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1.  The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome 
Current Neuropharmacology  2014;12(1):71-98.
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.
doi:10.2174/1570159X113116660046
PMCID: PMC3915351  PMID: 24533017
AMPA receptor; Arc; autism spectrum disorder; Fragile X syndrome; GRIP1/2; kainate receptor; MAP1B; memantine; metabotropic glutamate receptor; neuroligin; NMDA receptor.
2.  Should an Obsessive-Compulsive Spectrum Grouping of Disorders Be Included in DSM-V? 
Depression and anxiety  2010;27(6):528-555.
The obsessive-compulsive (OC) spectrum has been discussed in the literature for two decades. Proponents of this concept propose that certain disorders characterized by repetitive thoughts and/or behaviors are related to obsessive-compulsive disorder (OCD), and suggest that such disorders be grouped together in the same category (i.e., grouping, or “chapter”) in DSM. This paper addresses this topic and presents options and preliminary recommendations to be considered for DSM-V. The paper builds upon and extends prior reviews of this topic that were prepared for and discussed at a DSM-V Research Planning Conference on Obsessive-Compulsive Spectrum Disorders held in 2006. Our preliminary recommendation is that an OC-spectrum grouping of disorders be included in DSM-V. Furthermore, we preliminarily recommend that consideration be given to including this group of disorders within a larger supraordinate category of “Anxiety and Obsessive-Compulsive Spectrum Disorders.” These preliminary recommendations must be evaluated in light of recommendations for, and constraints upon, the overall structure of DSM-V.
doi:10.1002/da.20705
PMCID: PMC3985410  PMID: 20533367
obsessive compulsive spectrum; obsessive compulsive disorder; classification; DSM-V
3.  OBSESSIVE–COMPULSIVE DISORDER: A REVIEW OF THE DIAGNOSTIC CRITERIA AND POSSIBLE SUBTYPES AND DIMENSIONAL SPECIFIERS FOR DSM-V 
Depression and anxiety  2010;27(6):507-527.
Background
Since the publication of the DSM-IV in 1994, research on obsessive–compulsive disorder (OCD) has continued to expand. It is timely to reconsider the nosology of this disorder, assessing whether changes to diagnostic criteria as well as subtypes and specifiers may improve diagnostic validity and clinical utility.
Methods
The existing criteria were evaluated. Key issues were identified. Electronic databases of PubMed, ScienceDirect, and PsycINFO were searched for relevant studies.
Results
This review presents a number of options and preliminary recommendations to be considered for DSM-V. These include: (1) clarifying and simplifying the definition of obsessions and compulsions(criterion A); (2) possibly deleting the requirement that people recognize that their obsessions or compulsions are excessive or unreasonable (criterion B); (3) rethinking the clinical significance criterion (criterion C) and, in the interim, possibly adjusting what is considered “time-consuming” for OCD; (4) listing additional disorders to help with the differential diagnosis (criterion D); (5) rethinking the medical exclusion criterion (criterion E) and clarifying what is meant by a “general medical condition”; (6) revising the specifiers (i.e., clarifying that OCD can involve a range of insight, in addition to “poor insight,” and adding “tic-related OCD”); and (7) highlighting in the DSM-V text important clinical features of OCD that are not currently mentioned in the criteria (e.g., the major symptom dimensions).
Conclusions
A number of changes to the existing diagnostic criteria for OCD are proposed. These proposed criteria may change as the DSM-V process progresses.
doi:10.1002/da.20669
PMCID: PMC3974619  PMID: 20217853
Obsessive compulsive disorder; DSM-V; nosology; tic disorders; early onset; symptom dimensions
4.  Predicting Response to Opiate Antagonists and Placebo in the Treatment of Pathological Gambling 
Psychopharmacology  2008;200(4):521-527.
Rationale
Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG.
Objectives
We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists.
Methods
284 subjects (137 [48.2%] women) with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] with positive response defined as ≥ 35% reduction in PG-YBOCS score for at least one month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response.
