Important Findings Published in Biological Psychiatry
By Caleb M. Adler, MD.
July 1, 2011
Commentary by Thomas R. Insel, Sarah E. Morris, and Robert K. Heinssen
Carter CS, Barch DM, Bullmore E, et al (2011). Cognitive neuroscience treatment research to improve cognition in schizophrenia II: developing imaging biomarkers to enhance treatment development for schizophrenia and related disorders. Biol Psychiatry 70:7-12
In this review article, the authors give an overview of the first meeting of the second phase of the "cognitive neuroscience treatment research to improve cognition in schizophrenia." This meeting was concerned with exploring issues around the use of neuroscience techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). Later articles discuss the use of each of these techniques as biomarkers for treatment development.
Barch DM, Mathalon DH (2011). Using brain imaging measures in studies of procognitive pharmacologic agents in schizophrenia: psychometric and quality assurance considerations. Biol Psychiatry 70:13-18
In the article, the authors review psychometric issues that need to be considered in applying potential biomarkers to the process of drug discovery. In particular, the authors focus on multiple aspects of both reliability and quality assurance. The issues broached are widely applicable to a variety of psychiatric disorders and imaging modalities.
McClintock SM, Freitas C, Oberman L, et al (2011). Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia. Biol Psychiatry 70:19-27
While the clinical utility of transcranial magnetic stimulation (TMS) is briefly reviewed, the article largely focuses on the use of TMS in conjunction with electrophysiological and functional imaging modalities. Potential TMS research paradigms are reviewed at length, and the authors conclude that TMS is a useful probe of cortical function and might serve to help identify potential biomarkers in the future.
Luck SJ, Mathalon DH, O'Donnell BF, et al (2011). A roadmap for the development and validation of event-related potential biomarkers in schizophrenia research. Biol Psychiatry 70:28-34
In this article, the authors address the use of event-related potential (ERPs) as possible biomarkers. To place this discussion in context, Dr. Luck and colleagues review the neurophysiology of ERPs at some length before discussing application of ERPs as a potential biomarker of treatment for psychiatric illness. While the strengths of this technique are noted, the authors also discuss aspects of the technique that will need to be addressed prior to wide-spread implementation.
July 15, 2011
Commentary by Ola Sternäng and Åke Wahlin
Taylor AE, Guthrie PA, Smith GD, et al (2011). IQ, educational attainment, memory and plasma lipids: associations with apolipoprotein E genotype in 5995 children. Biol Psychiatry 70:152-158
Apolipoprotein E (APOE) genotype has been previously found to be associated with lipid levels, and with Alzheimer's disease in older adults. In this paper, the authors examined the relationship between apolipoprotein E (APOE) genotype and plasma lipids, IQ, and school performance in a large cohort of children. Dr. Taylor and colleagues found that APOE genotype was associated with measures of plasma lipids, but in contrast to older adults there was no relationship with IQ or school performance. In their commentary, Drs. Sternäng and Wahlin discuss the uniqueness of this study but note that some pertinent cognitive domains were not addressed, and that studying interactions between multiple factors such as lipids, cognition and gender might be useful in further elucidating the role of APOE genotype in cognitive decline.
Commentary by Francis Lotrich
Capuron L, Schroecksnadel S, Féart C, et al (2011). Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry 70:175-182
A number of recent studies have linked peripheral inflammatory processes to the development of mood symptoms. In this paper, the authors identify some potential pathways for interactions between inflammation and the biosynthesis of monoamines. The authors report evidence of indoleamine-2,3-dioxygenase (IDO) induced increases in tryptophan catabolism, as well as changes in neopterin and nitrite levels, and in the phenylalanine/tyrosine ratio, consistent with inflammatory effects on the guanosine-triphosphate-cyclohydrolase-1 (GTP-CH1) pathway. Furthermore, markers of the two pathways appeared to correlate with divergent depressive symptoms. The commentary points out however, that few of the subjects met criteria for a major depressive episode.
