in remission, Hasselbalch et al. [38] reported that the severity of cognitive impairment increases as a function of the cumulative duration of MDEs and, additionally, indicated that the occurrence of psychotic features is associated with worse cognitive performance.”

What the sources say

• Not checked yetcites [38] Hasselbalch BJ, Knorr U, Hasselbalch SG, Gade A, Kessing LV. The cumulative load of depressive illness is associated with cognitive function in the remitted state of unipolar depressive disorder. Eur Psychiatry. 2013;28(6):349–55. 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

“A recent systematic review further suggests a putative mediational role of neurocognitive impairment in functioning, including workforce performance, among individuals with MDD [30].”

What the sources say

• Not checked yetcites [30] Evans VC, Iverson GL, Yatham LN, Lam RW. The relationship between neurocognitive and psychosocial functioning in major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(12):1359–70. source

In the paper

“Despite both escitalopram and duloxetine improving measures of working memory, attention, executive function, mental processing and speed, and motor performance, the improvement induced by duloxetine was greater than that induced by escitalopram in episodic and working memory.”

What the sources say

• Not checked yetcites [19] Herrera-Guzman I, Gudayol-Ferre E, Herrera-Guzman D, Guardia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009;43(9):855–63. source

In the paper

“Importantly, improvements in cognitive performance were not correlated with the degree of amelioration of depressive symptoms, suggesting that they were not entirely accounted for by the resolution of the MDE.”

What the sources say

• Not checked yetcites [66] Borkowska A, Drozdz W, Ziolkowska-Kochan M, Rybakowski J. Enhancing effect of mirtazapine on cognitive functions associated with prefrontal cortex in patients with recurrent depression. Neuropsychopharmacol Hung. 2007;9(3):131–6.

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].”

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 [64] Soczynska JK, Ravindran LN, Styra R, McIntyre RS, Cyriac A, Manierka MS, et al. The effect of bupropion XL and escitalopram on memory and functional outcomes in adults with major depressive disorder: results from a randomized controlled trial. Psychiatry Res. 2014;220(1–2):245–50. source

In the paper

“The beneficial effects of mirtazapine on cognition after 3 months of treatment were reported in a study of individuals in an acute MDE [66].”

What the sources say

• Not checked yetcites [66] Borkowska A, Drozdz W, Ziolkowska-Kochan M, Rybakowski J. Enhancing effect of mirtazapine on cognitive functions associated with prefrontal cortex in patients with recurrent depression. Neuropsychopharmacol Hung. 2007;9(3):131–6.

In the paper

“Duloxetine treatment for 8 weeks was associated with an increase in a composite cognitive index relative to that measured for a placebo group.”

What the sources say

• Not checked yetcites [69] Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164(6):900–9. source

In the paper

“In recent decades, the target clinical endpoints for MDD treatment have evolved from response (i.e. a 50 % reduction in severity of depressive symptoms from baseline) to the objective of clinical remission [49].”

What the sources say

• Not checked yetcites [49] Carvalho AF, Berk M, Hyphantis TN, McIntyre RS. The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom. 2014;83(2):70–88. source

In the paper

“Changes in the cognitive composite index were partially independent of improvements in overall depression severity.”

What the sources say

• Not checked yetcites [69] Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164(6):900–9. source

In the paper

“In a recent 8-week, double-blind, comparative randomized controlled trial (RCT) of SSRIs (escitalopram) and bupropion on adults with MDD (n = 36), both treatments were significantly associated with improved immediate as well as delayed verbal and non-verbal memory, global function, and measures of work productivity [64].”

What the sources say

• Not checked yetcites [64] Soczynska JK, Ravindran LN, Styra R, McIntyre RS, Cyriac A, Manierka MS, et al. The effect of bupropion XL and escitalopram on memory and functional outcomes in adults with major depressive disorder: results from a randomized controlled trial. Psychiatry Res. 2014;220(1–2):245–50. source

In the paper

“However, inconsistent with these findings, duloxetine did not differ from a placebo in several assessed cognitive domains in a recent study on elderly individuals with MDD [71].”

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

“Interventions that target multiple neurochemical systems simultaneously (e.g. SNRIs) might be more likely to improve cognitive performance than treatments targeting only a single system (e.g. SSRIs) [68].”

