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By Caleb M. Adler, MD.
Important findings published in Biological Psychiatry
March 15, 2011
Commentary by Jordan W. Smoller
Muiños-Gimeno M, Espinosa-Parrilla Y, Guidi M, et al (2011).
Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways. Biol Psychiatry;69:526-533
Ernst C, Wanner B, Brezo J, et al (2011). A deletion in tropomyosin-related kinase B and the development of human anxiety. Biol Psychiatry;69:604-607
Despite increasing knowledge of the underlying neurophysiology of anxiety disorders, relatively few studies of the genetics of these disorders have been done. In this issue, two studies examining genetic aspects of anxiety disorders are reported. Muinos-Gimeno and colleagues identified single-nucleotide polymorphisms (SNPs) to be associated with panic disorder and related phenotypes; though the replication was not significant after controlling for multiple comparisons. Further studies showed that some of the relevant SNPs were involved in regulating candidate genes for anxiety disorders. Ernst and colleagues reported on a relatively rare, eleven base pair deletion in a candidate gene for mood and anxiety disorders that is associated with increased anxiety symptoms in children and the appearance of adult anxiety disorders. Although these reports are limited in power, they suggest the need for large-scale, collaborative follow-up studies.
Commentary by Natalina Salmaso and Flora M. Vaccarino
Eren-Koçak E, Turner CA, Watson SJ, et al (2011). Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior. Biol Psychiatry;69:534-540
Anxiety disorders affect almost 20% of Americans. Although pharmacological approaches have shown considerable efficacy, significant clinical limitations remain. Recent studies have suggested that fibroblast growth factor 2 (FGF2) may play a role in anxiety and mood disorders. In this issue, Eren-Koçak and colleagues report data that suggest that hippocampal levels of FGF2 correlate to individuals' vulnerability and resilience with respect to anxiety and mood disorders. These findings represent some of the first experimental evidence that FGF2 is involved in the development of anxiety.
Commentary by James W. Murrough and Dennis S. Charney
Pluess M , Velders FP, Belsky J, et al (2011). Serotonin Transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biol Psychiatry;69:520-525
Montag C, Fiebach CJ, Kirsch P, et al (2011). Interaction of 5-HTTLPR and a variation on the
oxytocin receptor gene influences negative emotionality. Biol Psychiatry;69:601-603
Homberg JR, Lesch K-P (2011). Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry;69:513-519
Despite the enormous promise of genetic research, little progress has been made in identifying specific gene variants in patients with psychiatric disorders. One approach might be to focus on links between candidate genes and intermediate phenotypes, rather than more complicated, DSM-IV diagnoses. Pleuss and colleagues report that the 5-HTTLPR short allele is associated with a link between prenatal maternal anxiety and increased negative emotionality in infants. Montag and colleagues showed an interaction between the 5-HTTLPR long allele and a variant of a single nucleotide polymorphism on the oxytocin receptor gene. Individuals homozygous for both showed an effect on personality assessments, suggesting an interaction between serotonergic and oxytocinergic systems in the expression of personality. Homberg and Lesch place these studies in further perspective in their review of recent findings suggesting that the 5-HTTLPR short allele may confer situational advantages related to enhanced reactivity of the corticolimbic neural circuitry.
April 1, 2011
Commentary by Theodora Duka
Andrews MM, Meda SA, Thomas AD, et al (2011). Individuals family history positive for alcoholism show functional magnetic resonance imaging differences in reward sensitivity that are related to impulsivity factors. Biol Psychiatry;69:675-683
Drug and alcohol abuse has been associated with both a reward deficiency syndrome and increased impulsivity. In this issue, Andrews and colleagues used fMRI to demonstrate blunted activation of the nucleus accumbens (NAcc) during performance of a monetary incentive delay task in subjects with a family history of alcoholism, as well as altered activation in other areas associated with reward. NAcc activity was inversely correlated with elements of impulsivity, linking these two constructs.
