Cognitive dysfunction in depression – pathophysiology and novel targets

Carvalho AF, Miskowiak KW, Hyphantis TN, Kohler CA, Alves GS, Bortolato B, G Sales PM, Machado-Vieira R, Berk M, McIntyre R

CNS Neurol Disord Drug Targets. 2014;13(10):1819-35.


Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.

Effects of Short-Term Cognitive Remediation on Cognitive Dysfunction in Partially or Fully Remitted Individuals with Bipolar Disorder: Results of a Randomised Controlled Trial

Demant KM, Vinberg M, Kessing LV, Miskowiak KW

PLoS One. 2015 Jun 12;10(6):e0127955.


INTRODUCTION: Cognitive dysfunction is common in bipolar disorder (BD) but is not sufficiently addressed by current treatments. Cognitive remediation (CR) may improve cognitive function in schizophrenia but no randomised controlled trial has investigated this intervention in BD. The present study aimed to investigate the effects of CR on persistent cognitive dysfunction in BD.

METHOD: Patients with BD in partial remission with cognitive complaints were randomised to 12 weeks group-based CR (n=23) or standard treatment (ST) (n=23). Outcomes were improved verbal memory (primary), sustained attention, executive and psychosocial function (secondary) and additional measures of cognitive and psychosocial function (tertiary). Participants were assessed at baseline and weeks 12 and 26.

RESULTS: Of the 46 randomised participants five dropped out and one was excluded after baseline. CR (n=18) had no effect on primary or secondary measures of cognitive or psychosocial function compared with ST (n=22). However, CR improved subjective sharpness at week 12, and quality of life and verbal fluency at week 26 follow-up (tertiary outcomes). Although the trial turned out to have suboptimal statistical power for the primary outcome analysis, calculation of the 95% confidence interval showed that it was highly unlikely that an increase in sample size would have rendered any beneficial effects of CR vs. ST on the verbal memory.

CONCLUSIONS: Short-term group-based CR did not seem to improve overall cognitive or psychosocial function in individuals with BD in full or partial remission. The present findings suggest that that longer-term, more intensive and individualised CR may be necessary to improve cognition in BD.


Dr Miskowiak and colleagues reply

Miskowiak KW, Ehrenreich H, Kessing LV, Vinberg M.

J Clin Psychiatry. 2015 Jun;76(6):e835-6. doi: 10.4088/JCP.15lr09809a.


To the Editor: We thank Dr Lozano and colleagues for their comments on our study “Recombinant Human Erythropoietin to Target Cognitive Dysfunction in Bipolar Disorder: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Trial,” which give us the opportunity to address some conceptually important points regarding the effects of erythropoietin (EPO) on cognition. Lozano et al note that it is a potential confound that patients remained on their mood-stabilizing treatment including lithium for the duration of the study for 2 reasons: first, lithium has dose-dependent procognitive effects in patients with amnestic mild cognitive impairment in doses from 150 mg to 600 mg but harmful effects on cognition at doses ≥ 1 g; second, lithium and EPO may activate similar signaling pathways and thus exert synergistic actions on neuroplasticity. Lozano et al point out that the EPO-associated improvement of cognition could have therefore been influenced by patients’ lithium treatment during or prior to the study and request (1) explicit data regarding lithium exposure for each study group and (2) analysis of whether EPO and lithium have independent cognitive effects, or whether the beneficial effects attributed to EPO could be partially due to lithium or an interaction between EPO and lithium … [see full reply in J Clin Psychiatry]