What the sources say

• Not checked yetcites [68] Herrera-Guzman I, Gudayol-Ferre E, Herrera-Abarca JE, Herrera-Guzman D, Montelongo-Pedraza P, Padros Blazquez F, et al. Major depressive disorder in recovery and neuropsychological functioning: effects of selective serotonin reuptake inhibitor and dual inhibitor depression treatments on residual cognitive deficits in patients with major depressive disorder in recovery. J Affect Disord. 2010;123(1–3):341–50. source

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].”

In the paper

“In fact, the acknowledgement that even subthreshold depressive symptoms may be associated with substantial psychosocial impairment has led some experts to postulate that functional recovery is likely to represent the proper target for MDD treatment [2].”

What the sources say

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

In the paper

“For instance, a trial including adults with MDD treated with escitalopram (SSRI; n = 36) or duloxetine (SNRI; n = 37) for 24 weeks showed that SNRIs were superior to SSRIs in ameliorating memory performance [19].”

What the sources say

• Not checked yetcites [19] Herrera-Guzman I, Gudayol-Ferre E, Herrera-Guzman D, Guardia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009;43(9):855–63. source

In the paper

“Moreover, two studies showed that treatment with sertraline is associated with significant improvements in psychomotor speed and executive functions [61, 62].”

What the sources say

• Not checked yetcites [61] Schrijvers D, Maas YJ, Pier MP, Madani Y, Hulstijn W, Sabbe BG. Psychomotor changes in major depressive disorder during sertraline treatment. Neuropsychobiology. 2009;59(1):34–42. source
• Not checked yetcites [62] Constant EL, Adam S, Gillain B, Seron X, Bruyer R, Seghers A. Effects of sertraline on depressive symptoms and attentional and executive functions in major depression. Depress Anxiety. 2005;21(2):78–89. source

In the paper

“Finally, tianepine treatment for 3 months significantly improved cognitive functions (i.e. short-term memory and learning, as well as reaction time and attention) in patients with mild and moderate MDD [67].”

What the sources say

• Not checked yetcites [67] Klasik A, Krysta K, Krupka-Matuszczyk I. Effect of tianeptine on cognitive functions in patients with depressive disorders during a 3-month observation. Psychiatr Danub. 2011;23 Suppl 1:S18–22.

In the paper

“Even a score of 7 on the HDRS, for example, may not reflect true remission [54], and it has been suggested that lower scores (<5) correlate with objective cutoff points.”

What the sources say

• Not checked yetcites [54] Berk M, Ng F, Wang WV, Calabrese JR, Mitchell PB, Malhi GS, et al. The empirical redefinition of the psychometric criteria for remission in bipolar disorder. J Affect Disord. 2008;106(1–2):153–8. source

In the paper

“A recent meta-analysis further indicates that standard antidepressant drugs may ameliorate certain cognitive domains in patients with MDD, namely psychomotor speed and delayed recall [20].”

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

“More recently, the cognitive-enhancing effects of duloxetine have been further supported by a 12-week study including adults presenting MDD with baseline cognitive deficits (n = 30) [70].”

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

“For example, it was reported that SSRI treatment led to a significant improvement in memory performance (i.e. immediate and delayed verbal, immediate visual, and declarative memory) in individuals with MDD [59, 60].”

What the sources say

• Not checked yetcites [59] Vythilingam M, Vermetten E, Anderson GM, Luckenbaugh D, Anderson ER, Snow J, et al. Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol Psychiatry. 2004;56(2):101–12. source
• Not checked yetcites [60] Wroolie TE, Williams KE, Keller J, Zappert LN, Shelton SD, Kenna HA, et al. Mood and neuropsychological changes in women with midlife depression treated with escitalopram. J Clin Psychopharmacol. 2006;26(4):361–6. source

In the paper

“Thus, these factors might represent trait-like markers of MDD [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

“Subjects with late-onset depression (i.e. >60 years old) are likely to experience increased impairment in verbal memory, processing speed, and executive function with respect to depressed adults [39].”

What the sources say

• Not checked yetcites [39] Bora E, Harrison BJ, Yucel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med. 2013;43(10):2017–26. source

In the paper

“Long-term therapy with certain antidepressants may also be linked to cognitive side effects in adult subjects with MDD.”