Commentary by Hitoshi Morikawa and R. Adron Harris
Mulholland PJ, Becker HC, Woodward JJ, et al (2011). Small conductance calcium-activated potassium type 2 channels regulate alcohol-associated plasticity of glutamatergic synapses. Biol Psychiatry;69:625-632
Hopf FW, Simms JA, Chang S-J, et al (2011). Chlorzoxazone, an SK-type potassium channel
activator used in humans, reduces excessive alcohol intake in rats. Biol Psychiatry;69:618-624
Several lines of recent evidence suggest that calcium-activated potassium (SK) channels might represent a target for novel therapeutics targeting alcohol use disorders. In this issue, Mulholland and colleagues report on data suggesting that alcohol exposure disrupts the SK channel-NMDA receptor feedback loop in the hippocampus of a Sprague-Dawley rat model. In addition, chronic alcohol exposure increased expression of NMDA receptor subunits, supporting suggestions that changes in SK channels and NMDA receptors are related to ethanol-related plasticity. In a related study, Hopf and colleagues examined whether the positive SK modulator, chlorzoxazone (CZX) would reduce alcohol consumption in a group of Wistar rats. Systemic injection of CZX into rats with intermittent access to alcohol (IAA) was associated with reduced alcohol preference and less initial alcohol consumption; these effects were not seen in rats with continuous access. CZX was also associated with enhanced excitability and increased CZX inhibition of core neurons in the nucleus accumbens, particularly in rats with IAA. Together these studies support suggestions that SK channel activators such as CZX might eventually be employed to treat alcohol withdrawal and decrease consumption in patients with alcohol use disorders.
Commentary by Joel Gelernter
Ducci F, Kaakinen M, Pouta A, et al (2011). TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biol Psychiatry;69:650-660
Several single nucleotide polymorphisms in gene clusters associated with smoking behavior were found to be associated with smoking. Carriers of three or more risk alleles had increased odds of smoking regularly, compared to individuals with no risk alleles. Some effects appeared to be mediated by early influence on smoking habits and others by novelty seeking, while some of these effects appeared to be more direct.
April 15, 2011
Commentary by James W. Murrough and Alexander Neumeister
McDevitt RA, Hiroi R, Mackenzie SM, et al (2011). Serotonin 1B autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression-like behavior. Biol Psychiatry;69:780-787
The 5HT1B serotonin receptor is being increasingly viewed as playing a potentially important role in depressive and anxiety disorders, raising the possibility of new treatments targeting this receptor. In this issue, McDevitt and colleagues report their findings that overexpression of
5HT1B through viral mediated gene transfer in the caudal dorsal raphe nucleus impacted expressions of helplessness and fear in Sprague-Dawley rats without affecting evidence of anxiety. They also observed decreased freezing behavior with administration of the 5HT1B agonist CP-94,253. Potential therapeutic applications are complicated however, by the functional disparities between subpopulations of the 5HT1B receptor.
Commentary by Jennifer A. Bartz
Bilderbeck AC, McCabe C, Wakeley J, et al (2011). Serotonergic activity influences the cognitive appraisal of close intimate relationships in healthy adults. Biol Psychiatry;69:720-725
Potential neurochemical mediators of human intimacy have recently come under increasing research focus. As part of this research, serotonin has been widely associated with effects on a variety of mood states. In this issue, Bilderbeck and colleagues report that tryptophan-depleted adults viewing pictures of couples judged them to be less "intimate" and "romantic" than did adults who had ingested a tryptophan-containing drink prior to testing. In addition, tryptophan depleted women viewed men as more dominant in the relationships pictured, and described couples pictured touching each other to be more able to resolve their conflicts. These findings emphasize the role that serotonin has been suggested to play in interpersonal relationships, and highlights the possible connection between serotonin dysfunction in numerous psychiatric disorders and interpersonal difficulties often associated with these disorders.