Results
The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p=.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50mg/d or 100mg/d or naltrexone 100mg/d or 150mg/d), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p=.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p=.012).
Conclusions
A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.
doi:10.1007/s00213-008-1235-3
PMCID: PMC3683409  PMID: 18581096
opiate antagonists; impulsivity; impulse control disorders; addiction; pharmacotherapy; placebo
5.  Effects of age and symptomatology on cortical thickness in autism spectrum disorders 
Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with ASD, between the ages of 7 and 39 years in comparison to typically developing controls. Additionally, we examined differences in cortical thickness in relation to symptomatology in the ASD group, and their association with age. Analyses were conducted using a general linear model, controlling for sex. Social and communication scores from the Autism Diagnostic Interview-Revised (ADI-R) were correlated with the thickness of regions implicated in those functions. Controls showed widespread cortical thinning relative to the ASD group. Within regions-of-interest, increased thickness in the rostral anterior cingulate cortex was associated with poorer social scores. Additionally, a significant interaction between age and social impairment was found in the orbitofrontal cortex, with more impaired younger children having decreased thickness in this region. These results suggest that differential neurodevelopmental trajectories are present in individuals with ASD and some differences are associated with diagnostic behaviours.
doi:10.1016/j.rasd.2012.08.004
PMCID: PMC3652338  PMID: 23678367
Autism spectrum disorders; Structural MRI; Cortical thickness; Social impairment; Developmental changes
6.  The 5-HT2A receptor and serotonin transporter in Asperger’s Disorder: a PET study with [11C]MDL 100907 and [11C]DASB 
Psychiatry research  2011;194(3):230-234.
Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [11C]MDL 100907 and [11C]DASB to characterize the 5-HT2A receptor and serotonin transporter in Asperger’s Disorder. 17 individuals with Asperger’s Disorder (age = 34.3 ± 11.1 yr) and 17 healthy controls (age = 33.0 ± 9.6 yr) were scanned with [11C]MDL 100907. Of the 17 patients, eight (age = 29.7 ± 7.0 yr) were also scanned with [11C]DASB, as were eight healthy controls (age = 28.7 ± 7.0 yr). Patients with Asperger’s Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by 2 tissue-compartment modeling. The primary outcome measure was regional binding potential BPND. Neither regional [11C]MDL 100907 BPND nor [11C]DASB BPND were statistically different between the Asperger’s and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT2A receptors and serotonin transporters in adult subjects with Asperger’s Disorder.
doi:10.1016/j.pscychresns.2011.04.007
PMCID: PMC3225493  PMID: 22079057
autism spectrum disorders; 5-HT2A receptor; Asperger’s Disorder; positron emission tomography; serotonin transporter; serotonin
7.  Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial 
Molecular Autism  2012;3:16.
Background
There are no effective medications for the treatment of social cognition/function deficits in autism spectrum disorder (ASD), and adult intervention literature in this area is sparse. Emerging data from animal models and genetic association studies as well as early, single-dose intervention studies suggest that the oxytocin system may be a potential therapeutic target for social cognition/function deficits in ASD. The primary aim of this study was to examine the safety/therapeutic effects of intranasal oxytocin versus placebo in adults with ASD, with respect to the two core symptom domains of social cognition/functioning and repetitive behaviors.
Methods
This was a pilot, randomized, double-blind, placebo-controlled, parallel design trial of intranasal oxytocin versus placebo in 19 adults with ASD (16 males; 33.20 ± 13.29 years). Subjects were randomized to 24 IU intranasal oxytocin or placebo in the morning and afternoon for 6 weeks. Measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised) were administered. Secondary measures included the Social Responsiveness Scale, Reading-the-Mind-in-the-Eyes Test and the Yale Brown Obsessive Compulsive Scale – compulsion subscale and quality of life (World Health Organization Quality of Life Questionnaire – emotional/social subscales). Full-information maximum-likelihood parameter estimates were obtained and tested using mixed-effects regression analyses.
