Descriptive Longitudinal Analysis of Stereotypy and Corresponding Changes in Psychotropic Medication.

INTRODUCTION: Psychotropic medication is often prescribed to individuals with intellectual and developmental disabilities who engage in challenging and other behavior (e.g., aggression and stereotypy, respectively), but there is limited understanding of the effects of these medications on behavior. OBJECTIVE: Within the context of a larger study that evaluated the effects of psychotropic medication regimen changes on the presentation of challenging behavior, this study describes the presentation of stereotypic behavior of three individuals diagnosed with autism spectrum disorder. METHODS: Stereotypy was measured during weekly, one-hour, direct observations and during the control and ignore conditions of functional analyses of challenging behavior (which were conducted following changes in psychotropic medication regimens). RESULTS: Patterns of stereotypy varied over time, but not significantly, and at times seemed to coincide with medication changes. DISCUSSION: Our results suggest stereotypy persists throughout adulthood; however, additional research is needed.

The SOFIA Study: Negative Multi-center Study of Low Dose Fluoxetine on Repetitive Behaviors in Children and Adolescents with Autistic Disorder.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that reduces obsessive-compulsive symptoms. There is limited evidence supporting its efficacy for repetitive behaviors (RRBs) in autistic spectrum disorder (ASD). We conducted a randomized controlled trial (RCT) of fluoxetine in 158 individuals with ASD (5-17 years). Following 14 treatment weeks (mean dose 11.8 mg/day), no significant differences were noted on the Children's Yale-Brown Obsessive Compulsive Scale; the proportion of responders was similar (fluoxetine: 36%; placebo: 41%). There were similar rates of AEs (e.g., insomnia, diarrhea, vomiting); high rates of activation were reported in both groups (fluoxetine: 42%; placebo: 45%). Overly cautious dosing/duration may have prevented attainment of a therapeutic level. Results are consistent with other SSRI RCTs treating RRBs in ASD.Trial Registration: clinicaltrials.gov Identifier: NCT00515320.

Effect of Fluoxetine on Obsessive-Compulsive Behaviors in Children and Adolescents With Autism Spectrum Disorders: A Randomized Clinical Trial.

Importance: Selective serotonin receptor inhibitors are prescribed to reduce the severity of core behaviors of autism spectrum disorders, but their efficacy remains uncertain. Objective: To determine the efficacy of fluoxetine for reducing the frequency and severity of obsessive-compulsive behaviors in autism spectrum disorders. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled clinical trial. Participants aged 7.5-18 years with autism spectrum disorders and a total score of 6 or higher on the Children's Yale-Brown Obsessive Compulsive Scale, modified for pervasive developmental disorder (CYBOCS-PDD) were recruited from 3 tertiary health centers across Australia. Enrollment began November 2010 and ended April 2017. Follow-up ended August 2017. Interventions: Participants were randomized to receive fluoxetine (n = 75) or placebo (n = 71). Study medication was commenced at 4 or 8 mg/d for the first week, depending on weight, and then titrated to a maximum dose of 20 or 30 mg/d over 4 weeks. Treatment duration was 16 weeks. Main Outcomes and Measures: The primary outcome was the total score on the CYBOCS-PDD (scores range from 0-20; higher scores indicate higher levels of maladaptive behaviors; minimal clinically important difference, 2 points) at 16 weeks postrandomization, analyzed with a linear regression model adjusted for stratification factors (site, age at baseline, and intellectual disability), with an additional prespecified model that included additional adjustment for baseline score, sex, communication level, and imbalanced baseline and demographic variables. Results: Among the 146 participants who were randomized (85% males; mean age, 11.2 years), 109 completed the trial; 31 in the fluoxetine group and 21 in the placebo group dropped out or did not complete treatment. The mean CYBOCS-PDD score from baseline to 16 weeks decreased in the fluoxetine group from 12.80 to 9.02 points (3.72-point decrease; 95% CI, -4.85 to -2.60) and in the placebo group from 13.13 to 10.89 points (2.53-point decrease; 95% CI, -3.86 to -1.19). The between-group mean difference at 16 weeks was -2.01 (95% CI, -3.77 to -0.25; P = .03) (adjusted for stratification factors), and in the prespecified model with further adjustment, it was -1.17 (95% CI, -3.01 to 0.67; P = .21). Conclusions and Relevance: In this preliminary study of children and adolescents with autism spectrum disorders, treatment with fluoxetine compared with placebo resulted in significantly lower scores for obsessive-compulsive behaviors at 16 weeks. Interpretation is limited by the high dropout rate, null findings of prespecified analyses that accounted for potentially confounding factors and baseline imbalances, and CIs for the treatment effect that included the minimal clinically important difference. Trial Registration: anzctr.org.au Identifier: ACTRN12608000173392.

