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.

Bias in peripheral depression biomarkers

BACKGROUND: To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted. METHODS: Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015. RESULTS: From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (I2 ≥ 50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects. CONCLUSIONS: Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of 'positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature.

The acceptability and efficacy of a group cognitive behavioural therapy programme in a community mental health setting

This paper presents data on a patient evaluation of a group cognitive behavioural therapy programme in an applied setting and its efficacy for reducing generalised anxiety and or depression, and distress. Patients (n=14) participated in one of two 8-week group cognitive behavioural therapy programmes for generalised anxiety or depression, within a mental health service. Patients’ perceptions of the programme were collected via an evaluation questionnaire, and data on clinical outcomes were sourced from patients’ case notes. Most patients who were invited to participate in the programme (n=14 of 17), and their evaluations were generally favourable. Almost all participants (93%) indicated that the programme either met or exceeded their expectations. The clinical outcomes of the intervention were similar to those found in efficacy studies reported in the published literature (approximately half to threequarters of one standard deviation improvement in anxiety, depression, and distress scores).

The China longitudinal ageing study: overview of the demographic, psychosocial and cognitive data of the Shanghai sample

BACKGROUND: China's ageing population will lead to increased neurodegenerative illness and age-related mental health problems. AIMS: The Chinese Longitudinal Ageing Study has been developed to better understand the impact of ageing on cognition and mental health. An overview of the sample, major diagnoses and results of the first wave of data collection is presented. METHOD: One thousand and sixty-eight elderly Chinese (42.2% male), mean age of 72.8 years (SD = 8.5) completed a comprehensive cognitive, psychosocial and mental health assessment. RESULTS: Mean MMSE score was 24.73 (SD = 6.17). Primary generalised anxiety was detected in 0.4% of the sample. Sub-clinical depression and depressive disorder were diagnosed in 1.7% and 2.4% of the sample, respectively. Most (84.5%) reported subjective memory decline, however 66.5% had no cognitive impairment. Mild Cognitive Impairment (MCI) was detected in 25%, Alzheimer's disease (AD) in 4.7%, vascular dementia in 2.5%, and mixed dementia in 1.3%. Cognition was worse in those 85+ years, but affective disorder rates were not. CONCLUSION: Higher rates of dementia were detected than previously reported in China. Normative data is presented for common cognitive and mental health assessment and screening tasks in a Chinese population. This suggests that the true incidence of dementia has been underestimated, and requires further investigation.

The microbiome and mental health: looking back, moving forward with lessons from allergic diseases

Relationships between gastrointestinal viscera and human emotions have been documented by virtually all medical traditions known to date. The focus on this relationship has waxed and waned through the centuries, with noted surges in interest driven by cultural forces. Here we explore some of this history and the emerging trends in experimental and clinical research. In particular, we pay specific attention to how the hygiene hypothesis and emerging research on traditional dietary patterns has helped re-ignite interest in the use of microbes to support mental health. At present, the application of microbes and their structural parts as a means to positively influence mental health is an area filled with promise. However, there are many limitations within this new paradigm shift in neuropsychiatry. Impediments that could block translation of encouraging experimental studies include environmental forces that work toward dysbiosis, perhaps none more important than westernized dietary patterns. On the other hand, it is likely that specific dietary choices may amplify the value of future microbial-based therapeutics. Pre-clinical and clinical research involving microbiota and allergic disorders has predated recent work in psychiatry, an early start that provides valuable lessons. The microbiome is intimately connected to diet, nutrition, and other lifestyle variables; microbial-based psychopharmacology will need to consider this contextual application, otherwise the ceiling of clinical expectations will likely need to be lowered.

The population cost-effectiveness of delivering universal and indicated school-based interventions to prevent the onset of major depression among youth in Australia

