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Latest Results for Psychopharmacology

Monday, April 6, 2015

April 2015

Zyprexa Relprevv (olanzapine pamoate): Drug Safety Communication - FDA Review of Study Sheds Light on Two Deaths Associated with the Injectable Schizophrenia Drug

ISSUE: FDA has concluded a review of a study undertaken to determine the cause of elevated levels of the injectable schizophrenia drug Zyprexa Relprevv (olanzapine pamoate) in two patients who died. The study results were inconclusive. FDA is unable to exclude the possibility that the deaths were caused by rapid, but delayed, entry of the drug into the bloodstream following intramuscular injection. The study suggested that much of the drug level increase could have occurred after death, a finding that could explain the extremely high blood levels found in the two patients who died 3 to 4 days after receiving injections of appropriate doses of Zyprexa Relprevv. On the basis of all of the information reviewed (refer to the Drug Safety Communication for a full data summary), FDA is not recommending any changes to the current prescribing or use of Zyprexa Relprevv injection at this time. Patients should not stop receiving treatment without first talking to their health care professionals.

BACKGROUND: Treatment with Zyprexa Relprevv may help improve the symptoms of schizophrenia, which include hearing voices, seeing things that are not there, and being suspicious or withdrawn. The labeling for Zyprexa Relprevv carries a boxed warning, FDA’s most serious type of warning, for post-injection delirium sedation (PDSS). This is an update to the MedWatch safety alert issued on June 18, 2013.

RECOMMENDATION: Patients should read the Medication Guide that comes with the Zyprexa Relprevv prescription each time before they get an intramuscular injection, as there may be new information. Patients receiving Zyprexa Relprevv or their caregivers should immediately report symptoms of PDSS to a health care professional.

Health care professionals should continue to follow the Zyprexa Relprevv Patient Care Program Risk Evaluation and Mitigation Strategy (REMS) requirements and current label recommendations. Notable requirements of the REMS include:

For a patient to receive treatment, the prescriber, health care facility, patient, and pharmacy must all be enrolled in the Zyprexa Relprevv Patient Care Program.
Zyprexa Relprevv injections must be administered at a REMS-certified health care facility with ready access to emergency response services.
Patients must be continuously monitored at the REMS-certified health care facility for at least 3 hours following an intramuscular injection.
Patients receiving Zyprexa Relprevv must be accompanied to their destination from the health care facility.


Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model

Science Translational Medicine

Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer’s disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD.


Antibodies to Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First Episode of Acute Psychosis in Children

Biological Psychiatry


The dopamine and glutamate hypotheses are well known in psychosis. Recently, the detection of autoantibodies against proteins expressed on the surface of cells in the central nervous system has raised the possibility that specific immune-mediated mechanisms may define a biological subgroup within psychosis, although no cohort of a first episode of psychosis in children has been investigated.

Serum taken during the acute presentation of 43 children with first episode of psychosis and serum from 43 pediatric control subjects was assessed for the presence of immunoglobulin (Ig)G, IgM, or IgA antibodies to dopamine-2 receptor (D2R) and NR1 subunit of the N-methyl-D-aspartate receptor using a flow cytometry live cell-based assay and immunolabeling of murine primary neurons.

Using a cutoff of three SD above the control mean, serum antibodies to D2R or NR1 were detected in 8 of 43 psychotic patients but not detected in any of 43 control subjects (p < .001). Positive immunoglobulin binding to D2R was found in 3 of 43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to N-methyl-D-aspartate receptor in 6 of 43 patients (5 IgG, 1 IgM, 1 IgA). Specificity of antibody was confirmed by immunoaffinity purification and immunoabsorption. Significant differences in antibody binding to live, fixed, and fixed and permeabilized neurons were observed, confirming that only live cells can define surface epitope immunolabeling.

This is the first report of serum antibodies to surface D2R and NR1 in pediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of patients may be immune-mediated.


The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study



To determine whether higher past exposure to particulate air pollution is associated with prevalent high symptoms of anxiety.

Observational cohort study.

Nurses’ Health Study.

71 271 women enrolled in the Nurses’ Health Study residing throughout the contiguous United States who had valid estimates on exposure to particulate matter for at least one exposure period of interest and data on anxiety symptoms.

Main outcome measures
Meaningfully high symptoms of anxiety, defined as a score of 6 points or greater on the phobic anxiety subscale of the Crown-Crisp index, administered in 2004.

The 71 271 eligible women were aged between 57 and 85 years (mean 70 years) at the time of assessment of anxiety symptoms, with a prevalence of high anxiety symptoms of 15%. Exposure to particulate matter was characterized using estimated average exposure to particulate matter <2.5 μm in diameter (PM2.5) and 2.5 to 10 μm in diameter (PM2.5-10) in the one month, three months, six months, one year, and 15 years prior to assessment of anxiety symptoms, and residential distance to the nearest major road two years prior to assessment. Significantly increased odds of high anxiety symptoms were observed with higher exposure to PM2.5 for multiple averaging periods (for example, odds ratio per 10 µg/m3 increase in prior one month average PM2.5: 1.12, 95% confidence interval 1.06 to 1.19; in prior 12 month average PM2.5: 1.15, 1.06 to 1.26). Models including multiple exposure windows suggested short term averaging periods were more relevant than long term averaging periods. There was no association between anxiety and exposure to PM2.5-10. Residential proximity to major roads was not related to anxiety symptoms in a dose dependent manner.