What the sources say

• Not checked yetcites [80] Fava M, Graves LM, Benazzi F, Scalia MJ, Iosifescu DV, Alpert JE, et al. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry. 2006;67(11):1754–9. source

In the paper

“Thus, the authors concluded that specific cognitive deficits per se do not offer a reliable basis for making clinical judgments about probable illness course, in contrast to the depression-executive dysfunction model, according to which the occurrence of executive dysfunction portends poor response to antidepressant medication.”

What the sources say

• Not checked yetcites [79] McLennan SN, Mathias JL. The depression-executive dysfunction (DED) syndrome and response to antidepressants: a meta-analytic review. Int J Geriatr Psychiatry. 2010;25(10):933–44. source

In the paper

“A systematic review showed that different antidepressant treatments induced smaller changes in measures of executive function and attention, despite clinically perceived changes in verbal learning, memory, verbal fluency, and psychomotor speed.”

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

“Significant impairment of executive functioning (i.e. phonemic fluency) has also been reported following treatment with SSRIs [60].”

What the sources say

• Not checked yetcites [60] Wroolie TE, Williams KE, Keller J, Zappert LN, Shelton SD, Kenna HA, et al. Mood and neuropsychological changes in women with midlife depression treated with escitalopram. J Clin Psychopharmacol. 2006;26(4):361–6. source

In the paper

“Indeed, the effects of antidepressants on cognitive performance in the elderly are likely negatively influenced by the combined effects of comorbidities and a greater likelihood of side effects.”

In the paper

“Accordingly, another cross-sectional study that investigated the effects of different antidepressants on cognitive performance suggested that class-specific side effects may account, at least in part, for the long-lasting cognitive deficits observed in subjects with MDD in remission [81].”

What the sources say

• Not checked yetcites [81] Nagane A, Baba H, Nakano Y, Maeshima H, Hukatsu M, Ozawa K, et al. Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants. Psychiatry Res. 2014;218(1–2):101–5. source

In the paper

“For instance, a small study that enrolled adults with MDD (n = 20) evaluated the effects of 8 weeks of bupropion treatment (150 mg/day) on cognitive performance and reported that lower pretreatment performance on visual memory and processing speed tasks predicts better treatment response [23], supporting the hypothesis that depressed patients with psychomotor slowing may show greater response to”

What the sources say

• Not checked yetcites [23] Herrera-Guzman I, Gudayol-Ferre E, Lira-Mandujano J, Herrera-Abarca J, Herrera-Guzman D, Montoya-Perez K, et al. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res. 2008;160(1):72–82. source

In the paper

“Despite evidence of cognitive impairment in medication-free individuals with MDD [83], different domains of global cognition might be negatively affected by class-specific antidepressant side effects.”

What the sources say

• Not checked yetcites [83] Weiland-Fiedler P, Erickson K, Waldeck T, Luckenbaugh DA, Pike D, Bonne O, et al. Evidence for continuing neuropsychological impairments in depression. J Affect Disord. 2004;82(2):253–8. source

In the paper

“Individuals from both antidepressant groups, but not from the medication-free group, showed poorer performance in visual memory with respect to healthy controls.”

What the sources say

• Not checked yetcites [81] Nagane A, Baba H, Nakano Y, Maeshima H, Hukatsu M, Ozawa K, et al. Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants. Psychiatry Res. 2014;218(1–2):101–5. source

In the paper

“The pathways whereby this effect occurs are opaque; changes in appetite and energy balance may have negative effects on cognition because interference in the metabolism of glucose may lead to insulin resistance [84], abnormal neurotransmitter turnover, mitochondrial dysfunction, and energy deficits, as well as changes in neural plasticity [85].”

What the sources say

• Not checked yetcites [84] McIntyre RS, Rasgon NL, Kemp DE, Nguyen HT, Law CW, Taylor VH, et al. Metabolic syndrome and major depressive disorder: co-occurrence and pathophysiologic overlap. Curr Diab Rep. 2009;9(1):51–9. source
• Not checked yetcites [85] Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012;11(2):141–68. source

In the paper

“This deleterious effect might be explained at least in part by the anticholinergic effects of some TCAs [82].”

What the sources say

• Not checked yetcites [82] Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 2000;403:17–25. source

In the paper

“Conversely, a neurocognitive profile characterized by psychomotor slowing may aid in the identification of a subgroup of patients with MDD who are less likely to respond to SSRI monotherapy [73].”

