Saturday, November 4, 2017

November 2017

Anti-inflammatory treatments for mood disorders: Systematic review and meta-analysis

Journal of Psychopharmacology


Recent studies suggest that anti-inflammatory medication may play a role in the treatment of mood disorders.

The purpose of this study was to determine the efficacy of anti-inflammatory drugs in patients with major depressive disorder and bipolar disorder.

The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and were searched from inception until 15 April 2017 for completed and on-going randomized controlled trials of anti-inflammatory agents for major depressive disorder and bipolar disorder. Data from randomized controlled trials assessing the antidepressant and anti-manic effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with placebo and/or treatment as usual.

Patients receiving anti-inflammatory agents showed lower post-treatment depressive symptom scores compared with those receiving placebo with a standard mean difference of −0.71 (six randomized controlled trials, n=214, 95% CI −1.24 to −0.17, p=0.009). Anti-inflammatory treatment was found to reduce post-treatment manic symptom scores with a standard mean difference of −0.72 (three randomized controlled trials, n=96, 95% CI −1.31 to −0.13, p=0.02). Anti-inflammatories did not show a statistically significant improvement in the secondary outcome measure (change in symptom scores from baseline to outcome). 

Further high quality trials are needed before making recommendations for the routine clinical use of anti-inflammatories in the treatment of mood disorders.

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study

Biological Psychiatry

Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation in vivo using positron emission tomography and TSPO-specific radioligands.

We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts.

Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p = .005). The elevation was of large effect size and significant in the ACC (p = .022, Cohen’s d = 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p = .342, Cohen’s d = 0.38) and insula (p = .466, Cohen’s d = 0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p = .008) and insula (p = .023).

We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.  

Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies

Molecular Psychiatry


The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Nature Scientific Reports 

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.


The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

The American Journal of Psychiatry


Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.

Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology–Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration.

Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen’s d=0.48–0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine’s effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.

Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine’s effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine’s long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Interpreting Biomarker Results in Individual Patients With Mild Cognitive Impairment in the Alzheimer’s Biomarkers in Daily Practice (ABIDE) Project

JAMA Neurology

Biomarkers do not determine conversion to Alzheimer disease (AD) perfectly, and criteria do not specify how to take patient characteristics into account. Consequently, biomarker use may be challenging for clinicians, especially in patients with mild cognitive impairment (MCI).

To construct biomarker-based prognostic models that enable determination of future AD dementia in patients with MCI.

Design, Setting, and Participants 
This study is part of the Alzheimer’s Biomarkers in Daily Practice (ABIDE) project. A total of 525 patients with MCI from the Amsterdam Dementia Cohort (longitudinal cohort, tertiary referral center) were studied. All patients had their baseline visit to a memory clinic from September 1, 1997, through August 31, 2014. Prognostic models were constructed by Cox proportional hazards regression with patient characteristics (age, sex, and Mini-Mental State Examination [MMSE] score), magnetic resonance imaging (MRI) biomarkers (hippocampal volume, normalized whole-brain volume), cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, tau), and combined biomarkers. Data were analyzed from November 1, 2015, to October 1, 2016.

Main Outcomes and Measures 
Clinical end points were AD dementia and any type of dementia after 1 and 3 years.

