FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared REMS program for all clozapine medicines
FDA
Treatment with clozapine may improve the symptoms of schizophrenia in patients who do not respond adequately to standard antipsychotic treatments. Symptoms of schizophrenia include hearing voices, seeing things that are not there, and being suspicious or withdrawn. Clozapine is also effective in reducing the risk of repeated suicidal behavior in patients with schizophrenia or schizoaffective disorder. We previously communicated safety information associated with clozapine in February 2011.
There are two parts to the changes in the requirements for treating patients with clozapine. First, we have clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. Second, we approved a new, shared risk evaluation and mitigation strategy (REMS) called the Clozapine REMS Programdisclaimer icon. The revised prescribing information and the Clozapine REMS Program will improve monitoring and management of patients with severe neutropenia. The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. The requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program.
The Clozapine REMS Programdisclaimer icon replaces the six existing clozapine registries maintained by individual clozapine manufacturers. The shared REMS requires prescribers, pharmacies, and patients to enroll in a single centralized program. Patients who are currently treated with clozapine will be automatically transferred to the Clozapine REMS Program. In order to prescribe and dispense clozapine, prescribers and pharmacies will be required to be certified in the Clozapine REMS Program according to a specific transition schedule starting October 12, 2015 (see Additional Information for Prescribers section and Additional Information for Pharmacies section for more details).
The monitoring recommendations for neutropenia caused by clozapine treatment have changed. Clozapine can decrease the number of neutrophils in the blood, in some cases causing severe neutropenia. As described in the revised clozapine prescribing information, and in the Clozapine REMS Programdisclaimer icon, neutropenia will be monitored by the absolute neutrophil count (ANC) only, rather than in conjunction with the white blood cell count. Moreover, in the Clozapine REMS Program, the requirements for ANC are being modified so that patients will be able to continue on clozapine treatment with a lower ANC, a change that will allow continued treatment for a greater number of patients. In addition, patients with benign ethnic neutropenia (BEN), who previously were not eligible for clozapine treatment, will now be able to receive the medicine. The revised prescribing information facilitates prescribers’ ability to make individualized treatment decisions if they determine that the risk of psychiatric illness is greater than the risk of recurrent severe neutropenia, especially in patients for whom clozapine may be the antipsychotic of last resort.
Source: http://www.fda.gov/
FDA approved Vraylar (cariprazine) capsules to treat schizophrenia and bipolar disorder in adults
FDA
The efficacy of Vraylar in treating bipolar disorder was shown in three three-week clinical trials of 1,037 participants. Vraylar was shown to reduce symptoms of bipolar disorder in each of the trials.
Vraylar and all other FDA-approved drugs used to treat schizophrenia and bipolar disorder have a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs in older people with dementia-related psychosis. Neither Vraylar nor any other drug in this class is approved to treat such patients.
The most common side effects reported by participants receiving Vraylar in the clinical trials for schizophrenia were extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements. The most common side effects reported by trial participants receiving Vraylar for bipolar disorder were extrapyramidal symptoms, the urge to move (akathisia), indigestion (dyspepsia), vomiting, drowsiness (somnolence) and restlessness.
Vraylar is manufactured by Forest Laboratories LLC of Jersey City, New Jersey and distributed by Actavis Pharma Inc. of Parsippany, New Jersey.
Source: http://www.fda.gov/
Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study
PLOS Medicine
Abstract
Background
Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain.
Methods and Findings
From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08–1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19–1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25–34 y (HR = 1.20, 95% CI 0.95–1.52, p = 0.125, absolute risk = 1.6%), in those aged 35–44 y (HR = 1.06, 95% CI 0.83–1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84–1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16–1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10–1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07–1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22–1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76–2.21, p < 0.001). With age and sex stratification, there was a significant association between SSRIs and violent crime convictions for males aged 15 to 24 y (HR = 1.40, 95% CI 1.13–1.73, p = 0.002) and females aged 15 to 24 y (HR = 1.75, 95% CI 1.08–2.84, p = 0.023). However, there were no significant associations in those aged 25 y or older. One important limitation is that we were unable to fully account for time-varying factors.
Conclusions
The association between SSRIs and violent crime convictions and violent crime arrests varied by age group. The increased risk we found in young people needs validation in other studies.
Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain.
Methods and Findings
From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08–1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19–1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25–34 y (HR = 1.20, 95% CI 0.95–1.52, p = 0.125, absolute risk = 1.6%), in those aged 35–44 y (HR = 1.06, 95% CI 0.83–1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84–1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16–1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10–1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07–1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22–1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76–2.21, p < 0.001). With age and sex stratification, there was a significant association between SSRIs and violent crime convictions for males aged 15 to 24 y (HR = 1.40, 95% CI 1.13–1.73, p = 0.002) and females aged 15 to 24 y (HR = 1.75, 95% CI 1.08–2.84, p = 0.023). However, there were no significant associations in those aged 25 y or older. One important limitation is that we were unable to fully account for time-varying factors.
Conclusions
The association between SSRIs and violent crime convictions and violent crime arrests varied by age group. The increased risk we found in young people needs validation in other studies.
Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults
JAMA Neurology
Abstract
Importance
Vitamin D (VitD) deficiency is associated with brain structural abnormalities, cognitive decline, and incident dementia.
Objective
To assess associations between VitD status and trajectories of change in subdomains of cognitive function in a cohort of ethnically diverse older adults.
Design, Setting, and Participants
Longitudinal multiethnic cohort study of 382 participants in an outpatient clinic enrolled between February 2002 and August 2010 with baseline assessment and yearly follow-up visits. Serum 25-hydroxyvitamin D (25-OHD) was measured, with VitD status defined as the following: deficient, less than 12 ng/mL (to convert to nanomoles per liter, multiply by 2.496); insufficient, 12 to less than 20 ng/mL; adequate, 20 to less than 50 ng/mL; or high, 50 ng/mL or higher. Subdomains of cognitive function were assessed using the Spanish and English Neuropsychological Assessment Scales. Associations were evaluated between 25-OHD levels (as continuous and categorical [deficient, insufficient, or adequate]) and trajectories of cognitive decline.
Main Outcomes and Measures
Serum 25-OHD levels, cognitive function, and associations between 25-OHD levels and trajectories of cognitive decline.
Results
Participants (N = 382 at baseline) had a mean (SD) age of 75.5 (7.0) years; 61.8% were women; and 41.4% were white, 29.6% African American, 25.1% Hispanic, and 3.9% other race/ethnicity. Diagnosis at enrollment included 17.5% with dementia, 32.7% with mild cognitive impairment, and 49.5% cognitively normal. The mean (SD) 25-OHD level was 19.2 (11.7) ng/mL, with 26.2% of participants being VitD deficient and 35.1% insufficient. The mean (SD) 25-OHD levels were significantly lower for African American and Hispanic participants compared with white participants (17.9 [15.8] and 17.2 [8.4] vs 21.7 [10.0] ng/mL, respectively; P < .001 for both). The mean (SD) 25-OHD levels were similarly lower in the dementia group compared with the mild cognitive impairment and cognitively normal groups (16.2 [9.4] vs 20.0 [10.3] and 19.7 [13.1] ng/mL, respectively; P = .006). The mean (SD) follow-up was 4.8 (2.5) years. Rates of decline in episodic memory and executive function among VitD-deficient (episodic memory: β = −0.04 [SE = 0.02], P = .049; executive function: β = −0.05 [SE = 0.02], P = .01) and VitD-insufficient (episodic memory: β = −0.06 [SE = 0.02], P < .001; executive function: β = −0.04 [SE = 0.02], P = .008) participants were greater than those with adequate status after controlling for age, sex, education, ethnicity, body mass index, season of blood draw, vascular risk, and apolipoprotein E4 genotype. Vitamin D status was not significantly associated with decline in semantic memory or visuospatial ability. Exclusion of participants with dementia did not substantially affect the associations between VitD status and rates of cognitive decline.
Conclusions and Relevance
Low VitD status was associated with accelerated decline in cognitive function domains in ethnically diverse older adults, including African American and Hispanic individuals who exhibited a high prevalence of VitD insufficiency or deficiency. It remains to be determined whether VitD supplementation slows cognitive decline.
Vitamin D (VitD) deficiency is associated with brain structural abnormalities, cognitive decline, and incident dementia.