Commentary by Pedro L. Delgado
Feder A, Skipper J, Blair JR,, et al (2011). Tryptophan depletion and emotional processing in healthy volunteers at high risk for depression. Biol Psychiatry;69:804-807
Tryptophan depletion has previously been associated with depression in high-risk individuals. In this issue, Feder and colleagues show that tryptophan depletion in adolescents at high risk for major depressive disorder is associated with increased rates of inappropriate responses to sad distractors in an affective go/no-go task. In contrast, there was no effect on emotionally neutral decision making. They conclude that serotonin might be more closely linked to affective processing than to mood state.
May 1, 2011 Commentary by Matthew W. State Stein MB, Yang BZ, Chavira DA, et al (2011). A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-related traits. Biol Psychiatry;69:825-831 Stein and colleagues report an association between a variation in the neuronal adhesion molecule, Contactin-Associated Protein-like 2 (CNTNAP2) which has been implicated in autism, and risk for selective mutism. These findings suggest some commonalities between autism spectrum disorders and social anxiety. In a larger context, these findings highlight the potentially pleiotropic effects of individual genes. Commentary by Robert R. Ring Sala M, Braida D, Lentini D, et al (2011). Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry;69:875-882 Autism spectrum disorders (ASD) are attracting increasing attention and funding as public awareness of these disorders grows. This growth has also fueled increased interest on the part of the pharmaceutical industry and emerging recognition of potential neurophysiological overlap between ASD and other psychiatric disorders such as schizophrenia. In this issue, Sala and colleagues show that oxytocin receptor null mice exhibit autistic-like behaviors including cognitive inflexibility that are alleviated by the intracerebral administration of oxytocin and vasopressin. Their increased seizure activity, also often observed in ASD, similarly responded to oxytocin administration. The authors suggest that in the absence of the oxytocin receptor activity is mediated through an arginine vasopressin receptor (V1a). In a linked finding, the authors note that hippocampal neurons from oxytocin receptor null mice showed decreased GABA-ergic synapses. They suggest that oxytocin receptor null mice might serve as a useful model for studying treatment of ASD. Commentary by Clyde Franks Recent studies have implicated a novel group of genes coding for a group of synaptic adhesion proteins, termed the leucine-rich repeat transmembrane neuronal family (LRRTM) in a range of psychiatric pathology. These studies suggest that LRRTMs may play a role in "fine tuning" synapse function. While the precise role of LRRTMs in the manifestation of psychiatric disorders remains unclear, hypotheses include effects on laterality, glutamatergic synaptic transmission, and synaptic pruning. Future studies will need to include epigenetic studies of the LRRTM gene family and examine the effects of these genes on cognition and other potential phenotypic expressions. May 15, 2011 Commentary by Maria Jalbrzikowski and Carrie E. Bearden Kates WR, Antshel KM, Faraone SV, et al (2011). Neuroanatomic predictors to prodromal psychosis in velocardiofacial syndrome (22q11.2 deletion syndrome): a longitudinal study. Biol Psychiatry;69:945-952 Recent evidence suggests that schizophrenia is associated with greater genetic heterogeneity than was previously thought, indicating a need to focus on rare, highly penetrant genetic variants. Velocardiofacial syndrome (VCFS) results from one such rare variant; while it accounts for only one to two percent of schizophrenic patients, almost one third of these individuals will go on to develop schizophrenia. In this issue, Kates and colleagues report increased frontal gray and white matter volumes, as well as increased amygdala and lateral ventricle in patients with VCFS. Over time, total schizophrenia prodromal symptoms were predicted by alterations in multiple brain regions, while decrements in temporal gray matter and verbal IQ were predicative of the development of positive prodromal symptoms. These findings are interpreted in light of previous studies of non-VCFS individuals at risk for schizophrenia. Commentary by Heike Tost and Andreas Meyer-Lindenberg Nixon DC, Prust MJ, Sambataro F, et al (2011). Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex. Biol Psychiatry;69:1006-1008 Schizophrenia research has long focused on two neurotransmitters, dopamine and glutamate. More recent evidence suggests extensive interactions between the two systems at both cellular and network levels. Using fMRI, Nixon and colleagues report a functional epistasis in healthy individuals, of D-amino acid oxidase activator (DAOA) by catechol-O-methyltransferase (COMT) manifested by effects on efficiency within the dorsolateral prefrontal cortex during performance of a working memory task. This study uses working memory as an intermediate phenotype to provide a functional confirmation of an epistasis suggested to impact schizophrenia risk.