Of the 525 patients, 210 (40.0%) were female, and the mean (SD) age was 67.3 (8.4) years. On the basis of age, sex, and MMSE score only, the 3-year progression risk to AD dementia ranged from 26% (95% CI, 19%-34%) in younger men with MMSE scores of 29 to 76% (95% CI, 65%-84%) in older women with MMSE scores of 24 (1-year risk: 6% [95% CI, 4%-9%] to 24% [95% CI, 18%-32%]). Three- and 1-year progression risks were 86% (95% CI, 71%-95%) and 27% (95% CI, 17%-41%) when MRI results were abnormal, 82% (95% CI, 73%-89%) and 26% (95% CI, 20%-33%) when CSF test results were abnormal, and 89% (95% CI, 79%-95%) and 26% (95% CI, 18%-36%) when the results of both tests were abnormal. Conversely, 3- and 1-year progression risks were 18% (95% CI, 13%-27%) and 3% (95% CI, 2%-5%) after normal MRI results, 6% (95% CI, 3%-9%) and 1% (95% CI, 0.5%-2%) after normal CSF test results, and 4% (95% CI, 2%-7%) and 0.5% (95% CI, 0.2%-1%) after combined normal MRI and CSF test results. The prognostic value of models determining any type of dementia were in the same order of magnitude although somewhat lower. External validation in Alzheimer’s Disease Neuroimaging Initiative 2 showed that our models were highly robust.

Conclusions and Relevance 
This study provides biomarker-based prognostic models that may help determine AD dementia and any type of dementia in patients with MCI at the individual level. This finding supports clinical decision making and application of biomarkers in daily practice.

Identification of the Niacin-Blunted Subgroup of Schizophrenia Patients from Mood Disorders and Healthy Individuals in Chinese Population

Schizophrenia Bulletin


Schizophrenia (SZ) is a devastating mental disease caused by complex genetic and environmental factors. The pathological process and clinical manifestation of SZ are heterogeneous among patients, which hampers precise diagnosis and treatment of the disease. Since no objective marker for SZ has been established today, to identify a subgroup of the patients with homogeneous biochemical traits will provide a new angle for both researchers and clinicians to understand and manage the disease. In this study, we employed the niacin skin-flushing test in Chinese population and confirmed a niacin-blunted subgroup of SZ patients distinguishable from mood disorders (MD) and normal individuals. This subgroup accounted for 30.67% of the total SZ patients with a specificity of 88.37% in male subjects and 83.75% in female subjects. We support the notion that bluntness in niacin skin test might reflect abnormalities in membrane fatty acid composition, which could be induced by increased PLA2 enzyme activity, in vivo oxidative stress or lipid metabolism imbalance in SZ. Further studies are encouraged to clarify the molecular origins of niacin-bluntness in SZ, which would provide extra clues for etiological research in schizophrenia and for new targeted treatment.

Machine learning of neural representations of suicide and emotion concepts identifies suicidal youth

Nature Human Behaviour


The clinical assessment of suicidal risk would be substantially complemented by a biologically based measure that assesses alterations in the neural representations of concepts related to death and life in people who engage in suicidal ideation. This study used machine-learning algorithms (Gaussian Naive Bayes) to identify such individuals (17 suicidal ideators versus 17 controls) with high (91%) accuracy, based on their altered functional magnetic resonance imaging neural signatures of death-related and life-related concepts. The most discriminating concepts were ‘death’, ‘cruelty’, ‘trouble’, ‘carefree’, ‘good’ and ‘praise’. A similar classification accurately (94%) discriminated nine suicidal ideators who had made a suicide attempt from eight who had not. Moreover, a major facet of the concept alterations was the evoked emotion, whose neural signature served as an alternative basis for accurate (85%) group classification. This study establishes a biological, neurocognitive basis for altered concept representations in participants with suicidal ideation, which enables highly accurate group membership classification.

FDA permits marketing of mobile medical application for substance use disorder


The U.S. Food and Drug Administration permitted marketing of the first mobile medical application to help treat substance use disorders (SUD). The Reset application is intended to be used with outpatient therapy to treat alcohol, cocaine, marijuana and stimulant SUDs. The application is not intended to be used to treat opioid dependence.

“This is an example of how innovative digital technologies can help provide patients access to additional tools during their treatment,” said Carlos Peña, Ph.D., M.S., director of the Division of Neurological and Physical Medicine Devices in FDA’s Center for Devices and Radiological Health. “More therapy tools means a greater potential to help improve outcomes, including abstinence, for patients with substance use disorder.”

