Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism
The American Journal of Psychiatry
Objective Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels.
Method
A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit.
Results
The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramate’s effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes.
Conclusions
These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate’s effects on heavy drinking.
Link: http://goo.gl/bsHjqS
Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans suffering from post-traumatic stress disorder
Biological Psychiatry
Background
Enhanced glucocorticoid receptor (GR) sensitivity is present in people with PTSD, but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptomatology given that PTSD develops in only a subset of trauma survivors.
Methods
Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter), and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal (HPA) axis function, were examined in a sample of 122 combat veterans.
Results
Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared to combat-exposed veterans who did not develop PTSD. Importantly, NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMC lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (0.50 mg) dexamethasone suppression test (DST), and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD.
Conclusions
Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. As epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop without PTSD.
Enhanced glucocorticoid receptor (GR) sensitivity is present in people with PTSD, but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptomatology given that PTSD develops in only a subset of trauma survivors.
Methods
Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter), and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal (HPA) axis function, were examined in a sample of 122 combat veterans.
Results
Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared to combat-exposed veterans who did not develop PTSD. Importantly, NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMC lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (0.50 mg) dexamethasone suppression test (DST), and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD.
Conclusions
Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. As epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop without PTSD.
Link: http://goo.gl/5jtHPi
JAMA
Importance
Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.
Objective
The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
Design, Setting and Participants
The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.
Interventions
Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.
Main Outcomes and Measures
Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.
Results
Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.
Conclusions and Relevance
Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.
Link: http://goo.gl/kMi6M4
Effect of citalopram on agitation in Alzheimer disea.e: the CitAD randomized clinical trial.
JAMA
Importance
Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.
Objective
The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
Design, Setting and Participants
The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.
Interventions
Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.
Main Outcomes and Measures
Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.
Results
Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.
Conclusions and Relevance
Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.
Link: http://goo.gl/kMi6M4
Preventive Effects of Ramelteon on Delirium
JAMA Psychiatry
Importance
No highly effective interventions to prevent delirium have been identified.
Objective
To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium.
Design, Setting, and Participants
A multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital. Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours.
Interventions
Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days.
Main Outcomes and Measures
Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).
Results
Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P = .01; odds ratio, 0.07 [95% CI, 0.008-0.54]). The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo. Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ2 = 9.83; P = .002).
Conclusions and Relevance
Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium. This finding supports a possible pathogenic role of melatonin neurotransmission in delirium.
Link: http://goo.gl/N0Uskw
No highly effective interventions to prevent delirium have been identified.
Objective
To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium.
Design, Setting, and Participants
A multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital. Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours.
Interventions
Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days.
Main Outcomes and Measures
Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).
Results
Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P = .01; odds ratio, 0.07 [95% CI, 0.008-0.54]). The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo. Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ2 = 9.83; P = .002).
Conclusions and Relevance
Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium. This finding supports a possible pathogenic role of melatonin neurotransmission in delirium.
Frontotemporal Dementia Associated With the C9ORF72 Mutation
JAMA Neurology
Importance
While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear.
While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear.
Objectives
To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)–FTD cohort.
Design, Setting, and Participants
A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD–amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained.
Main Outcomes and Measures
Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale.
Results
In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD.
Conclusions and Relevance
The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.
Speech Disturbs Face Scanning in 6-Month-Old Infants Who Develop Autism Spectrum Disorder
Biological Psychiatry
Background
From birth, infants show a preference for the faces, gaze, and voices of others. In individuals with autism spectrum disorders (ASDs) these biases seem to be disturbed. The source of these disturbances is not well-understood, but recent efforts have shown that the spontaneous deployment of attention to social targets might be atypical as early as 6 months of age. The nature of this atypical behavior and the conditions under which it arises are currently unknown.
Methods
We used eye-tracking to examine the gaze patterns of 6-month-old infants (n = 99) at high risk (n = 57) and low risk (n = 42) for developing ASD as they viewed faces that were: 1) still; 2) moving and expressing positive affect; or 3) speaking. Clinical outcomes were determined through a comprehensive assessment at the age of 3 years. The scanning patterns of infants later diagnosed with ASD were compared with infants without an ASD outcome.
Results
Infants who later developed ASD spent less time looking at the presented scenes in general than other infants. When these infants looked at faces, their looking toward the inner features of faces decreased compared with the other groups only when the presented face was speaking.
Conclusions
Our study suggests that infants later diagnosed with ASD have difficulties regulating attention to complex social scenes. It also suggests that the presence of speech might uniquely disturb the attention of infants who later develop ASD at a critical developmental point when other infants are acquiring language and learning about their social world.
Methods
We used eye-tracking to examine the gaze patterns of 6-month-old infants (n = 99) at high risk (n = 57) and low risk (n = 42) for developing ASD as they viewed faces that were: 1) still; 2) moving and expressing positive affect; or 3) speaking. Clinical outcomes were determined through a comprehensive assessment at the age of 3 years. The scanning patterns of infants later diagnosed with ASD were compared with infants without an ASD outcome.
Results
Infants who later developed ASD spent less time looking at the presented scenes in general than other infants. When these infants looked at faces, their looking toward the inner features of faces decreased compared with the other groups only when the presented face was speaking.
Conclusions
Our study suggests that infants later diagnosed with ASD have difficulties regulating attention to complex social scenes. It also suggests that the presence of speech might uniquely disturb the attention of infants who later develop ASD at a critical developmental point when other infants are acquiring language and learning about their social world.