Commentary by John C.S. Breitner
Schneider P, Buerger K, Teipel S, et al (2011). Antihypertensive therapy is associated with reduced rate of conversion to Alzheimer's disease in midregional proatrial natriuretic peptide stratified subjects with mild cognitive impairment. Biol Psychiatry 70:145-151
Several lines of evidence suggest that hypertension and vasculopathy represent significant risk factors for Alzheimer's disease (AD). In this paper Dr. Schneider and colleagues examined the relationship between conversion from mild cognitive impairment (MCI) to AD and midregional proatrial natriuretic peptide (MR-proANP). MR-proANP is a surrogate for atrial natriuretic peptide (ANP), a molecule involved in the regulation of blood pressure. The authors found that baseline MR-proANP was significantly increased in individuals who converted to AD. However, treatment with antihypertensive medication significantly decreased conversion to AD only in those individuals with baseline elevation of MR-proANP, suggesting that treatment of elevated blood pressure may be helpful in preventing progression to AD only in these patients.
August 1, 2011
Commentary by Michael W. Otto
Modi ME, Young LJ (2011). D-cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders. Biol Psychiatry 70:298-304
In this study the authors build on previous findings that the NMDA receptor partial agonist, d-cycloserine (DCS), may enhance extinction learning and provide a useful adjunct to psychotherapeutic interventions for a variety of anxiety disorders. The authors apply DCS to modify the formation of partner preference in prairie voles. A low dose of peripheral DCS or microinjection of DCS to the amygdala or nucleus accumbens was associated with more rapid preference formation. The authors suggest that this effect is mediated through oxytocin-mediated social learning systems, and further suggest that DCS may be useful for treating the social impairment associated with autism spectrum disorders (ASD). While noting the importance of this study, the commentary provides some alternate explanations for the study findings.
Commentary by Risto Näätänen and Teija Kujala
Roberts TP, Cannon KM, Tavabi K, et al (2011). Auditory magnetic mismatch field latency: a biomarker for language impairment in autism. Biol Psychiatry 70:263-269
Magnetic mismatch field latency (MMF) has previously been shown to be affected by autism spectrum disorders (ASD), and may be associated with clinical language impairment. In this study, the authors found evidence for prolonged MMF latency in children with ASD; delay was greatest in children with language impairments. The authors suggest that MMF may help provide a neurobiological marker for language impairments and serve as a potential biomarker for deficits in language development. The commentary elaborates on the authors' speculation as to how specific these findings might be to language development in ASD, and suggest that an association between MMF findings and a more general cognitive decline cannot be ruled out.
Commentary by Ahmad R. Hariri
Salatino-Oliveira A, Genro JP, Zeni C, et al (2011). Catechol-O-methyltransferase valine158methionine polymorphism moderates methylphenidate effects on oppositional symptoms in boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 70:216-221
The effects of the substitution of valine for methionine at codon 158 (val158met) on the function of the catechol-O-methyltransferase enzyme (COMT) have been well documented over the more than ten years since it was first linked to psychiatric symptomatology. In this paper, Salatino-Oliveira and colleagues report that the val158met polymorphism is associated with the effects of methylphenidate treatment in children with attention deficit hyperactivity disorder (ADHD). The commentary places these findings in the larger context of COMT studies and notes that these findings suggest the importance of developmental stage in the manifestation of val158met effects.
Dumontheil I, Roggeman C, Ziermans T, et al (2011). Influence of the COMT genotype on working memory and brain activity changes during development. Biol Psychiatry 70:222-229
The met allele of the val158met COMT polymorphism has been associated with decreased prefrontal activation and improved performance on working memory tasks in adults. In this study, the authors report that this improvement does not appear until after 10 years of age. They also note an age by genotype interaction with regard to functional activation and gray matter volume in some brain regions. The commentary juxtaposes these findings with those of Salatino-Oliveira and colleagues in demonstrating disparate developmental influences on the effects of this polymorphism.
August 15, 2011
Commentary by Mark D. Underwood and Victoria Arango
Ernst C, Nagy C, Kim S, et al (2011). Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers. Biol Psychiatry 70:312-319
There is increasing evidence that suicide may comprise a distinct phenotype separate or in addition to underlying psychiatric disorders. In this study Dr. Ernst and colleagues report that they found astrocyte connexins 30 and 40 to be down regulated in the dorsolateral prefrontal cortex (DLPFC) of suicide completers. The authors suggest that connexins may be related to mood symptoms and antidepressant response. In the commentary it is further suggested that these findings may have broader implications, including questions around the role of astrocytes in psychiatric disorders and the potential developmental nature of vulnerability to suicide.