Exposure to fine particulate matter (PM2.5) was associated with high symptoms of anxiety, with more recent exposures potentially more relevant than more distant exposures. Research evaluating whether reductions in exposure to ambient PM2.5 would reduce the population level burden of clinically relevant symptoms of anxiety is warranted.


Developmentally Stable Whole-Brain Volume Reductions and Developmentally Sensitive Caudate and Putamen Volume Alterations in Those With Attention-Deficit/Hyperactivity Disorder and Their Unaffected Siblings

JAMA Psychiatry


Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD.

To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD.

Design, Setting, and Participants  
In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years).

Main Outcomes and Measures  
Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation.

Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = −31.92; 95% CI, −52.69 to −11.16; P = .0027) and a 3% smaller total gray matter volume (β = −22.51; 95% CI, −35.07 to −9.96; P = .0005), while total white matter volume was unaltered (β = −10.10; 95% CI, −20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes.

Conclusions and Relevance  
Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.


The ratios of 2nd to 4th digit may be a predictor of schizophrenia in male patients.

Clinical Anatomy


The production of androgens (mostly testosterone) during the early fetal stage is essential for the differentiation of the male brain. Some authors have suggested a relationship between androgen exposure during the prenatal period and schizophrenia. These two separate relationships suggest that digit length ratios are associated with schizophrenia in males. The study was performed in a university hospital between October 2012 and May 2013. One hundred and three male patients diagnosed with schizophrenia according to DSM-IV using SCID-I, and 100 matched healthy males, were admitted to the study. Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) were used to assess schizophrenia symptoms. The second digit (2D) and fourth digit (4D) asymmetry index (AI), and the right- and left-hand 2D:4D ratios were calculated. All parametric data in the groups were compared using an independent t-test. The predictive power of the AI was estimated by receiver operating characteristics analysis. The 2D:4D AI was statistically significantly lower in the patient group than the healthy control comparison group. There were significant differences between the schizophrenia and the control groups in respect of left 2D:4D and right 2D:4D. There was no correlation between AI, left, or right 2D:4D, BPRS, or SAPS in the schizophrenia group. However, there was a negative correlation between left 2nd digit (L2D):4D and the SANS score. Our findings support the view that the 2D:4D AI can be used as a moderate indicator of schizophrenia. Even more simply, the right or left 2D:4D can be used as an indicator. L2D:4D could indicate the severity of negative symptoms.


Forever young: Meditation might slow the age-related loss of gray matter in the brain, say UCLA researchers


Since 1970, life expectancy around the world has risen dramatically, with people living more than 10 years longer. That’s the good news.

The bad news is that starting when people are in their mid-to-late-20s, the brain begins to wither — its volume and weight begin to decrease. As this occurs, the brain can begin to lose some of its functional abilities.

So although people might be living longer, the years they gain often come with increased risks for mental illness and neurodegenerative disease. Fortunately, a new study shows meditation could be one way to minimize those risks.

Building on their earlier work that suggested people who meditate have less age-related atrophy in the brain’s white matter, a new study by UCLA researchers found that meditation appeared to help preserve the brain’s gray matter, the tissue that contains neurons.

The scientists looked specifically at the association between age and gray matter. They compared 50 people who had mediated for years and 50 who didn’t. People in both groups showed a loss of gray matter as they aged. But the researchers found among those who meditated, the volume of gray matter did not decline as much as it did among those who didn’t.

The article appears in the current online edition of the journal Frontiers in Psychology.

Dr. Florian Kurth, a co-author of the study and postdoctoral fellow at the UCLA Brain Mapping Center, said the researchers were surprised by the magnitude of the difference.

“We expected rather small and distinct effects located in some of the regions that had previously been associated with meditating,” he said. “Instead, what we actually observed was a widespread effect of meditation that encompassed regions throughout the entire brain.”

As baby boomers have aged and the elderly population has grown, the incidence of cognitive decline and dementia has increased substantially as the brain ages.

“In that light, it seems essential that longer life expectancies do not come at the cost of a reduced quality of life,” said Dr. Eileen Luders, first author and assistant professor of neurology at the David Geffen School of Medicine at UCLA. “While much research has focused on identifying factors that increase the risk of mental illness and neurodegenerative decline, relatively less attention has been turned to approaches aimed at enhancing cerebral health.”

Each group in the study was made up of 28 men and 22 women ranging in age from 24 to 77. Those who meditated had been doing so for four to 46 years, with an average of 20 years.

The participants’ brains were scanned using high-resolution magnetic resonance imaging. Although the researchers found a negative correlation between gray matter and age in both groups of people — suggesting a loss of brain tissue with increasing age — they also found that large parts of the gray matter in the brains of those who meditated seemed to be better preserved, Kurth said.

The researchers cautioned that they cannot draw a direct, causal connection between meditation and preserving gray matter in the brain. Too many other factors may come into play, including lifestyle choices, personality traits, and genetic brain differences.

