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Sunday, September 6, 2015

September 2015

Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study 

Nature Communications


Long-chain omega-3 polyunsaturated fatty acids (PUFAs) are essential for neural development and function. As key components of brain tissue, omega-3 PUFAs play critical roles in brain development and function, and a lack of these fatty acids has been implicated in a number of mental health conditions over the lifespan, including schizophrenia. We have previously shown that a 12-week intervention with omega-3 PUFAs reduced the risk of progression to psychotic disorder in young people with subthreshold psychotic states for a 12-month period compared with placebo. We have now completed a longer-term follow-up of this randomized, double-blind, placebo-controlled trial, at a median of 6.7 years. Here we show that brief intervention with omega-3 PUFAs reduced both the risk of progression to psychotic disorder and psychiatric morbidity in general in this study. The majority of the individuals from the omega-3 group did not show severe functional impairment and no longer experienced attenuated psychotic symptoms at follow-up.

US FDA approves first treatment for sexual desire disorder: Addyi (flibanserin) approved to treat premenopausal women

FDA News Release

The U.S. Food and Drug Administration (FDA) approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

“Today’s approval provides women distressed by their low sexual desire with an approved treatment option,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation or the sexual partner.

“Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies,” continued Dr. Woodcock. “Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.”

Addyi can cause severely low blood pressure (hypotension) and loss of consciousness (syncope). These risks are increased and more severe when patients drink alcohol or take Addyi with certain medicines (known as moderate or strong CYP3A4 inhibitors) that interfere with the breakdown of Addyi in the body. Because of the alcohol interaction, the use of alcohol is contraindicated while taking Addyi. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

Addyi is also being approved with a Boxed Warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment with Addyi, in those who also use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment. Addyi is contraindicated in these patients. In addition, the FDA is requiring the company that owns Addyi to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol.

Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is taken once daily. It is dosed at bedtime to help decrease the risk of adverse events occurring due to possible hypotension, syncope and central nervous system depression (such as sleepiness and sedation). Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness of the 100 mg bedtime dose of Addyi was evaluated in three 24-week randomized, double-blind, placebo-controlled trials in about 2,400 premenopausal women with acquired, generalized HSDD. The average age of the trial participants was 36 years, with an average duration of HSDD of approximately five years. In these trials, women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks (scored on a range of 1.2 to 6.0) and reported distress related to low sexual desire (on a range of 0 to 4). On average, treatment with Addyi increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo increased the sexual desire score by 0.3 to 0.4 over placebo, and decreased the distress score related to sexual desire by 0.3 to 0.4 over placebo. Additional analyses explored whether the improvements with Addyi were meaningful to patients, taking into account the effects of treatment seen among those patients who reported feeling much improved or very much improved overall. Across the three trials, about 10 percent more Addyi-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire or distress. Addyi has not been shown to enhance sexual performance.

The 100 mg bedtime dose of Addyi has been administered to about 3,000 generally healthy premenopausal women with acquired, generalized HSDD in clinical trials, of whom about 1,700 received treatment for at least six months and 850 received treatment for at least one year.

The most common adverse reactions associated with the use of Addyi are dizziness, somnolence (sleepiness), nausea, fatigue, insomnia and dry mouth.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach

Molecular Psychiatry


Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner’s office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.

Meta-analysis of modifiable risk factors for Alzheimer's disease

Journal of Neurology & Psychiatry


The aetiology of Alzheimer's disease (AD) is believed to involve environmental exposure and genetic susceptibility. The aim of our present systematic review and meta-analysis was to roundly evaluate the association between AD and its modifiable risk factors.

We systematically searched PubMed and the Cochrane Database of Systematic Reviews from inception to July 2014, and the references of retrieved relevant articles. We included prospective cohort studies and retrospective case–control studies.

16 906 articles were identified of which 323 with 93 factors met the inclusion criteria for meta-analysis. Among factors with relatively strong evidence (pooled population >5000) in our meta-analysis, we found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD. We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD. We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreasing the risk) in influencing AD risk. We identified no evidence suggestive of significant association with occupational exposures.

Effective interventions in diet, medications, biochemical exposures, psychological condition, pre-existing disease and lifestyle may decrease new incidence of AD.