Cyprien F, Courtet P, Malafosse A, et al (2011). Suicidal behavior is associated with reduced corpus callosum area. Biol Psychiatry 70:320-326
The authors found reductions in the caudal third of the corpus callosum (CC) in older adults who had attempted suicide- even versus a group of affective controls. The commentary notes that these findings are in contrast to previous studies that have found changes in the anterior portion of the CC, which encompasses the majority of prefrontal interconnections. They speculate that these differences might be related to the older age of the subjects here, or their having failed to complete suicide; the latter presumably representing evidence of resilience. Taken together with the above study, the commentary further suggests that the phenotype of suicide may be related to multiple neurobiological substrates.
Commentary by Yvette I. Sheline
Gerritsen L, Comijs HC, van der Graaf Y, et al (2011). Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes--the SMART Medea study. Biol Psychiatry 70:373-380
In this large study of participants from the second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, the authors observed smaller hippocampal volumes in patients with a history of depression and in patients with early-onset depression. Remitted major depressive disorder was associated with smaller entorhinal volumes. Of particular interest were findings in patients with late-onset depression, first diagnosed at 50 years-of-age or older. The authors observed decreased entorhinal volumes in these patients, but they did not demonstrate reduced hippocampal volume. Although the authors did not observe evidence of any association with measures of hypothalamic-pituitary-adrenal (HPA) axis regulation, patients were not acutely depressed when these were obtained. The commentary places these findings in a larger context, as well as noting that the decreased entorhinal volume in late-onset patients might be related to early dementia-related changes rather than depression. The commentary further argues the need for prospective studies, and studies of the HPA during acute depressive episodes to better address issues with neurobiological causality in depression.
Commentary by Marc G. Berman and John Jonides
Hamilton JP, Furman DJ, Chang C, et al (2011). Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination. Biol Psychiatry 70:327-333
The authors compared activity in the default-mode network (DMN) versus the task-positive network (TPN) in a group of depressed adults. Individuals with depression significantly differed from healthy controls; furthermore, increased activity in the DMN was associated with more depressive rumination and lower levels of more adaptive, reflective rumination. Activation of the right fronto-insular cortex (RFIC) an area hypothesized to be involved in switching between DMN and TPN dominance, at the onset of DMN activity was reversed in depressed individuals versus healthy controls. The commentary expands on these findings and places them in a larger context.
September 1, 2011
Commentary by Rachel Yehuda
Dietz DM, Laplant Q, Watts EL, et al (2011). Paternal transmission of stress-induced pathologies. Biol Psychiatry 70:408-414
The transmission to offspring of the effects of maternal stress has generally been assumed to be rooted in the influence of the uterine environmental or to be transmitted through stress-related behavioral change in the mother. In this study the authors study the effects of paternal stress on male and female offspring. Dr. Dietz and colleagues report that exposure to chronic social defeat is associated with increased measures of depression- and anxiety-like behaviors in the offspring of adult male mice. Only male offspring however, showed concomitant hormonal changes. These findings were present only in offspring produced through copulation, and was not seen in offspring that resulted from in vitro fertilization. The authors suggest that this discrepancy is indicative of influences from the copulatory behavior rather than epigenetic changes in the fathers. These findings are discussed in the commentary, and the point is made that the discrepant IVF findings might be related to technical issues rather than ruling out potential epigenetic changes.
Commentary by Hymie Anisman
Olson VG, Rockett HR, Reh RK, et al (2011). The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. Biol Psychiatry 70:441-448
The authors utilize a sophisticated rodent model of posttraumatic stress disorder (PTSD) to study the effects of a single prolonged stress followed by repeated behavioral cues on behavioral change and brain activation during a force swim test- reflected in c-fos expression. Exposed rodents were divided into susceptible and resistant groups based on their response to the stressor. Susceptible mice showed aggressive and social behavioral correlates of PTSD that were normalized with pharmacologic manipulation of norepinephrine pathways, activation of inhibitory autoreceptors or blockade of postsynaptic α1-adrenoreceptors. In the commentary, Dr. Anisman places these findings in the context of recent PTSD research and suggests that the different phases of the illness might be associated with distinct neurobiological processes.
