Monday, June 8, 2015

June 2015

Clozapine-induced myocarditis, a widely overlooked adverse reaction


Acta Psychiatrica Scandinavica

Abstract

Objective
We review the published cases of clozapine-induced myocarditis and describe reasons for the higher incidence in Australia (>1%) than elsewhere (<0.1%).

Method
Medline was searched to September 2014 using ‘clozapine’ as the sole term.

Results
A total of around 250 cases of clozapine-induced myocarditis have been published. Fever among patients commencing clozapine has been reported internationally, and very few of these cases were investigated for myocarditis. The time to onset of fever is consistent with its being part of a prodrome of undiagnosed myocarditis, and the risk factors are similar to those for myocarditis. In more severe cases, clozapine is discontinued, avoiding fatalities which may occur with myocarditis. Furthermore, cases of sudden death and respiratory illness may well have been undiagnosed myocarditis. The diagnosis of myocarditis is confounded by the non-specific nature of the signs and symptoms, and it depends on appropriate investigations being conducted at the time of myocardial involvement or, for fatal cases, the affected area of the myocardium being sampled for histology.

Conclusion
It is likely that the incidence of myocarditis is around 3%. Implementation of monitoring procedures will increase case ascertainment and result in more patients benefiting from this valuable medication.



White Matter Differences Among Adolescents Reporting Psychotic Experiences


JAMA Psychiatry

Abstract

Importance  
Abnormal brain connectivity is thought to have a key role in the pathophysiology of schizophrenia and other psychotic disorders. White matter (WM) abnormalities have been reported in patients with schizophrenia and patients with prodromal syndromes. To our knowledge, no studies have yet reported on WM differences among adolescents who report psychotic experiences, a known vulnerability group for later severe psychopathology, including psychotic illness.

Objective  
To study WM differences using diffusion-weighted imaging (whole-brain and tractography analyses) in adolescents who report psychotic experiences.

Design, Setting, and Participants  
A population-based case-control study of 28 adolescents 13 to 16 years old who reported psychotic experiences and a matched sample of 28 adolescents who did not report psychotic experiences drawn from a sample of 212 young people recruited from primary schools in North Dublin and Kildare, Ireland. The study dates were 2008 to 2011.

Interventions  
High-angular resolution diffusion-weighted imaging data were used to conduct whole-brain WM analysis using tract-based spatial statistics. Based on this exploratory analysis, a tractography-based approach with constrained spherical deconvolution was performed.

Results  
Compared with control group participants, adolescents who reported psychotic experiences showed WM differences bilaterally in striatal regions in proximity to the putamen (increased fractional anisotropy, P = .01, false discovery rate corrected), and tractography identified significant WM differences bilaterally in the uncinate fasciculus (increased fractional anisotropy in the right [P = .001] and axial diffusivity in the left [P = .01] uncinate fasciculus, respectively). Similar patterns of WM differences between groups survived adjustment for other psychopathology, indicating some specificity for psychotic experiences. Exploratory along-tract analyses showed WM differences between groups in the frontal projections of the right inferior fronto-occipital fasciculus (reduced radial diffusivity in approximately 32% of the tract segment [P ≤ .0001] and increased fractional anisotropy in approximately 16% of the tract segment [P ≤ .0009]).

Conclusions and Relevance  
In a population-based study of adolescents reporting psychotic experiences, we found a number of WM differences in the region of the putamen located between the inferior fronto-occipital fasciculus and the uncinate fasciculus and in the left parietal regions that include the fiber bundle of the superior longitudinal fasciculus. These findings suggest that subtle structural changes to WM microstructure are not merely a consequence of disorder but may index vulnerability to psychosis even at a very early age.



Is Post-Traumatic Stress Disorder Associated with Premature Senescence?


The American Journal of Geriatric Psychiatry

Abstract 

Objective
Post-traumatic stress disorder (PTSD) has major public health significance. Evidence that PTSD may be associated with premature senescence (early or accelerated aging) would have major implications for quality of life and healthcare policy. We conducted a comprehensive review of published empirical studies relevant to early aging in PTSD.

Method
Our search included the PubMed, PsycINFO, and PILOTS databases for empirical reports published since the year 2000 relevant to early senescence and PTSD, including: 1) biomarkers of senescence (leukocyte telomere length [LTL] and pro-inflammatory markers), 2) prevalence of senescence-associated medical conditions, and 3) mortality rates.