Repetitive Behaviors Treated With N-Acetylcysteine: Case Series.

OBJECTIVES: Skin-picking disorders, trichotillomania, and nail biting are all characterized by repetitive behaviors resulting in functional deterioration and remarkable changes in physical appearance with repeated attempts to stop or decrease the behavior. While standard pharmacotherapy for obsessive-compulsive disorder and related disorders consists of serotonergic reuptake inhibitors, their moderate efficacy pushed researchers to find alternative treatment approaches. Some of these alternatives are glutamate-modulating agents. The most widely studied of these glutamate modulator agents is N-acetylcysteine (NAC), which is a derivative of the amino acid cysteine. METHODS: This report describes a case series of 3 patients in whom skin-picking disorders, trichotillomania, and nail biting were diagnosed at a center in Turkey. RESULTS: First case was a 42-year-old female patient who had been picking her skin from her arm area, especially in stressful times. Second case was a 31-year-old female patient who has a habit of pulling her hair for the last 20 years. The third case was 24-year-old male patient with a habit of eating his own nails that he has had for as long as he could remember. We successfully treated 3 of our patients who suffer from previously mentioned disorders with NAC. CONCLUSIONS: Outcome of our cases demonstrates the efficacy of NAC, which is effective and well tolerated on the treatment of obsessive-compulsive disorder-related disorders.

Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective.

INTRODUCTION: Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically. METHODS: We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. RESULTS: In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. CONCLUSION: Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS.

Pharmacological analysis of Poecilotheria spider venoms in mice provides clues for human treatment.

Bites of tiger spiders belonging to Poecilotheria genus cause moderate to severe pain and long-lasting local or generalized muscle cramps in humans. Bites occur in regions of the spiders' natural habitat, India and Sri Lanka, but the popularity of these colorful tarantulas as pets leads to reports of envenomation cases worldwide. Treatment is predominantly symptomatic and often inadequate since there is almost no clinical or toxicology research data available, and physicians outside India or Sri Lanka typically have no experience in treating such cases. We report toxicity studies of venom from nine Poecilotheria species in laboratory mice (Mus musculus Balb/C males). LD50 values are 5-14 mg of lyophilized crude venom per 1 kg (i.v.). The major symptoms of envenomation include tonic-clonic seizures, jerks, characteristic motor stereotypy, and hyperalgesia and point to voltage-gated sodium channels as a potential target of the venom components. Poecilotheria fasciata venom effects were studied in detail at a sub-lethal dose of 5 mg/kg (LD50 = 12 mg/kg). 13 widely used pharmacological agents (atropine, chloropyramine, chlorpromazine, diazepam, ethanol, flupirtine, haloperidol, ketotifen, lamotrigine, oxcarbazepine, tolperisone, xylazine, and CaCl2) were checked for ability to suppress the envenomation symptoms. Chlorpromazine (10 mg/kg, i.p.), oxcarbazepine (60 mg/kg, p.o.), tolperisone (50 mg/kg, s.c.) and xylazine (2.5 mg/kg, i.p.) were found effective as a pretreatment to mitigate muscle cramps and motor stereotypy. When administered after envenomation chlorpromazine (5 mg/kg, i.v.) effectively reduced the cramps, while oxcarbazepine (30 mg/kg, i.v.) and xylazine (1 mg/kg, i.v.) suppressed the stereotypy.