Link: http://goo.gl/B7bqfJ
Medication-Assisted Treatment With Buprenorphine: Assessing the Evidence
Psychiatric Services
Objective
Buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) are pharmacological treatment programs for individuals with opioid use disorders. MMT is discussed in a companion article. This article describes BMT and reviews available research on its efficacy.
Methods
Authors reviewed meta-analyses, systematic reviews, and individual studies of BMT from 1995 through 2012. Databases surveyed were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress. They chose from three levels of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness.
Results
Sixteen adequately designed randomized controlled trials of BMT indicated a high level of evidence for its positive impact on treatment retention and illicit opioid use. Seven reviews or meta-analyses were also included. When the medication was dosed adequately, BMT and MMT showed similar reduction in illicit opioid use, but BMT was associated with less risk of adverse events. Results suggested better treatment retention with MMT. BMT was associated with improved maternal and fetal outcomes in pregnancy, compared with no medication-assisted treatment. Rates of neonatal abstinence syndrome were similar for mothers treated with BMT and MMT during pregnancy, but symptoms were less severe for infants whose mothers were treated with BMT.
Conclusions
BMT is associated with improved outcomes compared with placebo for individuals and pregnant women with opioid use disorders. BMT should be considered for inclusion as a covered benefit.
More than two million individuals in the United States are addicted to opioids. Two common options for pharmacological maintenance treatment of opioid dependence are the opioid agonists methadone and buprenorphine. Over 300,000 individuals receive methadone through outpatient treatment programs (2). Over half of these programs and thousands of physicians now offer buprenorphine. Such pharmacological treatment is typically provided in combination with psychosocial or other support services.
This article reports the results of a literature review that was undertaken as part of the Assessing the Evidence Base Series (see box on next page). Methadone maintenance treatment (MMT) is reviewed in a companion article in this series (3). As discussed in that review, research has shown that MMT improves treatment outcomes for individuals with opioid dependence (4–7). However, MMT is associated with serious adverse events, such as respiratory depression and cardiac arrhythmias (8–10). Because of concern about these adverse events and medication diversion, MMT is restricted to dedicated opioid treatment programs that provide daily medication dosing and offer psychosocial treatment services. In this article, we review buprenorphine maintenance treatment (BMT) as an alternative to MMT for the long-term management of opioid use disorders.
For purposes of this initiative, the Substance Abuse and Mental Health Services Administration describes medication-assisted treatment as a direct service that provides a person who has a substance use or mental disorder with pharmacotherapy in conjunction with behavioral therapies as treatment for associated symptoms or disabilities. BMT is a medication-assisted treatment that uses buprenorphine or buprenorphine-naloxone to treat individuals with an opioid use disorder.
Buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) are pharmacological treatment programs for individuals with opioid use disorders. MMT is discussed in a companion article. This article describes BMT and reviews available research on its efficacy.
Methods
Authors reviewed meta-analyses, systematic reviews, and individual studies of BMT from 1995 through 2012. Databases surveyed were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress. They chose from three levels of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness.
Results
Sixteen adequately designed randomized controlled trials of BMT indicated a high level of evidence for its positive impact on treatment retention and illicit opioid use. Seven reviews or meta-analyses were also included. When the medication was dosed adequately, BMT and MMT showed similar reduction in illicit opioid use, but BMT was associated with less risk of adverse events. Results suggested better treatment retention with MMT. BMT was associated with improved maternal and fetal outcomes in pregnancy, compared with no medication-assisted treatment. Rates of neonatal abstinence syndrome were similar for mothers treated with BMT and MMT during pregnancy, but symptoms were less severe for infants whose mothers were treated with BMT.
Conclusions
BMT is associated with improved outcomes compared with placebo for individuals and pregnant women with opioid use disorders. BMT should be considered for inclusion as a covered benefit.
More than two million individuals in the United States are addicted to opioids. Two common options for pharmacological maintenance treatment of opioid dependence are the opioid agonists methadone and buprenorphine. Over 300,000 individuals receive methadone through outpatient treatment programs (2). Over half of these programs and thousands of physicians now offer buprenorphine. Such pharmacological treatment is typically provided in combination with psychosocial or other support services.
This article reports the results of a literature review that was undertaken as part of the Assessing the Evidence Base Series (see box on next page). Methadone maintenance treatment (MMT) is reviewed in a companion article in this series (3). As discussed in that review, research has shown that MMT improves treatment outcomes for individuals with opioid dependence (4–7). However, MMT is associated with serious adverse events, such as respiratory depression and cardiac arrhythmias (8–10). Because of concern about these adverse events and medication diversion, MMT is restricted to dedicated opioid treatment programs that provide daily medication dosing and offer psychosocial treatment services. In this article, we review buprenorphine maintenance treatment (BMT) as an alternative to MMT for the long-term management of opioid use disorders.
For purposes of this initiative, the Substance Abuse and Mental Health Services Administration describes medication-assisted treatment as a direct service that provides a person who has a substance use or mental disorder with pharmacotherapy in conjunction with behavioral therapies as treatment for associated symptoms or disabilities. BMT is a medication-assisted treatment that uses buprenorphine or buprenorphine-naloxone to treat individuals with an opioid use disorder.