June 1, 2011 Commentary by Eisuke Koya and Bruce T. Hope Kim J, Park BH, Lee JH, et al (2011). Cell type-specific alterations in the nucleus accumbens by repeated exposures to cocaine. Biol Psychiatry;69:1026-1034 Rothwell PE, Kourrich S, Thomas MJ (2011). Synaptic adaptations in the nucleus accumbens caused by experiences linked to relapse. Biol Psychiatry;69:1124-1126 Dopamine receptors in the nucleus accumbens have long been implicated in substance use disorders. Little is known however, about differences in cocaine related synaptic changes between D1 receptors (D1R) and D2 receptors (D2R). In this issue, Kim and colleagues analyzed the effects of injected cocaine on D1R and D2R medium spiny neurons of the nucleus accumbens of transgenic mice. They found that D1R neurons demonstrated increased spine density, coupled with decreased membrane excitability and increased frequency of miniature excitatory post-synaptic currents after repeated cocaine injections. In contrast, D2R showed decreased excitatory post-synaptic current and no change in membrane excitability. Miniature inhibitory post-synaptic currents were decreased in D1R neurons but unchanged in D2R neurons. In a complementary study, Rothwell and colleagues found that experiences associated with reinstatement, a rodent model of drug relapse are linked to reduced excitatory synaptic strength in the nucleus accumbens shell, as are stress and drug re-exposure. These findings suggest that this change in the nucleus accumbens represents a common synaptic modification associated with drug relapse. Together, these studies support the role of synaptic changes in the nucleus accumbens in substance use disorders. Commentary by Andrew Holmes Nam HW, Lee MR, Zhu Y, et al (2011). Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling. Biol Psychiatry;69:1043-1051 Although pharmacologic interventions for alcohol use disorders remain limited, there have been significant advances in understanding the neuropharmacology of alcohol exposure. In this issue, Nam and colleagues report on their study of mice lacking the equilibrative nucleoside transporter gene (ENT1), which have been previously demonstrated to exhibit increased ethanol preferring behavior. Using a range of techniques, the authors demonstrated that ENT1 is involved with NMDA glutamate receptor-mediated signaling in the nucleus accumbens, and is linked to the behavioral changes in ENT negative mice. These studies may suggest future areas for treatment of alcohol use disorders. Commentary by Stephanie S. O'Malley Garza D, Murphy M, Tseng LJ, et al (2011). A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo. Biol Psychiatry;69:1075-1082 The characterization of neuropsychiatric adverse effects (NPAEs) can be complicated; recent post marketing reports have suggested that varenicline may be associated with a range of NPAEs not observed in previous clinical trials. In this issue, Garza and colleagues report on a double-blind, placebo-controlled study of NPAEs in smokers receiving varenicline. They report no clinically significant differences on measures of mood, anxiety, or hostility. Efforts were made to control for potential confounds by selecting patients without existing psychiatric conditions and using a two week inpatient hospitalization to ensure comparable smoking cessation rates. The study was not however, powered to detect rare NPAEs, and did not test for the potential effects of stressful events. In addition, because smokers with a psychiatric history were excluded, these findings cannot be generalized to that large population. June 15, 2011 Commentary by Amy F.T. Arnsten and B.J. Casey Understanding of the role of prefrontal cortical networks in both healthy neurophysiology and neuropathological conditions has increased significantly over the past few years, impacting research into a range of mood, psychotic and attention disorders. This special issue includes a range of studies examining different aspects of prefrontal networks in preclinical and clinical populations. Together, these studies highlight the emerging role of clinical neuroscience in our conceptualization of psychiatric illnesses- and the potential this increased understanding might play have for facilitating early identification and treatment of these illnesses.
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