Prenatal lipopolysaccharide induces hypothalamic dopaminergic hypoactivity and autistic-like behaviors: Repetitive self-grooming and stereotypies.

Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces social, cognitive, and communication deficits. For a complete screening of autistic-like behaviors, the objective of this study was to evaluate if our rat model also induces restricted and repetitive stereotyped behaviors. Thus, we studied the self-grooming microstructure. We also studied the neurochemistry of hypothalamus and frontal cortex, which are brain areas related to autism to better understand central mechanisms involved in our model. Prenatal LPS exposure on gestational day 9.5 increased the head washing episodes (frequency and time), as well as the total self-grooming. However, body grooming, paw/leg licking, tail/genital grooming, and circling behavior/tail chasing did not vary significantly among the groups. Moreover, prenatal LPS induced dopaminergic hypoactivity (HVA metabolite and turnover) in the hypothalamus. Therefore, our rat model induced restricted and repetitive stereotyped behaviors and the other main symptoms of autism experimentally studied in rodent models and also found in patients. The hypothalamic dopaminergic impairments seem to be associated with the autistic-like behaviors.

Galantamine reverses scopolamine-induced behavioral alterations in Dugesia tigrina.

In planaria (Dugesia tigrina), scopolamine, a nonselective muscarinic receptor antagonist, induced distinct behaviors of attenuated motility and C-like hyperactivity. Planarian locomotor velocity (pLMV) displayed a dose-dependent negative correlation with scopolamine concentrations from 0.001 to 1.0 mM, and a further increase in scopolamine concentration to 2.25 mM did not further decrease pLMV. Planarian hyperactivity counts was dose-dependently increased following pretreatment with scopolamine concentrations from 0.001 to 0.5 mM and then decreased for scopolamine concentrations ≥ 1 mM. Planarian learning and memory investigated using classical Pavlovian conditioning experiments demonstrated that scopolamine (1 mM) negatively influenced associative learning indicated by a significant decrease in % positive behaviors from 86 % (control) to 14 % (1 mM scopolamine) and similarly altered memory retention, which is indicated by a decrease in % positive behaviors from 69 % (control) to 27 % (1 mM scopolamine). Galantamine demonstrated a complex behavior in planarian motility experiments since co-application of low concentrations of galantamine (0.001 and 0.01 mM) protected planaria against 1 mM scopolamine-induced motility impairments; however, pLMV was significantly decreased when planaria were tested in the presence of 0.1 mM galantamine alone. Effects of co-treatment of scopolamine and galantamine on memory retention in planaria via classical Pavlovian conditioning experiments showed that galantamine (0.01 mM) partially reversed scopolamine (1 mM)-induced memory deficits in planaria as the % positive behaviors increased from 27 to 63 %. The results demonstrate, for the first time in planaria, scopolamine's effects in causing learning and memory impairments and galantamine's ability in reversing scopolamine-induced memory impairments.

Crocins, the active constituents of Crocus Sativus L., counteracted ketamine-induced behavioural deficits in rats.

RATIONALE: Experimental evidence indicates that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders including anxiety and depression. OBJECTIVES: The present study was designed to investigate the ability of crocins to counteract schizophrenia-like behavioural deficits produced by ketamine in rats. METHODS: Crocin's ability to counteract hypermotility, stereotypies and ataxia induced by ketamine was evaluated in a motor activity cage. The ability of crocins to reverse ketamine-induced memory deficits was assessed using the novel object recognition task (NORT). The social interaction test was used in order to examine the effects of crocins on ketamine-induced social withdrawal. RESULTS: Crocins (50 but not 30 mg/kg, i.p.) attenuated ketamine (25 mg/kg, i.p.)-induced hypermotility, stereotypies and ataxia. In a subsequent study, post-training administration of crocins (15 and 30 mg/kg, i.p.) reversed ketamine (3 mg/kg, i.p.)-induced performance deficits in the NORT. Finally, crocins (50 but not 30 mg/kg, i.p.) counteracted the ketamine (8 mg/kg, i.p.)-induced social isolation in the social interaction test. CONCLUSIONS: Our findings show that crocins attenuated schizophrenia-like behavioural deficits induced by the non-competitive NMDA receptor antagonist ketamine in rats.

