Cognitive dysfunction in depression - pathophysiology and novel targets

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 (eg, 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.

N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.

Acute mood but not cognitive improvements following administration of a single multivitamin and mineral supplement in healthy women aged 50 and above : a randomised controlled trial

A number of randomised controlled trials have indicated that multivitamin/mineral supplementation for a period of 4 weeks or greater can enhance mood and cognition. To date, no studies have investigated whether a single multivitamin dose can benefit mental function in older adults. This study investigated the acute effects of a single multivitamin and mineral and herbal (MVMH) supplement versus placebo on self ratings of mood and the performance of an effortful computerised cognitive battery in a sample of 76 healthy women aged 50-75 years. Mood was assessed using the depression anxiety stress scale (DASS), state trait anxiety inventory-state anxiety scale and visual analogue scales (VAS). Mood was rated at 1 h post supplementation and again after the competition of the cognitive assessments at 2 h post supplementation. It was demonstrated that the MVMH supplement improved overall DASS mood ratings; however, the most prominent effects appeared to be a reduction in ratings of perceived mental stress. These findings were confirmed using visual analogue scales, with these measures also demonstrating MVMH-related increased ratings of calmness. There were no benefits of the MVMH to mood ratings of depression and performance was not enhanced on the cognitive battery. Supplementation with a single multivitamin, mineral and herbal supplement reduces stress several hours after intake in healthy older people.

Switching to a 10-day Mediterranean-style diet improves mood and cardiovascular function in a controlled crossover study

OBJECTIVES: Even short-term adherence to a Mediterranean-style diet may benefit aspects of psychological functioning. The aim of the present study was to assess the effects of switching to a 10-d Mediterranean-style diet on mood, cognition, and cardiovascular measures. METHODS: Using a crossover design, 24 women were randomly assigned to either the diet change (where they switched to a Mediterranean-style diet) or no diet change (normal diet) condition for 10 days before switching to the other condition for the same duration. Mood, cognition, and cardiovascular measures of blood pressure, blood flow velocity, and arterial stiffness were assessed at baseline and at the completion of the two diets (days 11 and 22). RESULTS: Independent of whether the Mediterranean-style diet was undertaken before or after the crossover, it was associated with significantly elevated contentment and alertness, and significantly reduced confusion. Additionally, aspects of cognition, such as memory recall, improved significantly as a result of switching to the Mediterranean-style diet. Regarding cardiovascular measures, there was a significant reduction in augmentation pressure associated with the Mediterranean-style diet intervention, but blood flow velocity through the common carotid artery did not change. CONCLUSIONS: This Mediterranean-style diet has the potential to enhance aspects of mood, cognition, and cardiovascular function in a young, healthy adult sample.

Improved processing speed: online computer-based cognitive training in older adults

In an increasingly aging population, a number of adults are concerned about declines in their cognitive abilities. Online computer-based cognitive training programs have been proposed as an accessible means by which the elderly may improve their cognitive abilities; yet, more research is needed in order to assess the efficacy of these programs. In the current study, a commercially available 21-day online computer-based cognitive training intervention was administered to 34 individuals aged between 53 and 75 years. The intervention consisted of computerized training in reaction time, inspection time, short-term memory for words, executive function, visual spatial acuity, arithmetic, visual spatial memory, visual scanning/discrimination, and n-back working memory. An active solitaire control group was also included. Participants were tested at baseline, posttraining and at three-weeks follow-up using a battery of neuropsychological outcome measures. These consisted of simple reaction time, complex reaction time, digit forwards and backwards, spatial working memory, digit symbol substitution, RAVLT, and trail making. Significant improvement in simple reaction time and choice reaction time task was found in the cognitive training group both posttraining and at three-weeks follow-up. However, no significant improvements on the other cognitive tasks were found. The training program was found to be successful in achieving transfer of trained cognitive abilities in speed of processing to similar untrained tasks. © 2012 Copyright Taylor and Francis Group, LLC.

The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial.

Cocoa supplementation has been associated with benefits to cardiovascular health. However, cocoa's effects on cognition are less clear. A randomized, placebo-controlled, double-blind clinical trial (n = 40, age M = 24.13 years, SD = 4.47 years) was conducted to investigate the effects of both acute (same-day) and sub-chronic (daily for four-weeks) 250 mg cocoa supplementation on mood and mental fatigue, cognitive performance and cardiovascular functioning in young, healthy adults. Assessment involved repeated 10-min cycles of the Cognitive Demand Battery (CDB) encompassing two serial subtraction tasks (Serial Threes and Sevens), a Rapid Visual Information Processing task, and a mental fatigue scale over the course of half an hour. The Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) was also completed to evaluate cognition. Cardiovascular function included measuring both peripheral and central blood pressure and cerebral blood flow. At the acute time point, consumption of cocoa significantly improved self-reported mental fatigue and performance on the Serial Sevens task in cycle one of the CDB. No other significant effects were found. This trial was registered with the Australian and New Zealand Clinical Trial Registry (Trial ID: ACTRN12613000626763). Accessible via http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12613000626763&ddlSearch=Registered.

