Eric Hollander

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Oxytocin increases retention of social cognition in autism.

BACKGROUND Oxytocin dysfunction might contribute to the development of social deficits in autism, a core symptom domain and potential target for intervention. This study explored the effect of intravenous oxytocin administration on the retention of social information in autism. METHODS Oxytocin and placebo challenges were administered to 15 adult subjects diagnosed with autism or Aspergers disorder, and comprehension of affective speech (happy, indifferent, angry, and sad) in neutral content sentences was tested. RESULTS All subjects showed improvements in affective speech comprehension from pre- to post-infusion; however, whereas those who received placebo first tended to revert to baseline after a delay, those who received oxytocin first retained the ability to accurately assign emotional significance to speech intonation on the speech comprehension task. CONCLUSIONS These results are consistent with studies linking oxytocin to social recognition in rodents as well as studies linking oxytocin to prosocial behavior in humans and suggest that oxytocin might facilitate social information processing in those with autism. These findings also provide preliminary support for the use of oxytocin in the treatment of autism.

Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger's disorders.

Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral domains: repetitive behaviors, social deficits, and language abnormalities. There is evidence that abnormalities exist in peptide systems, particularly the oxytocin system, in autism spectrum patients. Furthermore, oxytocin and the closely related peptide vasopressin are known to play a role in social and repetitive behaviors. This study examined the impact of oxytocin on repetitive behaviors in 15 adults with autism or Aspergers disorder via randomized double-blind oxytocin and placebo challenges. The primary outcome measure was an instrument rating six repetitive behaviors: need to know, repeating, ordering, need to tell/ask, self-injury, and touching. Patients with autism spectrum disorders showed a significant reduction in repetitive behaviors following oxytocin infusion in comparison to placebo infusion. Repetitive behavior in autism spectrum disorders may be related to abnormalities in the oxytocin system, and may be partially ameliorated by synthetic oxytocin infusion.

Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review.

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.

Evidence for a Susceptibility Gene for Autism on Chromosome 2 and for Genetic Heterogeneity

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.

Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism.

CONTEXT Selective serotonin reuptake inhibitors are widely prescribed for children with autism spectrum disorders. OBJECTIVES To determine the efficacy and safety of citalopram hydrobromide therapy for repetitive behavior in children with autism spectrum disorders. DESIGN National Institutes of Health-sponsored randomized controlled trial. SETTING Six academic centers, including Mount Sinai School of Medicine, North Shore-Long Island Jewish Health System, University of North Carolina at Chapel Hill, University of California at Los Angeles, Yale University, and Dartmouth Medical School. PARTICIPANTS One hundred forty-nine volunteers 5 to 17 years old (mean [SD] age, 9.4 [3.1] years) were randomized to receive citalopram (n = 73) or placebo (n = 76). Participants had autistic spectrum disorders, Asperger disorder, or pervasive developmental disorder, not otherwise specified; had illness severity ratings of at least moderate on the Clinical Global Impressions, Severity of Illness Scale; and scored at least moderate on compulsive behaviors measured with the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. INTERVENTIONS Twelve weeks of citalopram hydrobromide (10 mg/5 mL) or placebo. The mean (SD) maximum dosage of citalopram hydrobromide was 16.5 (6.5) mg/d by mouth (maximum, 20 mg/d). MAIN OUTCOME MEASURES Positive response was defined by a score of much improved or very much improved on the Clinical Global Impressions, Improvement subscale. An important secondary outcome was the score on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders. Adverse events were systematically elicited using the Safety Monitoring Uniform Report Form. RESULTS There was no significant difference in the rate of positive response on the Clinical Global Impressions, Improvement subscale between the citalopram-treated group (32.9%) and the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P > .99). There was no difference in score reduction on the Childrens Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders from baseline (mean [SD], -2.0 [3.4] points for the citalopram-treated group and -1.9 [2.5] points for the placebo group; P = .81). Citalopram use was significantly more likely to be associated with adverse events, particularly increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus. CONCLUSION Results of this trial do not support the use of citalopram for the treatment of repetitive behavior in children and adolescents with autism spectrum disorders. Trial Registration clinicaltrials.gov Identifier: NCT00086645.

Oxytocin Selectively Improves Empathic Accuracy

Oxytocin is known to regulate prosocial behavior and social cognition in animals (Ross & Young, 2009), and recent studies suggest that oxytocin may have similar functions in humans. For example, oxytocin increases trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005) and accuracy in mental-state attribution (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007; Guastella et al., 2009). These findings have generated excitement about oxytocin’s potential to ameliorate social deficits in such disorders as social phobia and autism (Bartz & Hollander, 2006; Guastella et al., 2009; Kosfeld et al., 2005). This excitement has not been confined to the scientific community: Dubbed the “hormone of love,” oxytocin is a common topic in the popular press. Is oxytocin truly a universal social panacea? Although some studies have shown that oxytocin improves social cognition and empathy (Domes et al., 2007; Guastella et al., 2009), others have not (Singer et al., 2008). Even studies demonstrating positive effects have ambiguities: Domes et al. (2007) found that oxytocin improved performance for difficult—but not easy—test items. These observations imply that rather than working universally, oxytocin may selectively facilitate social cognition given certain constraints. For example, by altering specific motivational or cognitive states, oxytocin might increase the salience of social cues, which in turn could improve social-cognitive performance for some individuals, but not others. The effects of oxytocin, then, should be most pronounced in individuals who—at baseline—are less socially proficient; this would be consistent with broader interactionist views emphasizing that individual differences in competencies interact with situational variables to determine behavior (Mischel & Shoda, 1995). To test whether normal variance in social proficiency moderates the effects of oxytocin on social-cognitive performance, we used a randomized, double-blind, placebo-controlled, crossover challenge in which participants received either intranasal oxytocin or a placebo and performed an empathicaccuracy task that naturalistically measures social-cognitive abilities (Zaki, Bolger, & Ochsner, 2008). We measured variance in baseline social competencies with the Autism Spectrum Quotient (AQ; Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001), a self-report instrument that predicts social-cognitive performance (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001). We hypothesized that drug condition and AQ score would interact to predict performance on the empathic-accuracy task, with oxytocin having the most pronounced effects for less socially proficient individuals (i.e., those with higher AQ scores).

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.

A Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9±4.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.

Striatal Volume on Magnetic Resonance Imaging and Repetitive Behaviors in Autism

BACKGROUND The repetitive behaviors seen in autism phenotypically resemble those seen in obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), disorders in which structural and functional abnormalities of the basal ganglia (BG) are present and correspond to the severity of repetitive behaviors. METHODS Seventeen subjects with autism by DSM-IV and Autism Diagnostic Interview (ADI) and 17 matched controls completed a 1.5 T magnetic resonance image (MRI) of the brain. Two blinded researchers, with good inter-rater reliability, outlined the right and left caudate and putamen. Autistic and control BG volumes covaried for total brain volume were compared using analysis of covariance. BG volumes within the autistic group were correlated with the ADI Repetitive Behavior scores (ADI-C domain). RESULTS Right caudate volume controlled for total brain volume was significantly larger in autistic subjects than in controls. In addition, right caudate and total putamen volumes correlated positively with repetitive behavior scores on the ADI-C domain, particularly the higher order OCD-like repetitive behaviors. CONCLUSIONS Increased right caudate volume in autism is of interest, since this has also been observed in OCD patients. Increased volume of the right caudate and total putamen positively correlated with greater repetitive behaviors, supporting the hypothesis of BG dysfunction associated with repetitive behaviors in autistic adults.