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Tuesday, May 7, 2019

May 2019

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report



We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines


The Food and Drug Administration (FDA) is advising that rare but serious injuries have happened with certain common prescription insomnia medicines because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake. These complex sleep behaviors have also resulted in deaths. These behaviors appear to be more common with eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist) than other prescription medicines used for sleep.

As a result, we are requiring a Boxed Warning, our most prominent warning, to be added to the prescribing information and the patient Medication Guides for these medicines. We are also requiring a Contraindication, our strongest warning, to avoid use in patients who have previously experienced an episode of complex sleep behavior with eszopiclone, zaleplon, and zolpidem.

Serious injuries and death from complex sleep behaviors have occurred in patients with and without a history of such behaviors, even at the lowest recommended doses, and the behaviors can occur after just one dose. These behaviors can occur after taking these medicines with or without alcohol or other central nervous system depressants that may be sedating such as tranquilizers, opioids, and anti-anxiety medicines.

Compulsivity and impulsivity traits linked to attenuated developmental frontostriatal myelination trajectories

Nature Neuroscience

The transition from adolescence to adulthood is a period when ongoing brain development coincides with a substantially increased risk of psychiatric disorders. The developmental brain changes accounting for this emergent psychiatric symptomatology remain obscure. Capitalizing on a unique longitudinal dataset that includes in vivo myelin-sensitive magnetization transfer (MT) MRI scans, we show that this developmental period is characterized by brain-wide growth in MT trajectories within both gray matter and adjacent juxtacortical white matter. In this healthy population, the expression of common developmental traits, namely compulsivity and impulsivity, is tied to a reduced growth of these MT trajectories in frontostriatal regions. This reduction is most marked in dorsomedial and dorsolateral prefrontal regions for compulsivity and in lateral and medial prefrontal regions for impulsivity. These findings highlight that psychiatric traits of compulsivity and impulsivity are linked to regionally specific reductions in myelin-related growth in late adolescent brain development.

Efficacy of anti‐inflammatory treatment on major depressive disorder or depressive symptoms: meta‐analysis of clinical trials

Acta Psychiatrica Scandinavica 


No study has gathered evidence from all randomized clinical trials (RCTs) with anti‐inflammatory drugs measuring antidepressant effects including a detailed assessment of side‐effects and bias.

We performed a systematic review identifying RCTs published prior to January 1, 2018, studying antidepressant treatment effects and side‐effects of pharmacological anti‐inflammatory intervention in adults with major depressive disorder (MDD) or depressive symptoms. Outcomes were depression scores after treatment, remission, response, and side‐effects. Pooled standard mean differences (SMD) and risk ratios (RR) including 95% confidence intervals (95%‐CI) were calculated.

We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti‐inflammatory agents improved depressive symptoms compared to placebo as add‐on in patients with MDD (SMD = −0.64; 95%‐CI = −0.88, −0.40; I2 = 51%; N = 597) and as monotherapy (SMD = −0.41; 95%‐CI = −0.60, −0.22; I2 = 93%, N = 8825). Anti‐inflammatory add‐on improved response (RR = 1.76; 95%‐CI = 1.44–2.16; I2 = 16%; N = 341) and remission (RR = 2.14; 95%‐CI = 1.03–4.48; I2 = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias.

Anti‐inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow‐up, identify optimal doses and subgroups of patients that can benefit from anti‐inflammatory intervention.

Global alcohol exposure between 1990 and 2017 and forecasts until 2030: a modelling study

The Lancet


Alcohol use is a leading risk factor for global disease burden, and data on alcohol exposure are crucial to evaluate progress in achieving global non-communicable disease goals. We present estimates on the main indicators of alcohol exposure for 189 countries from 1990–2017, with forecasts up to 2030.

Adult alcohol per-capita consumption (the consumption in L of pure alcohol per adult [≥15 years]) in a given year was based on country-validated data up to 2016. Forecasts up to 2030 were obtained from multivariate log-normal mixture Poisson distribution models. Using survey data from 149 countries, prevalence of lifetime abstinence and current drinking was obtained from Dirichlet regressions. The prevalence of heavy episodic drinking (30-day prevalence of at least one occasion of 60 g of pure alcohol intake among current drinkers) was estimated with fractional response regressions using survey data from 118 countries.