Results
All six studies examining LTL indicated reduced LTL in PTSD (pooled Cohen's d = 0.76). We also found consistent evidence of increased pro-inflammatory markers in PTSD (mean Cohen's ds), including C-reactive protein = 0.18, Interleukin-1 beta = 0.44, Interleukin-6 = 0.78, and tumor necrosis factor alpha = 0.81. The majority of reviewed studies also indicated increased medical comorbidity among several targeted conditions known to be associated with normal aging, including cardiovascular disease, type 2 diabetes mellitus, gastrointestinal ulcer disease, and dementia. We also found seven of 10 studies indicated PTSD to be associated with earlier mortality (average hazard ratio: 1.29).

Conclusion
In short, evidence from multiple lines of investigation suggests that PTSD may be associated with a phenotype of accelerated senescence. Further research is critical to understand the nature of this association. There may be a need to re-conceptualize PTSD beyond the boundaries of mental illness, and instead as a full systemic disorder.


Citicoline Appears to Reduce Cocaine Use in Patients With Bipolar Disorder


The American Journal of Psychiatry

Abstract

Objective:
Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use.

Method:
A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology–Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale.

Results:
In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed.

Conclusions:
Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.



The FDA approved Janssen's 3-month paliperidone palmitate (Invega Trinza), an atypical antipsychotic to treat schizophrenia in adults


Invega Trinza is the first and only FDA-approved schizophrenia medication administered just 4 times a year. Janssen initially submitted the New Drug Application for a 3-month formulation of its 1-month paliperidone palmitate (Invega Sustenna) schizophrenia treatment in November 2014, and the FDA granted it priority review designation in January 2015.

Before starting Invega Trinza, patients must be adequately treated with Invega Sustenna for at least 4 months.

“With a dosing interval that can be measured in seasons, not days, people living with schizophrenia and their treatment teams can focus on recovery goals beyond short-term symptom control,” said Invega Trinza trial investigator Joseph Kwentus, MD, in a press release. “Recovery looks different for everyone, and the long-term symptom control offered by Invega Trinza can help patients work toward their own personal goals.”

The FDA based its nod on the results of a phase 3 long-term maintenance trial in which 93% of patients treated with Invega Trinza did not experience a significant return of schizophrenia symptoms. The drug’s safety and tolerability were also found to be consistent with those of Invega Sustenna, and the study raised no new risk-benefit concerns.

“It's encouraging to see continued progress in the treatment of schizophrenia, since access to a range of treatment options is a critical success factor in the treatment journey of individuals living with this disease,” stated Mental Health America president and CEO Paul Gionfriddo. “As both an advocate and a parent of an adult son with schizophrenia, I can attest to the importance of novel therapies that enable our loved ones to spend more time focusing on their recovery and less time worrying about taking medications.”

Janssen plans to launch Invega Trinza by mid-June, according to a press release.



The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression


Journal of Translational Psychiatry

Abstract

Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed. 



Young Adults Who Drink Heavily Show Abnormal Brain Changes


The American Journal of Psychiatry

Abstract

Objective:
Heavy alcohol use during adolescence may alter the trajectory of normal brain development. The authors measured within-subject changes in regional brain morphometry over longer intervals and in larger samples of adolescents than previously reported and assessed differences between adolescents who remained nondrinkers and those who drank heavily during adolescence as well as differences between the sexes.

Method:
The authors examined gray and white matter volume trajectories in 134 adolescents, of whom 75 transitioned to heavy drinking and 59 remained light drinkers or nondrinkers over roughly 3.5 years. Each underwent MRI scanning two to six times between ages 12 and 24 and was followed for up to 8 years. The volumes of the neocortex, allocortex, and white matter structures were measured using atlas-based parcellation with longitudinal registration. Linear mixed-effects models described differences in trajectories of heavy drinkers and nondrinkers over age; secondary analyses considered the contribution of other drug use to identified alcohol use effects.

Results:
Heavy-drinking adolescents showed accelerated gray matter reduction in cortical lateral frontal and temporal volumes and attenuated white matter growth of the corpus callosum and pons relative to nondrinkers. These results were largely unchanged when use of marijuana and other drugs was examined. Male and female drinkers showed similar patterns of development trajectory abnormalities.

Conclusions:
Longitudinal analysis enabled detection of accelerated typical volume decline in frontal and temporal cortical volumes and attenuated growth in principal white matter structures in adolescents who started to drink heavily. These results provide a call for caution regarding heavy alcohol use during adolescence, whether heavy drinking is the sole cause or one of several in these alterations in brain development.



Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression


JAMA Psychiatry

Abstract

Importance  
Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that “withdrawal” from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD).