What the sources say

• Not checked yetcites [73] Taylor BP, Bruder GE, Stewart JW, McGrath PJ, Halperin J, Ehrlichman H, et al. Psychomotor slowing as a predictor of fluoxetine nonresponse in depressed outpatients. Am J Psychiatry. 2006;163(1):73–8. source

In the paper

“However, a meta-analysis of 17 studies of late-life MDD indicated that better performance on tests of executive function (i.e. Dementia Rating Scale initiation and perseveration subtest) and non-executive function (including two tests of psychomotor speed, one test of construction, and one test of memory) is associated with response to antidepressant treatment [79].”

What the sources say

• Not checked yetcites [79] McLennan SN, Mathias JL. The depression-executive dysfunction (DED) syndrome and response to antidepressants: a meta-analytic review. Int J Geriatr Psychiatry. 2010;25(10):933–44. source

In the paper

“For instance, treatment with antidepressants has been associated with increased cognitive deficits, such as apathy, inattentiveness, forgetfulness, word-finding difficulty, and mental slowing, in depressed individuals reaching partial or full remission (n = 117) [80].”

What the sources say

• Not checked yetcites [80] Fava M, Graves LM, Benazzi F, Scalia MJ, Iosifescu DV, Alpert JE, et al. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry. 2006;67(11):1754–9. source

In the paper

“The major caveat of studies showing the efficacy of antidepressant therapy in treating cognitive deficits is the over-representation of elderly subjects (age >65 years) in the samples, which limits their external validity.”

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

“Regarding executive function, only subjects in the TCA group showed worse performance than the controls.”

What the sources say

• Not checked yetcites [81] Nagane A, Baba H, Nakano Y, Maeshima H, Hukatsu M, Ozawa K, et al. Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants. Psychiatry Res. 2014;218(1–2):101–5. source

In the paper

“Although EPO did not show effects distinct from those of a placebo on the primary outcome measure (i.e. HDRS scores), it produced long-term mood-independent improvement in verbal learning and memory on the RAVLT.”

What the sources say

• Not checked yetcites [97] Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacol. 2014;39(6):1399–408. source

In the paper

“Preclinical studies have shown that vortioxetine may influence learning and memory processes by improving hippocampal synaptic plasticity and increasing the output of pyramidal cells [89].”

What the sources say

• Not checked yetcites [89] Dale E, Zhang H, Leiser SC, Xiao Y, Lu D, Yang CR, et al. Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus. J Psychopharmacol. 2014;28(10):891–902. source

In the paper

“Notably, these effects were accompanied by (and correlated with) reversal of subfield hippocampal volume loss [98].”

What the sources say

• Not checked yetcites [98] Miskowiak KW, Vinberg M, Macoveanu J, Ehrenreich H, Koster N, Inkster B, et al. Effects of erythropoietin on hippocampal volume and memory in mood disorders. Biol Psychiatry. 2015;78(4):270–7. source

In the paper

“However, one limitation of this study was the use of a self-report questionnaire to assess executive function since subjective ratings of cognitive deficits do not necessarily correlate with objective impairments [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

“Although EPO did not show effects distinct from those of a placebo on the primary outcome measure (i.e. HDRS scores), it produced long-term mood-independent improvement in verbal learning and memory on the RAVLT.”

What the sources say

• Not checked yetcites [97] Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacol. 2014;39(6):1399–408. source

In the paper

“The procognitive effects of LDX in MDD were suggested by an RCT that investigated LDX effects on cognitive performance in adult subjects with mild MDD (n = 143) and long-lasting executive impairment as assessed by the Behavior Rating Inventory of Executive Function – Adult Version self-report global executive composite T score. LDX (20–70 mg/day) used as augmentation therapy improved the executive”

What the sources say

• Not checked yetcites [94] Madhoo M, Keefe RS, Roth RM, Sambunaris A, Wu J, Trivedi MH, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacol. 2014;39(6):1388–98. source

In the paper

“Taken together, these findings suggest that EPO may have cognitive-enhancing effects in MDD.”

In the paper

“add-on administration of minocycline for 22 weeks was associated with improvements in executive functions in individuals with early-phase schizophrenia [107].”

What the sources say

• Not checked yetcites [107] Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71(2):138–49. source

In the paper

“Preliminary findings from an open-label study confirmed minocycline antidepressant potential in individuals with unipolar psychotic depression [108].”