Interventions to Address Medical Conditions and Health-Risk Behaviors Among Persons With Serious Mental Illness: A Comprehensive Review

Schizophrenia Bulletin


People with serious mental illness (SMI) have mortality rates 2 to 3 times higher than the overall US population, largely due to cardiovascular disease. The prevalence of cardiovascular risk factors such as obesity and diabetes mellitus and other conditions, such as HIV/AIDS, is heightened in this group. Based on the recommendations of a National Institute of Mental Health stakeholder meeting, we conducted a comprehensive review examining the strength of the evidence surrounding interventions to address major medical conditions and health-risk behaviors among persons with SMI. Peer-reviewed studies were identified using 4 major research databases. Randomized controlled trials and observational studies testing interventions to address medical conditions and risk behaviors among persons with schizophrenia and bipolar disorder between January 2000 and June 2014 were included. Information was abstracted from each study by 2 trained reviewers, who also rated study quality using a standard tool. Following individual study review, the quality of the evidence (high, medium, low) and the effectiveness of various interventions were synthesized. 108 studies were included. The majority of studies examined interventions to address overweight/obesity (n = 80). The strength of the evidence was high for 4 interventions: metformin and behavioral interventions had beneficial effects on weight loss; and bupropion and varenicline reduced tobacco smoking. The strength of the evidence was low for most other interventions reviewed. Future studies should test long-term interventions to cardiovascular risk factors and health-risk behaviors. In addition, future research should study implementation strategies to effectively translate efficacious interventions into real-world settings.

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease

Circulation Journal (American Heart Association)


In the 2011 “Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents,” several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ≈10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications.

A randomised trial of nutrient supplements to minimise psychological stress after a natural disaster

Psychiatry Research


After devastating flooding in southern Alberta in June 2013, we attempted to replicate a New Zealand randomised trial that showed that micronutrient (minerals, vitamins) consumption after the earthquakes of 2010–11 resulted in improved mental health. Residents of southern Alberta were invited to participate in a study on the potential benefit of nutrient supplements following a natural disaster. Fifty-six adults aged 23–66 were randomised to receive a single nutrient (vitamin D, n=17), a few-nutrients formula (B-Complex, n=21), or a broad-spectrum mineral/vitamin formula (BSMV, n=18). Self-reported changes in depression, anxiety and stress were monitored for six weeks. Although all groups showed substantial decreases on all measures, those consuming the B-Complex and the BSMV formulas showed significantly greater improvement in stress and anxiety compared with those consuming the single nutrient, with large effect sizes (Cohen's d range 0.76–1.08). There were no group differences between those consuming the B-Complex and BSMV. The use of nutrient formulas with multiple minerals and/or vitamins to minimise stress associated with natural disasters is now supported by three studies. Further research should be carried out to evaluate the potential population benefit that might accrue if such formulas were distributed as a post-disaster public health measure

Weight Loss Associated with Cholinesterase Inhibitors in Individuals with Dementia in a National Healthcare System

Journal of the American Geriatrics Society


To determine whether initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting.

Retrospective cohort study from 2007 to 2010 comparing weight loss in individuals with dementia newly prescribed cholinesterase inhibitors and those newly prescribed other chronic medications.

National Veterans Affairs data.

Individuals aged 65 and older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication.

The primary outcome was time to 10-pound weight loss over 12 months. Propensity score matching was used to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups according to age, comorbid burden, and initial weight.

Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI)  = 1.07–1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5–71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups.

These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors.

Lifestyles and Cognitive Health

What Older Individuals Can Do to Optimize Cognitive Outcomes



Loss of cognitive function and the development of dementia are among the greatest concerns confronting older individuals. As populations around the world age, the global prevalence of dementia is predicted to increase substantially from an estimated 35.6 million in 2010 to 65.7 million in 2030, and 115.4 million in 2050.1 In the United States in 1990, Alzheimer disease ranked 25th in terms of disability-adjusted life-years lost. In 2010, it ranked 12th, with the greatest median percentage change of any of the leading 30 diseases.2 The burden of mild cognitive impairment (MCI) is even larger.3 Discussions between physicians and patients about strategies to prevent cognitive decline and dementia have become commonplace, and there is great interest in new evidence of lifestyle modifications that might improve cognitive aging and prevent the onset of dementia. These lifestyle modifications include exercise, dietary changes, cognitive training (ie, “brain games”), and multimodal treatments. A meta-analysis of observational studies found that the modifiable risk factors that have most consistently been associated with a reduced risk of dementia include higher educational attainment, increased physical activity, and avoidance of smoking.

Mediterranean diet and preserved brain structural connectivity in older subjects

Alzheimer's & Dementia


The Mediterranean diet (MeDi) has been related to a lower risk of Alzheimer's disease; yet, the underlying mechanisms are unknown. We hypothesized that protection against neurodegeneration would translate into higher gray matter volumes, whereas a specific association with preserved white matter microstructure would suggest alternative mechanisms (e.g., vascular pathways).

We included 146 participants from the Bordeaux Three-City study nondemented when they completed a dietary questionnaire and who underwent a 3-T magnetic resonance imaging at an average of 9 years later, including diffusion tensor imaging.

In multivariate voxel-by-voxel analyses, adherence to the MeDi was significantly associated with preserved white matter microstructure in extensive areas, a gain in structural connectivity that was related to strong cognitive benefits. In contrast, we found no relation with gray matter volumes.

The MeDi appears to benefit brain health through preservation of structural connectivity. Potential mediation by a favorable impact on brain vasculature deserves further research.

Online Journals:

Biological Psychiatry - Volume 78, Issue 6, September 2015

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