Objective
To assess associations between VitD status and trajectories of change in subdomains of cognitive function in a cohort of ethnically diverse older adults.
Design, Setting, and Participants
Longitudinal multiethnic cohort study of 382 participants in an outpatient clinic enrolled between February 2002 and August 2010 with baseline assessment and yearly follow-up visits. Serum 25-hydroxyvitamin D (25-OHD) was measured, with VitD status defined as the following: deficient, less than 12 ng/mL (to convert to nanomoles per liter, multiply by 2.496); insufficient, 12 to less than 20 ng/mL; adequate, 20 to less than 50 ng/mL; or high, 50 ng/mL or higher. Subdomains of cognitive function were assessed using the Spanish and English Neuropsychological Assessment Scales. Associations were evaluated between 25-OHD levels (as continuous and categorical [deficient, insufficient, or adequate]) and trajectories of cognitive decline.
Main Outcomes and Measures
Serum 25-OHD levels, cognitive function, and associations between 25-OHD levels and trajectories of cognitive decline.
Results
Participants (N = 382 at baseline) had a mean (SD) age of 75.5 (7.0) years; 61.8% were women; and 41.4% were white, 29.6% African American, 25.1% Hispanic, and 3.9% other race/ethnicity. Diagnosis at enrollment included 17.5% with dementia, 32.7% with mild cognitive impairment, and 49.5% cognitively normal. The mean (SD) 25-OHD level was 19.2 (11.7) ng/mL, with 26.2% of participants being VitD deficient and 35.1% insufficient. The mean (SD) 25-OHD levels were significantly lower for African American and Hispanic participants compared with white participants (17.9 [15.8] and 17.2 [8.4] vs 21.7 [10.0] ng/mL, respectively; P < .001 for both). The mean (SD) 25-OHD levels were similarly lower in the dementia group compared with the mild cognitive impairment and cognitively normal groups (16.2 [9.4] vs 20.0 [10.3] and 19.7 [13.1] ng/mL, respectively; P = .006). The mean (SD) follow-up was 4.8 (2.5) years. Rates of decline in episodic memory and executive function among VitD-deficient (episodic memory: β = −0.04 [SE = 0.02], P = .049; executive function: β = −0.05 [SE = 0.02], P = .01) and VitD-insufficient (episodic memory: β = −0.06 [SE = 0.02], P < .001; executive function: β = −0.04 [SE = 0.02], P = .008) participants were greater than those with adequate status after controlling for age, sex, education, ethnicity, body mass index, season of blood draw, vascular risk, and apolipoprotein E4 genotype. Vitamin D status was not significantly associated with decline in semantic memory or visuospatial ability. Exclusion of participants with dementia did not substantially affect the associations between VitD status and rates of cognitive decline.
Conclusions and Relevance
Low VitD status was associated with accelerated decline in cognitive function domains in ethnically diverse older adults, including African American and Hispanic individuals who exhibited a high prevalence of VitD insufficiency or deficiency. It remains to be determined whether VitD supplementation slows cognitive decline.
Source: http://archneur.jamanetwork.com/
One night of sleep loss can alter clock genes in your tissues
Uppsala University
Swedish researchers at Uppsala University and the Karolinska Institute have found that genes that control the biological clocks in cells throughout the body are altered after losing a single night of sleep, in a study that is to be published in the Journal of Clinical Endocrinology and Metabolism.
“Previous research has shown that our metabolism is negatively affected by sleep loss, and sleep loss has been linked to an increased risk of obesity and type 2 diabetes. Since ablation of clock genes in animals can cause these disease states, our current results indicate that changes of our clock genes may be linked to such negative effects caused by sleep loss”, says Jonathan Cedernaes, lead author on the study and a researcher at Uppsala University.
For the study the researchers studied 15 healthy normal-weight men who on two separate occasions came to the lab for almost 2-night long stays. During the second night the participants slept as usual (over 8 hours) in one of the two sessions, while they were kept awake in the other of these sessions, but in random order. To minimize the influence of various environmental factors, light conditions, food intake and activity levels in the lab were strictly controlled and the participants were bed-restricted when they were kept awake.