Objective  
To examine the role of estradiol withdrawal in PMD.

Design, Setting, and Participants  
Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance.

Interventions  
After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions.

Main Outcomes and Measures  
Center for Epidemiologic Studies–Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits.

Results  
None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies–Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo.

Conclusions and Relevance  
In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy.




Study Finds Long-Term Depression Increases Risk for Stroke in Older Adults


Journal of the American Heart Association

Abstract

Background 
Although research has demonstrated that depressive symptoms predict stroke incidence, depressive symptoms are dynamic. It is unclear whether stroke risk persists if depressive symptoms remit.

Methods and Results 
Health and Retirement Study participants (n=16 178, stroke free and noninstitutionalized at baseline) were interviewed biennially from 1998 to 2010. Stroke and depressive symptoms were assessed through self‐report of doctors’ diagnoses and a modified Center for Epidemiologic Studies ‐ Depression scale (high was ≥3 symptoms), respectively. We examined whether depressive symptom patterns, characterized across 2 successive interviews (stable low/no, onset, remitted, or stable high depressive symptoms) predicted incident stroke (1192 events) during the subsequent 2 years. We used marginal structural Cox proportional hazards models adjusted for demographics, health behaviors, chronic conditions, and attrition. We also estimated effects stratified by age (≥65 years), race or ethnicity (non‐Hispanic white, non‐Hispanic black, Hispanic), and sex. Stroke hazard was elevated among participants with stable high (adjusted hazard ratio 2.14, 95% CI 1.69 to 2.71) or remitted (adjusted hazard ratio 1.66, 95% CI 1.22 to 2.26) depressive symptoms compared with participants with stable low/no depressive symptoms. Stable high depressive symptom predicted stroke among all subgroups. Remitted depressive symptoms predicted increased stroke hazard among women (adjusted hazard ratio 1.86, 95% CI 1.30 to 2.66) and non‐Hispanic white participants (adjusted hazard ratio 1.66, 95% CI 1.18 to 2.33) and was marginally associated among Hispanics (adjusted hazard ratio 2.36, 95% CI 0.98 to 5.67).

Conclusions 
In this cohort, persistently high depressive symptoms were associated with increased stroke risk. Risk remained elevated even if depressive symptoms remitted over a 2‐year period, suggesting cumulative etiologic mechanisms linking depression and stroke.



Can Hyperlipidemia Improve Negative Symptoms of Schizophrenia?


Hyperlipidemia may increase risk of cardiovascular disease, but it also may improve cognition in patients with schizophrenia. The study, based on data from the Clinical Antipsychotic Trial of Interventional Effectiveness (CATIE) trial, was presented at the 168th meeting of the American Psychiatric Association.

“We believe the cognitive deficits of schizophrenia, among schizophrenia researchers, to be the core feature of schizophrenia and the reason for functional disability, in addition to the regular symptoms,” said lead author Henry Nasrallah, MD, of the Department of Neurology & Psychiatry, Saint Louis University School of Medicine in Missouri.

Schizophrenia patients often are treated with atypical antipsychotics, which are known to cause metabolic dysregulation that is associated with poor cardiovascular health. However, some reports have suggested that antipsychotic-induced hypercholesterolemia might be linked with cognitive improvement in patients with schizophrenia.

To better understand this possibility, Dr. Nasrallah and a colleague examined a sample of 1,460 individuals ages 18 to 67 (mean age, 40) and looked for evidence of a relationship between neurocognition and high total cholesterol, high triglyceride levels, and low HDL levels. The Composite Neurocognitive Score, which was used in the CATIE study, allowed the researchers to evaluate this relationship.

Data analysis revealed a statistically significant association between high cholesterol and better neurocognition scores. The same trend was seen among people in the high triglyceride group, who had significantly better cognitive scores than people in the low triglyceride group. In addition, people with low HDL scores fared worse on neurocognitive measures than people with high HDL scores.

“We psychiatrists are caught in a bind. High lipids increase cardiovascular mortality, but high lipids are also associated with better cognition. And there is no treatment for cognition in schizophrenia. It’s a big challenge, a huge unmet need,” Dr. Nasrallah said.

—Lauren LeBano

Reference

1. Nasrallah H. Elevated Cholesterol and Triglycerides are Associated with Better Cognitive Functioning in Schizophrenia Data From the CATIE Study. Poster presented at the 168th meeting of the American Psychiatric Association. 16 May 2015.


Online Journals:




Biological Psychiatry - Volume 78, Issue 1, July 2015



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