AIMS: School-based psychological interventions encompass: universal interventions targeting youth in the general population; and indicated interventions targeting youth with subthreshold depression. This study aimed to: (1) examine the population cost-effectiveness of delivering universal and indicated prevention interventions to youth in the population aged 11-17 years via primary and secondary schools in Australia; and (2) compare the comparative cost-effectiveness of delivering these interventions using face-to-face and internet-based delivery mechanisms. METHODS: We reviewed literature on the prevention of depression to identify all interventions targeting youth that would be suitable for implementation in Australia and had evidence of efficacy to support analysis. From this, we found evidence of effectiveness for the following intervention types: universal prevention involving group-based psychological interventions delivered to all participating school students; and indicated prevention involving group-based psychological interventions delivered to students with subthreshold depression. We constructed a Markov model to assess the cost-effectiveness of delivering universal and indicated interventions in the population relative to a 'no intervention' comparator over a 10-year time horizon. A disease model was used to simulate epidemiological transitions between three health states (i.e., healthy, diseased and dead). Intervention effect sizes were based on meta-analyses of randomised control trial data identified in the aforementioned review; while health benefits were measured as Disability-adjusted Life Years (DALYs) averted attributable to reductions in depression incidence. Net costs of delivering interventions were calculated using relevant Australian data. Uncertainty and sensitivity analyses were conducted to test model assumptions. Incremental cost-effectiveness ratios (ICERs) were measured in 2013 Australian dollars per DALY averted; with costs and benefits discounted at 3%. RESULTS: Universal and indicated psychological interventions delivered through face-to-face modalities had ICERs below a threshold of $50 000 per DALY averted. That is, $7350 per DALY averted (95% uncertainty interval (UI): dominates - 23 070) for universal prevention, and $19 550 per DALY averted (95% UI: 3081-56 713) for indicated prevention. Baseline ICERs were generally robust to changes in model assumptions. We conducted a sensitivity analysis which found that internet-delivered prevention interventions were highly cost-effective when assuming intervention effect sizes of 100 and 50% relative to effect sizes observed for face-to-face delivered interventions. These results should, however, be interpreted with caution due to the paucity of data. CONCLUSIONS: School-based psychological interventions appear to be cost-effective. However, realising efficiency gains in the population is ultimately dependent on ensuring successful system-level implementation.

Deep brain stimulation mediates neurotrophin signaling in an animal model of antidepressant resistance

Chronic adrenocorticotropic hormone administration at circadian nadir produces an antidepressant resistance animal model that does not present with an altered plasma corticosterone profile nor changes in hippocampal brain derived neurotrophic factor and its receptor. Acute and chronic infralimbic deep brain stimulation elicited an antidepressant response in this animal model, which appears to be associated with changes in gene and protein expression of key intracellular mediators of neurotrophic factor signaling. Together, these findings stand to make important positive impacts on treatment strategies for one of the most debilitating and prevalent disorders of the modern era and suggest that antidepressant treatment response may involve mechanisms distinct from chronic stress-mediated induction of depression-like behavioral phenotypes.

N-acetyl cysteine for depressive symptoms in bipolar disorder - a double blind, randomized, placebo-controlled trial

Background: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorderare complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Methods: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.

Results: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: 8.05 [13.16, 2.95], p .002) a n d most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p .968) and no significant between-group differences inadverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.

Conclusions: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar  disorder.

Physical activity correlates in young women with depressive symptoms : a qualitative study

Background
Young women are at high risk for developing depression and participation in physical activity may prevent or treat the disorder. However, the influences on physical activity behaviors of young women with depression are not well understood. The aim of this study was to gather in-depth information about the correlates of physical activity among young women with and without depressive symptoms.

Methods
A sample of 40 young women (aged 18-30 years), 20 with depressive symptoms (assessed using the CES-D 10) and 20 without depressive symptoms participated in one-on-one semi-structured interviews. A social-ecological framework was used, focusing on the individual, social and physical environmental influences on physical activity. Thematic analyses were performed on transcribed interview data.

Results
The results indicated several key themes that were unique to women with depressive symptoms. These women more often described negative physical activity experiences during their youth, more barriers to physical activity, participating in more spontaneous than planned activity, lower self-efficacy for physical activity and being influenced by their friends' and family's inactivity.

Conclusions
Interventions designed to promote physical activity in this important target group should consider strategies to reduce/overcome early life negative experiences, engage support from family and friends and plan for activity in advance.

Diet quality in bipolar disorder in a population-based sample of women

Background : Recent epidemiological evidence has indicated a role for diet quality in unipolar depressive illness. This study examined the association between diet quality and bipolar disorder (BD) in an epidemiological cohort of randomly selected, population-based women aged 20–93 years.