Results
Although no significant changes were detected in the primary outcome measures after correcting for baseline differences, results suggested improvements after 6 weeks in measures of social cognition (Reading-the-Mind-in-the-Eyes Test, p = 0.002, d = 1.2), and quality of life (World Health Organization Quality of Life Questionnaire – emotion, p = 0.031, d = 0.84), both secondary measures. Oxytocin was well tolerated and no serious adverse effects were reported.
Conclusions
This pilot study suggests that there is therapeutic potential to daily administration of intranasal oxytocin in adults with ASD and that larger and longer studies are warranted.
Trial registration
NCT00490802
doi:10.1186/2040-2392-3-16
PMCID: PMC3539865  PMID: 23216716
Autism; Adults; Oxytocin; Clinical trial; Social cognition
8.  Development and Validation of the Appearance and Performance Enhancing Drug Use Schedule 
Addictive behaviors  2011;36(10):949-958.
Appearance-and-performance enhancing drug (APED) use is a form of drug use that includes use of a wide range of substances such as anabolic-androgenic steroids (AASs) and associated behaviors including intense exercise and dietary control. To date, there are no reliable or valid measures of the core features of APED use. The present study describes the development and psychometric evaluation of the Appearance and Performance Enhancing Drug Use Schedule (APEDUS) which is a semi-structured interview designed to assess the spectrum of drug use and related features of APED use. Eighty-five current APED using men and women (having used an illicit APED in the past year and planning to use an illicit APED in the future) completed the APEDUS and measures of convergent and divergent validity. Inter-rater agreement, scale reliability, one-week test-retest reliability, convergent and divergent validity, and construct validity were evaluated for each of the APEDUS scales. The APEDUS is a modular interview with 10 sections designed to assess the core drug and non-drug phenomena associated with APED use. All scales and individual items demonstrated high inter-rater agreement and reliability. Individual scales significantly correlated with convergent measures (DSM-IV diagnoses, aggression, impulsivity, eating disorder pathology) and were uncorrelated with a measure of social desirability. APEDUS subscale scores were also accurate measures of AAS dependence. The APEDUS is a reliable and valid measure of APED phenomena and an accurate measure of the core pathology associated with APED use. Issues with assessing APED use are considered and future research considered.
doi:10.1016/j.addbeh.2011.05.002
PMCID: PMC3159027  PMID: 21640487
ANABOLIC-ANDROGENIC STEROID; POLYSUBSTANCE USE; BODY IMAGE DISTURBANCE; COMPULSIVE EXERCISE; PSYCHOMETRICS; RELIABILITY; VALIDY; APPEARANCE AND PERORMANCE ENHANCING DRUG USE
9.  Oxytocin can hinder trust and cooperation in borderline personality disorder 
We investigated the effects of intranasal oxytocin (OXT) on trust and cooperation in borderline personality disorder (BPD), a disorder marked by interpersonal instability and difficulties with cooperation. Although studies in healthy adults show that intranasal OXT increases trust, individuals with BPD may show an altered response to exogenous OXT because the effects of OXT on trust and pro-social behavior may vary depending on the relationship representations and expectations people possess and/or altered OXT system functioning in BPD. BPD and control participants received intranasal OXT and played a social dilemma game with a partner. Results showed that OXT produced divergent effects in BPD participants, decreasing trust and the likelihood of cooperative responses. Additional analyses focusing on individual differences in attachment anxiety and avoidance across BPD and control participants indicate that these divergent effects were driven by the anxiously attached, rejection-sensitive participants. These data suggest that OXT does not uniformly facilitate trust and pro-social behavior in humans; indeed, OXT may impede trust and pro-social behavior depending on chronic interpersonal insecurities, and/or possible neurochemical differences in the OXT system. Although popularly dubbed the ‘hormone of love’, these data suggest a more circumspect answer to the question of who will benefit from OXT.
doi:10.1093/scan/nsq085
PMCID: PMC3190211  PMID: 21115541
oxytocin; trust; cooperation; social dilemma; borderline personality disorder; adult attachment
10.  Functional deficits of the attentional networks in autism 
Brain and Behavior  2012;2(5):647-660.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
doi:10.1002/brb3.90
PMCID: PMC3489817  PMID: 23139910
Alerting; anterior cingulate cortex; attentional networks; autism; executive control
11.  Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly 
American Journal of Medical Genetics  2007;144B(4):484-491.
Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTENmutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.
doi:10.1002/ajmg.b.30493
PMCID: PMC3381648  PMID: 17427195
Cowden syndrome; Bannayan–Riley–Ruvalcaba syndrome; polydactyly; sequence analysis; multiplex ligation-dependent probe amplification
12.  In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism 
Brain research  2010;1380:198-205.
Attentional dysfunction is one of the most consistent findings in individuals with autism spectrum disorders (ASD). However, the significance of such findings for the pathophysiology of autism is unclear. In this study, we investigated cellular neurochemistry with proton magnetic resonance spectroscopy imaging (1H-MRS) in brain regions associated with networks subserving alerting, orienting, and executive control of attention in patients with ASD. Concentrations of cerebral N-acetyl-aspartate (NAA), creatinine + phosphocreatinine, choline-containing compounds, myo-inositol (Ins) and glutamate + glutamine (Glx) were determined by 3 T 1H-MRS examinations in 14 high-functioning medication-free adults with a diagnosis of ASD and 14 age- and IQ-matched healthy controls (HC) in the anterior cingulate cortex (ACC), thalamus, temporoparietal junction (TPJ), and areas near or along the intraparietal sulcus (IPS). Compared to HC group, the ASD group showed significantly lower Glx concentrations in right ACC and reduced Ins in left TPJ. This study provides evidence of abnormalities in neurotransmission related to networks subserving executive control and alerting of attention, functions which have been previously implicated in ASD pathogenesis.
doi:10.1016/j.brainres.2010.12.057
PMCID: PMC3073642  PMID: 21185269
autism; spectroscopy; glutamate; anterior cingulate cortex; intraparietal sulcus; myo-inositol
13.  Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study 
PLoS ONE  2011;6(11):e28044.
Background
Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.
Methods/Principal Findings
DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.
Conclusions/Significance
Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.
doi:10.1371/journal.pone.0028044
PMCID: PMC3223195  PMID: 22132206
14.  A Replication of the Autism Diagnostic Observation Schedule (ADOS) Revised Algorithms 
Objective
To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282).
Method
Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment.
Results
Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified.
Conclusions
Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.
doi:10.1097/CHI.0b013e31816bffb7
PMCID: PMC3057666  PMID: 18434924
autism; pervasive developmental disorders not otherwise specified; Autism Diagnostic Observation Schedule; diagnosis
15.  Brief Report: Parental Age and the Sex Ratio in Autism 
The male-to-female (M:F) ratio for autism spectrum disorders (ASD), typically about 4:1, appears to decrease with increasing paternal age, but this relationship has not been systematically tested. With 393 ASD cases from families with two or more ASD cases, we categorized paternal age into five age groups (<30, 30–34, 35–39, 40–44, 45+) and found that the M:F ratio was significantly decreased with increasing paternal age groups and remained so after also adjusting for maternal age. No significant relationship between maternal age group and the M:F ratio was observed. This study suggests that the M:F ratio is reduced with increasing paternal age consistent with de novo genetic or genomic anomalies arising more frequently as men age and then conceive children.
doi:10.1007/s10803-009-0755-y
PMCID: PMC3056272  PMID: 19452267
Paternal age; Maternal age; Sex ratio; Genetics; Genomic anomalies; Copy number variants
16.  Divalproex Sodium vs Placebo for the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorders 
Neuropsychopharmacology  2009;35(4):990-998.