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

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD.

DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

High-intensity interval training on cognitive and mental health in adolescents

PURPOSE: Emerging literature suggests that physical activity and fitness may have a positive impact on cognitive and mental health for adolescents. The purpose of the current study was to evaluate the efficacy of two high intensity interval training (HIIT) protocols for improving cognitive and mental health outcomes (executive function, psychological wellbeing, psychological distress and physical self-concept) in adolescents.

METHODS: Participants (n=65; mean age=15.8±0.6) were randomized to three conditions: aerobic exercise program (AEP; n=21), resistance and aerobic exercise program (RAP; n=22) and control (n=22). HIIT sessions (8-10min/session) were delivered during physical education lessons or at lunchtime three times/week for 8-weeks. Assessments were conducted at baseline and immediate post-intervention to detect changes in executive function (Trail Making Test, TMT), psychological wellbeing, psychological distress and physical self-description, by researchers blinded to treatment allocation. Intervention effects were examined using linear mixed models. Cohen's d effect sizes and clinical inference were also calculated.

RESULTS: Small improvements in executive function (d=-0.32, 95%CI -9.12 to 9.77; p=0.386) and psychological wellbeing (d=0.34, 95%CI -1.73 to 2.37; p=0.252) were evident in the AEP group. Moderate improvements in executive function (d=-0.51, 95% CI -8.92 to 9.73; p=0.171), and small improvements in wellbeing (d=0.35, 95%CI -1.46 to 2.53; p=0.219) and perceived appearance (d=0.35, 95%CI -0.74 to 0.41; p=0.249), were observed for the RAP group. Mean feelings state scores improved from pre-workout to post-post workout in both HIIT conditions, with significant results for the AEP (p=0.001).

CONCLUSIONS: This study highlights the potential of embedding HIIT within the school day for improving cognitive and mental health among adolescents.

Systematic review of physical activity and cognitive development in early childhood

OBJECTIVES: To comprehensively review all observational and experimental studies examining the relationship between physical activity and cognitive development during early childhood (birth to 5 years). DESIGN: Systematic review. METHODS: Electronic databases were searched in July, 2014. No study design, date, or language limits were imposed on the search. Included studies had to be published, peer reviewed articles that satisfied the a priori determined population (apparently healthy children aged birth to 5 years), intervention (duration, intensity, frequency, or patterns of physical activity), comparator (various durations, intensity, or patterns of physical activity), and outcome (cognitive development) study criteria. Study quality and risk of bias were assessed in December 2014. RESULTS: A total of seven studies, representing 414 participants from five different countries met the inclusion criteria, including two observational and five experimental studies. Six studies found increased or higher duration/frequency of physical activity had statistically significant (p<0.05) beneficial effects on at least one cognitive development outcome, including 67% of the outcomes assessed in the executive function domain and 60% in the language domain. No study found that increased or higher duration/frequency of physical activity had statistically significant detrimental effects on cognitive development. Six of the seven studies were rated weak quality with a high risk of bias. CONCLUSIONS: This review provides some preliminary evidence that physical activity may have beneficial effects on cognitive development during early childhood. Given the shortage of the information and the weak quality of available evidence, future research is needed to strengthen the evidence base in this area.

Systematic review of sedentary behavior and cognitive development in early childhood

OBJECTIVE: To comprehensively review observational and experimental studies examining the relationship between sedentary behavior and cognitive development during early childhood (birth to 5years). METHOD: Electronic databases were searched in July, 2014 and no limits were imposed on the search. Included studies had to be peer-reviewed, published, and meet the a priori determined population (apparently healthy children aged birth to 5years), intervention (duration, types, and patterns of sedentary behavior), comparator (various durations, types, or patterns of sedentary behavior), and outcome (cognitive development) study criteria. Data extraction occurred in October and November 2014 and study quality and risk of bias were assessed in December 2014. RESULTS: A total of 37 studies, representing 14,487 participants from nine different countries were included. Thirty-one studies used observational study designs and six studies used experimental study designs. Across study designs, increased or higher screen time (most commonly assessed as television viewing (TV)), reading, child-specific TV content, and adult-specific TV content had detrimental (negative) associations with cognitive development outcomes for 38%, 0%, 8%, and 25% of associations reported, respectively, and beneficial (positive) associations with cognitive development outcomes for 6%, 60%, 13%, and 3% of associations reported, respectively. Ten studies were moderate quality and 27 studies were weak quality. CONCLUSIONS: The type of sedentary behavior, such as TV versus reading, may have different impacts on cognitive development in early childhood. Future research with reliable and valid tools and adequate sample sizes that examine multiple cognitive domains (e.g., language, spatial cognition, executive function, memory) are needed. Registration no. CRD42014010004.

The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial

BACKGROUND: Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting.

METHODS AND DESIGN: This is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress.

DISCUSSION: The PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial.