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Biological Psychiatry

Thursday, September 7, 2017

September 2017

FDA Approves Deutetrabenazine for Treatment of Tardive Dyskinesia

Psychiatric News

Teva Pharmaceuticals Ltd. on Wednesday announced that the Food and Drug Administration has approved Austedo (deutetrabenazine) tablets for the treatment of adults with tardive dyskinesia (TD). Deutetrabenazine is a small molecule vesicular monoamine 2 transporter (VMAT2) inhibitor that has FDA approval for the treatment of chorea associated with Huntington’s disease.

The approval was based in part on the results of two 12-week, randomized, double-blind, placebo-controlled, multicenter trials, which compared changes in involuntary movements in 335 patients with TD who took deutetrabenazine or placebo. A total of 62% of the patients had concurrent diagnoses of schizophrenia/schizoaffective disorder, and 33% had a mood disorder; 86% were receiving concomitant antipsychotics. 

Progress on the Neuroscience-Based Nomenclature (NbN) for Psychotropic Medications


There has not been, until recently, a comprehensive classification of psychotropic agents (Nutt, 2009). Indeed, these medications are generally considered to belong to one of the five classes: antipsychotics, antidepressants, anxiolytics, hypnotics, and mood stabilizers. It is obvious that, even when considering the strict regulatory guidelines, there are numerous medications that cross such denominations (Stahl, 2013). For instance, the ‘atypical antipsychotic’ aripiprazole has official indications for the treatment of schizophrenia, bipolar mania, and unipolar major depressive disorder (MDD) with inadequate response to antidepressants. Furthermore, another drug of that same family, quetiapine, is often used at doses of 100 mg or less at bedtime as a sedative, at doses of 150–300 mg per day in the treatment of MDD (alone or in combination with an antidepressant), at 300–600 mg per day in bipolar disorder, and at regimens above 600 mg per day for schizophrenia. Using the existing classification, quetiapine could actually belong to all five of the above-mentioned categories. The current approach is thus outdated and untenable.

A task force of members of five scientific organizations (the American, Asian, European, and International Colleges of Neuropsychopharmacology, as well as the International Union of Basic and Clinical Pharmacology) started developing in 2008 a neuroscience-based nomenclature (NbN) with primary focus on neuronal targets rather than on clinical indications. This approach was deemed feasible and radically new because the pre-existing categories could not be logically enriched. The task force recognized that the current knowledge base would not always be sufficient to define the primary target or the correct mechanism of action for certain drugs. Consequently, a cutting-edge scientific framework as developed. The task force realized that as knowledge increases regarding targets and mechanisms of action, and new medications are developed, the framework may need to be adjusted. As such, the committee will continue to meet twice a year to update classifications.  

Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults



To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife.

We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (β-amyloid 42 [Aβ42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein–1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aβ42 was expressed relative to Aβ40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aβ42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch.

Worse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aβ42/Aβ40 and higher t-tau/Aβ42, p-tau/Aβ42, MCP-1/Aβ42, and YKL-40/Aβ42. There were no significant associations between sleep and NFL or neurogranin.

Self-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.

Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring

JAMA Psychiatry 

Maternal antidepressant medication use during pregnancy has previously been associated with adverse outcomes in offspring, but to our knowledge, the association with intellectual disability (ID) has not been investigated.

To examine the association of maternal antidepressant medication use during pregnancy with ID in offspring and investigate the importance of parental mental illness for such an association.

Design, Setting, and Participants
A population-based cohort study of 179 007 children born from January 1, 2006, through December 31, 2007, with complete parental information from national registers who were followed up from birth throughout 2014.

Main Outcomes and Measures
We estimated relative risks (RRs) and 95% CIs of ID in children exposed during pregnancy to any antidepressant medication or specifically to selective serotonin reuptake inhibitor (SSRI) antidepressants, all other non-SSRI antidepressants, or other nonantidepressant psychotropic medications. Analyses were adjusted for potential confounders. In addition to full population analyses, we used a subsample to compare mothers who used antidepressants during pregnancy with mothers who had at least one diagnosis of depression or anxiety before childbirth but did not use antidepressants during pregnancy.

Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. With adjustment for potential confounders, the RR of ID after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Results from analyses of SSRI antidepressants, non-SSRI antidepressants, and nonantidepressant psychotropic medications and analyses in the clinically relevant subsample did not deviate from the full-sample results.

Conclusions and Relevance
The unadjusted RR of ID was increased in offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to a mechanism integral to other factors, such as parental age and mother’s psychiatric disorder.


The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations

Psychiatry Research


Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three “next-step” strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed “efficacy-effectiveness” trial.

FDA Approves Long-acting Injectable ARIPIPRAZOLE for Bipolar I Disorder IN ADULTS


The extended-release formulation of aripiprazole (Abilify Maintena, Otsuka Pharmaceutical Co, Ltd, and H. Lundbeck A/S) has been approved by the US Food and Drug Administration (FDA) for use as an injectable suspension for maintenance monotherapy of bipolar I disorder (BP-I) in adults, the companies have announced.
Abilify Maintena, an atypical antipsychotic, is a sterile lyophilized powder that, when reconstituted with sterile water, forms a suspension that can be administered by injection. It was created by Otsuka in Japan and has been jointly developed and commercialized by Otsuka and Lundbeck.
"Abilify Maintena provides healthcare professionals a new treatment option for their patients who have established tolerability with oral aripiprazole," Joseph Calabrese, MD, director, Mood Disorders Program, University Hospitals Cleveland Medical Center, and professor of psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, said in a press release.
"Receiving Abilify Maintena each month as prescribed and administered by a healthcare professional provides patients an opportunity to be free from taking their daily antipsychotic for bipolar I disorder."
He stressed that concomitant oral antipsychotic medication must be administered for 14 days after the first injection.

Association of Lithium in Drinking Water With the Incidence of Dementia

JAMA Psychiatry


Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition.

To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water.

Design, Setting, and Participants  
This Danish nationwide, population-based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013.

Main Outcomes and Measures
A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls.

A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 µg/L; interquartile range, 6.5-14.9 µg/L) and controls (median, 12.2 µg/L; interquartile range, 7.3-16.0 µg/L; P < .001). A nonlinear association was observed. Compared with individuals exposed to 2.0 to 5.0 µg/L, the incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 µg/L (IRR, 0.83; 95% CI, 0.81-0.85; P < .001) and 10.1 to 15.0 µg/L (IRR, 0.98; 95% CI, 0.96-1.01; P = .17) and increased with 5.1 to 10.0 µg/L (IRR, 1.22; 95% CI, 1.19-1.25; P < .001). Similar patterns were found with Alzheimer disease and vascular dementia as outcomes.

Conclusions and Relevance  
Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

JCI Insight


BackgroundNoninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits.

Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients.

Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031).

The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia



Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The ‘real’ and ‘sham’ groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.

Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia

The American Journal of Psychiatry


This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia.

A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates.

The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16–3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50–4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86–2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47–4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04–1.78).

The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.

Online Journals:

Biological Psychiatry - Volume 82, Issue 7, October 2017

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