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46±2.46, mean nonverbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.
doi:10.1038/npp.2009.202
PMCID: PMC2846602  PMID: 20010551
ASD; irritability; divalproex; children; adolescents; Development/Developmental Disorders; Psychiatry & Behavioral Sciences; Psychopharmacology; Clinical Pharmacology/Trials; autism; adolescents; children; EEG; divalproex
17.  THE RELATIONSHIP BETWEEN WHOLE BLOOD SEROTONIN AND REPETITIVE BEHAVIORS IN AUTISM 
Psychiatry research  2009;175(3):274.
This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.
doi:10.1016/j.psychres.2009.02.008
PMCID: PMC2815211  PMID: 20044143
autism; serotonin; repetitive behavior; self-injury; aggression
18.  Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review 
Neuropsychopharmacology  2009;35(3):591-604.
Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
doi:10.1038/npp.2009.185
PMCID: PMC3055606  PMID: 19940844
impulsive; compulsive; endophenotypes; serotonin; dopamine; Cognition; Psychiatry & Behavioral Sciences; Animal models; Biological Psychiatry; OCD; impulsivity; compulsivity; translational
19.  DIVALPROEX SODIUM VS. PLACEBO FOR THE TREATMENT OF IRRITABILITY IN CHILDREN AND ADOLESCENTS WITH AUTISM SPECTRUM DISORDERS 
Objective
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and repetitive behaviors and interests. Irritability/aggression is a significant co-morbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability / aggression in children and adolescents with ASD.
Methods
This was a 12 week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. Fifty five subjects signed consent and 27 were randomized in a 1:1 fashion (mean age 9.46±2.46, mean non verbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study due to either lack of efficacy or side effects (increased irritability).
Results
The primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, focused on irritability. 62.5% of divalproex subjects vs. 9% of placebo subjects were responders (CGI-irritability OR:16.7, Fisher’s exact p=0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale (p=0.048). There was a trend for the responders to have higher valproate blood levels than the non-responders.
Conclusions
This study suggests efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.
doi:10.1038/npp.2009.202
PMCID: PMC2846602  PMID: 20010551
ASD; irritability; divalproex; children; adolescents
20.  Treating Body Dysmorphic Disorder with Medication: Evidence, Misconceptions, and a Suggested Approach 
Body image  2008;5(1):13-27.
Body dysmorphic disorder (BDD) is a relatively common and often disabling disorder with high morbidity and mortality. Both psychotropic medication and cognitive behavioral therapy (CBT) are considered first-line treatments for BDD, and medication treatment is often essential for more severely ill and suicidal patients. In this practical overview of the pharmacotherapy of BDD, we briefly describe BDD’s clinical features, associated morbidity, and how to recognize and diagnose BDD. We describe the importance of forming a therapeutic alliance with the patient, the need for psychoeducation, and other essential groundwork for successful treatment of BDD. We review available pharmacotherapy research, with a focus on serotonin-reuptake inhibitors (SSRIs, or SRIs), which are currently considered the medication of choice for BDD. Many patients have substantial improvement in core BDD symptoms, psychosocial functioning, quality of life, suicidality, and other aspects of BDD when treated with appropriate pharmacotherapy that targets BDD symptoms. We also discuss practical issues such as dosing, length of treatment, and potential side effects associated with the use of SRIs. In addition, we discuss pharmacotherapy approaches that can be tried if SRI treatment alone is not adequately helpful. Finally, some misconceptions about pharmacotherapy, gaps in knowledge about BDD’s treatment, and the need for additional research are discussed.
doi:10.1016/j.bodyim.2007.12.003
PMCID: PMC2705931  PMID: 18325859
21.  Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT 
BMC Medical Genomics  2008;1:50.
Background
It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.
Methods
In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.
Results
MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).