Commentary by Laura M. Rowland
Delgado y Palacios R, Campo A, Henningsen K, et al (2011). Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol Psychiatry 70:449-457
In this paper, the authors examine the results of chronic mild stress (CMS) in a group of twelve week-old rats. After the CMS, rats were divided by response into resilient and anhedonic categories based on sucrose intake. Both resilient and anhedonic rats showed hippocampal diffusion and histological changes, compared with a group of control rats. Susceptible rats differed from their resilient counterparts however, on some morphological features of the hippocampus and magnetic resonance spectroscopy measures of glutamate/creatine and N-acetylaspartylglutamate (NAAG)/creatine ratios. The authors note that their findings emphasize the potential role played by hippocampal pathology in depression and suggest that stress-induced hippocampal reorganization differs between resilient and susceptible rats. While some weaknesses in the study design are discussed in the commentary, findings are placed in a clinical context and used to illustrate the promise of multi-modal imaging.
September 15, 2011
Commentary by Howard J. Edenberg
Heath AC, Whitfield JB, Martin NG, et al (2011). A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biol Psychiatry 70:513-518
The authors have performed a genome-wide single nucleotide polymorphism (SNP) genotyping with a large group of sibships. They performed family-based association tests for measures of alcohol abuse and dependence, as well as consumption. Dr. Heath and colleagues did not report any findings achieving genome-wide significance but note data suggesting roles for two genes and a number of SNPs with small effect sizes. They conclude that applying GWAS results clinically may be difficult. The commentary discusses the use of this technique in studying alcohol use disorders and notes that it may show more clinical promise than credited by the authors.
Commentary by Kent E. Hutchinson and Lara A. Ray
Xie P, Kranzler HR, Krauthammer M, et al (2011). Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biol Psychiatry 70:528-536
Previous studies have suggested an association between alpha-4 nicotinic receptors coded by CHRNA4, and nicotine dependence (ND). In this paper, the authors report on their sequencing of coding exons and flanking intronic regions of CHRNA4 in patients with ND and controls- with a larger analysis of exon 5. A protective effect of rare nonsynonymous variants was suggested by the higher frequency in control subjects. Exploratory SPECT scans suggest that some of these variants may be associated with differences in receptor binding. The commentary places these findings into a larger context and notes that this paper demonstrates both the role that rare variants may play in ND and the potential power of cross-modality studies for generating new neurophysiologic insights.
Commentary by Mary Jeanne Kreek, Yan Zhou, and Orna Levran
Maher BS, Vladimirov VI, Latendresse SJ, et al (2011). The AVPR1A Gene and Substance Use Disorders: Association, Replication, and Functional Evidence. Biol Psychiatry 70:519-527
The authors report their findings of an association between three single nucleotide polymorphisms (SNPs) and substance use disorder (SUD). These SNPs were in the arginine vasopressin (AVP) 1A receptor gene, AVPR1A which has been associated with social behavior and emotional arousal. The effects of one of these SNPs on SUD was found to be mediated by spousal satisfaction. This genotype was also found to impact AVPR1A expression in a collection of postmortem brain samples. While the associate with SUD was not replicated in a population-based sample, the authors suggest that the relatively lower severity of use in these subjects may be germane. In the commentary, these AVP findings are placed in the context of the commentators' previous work.
October 1, 2011
Commentary by Daniel H. Mathalon
Wood SJ, Yung AR, McGorry PD, et al (2011). Neuroimaging and treatment evidence for clinical staging in psychotic disorders: from the at-risk mental state to chronic schizophrenia. Biol Psychiatry 70:619-625
In this paper, Wood and colleagues apply a proposed staging model of psychiatric disorders to schizophrenia. The authors propose defined stages from 0 through IV (with I divided into Ia and Ib). They review both imaging and clinical data supporting the use of staging in schizophrenia. The commentary reviews the proposed use of staging in psychiatry but notes that the data cited by Wood and colleagues could equally support a continuum-based model of schizophrenia, and the lack of clear therapeutic application of these stages. Nonetheless, the commentary notes that the approach holds potential promise.
Commentary by Margaret A. Cooper and Anthony J. Koleske
Neddens J, Fish KN, Tricoire L, et al (2011). Conserved Interneuron-Specific ErbB4 Expression in Frontal Cortex of Rodents, Monkeys, and Humans: Implications for Schizophrenia. Biol Psychiatry 70:636-645
The neuroregulin-1 ErbB4 signaling pathway has been widely implicated in the pathophysiology of schizophrenia. Localization of ErbB4 in primates however, has remained controversial. In this paper, the authors examined ErbB4 expression across rodent, non-human primate, and human subjects. No presynaptic expression was observed, and predominate localization to interneurons was conserved across species. The commentary discusses these findings in depth and notes that this study is particularly important in validating the use of rodent models to study the possible role of ErbB4 in schizophrenia.
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