Following the second night on both occasions that the men were studied, small tissue samples were taken from the superficial fat on the stomach, and from the muscle on the thigh – two kinds of tissues that are important for regulating metabolism and controlling blood sugar levels. Blood samples were also taken before and after the participants had consumed a sugar solution to test their insulin sensitivity, a practice commonly done to exclude the presence of diabetes or a metabolic state called impaired insulin sensitivity, which can precede type-2 diabetes.
Molecular analyses of the collected tissue samples showed that the regulation and activity of clock genes was altered after one night of sleep loss. The activity of genes is regulated by a mechanism called epigenetics. This involves chemical alterations to the DNA molecule such as methyl groups – a process called methylation – which regulates how the genes are switched on or off. The researchers found that clock genes had increased numbers of such DNA marks after sleep loss. They also found that the expression of the genes, which is indicative of how much of the genes’ product is made, was altered.
“As far as we know, we are the first to directly show that epigenetic changes can occur after sleep loss in humans, but also in these important tissues”, says Dr. Cedernaes. “It was interesting that the methylation of these genes could be altered so quickly, and that it could occur for these metabolically important clock genes”, he continues.
The changes that the researchers observed were however different in the adipose tissue and the skeletal muscle. “This could suggest that these important molecular clocks are no longer synchronized between these two tissues”, Dr. Cedernaes says. “As such, ‘clock desynchrony’ between tissues has been linked to metabolic pathologies, this could suggest that these tissue-specific changes were linked to the impaired glucose tolerance that our participants demonstrated after the night that they had been kept awake”
The researchers do not at this stage know how persistent these changes are. “It could be that these changes are reset after one or several nights of good sleep. On the other hand, epigenetic marks are suggested to be able to function a sort of metabolic memory, and have been found to be altered in e.g. shift workers and people suffering from type 2 diabetes”, Dr. Cedernaes points out. “This could mean that at least some types of sleep loss or extended wakefulness, as in shift work, could lead to changes in the genome of your tissues that can affect your metabolism for longer periods”, Dr. Cedernaes concludes.
Jesper Lodin
Swedish researchers at Uppsala University and the Karolinska Institute have found that genes that control the biological clocks in cells throughout the body are altered after losing a single night of sleep, in a study that is to be published in the Journal of Clinical Endocrinology and Metabolism.
“Previous research has shown that our metabolism is negatively affected by sleep loss, and sleep loss has been linked to an increased risk of obesity and type 2 diabetes. Since ablation of clock genes in animals can cause these disease states, our current results indicate that changes of our clock genes may be linked to such negative effects caused by sleep loss”, says Jonathan Cedernaes, lead author on the study and a researcher at Uppsala University.
For the study the researchers studied 15 healthy normal-weight men who on two separate occasions came to the lab for almost 2-night long stays. During the second night the participants slept as usual (over 8 hours) in one of the two sessions, while they were kept awake in the other of these sessions, but in random order. To minimize the influence of various environmental factors, light conditions, food intake and activity levels in the lab were strictly controlled and the participants were bed-restricted when they were kept awake.
Following the second night on both occasions that the men were studied, small tissue samples were taken from the superficial fat on the stomach, and from the muscle on the thigh – two kinds of tissues that are important for regulating metabolism and controlling blood sugar levels. Blood samples were also taken before and after the participants had consumed a sugar solution to test their insulin sensitivity, a practice commonly done to exclude the presence of diabetes or a metabolic state called impaired insulin sensitivity, which can precede type-2 diabetes.
Molecular analyses of the collected tissue samples showed that the regulation and activity of clock genes was altered after one night of sleep loss. The activity of genes is regulated by a mechanism called epigenetics. This involves chemical alterations to the DNA molecule such as methyl groups – a process called methylation – which regulates how the genes are switched on or off. The researchers found that clock genes had increased numbers of such DNA marks after sleep loss. They also found that the expression of the genes, which is indicative of how much of the genes’ product is made, was altered.
“As far as we know, we are the first to directly show that epigenetic changes can occur after sleep loss in humans, but also in these important tissues”, says Dr. Cedernaes. “It was interesting that the methylation of these genes could be altered so quickly, and that it could occur for these metabolically important clock genes”, he continues.