Methods : An a priori diet quality score was derived from food frequency questionnaire data, a factor analysis identified habitual dietary patterns and glycemic load was assessed. Mental health was assessed using the SCID-I/NP.

Results : BD was identified in 23 women and there were 691 participants with no history of psychopathology. Compared to those with no psychopathology, those with BD had a higher glycemic load (p = 0.06) and higher scores on a ‘western’ dietary factor (p = 0.03) and the ‘modern’ dietary factor (p = 0.02). For each standard deviation increase in a ‘western’ and ‘modern’ dietary pattern and glycemic load, the odds ratios for BD were increased (‘western’ OR = 1.88, 95% CI 1.33–2.65; ‘modern’ OR = 1.72, 95% CI 1.14–2.39; GL OR = 1.56, 95% CI 1.13–2.14). Conversely, a ‘traditional’ dietary pattern was associated with reduced odds for BD (OR = 0.53 95% CI 0.32–0.89) after adjustments for overall energy intake.

Limitations : The small sample size did not allow for multivariate analyses and the cross-sectional study design precludes any determinations regarding the direction of the relationships between diet quality and BD.

Conclusion : These data are largely concordant with results from dietary studies in unipolar depression. However, clinical recommendations cannot be made until the direction of the relationship between diet quality and BD is determined. Longitudinal studies are warranted.

Diagnosing bipolar disorder : how can we do it better?

• Accurate diagnosis of bipolar disorder is essential for effective treatment.

• The diagnosis of bipolar disorder is particularly complex, resulting in lengthy delays between first presentation and initiation of appropriate therapy. Inappropriate therapy destabilises the course and outcome of the disease.

• Although the defining features of bipolar disorder are manic or hypomanic episodes, patients typically present for treatment of depression and commonly deny symptoms of mood elevation.

• A correct diagnosis can easily be masked by comorbidities, personality issues and complex phenomenology.

• A diagnosis of bipolar disorder can be assisted by:

   → asking about symptoms of mania or hypomania in every patient presenting with symptoms of depression.

   → recognising mixed states in which manic and depressive symptoms occur simultaneously.

   → identifying the features of bipolar depression that distinguish it from unipolar depression.

• There is a risk of over-diagnosis of bipolar disorder among patients who are histrionic, show abnormal illness behaviour MJA 2006; 184: 459–462 and/or have issues of secondary gain.

Bipolar II disorder : a review

Objectives: To review the current knowledge of bipolar II disorder.

Methods: Literature was reviewed after conducting a Medline search and a hand search of relevant literature.

Results: Bipolar II disorder is a common disorder, with a prevalence of approximately 3–5%. Distinct clinical features of bipolar II disorder have been described. The key to diagnosis is the recognition of past hypomania, while depression is the typical presenting feature of the illness. This is responsible for a significant rate of missed diagnosis, and consequent management according to unipolar guidelines. It is unclear if bipolar II disorder is over-represented amongst resistant depression populations and if abrupt offset of antidepressant action is a phenomenon over represented in bipolar II disorder, reflecting induction of predominantly depressive cycling. A few mood-stabilizer studies available provide provisional suggestion of utility. A supportive role for psychosocial therapies is suggested, however, there is a sparsity of published studies specific to bipolar II disorder cohorts. A small number of short-term antidepressant trials have suggested efficacy, however, compelling long-term maintenance data is absent.

Conclusions: An emerging literature on the specific clinical signature and management of the disorder exists, however, this is disproportionately small relative to the epidemiology and clinical significance of the disorder.

The management of bipolar disorder in primary care : a review of existing and emerging therapies

Recent evidence suggests that the prevalence of bipolar disorder is as much as fivefold higher than previously believed, and may amount to nearly 5% of the population, making it almost as common as unipolar major depression. It is, therefore, not unrealistic to assume that primary care or family physicians will frequently encounter bipolar patients in their practice. Such patients may present with a depressive episode, for a variety of medical reasons, for longer-term maintenance after stabilization, and even with an acute manic episode. Whatever the reason, a working knowledge of current trends in the acute and longer-term management of bipolar disorder would be helpful to the primary care physician. In addition, an understanding of important side-effects and drug interactions that occur with drugs used to treat bipolar disorder, which may be encountered in the medical setting, are paramount. This paper will attempt to review existing and emerging therapies in bipolar disorder, as well as their common drug interactions and side-effects.