Cannabidiol reverses the mCPP-induced increase in marble-burying behavior.

Cannabidiol (CBD), one of the main components of Cannabis sp., presents clinical and preclinical anxiolytic properties. Recent results using the marble-burying test (MBT) suggest that CBD can also induce anticompulsive-like effects. Meta-chloro-phenyl-piperazine (mCPP) is a nonspecific serotonergic agonist (acting mainly at 5HT1A, 5HT2C and 5HT1D receptors) reported to increase symptoms in OCD patients and block the anticompulsive-like effect of serotonin reuptake inhibitors (SRIs) in animal models. The aim of this study was to investigate the interference of CBD on mCPP effects in repetitive burying. Administration of mCPP showed dual effects in the MBT, increasing the number of buried marbles at lower (0.1 mg/kg) while decreasing it at higher doses (1 mg/kg), an effect not related to a general increase in anxiety-like behavior. As found previously, CBD (30 mg/kg) and the positive control fluoxetine (FLX; 10 mg/kg) decreased burying behavior without changing general exploratory activity. A similar effect was found when subeffective doses of CBD (15 mg/kg) and FLX (3 mg/kg) were administered together. These subeffective doses alone were also able to block mCPP-induced repetitive burying. The results, in addition to reinforcing a possible anticompulsive effect of CBD, also suggest that mCPP-induced repetitive burying could be a useful test for the screening of compounds with presumed anticompulsive properties.

Atypical headbanging presentation of idiopathic sleep related rhythmic movement disorder: three cases with video-polysomnographic documentation.

STUDY OBJECTIVES: To describe three cases of sleep related, idiopathic rhythmic movement disorder (RMD) with atypical headbanging, consisting of head punching and head slapping. METHODS: Three consecutive patients (2 males [11 and 13 years old) and one female [22 years old]) presented with atypical headbanging of 6 years, 7 years, and 17 years duration. In 2 cases, typical rhythmic headbanging (with use of the head) shifted after 3-4 years to atypical headbanging, with frontal head punching that was quasi-rhythmic. In one case, atypical headbanging (head-slapping) was the initial and only RMD. There was no injury from the headbanging. Prenatal, perinatal, developmental, behavioral-psychological, medical-neurological, and family histories were negative. Clinical evaluations and nocturnal video-polysomnography with seizure montage were performed on all patients. RESULTS: Atypical headbanging was documented in all 3 cases; episodes always emerged late in the sleep cycle: from N2 sleep in 11 episodes, from REM sleep in 4 episodes, and from N1 sleep in 1 episode. Epileptiform activity was not detected. Clonazepam therapy was substantially effective in 1 case but not effective in 2 cases. CONCLUSIONS: These 3 cases of idiopathic atypical headbanging expand the literature on this RMD variant, as to our knowledge only one previously documented case has been reported.

Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine-induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits.

Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits.

Tetrabenazine treatment for stereotypies and tics associated with dementia.

Stereotypies are frequently reported in frontotemporal dementia. Their pathophysiology and optimal treatment are largely unexplored. The author reports seven cases of marked stereotype in patients with probable frontotemporal dementia who were treated with tetrabenazine, a monoamine inhibitor. All patients had near-complete resolution of stereotypy. Six patients stopped tetrabenazine at some point, with return of their stereotype within 24 hours, which again improved in the four who restarted therapy. Efficacy has not waned over time. Tetrabenazine dramatically improved stereotypies in patients with dementia. This observation could increase understanding of this interesting phenotype.

Pharmacologic treatment of repetitive behaviors in autism spectrum disorders: evidence of publication bias.