The changes that the researchers observed were however different in the adipose tissue and the skeletal muscle. “This could suggest that these important molecular clocks are no longer synchronized between these two tissues”, Dr. Cedernaes says. “As such, ‘clock desynchrony’ between tissues has been linked to metabolic pathologies, this could suggest that these tissue-specific changes were linked to the impaired glucose tolerance that our participants demonstrated after the night that they had been kept awake”
The researchers do not at this stage know how persistent these changes are. “It could be that these changes are reset after one or several nights of good sleep. On the other hand, epigenetic marks are suggested to be able to function a sort of metabolic memory, and have been found to be altered in e.g. shift workers and people suffering from type 2 diabetes”, Dr. Cedernaes points out. “This could mean that at least some types of sleep loss or extended wakefulness, as in shift work, could lead to changes in the genome of your tissues that can affect your metabolism for longer periods”, Dr. Cedernaes concludes.
Jesper Lodin
Source: http://www.uu.se/
Cortical Representation of Afferent Bodily Signals in Borderline Personality Disorder
JAMA Psychiatry
Abstract
Importance
The ability to perceive and regulate one’s own emotions has been tightly linked to the processing of afferent bodily signals (interoception). Thus, disturbed interoception might contribute to the core feature of emotional dysregulation in borderline personality disorder (BPD), as increased levels of depersonalization, body image disturbances, and reduced sensitivity to physical pain suggest poor body awareness in BPD.
Objective
To determine neural correlates of disturbed body awareness in BPD and its associations with emotional dysregulation and to explore improvements in body awareness with BPD symptom remission.
Design, Setting, and Participants
Case-control study performed at Heidelberg University Hospital, Heidelberg, Germany. Heartbeat evoked potentials (HEPs), an indicator of the cortical representation of afferent signals from the cardiovascular system, were investigated in 34 medication-free patients with BPD, 31 healthy volunteers, and 17 medication-free patients with BPD in remission. The HEPs were assessed using 5-minute resting-state electroencephalograms and parallel electrocardiograms. Core BPD symptoms, history of childhood traumatization, and psychiatric disorders were assessed by means of self-reports and structured interviews. To measure neural correlates of disturbed body awareness, high-resolution T1-weighted structural magnetic resonance imaging scans were collected and analyzed using voxel-based morphometry and region-of-interest–based approaches. The study was performed between 2012 and 2014, and data analysis was performed in 2014.
Main Outcomes and Measures
Mean HEP amplitudes in resting-state electroencephalograms and their correlation with self-reported emotional dysregulation, as well as with gray matter volume.
Results
Patients with BPD had significantly reduced mean HEP amplitudes compared with healthy volunteers (F1,61 = 11.32, P = .001), whereas the mean HEP amplitudes of patients with BDP in remission lie somewhere in between these 2 groups of participants (P > .05). The HEP amplitudes were negatively correlated with emotional dysregulation (R = −0.30, P = .01) and positively associated with gray matter volume in the left anterior insula (R = 0.53, P < .05) and the bilateral dorsal anterior cingulate cortex (R = 0.47, P < .05), 2 structures that have been identified as core regions for interoception.
Conclusions and Relevance
The results indicate state-dependent deficits in the cortical processing of bodily signals in patients with BPD, which appear to be associated with core features of BPD. The analysis of patients with BPD in remission suggests an improvement in cortical representation of bodily signals with symptom remission. Results recommend the integration of techniques to strengthen bodily awareness in psychotherapeutic interventions of BPD.
The ability to perceive and regulate one’s own emotions has been tightly linked to the processing of afferent bodily signals (interoception). Thus, disturbed interoception might contribute to the core feature of emotional dysregulation in borderline personality disorder (BPD), as increased levels of depersonalization, body image disturbances, and reduced sensitivity to physical pain suggest poor body awareness in BPD.
Objective
To determine neural correlates of disturbed body awareness in BPD and its associations with emotional dysregulation and to explore improvements in body awareness with BPD symptom remission.
Design, Setting, and Participants
Case-control study performed at Heidelberg University Hospital, Heidelberg, Germany. Heartbeat evoked potentials (HEPs), an indicator of the cortical representation of afferent signals from the cardiovascular system, were investigated in 34 medication-free patients with BPD, 31 healthy volunteers, and 17 medication-free patients with BPD in remission. The HEPs were assessed using 5-minute resting-state electroencephalograms and parallel electrocardiograms. Core BPD symptoms, history of childhood traumatization, and psychiatric disorders were assessed by means of self-reports and structured interviews. To measure neural correlates of disturbed body awareness, high-resolution T1-weighted structural magnetic resonance imaging scans were collected and analyzed using voxel-based morphometry and region-of-interest–based approaches. The study was performed between 2012 and 2014, and data analysis was performed in 2014.