What the sources say

• Not checked yetcites [108] Miyaoka T, Wake R, Furuya M, Liaury K, Ieda M, Kawakami K, et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(2):222–6. source

In the paper

“In a proof-of-concept RCT on MDD patients exhibiting residual symptoms after treatment with the SSRI escitalopram, add-on LDX administration was effective in reducing depressive symptoms (assessed by MADRS) [93].”

What the sources say

• Not checked yetcites [93] Trivedi MH, Cutler AJ, Richards C, Lasser R, Geibel BB, Gao J, et al. A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802–9. source

In the paper

“Preclinical evidence suggests that minocycline may reduce cognitive impairment [103, 104].”

What the sources say

• Not checked yetcites [103] Kong F, Chen S, Cheng Y, Ma L, Lu H, Zhang H, et al. Minocycline attenuates cognitive impairment induced by isoflurane anesthesia in aged rats. PLoS One. 2013;8(4):e61385. source
• Not checked yetcites [104] Haber M, Abdel Baki SG, Grinkina NM, Irizarry R, Ershova A, Orsi S, et al. Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury. Exp Neurol. 2013;249:169–77. source

In the paper

“there is evidence that pro-inflammatory status may also correlate with poor neurocognitive performance [102].”

What the sources say

• Not checked yetcites [102] Chang HH, Lee IH, Gean PW, Lee SY, Chi MH, Yang YK, et al. Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun. 2012;26(1):90–5. source

In the paper

“Two separate RCTs on HIV-1-infected individuals with progressive neurocognitive decline reported that treatment with adjunctive minocycline for 24 weeks was not associated with significant improvements in cognitive performance [105, 106].”

What the sources say

• Not checked yetcites [105] Nakasujja N, Miyahara S, Evans S, Lee A, Musisi S, Katabira E, et al. Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment. Neurology. 2013;80(2):196–202. source
• Not checked yetcites [106] Sacktor N, Miyahara S, Deng L, Evans S, Schifitto G, Cohen BA, et al. Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial. Neurology. 2011;77(12):1135–42. source

In the paper

“Four separate RCTs suggested the efficacy of ALC over a placebo in mitigating depressive symptoms in MDD [128].”

What the sources say

• Not checked yetcites [128] Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU. A review of current evidence for acetyl-l-carnitine in the treatment of depression. J Psychiatr Res. 2014;53:30–7. source

In the paper

“The procognitive potential of SAMe was preliminarily documented in a 6-week RCT on 40 SSRI-resistant outpatients with MDD [127].”

What the sources say

• Not checked yetcites [127] Levkovitz Y, Alpert JE, Brintz CE, Mischoulon D, Papakostas GI. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. J Affect Disord. 2012;136(3):1174–8. source

In the paper

“In a 6-week RCT on individuals with moderate-to-severe MDD (n = 40) without diabetes or metabolic syndrome, adjunctive treatment with pioglitazone was associated with greater decrements in HDRS compared with a placebo group, in line with the hypothesis that antidepressant effects are mediated by anti-inflammatory, anti-excitotoxic, and neuroprotective properties [120].”

What the sources say

• Not checked yetcites [120] Sepanjnia K, Modabbernia A, Ashrafi M, Modabbernia MJ, Akhondzadeh S. Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacol. 2012;37(9):2093–100. source

In the paper

“Moreover, preclinical studies and investigations in individuals affected by Alzheimer’s disease [132] provided evidence that ALA may promote neurocognitive enhancement via pleiotropic mechanisms, including antioxidant mitochondrial activity and anti-inflammatory properties [133]”

What the sources say

• Not checked yetcites [132] Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease. J Alzheimers Dis. 2014;38(1):111–20. source
• Not checked yetcites [133] Soczynska JK, Kennedy SH, Chow CS, Woldeyohannes HO, Konarski JZ, McIntyre RS. Acetyl-L-carnitine and alpha-lipoic acid: possible neurotherapeutic agents for mood disorders? Expert Opin Investig Drugs. 2008;17(6):827–43. source

In the paper

“In keeping with the view outlined above, enhanced insulin signaling with antidiabetic treatments, for example, thiazolidinediones such as rosiglitazone and pioglitazone, may preserve and/or augment cognitive function at least in a subset of MDD patients exhibiting comorbid metabolic conditions [115].”