Conclusion
MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.
doi:10.1186/1755-8794-1-50
PMCID: PMC2588447  PMID: 18925931
22.  Obsessive compulsive disorder comorbidity in DBA 
Diamond-Blackfan Anemia (DBA) is a congenital erythroid aplasia characterized as a normochromic macrocytic anemia with a selective deficiency in red blood cell precursors in otherwise normocelullar bone marrow. DBA is known to be associated with mental retardation and learning disabilities. Although comorbidities with other psychiatric conditions have not been reported in the existing literature, we report in this paper a case of a DBA patient with previously undiagnosed comorbidity of obsessive compulsive disorder (OCD), successfully treated with sertaline 200 mg/day and valproic acid 600 mg/day. This case of comorbid presentation has clinical, therapeutic and pathophysiological implications. Given the difficulty of distinguishing among mental retardation, learning disabilities and OCD and the importance of precocious diagnosis in treating OCD especially since there are treatment methods interfering with anemia symptoms, physicians should adapt an adequate screening tool treating a child with DBA and comorbid mental disorder.
doi:10.1186/1745-0179-4-6
PMCID: PMC2322982  PMID: 18331650
23.  Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly 
BMC Medical Genetics  2007;8:68.
Background
Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the NSD1 gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that NSD1 could be involved in other cases of autism and macrocephaly.
Methods
We screened the NSD1 gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of NSD1 was carried out using multiplex ligation-dependent probe amplification.
Results
We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.
Conclusion
Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for NSD1 mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.
doi:10.1186/1471-2350-8-68
PMCID: PMC2248565  PMID: 18001468
24.  Epidemiologic and clinical updates on impulse control disorders: a critical review 
The article reviews the current knowledge about the impulse control disorders (ICDs) with specific emphasis on epidemiological and pharmacological advances. In addition to the traditional ICDs present in the DSM-IV—pathological gambling, trichotillomania, kleptomania, pyromania and intermittent explosive disorder—a brief description of the new proposed ICDs—compulsive–impulsive (C–I) Internet usage disorder, C–I sexual behaviors, C–I skin picking and C–I shopping—is provided. Specifically, the article summarizes the phenomenology, epidemiology and comorbidity of the ICDs. Particular attention is paid to the relationship between ICDs and obsessive–compulsive disorder (OCD). Finally, current pharmacological options for treating ICDs are presented and discussed.
doi:10.1007/s00406-006-0668-0
PMCID: PMC1705499  PMID: 16960655
impulse control disorders (ICDs); obsessive–compulsive disorder (OCD); pathological gambling (PG); kleptomania; compulsive–impulsive (C–I) shopping; trichotillomania (TTM); intermittent explosive disorder (IED); C–I Internet usage disorder; C–I sexual behaviors (C–ISBs); C–I skin picking; pyromania
25.  Comorbidity issues in the pharmacological treatment of pathological gambling: a critical review 
Background
Pathological Gambling (PG) is an impulse control disorder often comorbid with other psychopathology, particularly bipolar spectrum disorders, attention deficit/hyperactivity disorder, obsessive-compulsive disorder (OCD) and substance abuse. This paper reviews the published literature on the pharmacological management of PG, highlighting how clinical and subclinical comorbid psychopathology influences the choice of pharmacological treatment.
Methods
Using Medline, the authors reviewed relevant articles published on this topic from1995 to 2005, focusing on the best-designed studies for inclusion.
Results
Much of the literature on PG-treatment presupposes different theories regarding this disorder. Data suggest the utility of differentiating the pharmacotherapy of pathological gamblers in light of their comorbid profile, specifically assessing for comorbid bipolar, ADHD, OCD, and substance abuse disorders.
Conclusion
Decisions about pharmacological treatment of PG should take into account current and previous comorbid disorders which influence treatment selection.
doi:10.1186/1745-0179-1-21
PMCID: PMC1283978  PMID: 16216125
Pathological Gambling; Impulse Control Disorders; Comorbidity; Compulsive-Impulsive Spectrum; Subthreshold symptoms

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