Main Outcomes and Measures
Mean HEP amplitudes in resting-state electroencephalograms and their correlation with self-reported emotional dysregulation, as well as with gray matter volume.
Results
Patients with BPD had significantly reduced mean HEP amplitudes compared with healthy volunteers (F1,61 = 11.32, P = .001), whereas the mean HEP amplitudes of patients with BDP in remission lie somewhere in between these 2 groups of participants (P > .05). The HEP amplitudes were negatively correlated with emotional dysregulation (R = −0.30, P = .01) and positively associated with gray matter volume in the left anterior insula (R = 0.53, P < .05) and the bilateral dorsal anterior cingulate cortex (R = 0.47, P < .05), 2 structures that have been identified as core regions for interoception.
Conclusions and Relevance
The results indicate state-dependent deficits in the cortical processing of bodily signals in patients with BPD, which appear to be associated with core features of BPD. The analysis of patients with BPD in remission suggests an improvement in cortical representation of bodily signals with symptom remission. Results recommend the integration of techniques to strengthen bodily awareness in psychotherapeutic interventions of BPD.
Source: http://archpsyc.jamanetwork.com/
Automated analysis of free speech predicts psychosis onset in high-risk youths
NPJ Schizophrenia
Background/Objectives
Psychiatry lacks the objective clinical tests routinely used in other specializations. Novel computerized methods to characterize complex behaviors such as speech could be used to identify and predict psychiatric illness in individuals.
AIMS
In this proof-of-principle study, our aim was to test automated speech analyses combined with Machine Learning to predict later psychosis onset in youths at clinical high-risk (CHR) for psychosis.
Methods
Thirty-four CHR youths (11 females) had baseline interviews and were assessed quarterly for up to 2.5 years; five transitioned to psychosis. Using automated analysis, transcripts of interviews were evaluated for semantic and syntactic features predicting later psychosis onset. Speech features were fed into a convex hull classification algorithm with leave-one-subject-out cross-validation to assess their predictive value for psychosis outcome. The canonical correlation between the speech features and prodromal symptom ratings was computed.
Results
Derived speech features included a Latent Semantic Analysis measure of semantic coherence and two syntactic markers of speech complexity: maximum phrase length and use of determiners (e.g., which). These speech features predicted later psychosis development with 100% accuracy, outperforming classification from clinical interviews. Speech features were significantly correlated with prodromal symptoms.
Conclusions
Findings support the utility of automated speech analysis to measure subtle, clinically relevant mental state changes in emergent psychosis. Recent developments in computer science, including natural language processing, could provide the foundation for future development of objective clinical tests for psychiatry.
Source: http://www.nature.com/
A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease
Neurology
Abstract
Objective
A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).
Methods
Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.
Results
Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.
Conclusions
Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood–brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.
Classification of evidence
This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.
A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).
Methods
Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.
Results
Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.
Conclusions
Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood–brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.
Classification of evidence
This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.
Source: http://www.neurology.org/
New Data Support Whole Body Hyperthermia for Rapid Treatment of Major Depression
PsychCongress
Whole body hyperthermia shows potential to treat depression, said Charles Raison, MD, during the Welcome Session of the 28th Annual U.S. Psychiatric and Mental Health Congress. Dr. Raison presented data on his recently completed study of whole body hyperthermia as a novel therapeutic for depression.
“Whole body hyperthermia grows out of a way of thinking of depression that’s somewhat at odds with the rank-and-file standard thinking,” said Dr. Raison.
He noted that the field believes that mental disorders are brain disorders and that many scientists take the idea literally, to the point that they believe the brain is the only cause and location of mental illnesses.
That way of thinking is incorrect, he said, given the extensive research showing that many factors outside the brain cause major depression. For example, family relationships drive depression. In one study, the children of parents who were treated with and responded to an antidepressant had a greater response than their parents, even though none of the chemical touched their bodies.