“Still, our results are promising,” Luders said. “Hopefully they will stimulate other studies exploring the potential of meditation to better preserve our aging brains and minds. Accumulating scientific evidence that meditation has brain-altering capabilities might ultimately allow for an effective translation from research to practice, not only in the framework of healthy aging but also pathological aging.”


Skin Test May Shed New Light on Alzheimer’s and Parkinson’s Diseases

American Academy of Neurology


To demonstrate the presence of phosphorylated Tau (p-Tau) and α-synuclein (α-Syn) in the skin from patients with the two most frequent neurodegenerative disorders, Alzheimer´s (AD) and Parkinson´s (PD) diseases

The presence of misfolded proteins is the hallmark of neurodegeneration, which iscurrently demonstrated through the analysis of brain tissue obtained postmortem. The brain and skin share the same embryological origin; therefore they may also express the same abnormal deposits of proteins.

We took skin biopsies from the retro-auricular area in 65 subjects: 20 with AD, 16 with PD, 17 with non-neurodegenerative dementia, and 12 age-matched healthy controls. We measured the reactivity against the antibodies p-Tau (PHF: p-S296 and AT8: p-S202) and α-Syn both in sections of paraffin embedded tissue and in proteins extracted from tissue homogenates. Light and confocal microscopy were employed to localize protein aggregates by immunohistochemistry and their presence in the skin was confirmed through Western blots. Immunopositivity was assessed by means of three different methods (percentage of positive cells, a semi-quantitative scale, 0 null, + mild, ++ moderate, +++ frequent, and through image analysis using the software Image-Pro Plus Analyzer 7.0, [Media Cybernetics Inc]).

The skin biopsies taken from AD and PD patients presented significantly higher levels of p-Tau immunopositivity when compared both to control subjects and patients with non-degenerative dementia (P<0.001). In PD patients, the presence of α-synuclein immunopositivity was significantly higher than in control subjects (P = 0.0004).

This study demonstrates the presence of p-Tau and α-synuclein in skin biopsies by
immunoreactivity. This procedure could be used to open opportunity to study neurodegenerative diseases.


Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment

The American Journal of Psychiatry


The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients’ stress to test hypotheses about clonidine’s behavioral mechanism of action.

The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5–6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data were examined with generalized linear mixed models.

In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7]; Cohen’s d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% CI=0.45–1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors’ hypothesized mechanism for clonidine’s benefits.

Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life.


FDA Drug Safety Communication: FDA updates label for stop smoking drug Chantix (varenicline) to include potential alcohol interaction, rare risk of seizures, and studies of side effects on mood, behavior, or thinking

The U.S. Food and Drug Administration (FDA) is warning that the prescription smoking cessation medicine Chantix (varenicline) can change the way people react to alcohol. In addition, rare accounts of seizures in patients treated with Chantix have been reported. We have approved changes to the Chantix label to warn about these risks. Until patients know how Chantix affects their ability to tolerate alcohol, they should decrease the amount of alcohol they drink. Patients who have a seizure while taking Chantix should stop the medicine and seek medical attention immediately.
Millions of Americans have serious health problems caused by smoking, which can be reduced by quitting. Chantix is a prescription medicine that is FDA-approved to help adults quit smoking. In clinical trials, Chantix increased the likelihood of quitting smoking and “staying quit” for as long as 1 year compared to treatment with a placebo, an inactive treatment.

We reviewed the case series submitted by Pfizer, the manufacturer of Chantix, as well as the cases in the FDA Adverse Event Reporting System (FAERS) database describing patients who drank alcohol during treatment with Chantix and experienced adverse reactions. Some patients experienced decreased tolerance to alcohol, including increased drunkenness, unusual or aggressive behavior, or they had no memory of things that happened (see Data Summary).

We also reviewed FAERS and the medical literature1 for cases of seizures with Chantix and identified cases in which the patients who had seizures while taking Chantix either had no history of seizures or had a seizure disorder that had been well-controlled. In most of these cases, the seizures occurred within the first month of starting Chantix. Information about these risks has been added to the Warnings and Precautions section of the drug label and to the patient Medication Guide.

We also updated the Warnings and Precautions section of the label to include information about several studies that investigated the risk of neuropsychiatric side effects on mood, behavior, or thinking occurring with Chantix. These included observational studies,2-5 as well as analyses that Pfizer conducted of randomized controlled clinical trial data.6 These studies did not show an increased risk of neuropsychiatric side effects with Chantix; however, they did not examine all types of neuropsychiatric side effects, and they had limitations that prevented us from drawing reliable conclusions.

We previously communicated about possible serious neuropsychiatric side effects with Chantix in 2009 and 2011, and these recent studies were discussed at an FDA Advisory Committee meeting in October 2014. Pfizer is conducting a large clinical safety trial of Chantix to investigate this risk and results from this study are expected in late 2015. We will update the public as appropriate when this new information becomes available.


Online Journals:

Journal of Clinical Psychopharmacology - April 2015 - Volume 35, Issue 2

Biological Psychiatry - Volume 77, Issue 9, April 2015

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