According to the Substance Abuse and Mental Health Services Administration, SUD occurs when an individual’s recurrent use of alcohol and/or drugs causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school or home. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, a diagnosis of substance use disorder is based on evidence of impaired control, social impairment, risky use and pharmacological criteria.

The Reset device is a mobile medical application system containing a patient application and clinician dashboard. The device delivers cognitive behavioral therapy to patients to teach the user skills that aid in the treatment of SUD and are intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs. The system is intended to be used in conjunction with outpatient therapy and in addition to a contingency management system, a widely-used program for treating SUD that uses a series of incentives to reward patients for adherence to their treatment program.

Potential Biomarkers Of Tardive Dyskinesia: A Multiplex Analysis Of Blood Serum

Neuroscience Applied


Long-term antipsychotic treatment of schizophrenia is associated with the emergence of tardive dyskinesia (TD), a motor syndrome consisting of involuntary and hyperkinetic movements [1].
Pathogenesis of this drug-induced movement disorder is not yet fully established, but may be connected to oxidative stress-related indirect pathway neurotoxicity [2]. Dysregulations in immune, hormonal and neurotrophic systems have been postulated to be one of the mechanisms underlying this form of neurotoxicity [3, 4]. Principle aims of translational psychiatric research are searching for biomarkers which can be used to diagnose pathological biochemical processes and to identify molecular targets for treatment as well as development of pharmacogenetic approaches to personalize this therapy.

The aim is to study potential endocrine, neurotrophic and immunological markers of tardive dyskinesia in the blood serum of patients with schizophrenia with antipsychotic therapy.

After obtaining approval of the study protocol by the local ethical committee, suitable participants were recruited from psychiatric hospitals. All subjects gave informed consent after proper explanation of the study. TD was assessed cross-sectionally by the use of the Abnormal Involuntary Movement Scale (AIMS) [1, 5]. The concentrations of cortisol, brain-derived neurotrophic factor (BDNF), prolactin, cytokines (tumor necrosis factor (TNFa), interleukin 1 (IL-
1β), interleukin 3 (IL-3), interleukin 6 (IL-6), interferon gamma (INF-γ) and S100β were measured in blood serum using the MILLIPLEX® MAP panels (Merck, Darmstadt, Germany) by the multiplex analyzer MAGPIX (Luminex, USA). Statistical analyses were performed using SPSS software for Windows. Results were expressed as median and quartile intervals (Me [Q1; Q3]) or mean and standard deviation (M±SD). Differences were considered significant at p≤0.05.

In total 180 patients with schizophrenia, 128 males and 52 females (age 39.2±12.1 years), receiving long-term antipsychotic treatment were included. These patients were divided into two groups: 71 patients with tardive dyskinesia and 109 patients without this movement disorder. A significant (p=0.04) decrease in BDNF concentration was observed in patients with TD (1.9 [1.01; 2.99] ng/ml) in comparison to patients without TD (2.66 [1.29; 3.89] ng/ml) (Fig.1). An increase
(p=0.05) of the serum IL-6 level of patients with TD (5.69 [3.55; 7.4] pg/ml) was detected relative to patients without TD (4.69 [2.82; 6.13] pg/ml) (Fig.2). In addition, a statistical trend (p=0.06) of increased serum S100β concentration was found in TD patients (85.29±5.53 ng/L) compared to patients without this side effect (75.14±2.81 ng/L) (Fig.3). No other significant differences were established concerning the other assayed biomarkers.

The biological processes that might play a role in the development of TD are not confined to the human brain per se. Hormonal and immune systems are also involved, which may be
related to these systems being closely interrelated. Furthermore, these parameters may provide information about risk factors of the movement disorder. Identifying markers that can be used as
diagnostics or predictors of treatment response in people with tardive dyskinesia will be an important step towards being able to provide personalized treatment.

Online Journals:

Biological Psychiatry - Volume 82, Issue 12, December 2017

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