“Human relationships are biological entities that drive states of mind. We’re medicines for each other or poison for each other,” said Dr. Raison.
He added, “Just because the brain is the proximal cause of all mental states does not mean it is the most important, interesting, or therapeutically useful cause for all cases of major depression.”
Beyond the Brain
If we accept that factors outside the brain can cause depression, then that opens the door to the possibility that factors outside the brain can also treat depression. Dr. Raison first explored this approach in a study of infliximab for major depression that investigated whether blocking inflammation could block depression.
Sixty medically healthy patients with major depression were randomized to receive either a saline solution or an infusion of infliximab, a powerful biological molecule that only blocks inflammatory cytokines. The molecule is large, “the size of a school bus,” said Dr. Raison, and it doesn’t penetrate the blood-brain barrier.
After breaking the blind on the study, Dr. Raison and his colleagues found that only patients who had high levels of inflammation prior to the infusion experienced antidepressant effects. The study suggested that turning off depression in the body, in the form of inflammation, also worked to turn off depression in the brain.
“This was the beginning of the realization that the immune system, which is a sensory pathway, might provide access to deep brain stimuli,” he said.
Some Like it Hot
From there, Dr. Raison’s research interest turned to temperature, a sensory pathway that has shown a strong association with depression. People with depression have higher body temperatures and sweat less, suggesting that mood disorders are thermoregulatory disorders.
“There are a few things that people have done over and over throughout history to feel better and have spiritual experiences. Sweat lodges are near the top of the list. It’s amazing how many indigenous cultures around the world semi-independently invented sweat lodges,” said Dr. Raison.
This phenomenon points to a pathway that runs from the skin to specific areas of the brain that are turned on by warm temperatures and turned off abruptly by temperatures that hurt. “We think that pathway is an antidepressant modality,” said Dr. Raison.
Putting the Pathway to the Test
When people with depression enter a hyperthermia chamber their depression decreases and their body temperature drops as well. The body temperature reduction may seem counterintuitive, but it makes sense, explained Dr. Raison.
“Think about it—why does this pathway exist? The brain wants to stay the same temperature. When this pathway is activated, it makes you sweat, it makes you try to cool down,” he said.
For his study on whole body hyperthermia, Dr. Raison predicted that people would feel less depressed and have a lower body temperature after undergoing treatment.
Results confirmed his hypothesis. People who were treated with whole body hyperthermia experienced a large reduction in depression after treatment, as well as a reduction in core body temperature. Interestingly, the 3 people who did not experience an antidepressant effect were taking an SSRI, and the hotter the body temperature of the participants at the start of the study, the better their antidepressant response.
“Why were these people hot? We think it’s because the pathway wasn’t working correctly so they couldn’t lose heat, which elevated their body temperature. But giving the treatment lowers body temperature and makes the pathway more sensitive,” he said.
One of the challenges with this study, said Dr. Raison, was developing a convincing placebo. With some creativity, the researchers devised a sham therapy that convinced 75% of the patients that they were receiving the active treatment.
Those in the active treatment group experienced reduction in depression with effect sizes (1.4 at one week) compared to placebo that dwarf those of SSRIs and their placebos. “This is almost two and a half times larger an effect,” said Dr. Raison.
In addition, although Dr. Raison and his colleagues predicted that the effects would disappear after 6 weeks, many people were still significantly improved compared with placebo.
“Like ketamine, like scopolamine, and other rapid treatments for depression that are of intense interest in psychiatry, hyperthermia shows the same effect. It doesn’t take a week or two to work. People feel better very, very quickly, and the effects appear to persist for an extended period of time,” said Dr. Raison.
—Lauren LeBano
Source: http://www.psychcongress.com/
Whole body hyperthermia shows potential to treat depression, said Charles Raison, MD, during the Welcome Session of the 28th Annual U.S. Psychiatric and Mental Health Congress. Dr. Raison presented data on his recently completed study of whole body hyperthermia as a novel therapeutic for depression.
“Whole body hyperthermia grows out of a way of thinking of depression that’s somewhat at odds with the rank-and-file standard thinking,” said Dr. Raison.
He noted that the field believes that mental disorders are brain disorders and that many scientists take the idea literally, to the point that they believe the brain is the only cause and location of mental illnesses.