Between 1990 and 2017, global adult per-capita consumption increased from 5·9 L (95% CI 5·8–6·1) to 6·5 L (6·0–6·9), and is forecasted to reach 7·6 L (6·5–10·2) by 2030. Globally, the prevalence of lifetime abstinence decreased from 46% (42–49) in 1990 to 43% (40–46) in 2017, albeit this was not a significant reduction, while the prevalence of current drinking increased from 45% (41–48) in 1990 to 47% (44–50) in 2017. We forecast both trends to continue, with abstinence decreasing to 40% (37–44) by 2030 (annualised 0·2% decrease) and the proportion of current drinkers increasing to 50% (46–53) by 2030 (annualised 0·2% increase). In 2017, 20% (17–24) of adults were heavy episodic drinkers (compared with 1990 when it was estimated at 18·5% [15·3–21·6%], and this prevalence is expected to increase to 23% (19–27) in 2030.

Based on these data, global goals for reducing the harmful use of alcohol are unlikely to be achieved, and known effective and cost-effective policy measures should be implemented to reduce alcohol exposure.

FDA approves ESKETAMINE nasal spray medication for treatment-resistant depression


The U.S. Food and Drug Administration approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression). Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by Spravato administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

"There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment. Because of safety concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient."

Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.

The Spravato labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Because of the risk of sedation and dissociation, patients must be monitored by a health care provider for at least two hours after receiving their Spravato dose. 

Association of Antipsychotic Treatment With Risk of Unexpected Death Among Children and Youths

JAMA Psychiatry


Children and youths who are prescribed antipsychotic medications have multiple, potentially fatal, dose-related cardiovascular, metabolic, and other adverse events, but whether or not these medications are associated with an increased risk of death is unknown.

To compare the risk of unexpected death among children and youths who are beginning treatment with antipsychotic or control medications.

Design, Setting, and Participants 
This retrospective cohort study was conducted from 1999 through 2014 and included Medicaid enrollees aged 5 to 24 years in Tennessee who had no diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder. Data analysis was performed from January 1, 2017, to August 15, 2018.

Current, new antipsychotic medication use at doses higher than 50 mg (higher-dose group) or 50 mg or lower chlorpromazine equivalents (lower-dose group) as well as control medications (ie, attention-deficit/hyperactivity disorder medications, antidepressants, or mood stabilizers) (control group).

Main Outcomes and Measures 
Deaths during study follow-up while out of hospital or within 7 days after hospital admission, classified as either deaths due to injury or suicide or unexpected deaths. Secondary outcomes were unexpected deaths not due to overdose and death due to cardiovascular or metabolic causes.

This study included 189 361 children and youths in the control group (mean [SD] age, 12.0 [5.1] years; 43.4% female), 28 377 in the lower-dose group (mean [SD] age, 11.7 [4.4] years; 32.3% female), and 30 120 in the higher-dose group (mean [SD] age, 14.5 [4.8] years; 39.2% female). The unadjusted incidence of death in the higher-dose group was 146.2 per 100 000 person-years (40 deaths per 27 354 person-years), which was significantly greater than that in the control group (54.5 per 100 000 population; 67 deaths per 123 005 person-years) (P < .001). The difference was primarily attributable to the increased incidence of unexpected deaths in the higher-dose group (21 deaths; 76.8 per 100 000 population) compared with the control group (22 deaths; 17.9 per 100 000 population). The propensity score–adjusted hazard ratios were as follows: all deaths (1.80; 95% CI, 1.06-3.07), deaths due to unintentional injury or suicide (1.03; 95% CI, 0.53-2.01), and unexpected deaths (3.51; 95% CI, 1.54-7.96). The hazard ratio was 3.50 (95% CI, 1.35-9.11) for unexpected deaths not due to overdose and 4.29 (95% CI, 1.33-13.89) for deaths due to cardiovascular or metabolic causes. Neither the unadjusted nor adjusted incidence of death in the lower-dose group differed significantly from that in the control group.

Conclusions and Relevance 
The findings suggest that antipsychotic use is associated with increased risk of unexpected death and appear to reinforce recommendations for careful prescribing and monitoring of antipsychotic treatment for children and youths and to underscore the need for larger antipsychotic treatment safety studies in this population.

Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia

American Journal of Psychiatry

Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.

This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan.

Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group.

The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Mood stabilisers and risk of stroke in bipolar disorder

The British Journal of Psychiatry


Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.

In this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder.

Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case–crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder.

Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke.

Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.

Psychosis with Methylphenidate or Amphetamine in Patients with ADHD

The New England Journal of Medicine


The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit–hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied.

We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases.

We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).

Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. 


Online Journals:

Biological Psychiatry - Volume 85, Issue 10, May 2019

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