What the sources say

• Not checked yetcites [115] McIntyre RS, Soczynska JK, Woldeyohannes HO, Lewis GF, Leiter LA, MacQueen GM, et al. Thiazolidinediones: novel treatments for cognitive deficits in mood disorders? Expert Opin Pharmacother. 2007;8(11):1615–28. source

In the paper

“The localization of insulin receptors in the hippocampus and medial temporal cortex suggests that insulin and glucose homeostasis play a role in physiological memory functions through their effect on synaptic plasticity and cellular survival [110].”

What the sources say

• Not checked yetcites [110] Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3(3):169–78. source

In the paper

“In accord, a subsequent 6-week RCT confirmed the antidepressant efficacy of pioglitazone in obese patients with concomitant polycystic ovarian syndrome and MDD (n = 50), reporting significant reductions in HDRS scores [118].”

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

In the paper

“In middle-aged to elderly healthy individuals (n = 40), n-3 PUFA supplementation (3 mg/day) significantly improved cognitive performance (i.e. working memory and attention) compared with that of a placebo group in a 5-week RCT [137].”

What the sources say

• Not checked yetcites [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

“Results obtained from preclinical studies and controlled trials on healthy volunteers and individuals with mild cognitive impairment or Alzheimer’s disease have supported the potential of intranasal insulin in improving memory performance [113].”

What the sources say

• Not checked yetcites [113] Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012;97(2):366–76. source

In the paper

“ALC’s beneficial effects on cognition have been documented in the treatment of mild cognitive impairment and Alzheimer’s disease, as well as of hepatic encephalopathy [129, 130].”

What the sources say

• Not checked yetcites [129] Malaguarnera M, Vacante M, Motta M, Giordano M, Malaguarnera G, Bella R, et al. Acetyl-L-carnitine improves cognitive functions in severe hepatic encephalopathy: a randomized and controlled clinical trial. Metabol Brain Dis. 2011;26(4):281–9. source
• Not checked yetcites [130] Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol. 2003;18(2):61–71. source

In the paper

“Participants allocated to SAMe therapy showed significant improvements in recall and word-finding scores on the self-rated Cognitive and Physical Symptoms Questionnaire compared with a placebo group.”

What the sources say

• Not checked yetcites [127] Levkovitz Y, Alpert JE, Brintz CE, Mischoulon D, Papakostas GI. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. J Affect Disord. 2012;136(3):1174–8. source

In the paper

“The effect of metformin was superior to that of placebo in improving depressive symptoms in a sample of depressive patients with type II diabetes mellitus [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

“Finally, the anti-diabetic drug metformin holds promise as an agent capable of attenuating and/or reverting neurotoxic effects mediated by inflammatory mechanisms, metabolic and mitochondrial dysfunction, as well as increased oxidative stress [121].”

What the sources say

• Not checked yetcites [121] Ying MA, Maruschak N, Mansur R, Carvalho AF, Cha DS, McIntyre RS. Metformin: repurposing opportunities for cognitive and mood dysfunction. CNS Neurol Disord Drug Targets. 2014;13(10):1836–45. source

In the paper

“Preliminary clinical evidence suggests that chronic therapy with these agents in individuals with mild-to-moderate hypertension may improve memory performance, as assessed by the RAVLT and the Wechsler Memory Scale [125].”

What the sources say

• Not checked yetcites [125] Braszko JJ, Karwowska-Polecka W, Halicka D, Gard PR. Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol. 2003;14(4):323–43. source

In the paper

“Thus, this evidence provides proof of principle for direct procognitive effects of ACE inhibitors in humans”

In the paper

“Preclinical studies have documented that ACE inhibitors exert memory-improving effects [124].”

What the sources say

• Not checked yetcites [124] Mondadori C, Etienne P. Nootropic effects of ACE inhibitors in mice. Psychopharmacol. 1990;100(3):301–7. source

In the paper

“An RCT among euthymic patients with bipolar disorder documented that individuals treated with intranasal insulin exhibited significant improvements in one measure of executive function (in the absence of improvement across other cognitive domains) compared with a placebo group [114].”

What the sources say

• Not checked yetcites [114] McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, Macqueen G, et al. A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord. 2012;14(7):697–706. source