That way of thinking is incorrect, he said, given the extensive research showing that many factors outside the brain cause major depression. For example, family relationships drive depression. In one study, the children of parents who were treated with and responded to an antidepressant had a greater response than their parents, even though none of the chemical touched their bodies.
“Human relationships are biological entities that drive states of mind. We’re medicines for each other or poison for each other,” said Dr. Raison.
He added, “Just because the brain is the proximal cause of all mental states does not mean it is the most important, interesting, or therapeutically useful cause for all cases of major depression.”
Beyond the Brain
If we accept that factors outside the brain can cause depression, then that opens the door to the possibility that factors outside the brain can also treat depression. Dr. Raison first explored this approach in a study of infliximab for major depression that investigated whether blocking inflammation could block depression.
Sixty medically healthy patients with major depression were randomized to receive either a saline solution or an infusion of infliximab, a powerful biological molecule that only blocks inflammatory cytokines. The molecule is large, “the size of a school bus,” said Dr. Raison, and it doesn’t penetrate the blood-brain barrier.
After breaking the blind on the study, Dr. Raison and his colleagues found that only patients who had high levels of inflammation prior to the infusion experienced antidepressant effects. The study suggested that turning off depression in the body, in the form of inflammation, also worked to turn off depression in the brain.
“This was the beginning of the realization that the immune system, which is a sensory pathway, might provide access to deep brain stimuli,” he said.
Some Like it Hot
From there, Dr. Raison’s research interest turned to temperature, a sensory pathway that has shown a strong association with depression. People with depression have higher body temperatures and sweat less, suggesting that mood disorders are thermoregulatory disorders.
“There are a few things that people have done over and over throughout history to feel better and have spiritual experiences. Sweat lodges are near the top of the list. It’s amazing how many indigenous cultures around the world semi-independently invented sweat lodges,” said Dr. Raison.
This phenomenon points to a pathway that runs from the skin to specific areas of the brain that are turned on by warm temperatures and turned off abruptly by temperatures that hurt. “We think that pathway is an antidepressant modality,” said Dr. Raison.
Putting the Pathway to the Test
When people with depression enter a hyperthermia chamber their depression decreases and their body temperature drops as well. The body temperature reduction may seem counterintuitive, but it makes sense, explained Dr. Raison.
“Think about it—why does this pathway exist? The brain wants to stay the same temperature. When this pathway is activated, it makes you sweat, it makes you try to cool down,” he said.
For his study on whole body hyperthermia, Dr. Raison predicted that people would feel less depressed and have a lower body temperature after undergoing treatment.
Results confirmed his hypothesis. People who were treated with whole body hyperthermia experienced a large reduction in depression after treatment, as well as a reduction in core body temperature. Interestingly, the 3 people who did not experience an antidepressant effect were taking an SSRI, and the hotter the body temperature of the participants at the start of the study, the better their antidepressant response.
“Why were these people hot? We think it’s because the pathway wasn’t working correctly so they couldn’t lose heat, which elevated their body temperature. But giving the treatment lowers body temperature and makes the pathway more sensitive,” he said.
One of the challenges with this study, said Dr. Raison, was developing a convincing placebo. With some creativity, the researchers devised a sham therapy that convinced 75% of the patients that they were receiving the active treatment.
Those in the active treatment group experienced reduction in depression with effect sizes (1.4 at one week) compared to placebo that dwarf those of SSRIs and their placebos. “This is almost two and a half times larger an effect,” said Dr. Raison.
In addition, although Dr. Raison and his colleagues predicted that the effects would disappear after 6 weeks, many people were still significantly improved compared with placebo.
“Like ketamine, like scopolamine, and other rapid treatments for depression that are of intense interest in psychiatry, hyperthermia shows the same effect. It doesn’t take a week or two to work. People feel better very, very quickly, and the effects appear to persist for an extended period of time,” said Dr. Raison.
—Lauren LeBano
Source: http://www.psychcongress.com/
American Society of Addiction Medicine (ASAM) National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use
Journal of Addicition Medicine
Online Journals:
Molecular Psychiatry - Volume 20, Issue 11, Octobe 2015
Biological Psychiatry - Volume 78, Issue 9, November 2015