OBJECTIVE: The goal of this study was to examine the efficacy of serotonin receptor inhibitors (SRIs) for the treatment of repetitive behaviors in autism spectrum disorders (ASD). METHODS: Two reviewers searched PubMed and Clinicaltrials.gov for randomized, double-blind, placebo-controlled trials evaluating the efficacy of SRIs for repetitive behaviors in ASD. Our primary outcome was mean improvement in ratings scales of repetitive behavior. Publication bias was assessed by using a funnel plot, the Egger's test, and a meta-regression of sample size and effect size. RESULTS: Our search identified 5 published and 5 unpublished but completed trials eligible for meta-analysis. Meta-analysis of 5 published and 1 unpublished trial (which provided data) demonstrated a small but significant effect of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.22 [95% confidence interval: 0.07-0.37], z score = 2.87, P < .005). There was significant evidence of publication bias in all analyses. When Duval and Tweedie's trim and fill method was used to adjust for the effect of publication bias, there was no longer a significant benefit of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.12 [95% confidence interval: -0.02 to 0.27]). Secondary analyses demonstrated no significant effect of type of medication, patient age, method of analysis, trial design, or trial duration on reported SRI efficacy. CONCLUSIONS: Meta-analysis of the published literature suggests a small but significant effect of SRI in the treatment of repetitive behaviors in ASD. This effect may be attributable to selective publication of trial results. Without timely, transparent, and complete disclosure of trial results, it remains difficult to determine the efficacy of available medications.

A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders.

OBJECTIVE: The effects of fluoxetine and placebo on repetitive behaviors and global severity were compared in adults with autism spectrum disorders (ASDs). METHOD: Adults with ASDs were enrolled in a 12-week double-blind placebo-controlled fluoxetine trial. Thirty-seven were randomly assigned to fluoxetine (N=22) or placebo (N=15). Dosage followed a fixed schedule, starting at 10 mg/day and increasing as tolerated up to 80 mg/day. Repetitive behaviors were measured with the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale; the Clinical Global Impression (CGI) improvement scale was used to rate improvement in obsessive-compulsive symptoms and overall severity. RESULTS: There was a significant treatment-by-time interaction indicating a significantly greater reduction in repetitive behaviors across time for fluoxetine than for placebo. With overall response defined as a CGI global improvement score of 2 or less, there were significantly more responders at week 12 in the fluoxetine group than in the placebo group. The risk ratio was 1.5 for CGI global improvement (responders: fluoxetine, 35%; placebo, 0%) and 1.8 for CGI-rated improvement in obsessive-compulsive symptoms (responders: fluoxetine, 50%; placebo, 8%). Only mild and moderate side effects were observed. CONCLUSIONS: Fluoxetine treatment, compared to placebo, resulted in significantly greater improvement in repetitive behaviors, according to both the Yale-Brown compulsion subscale and CGI rating of obsessive-compulsive symptoms, as well as on the CGI overall improvement rating. Fluoxetine appeared to be well tolerated. These findings stand in contrast to findings in a trial of citalopram for childhood autism.

The prevalence and clinical characteristics of punding in Parkinson's disease.

BACKGROUND: Punding (the display of stereotyped, repetitive behaviors) is a relatively recently discovered feature of Parkinson's disease (PD). Little is known about the prevalence and clinical characteristics of punding in PD. METHODS: In this review, four large scientific databases were comprehensively searched for literature in relation to punding prevalence and clinical correlates in the context of PD. RESULTS: Prevalence was found to vary greatly (between 0.34 to 14%), although there were large disparities in study populations, assessment methods, and criteria. We observed an association between punding, dopaminergic medications, and impulse control disorder. Other characteristics, which may be more common among punders, include a higher severity of dyskinesia, younger age of disease onset, longer disease duration, and male gender. DISCUSSION: More research in large clinical datasets is required in many areas before conclusions are drawn. The pathophysiology behind the punding phenomenon is also poorly understood at present, rendering it difficult to develop targeted therapy. The current mainstay of treatment is the reduction in the dose of dopaminergic medications, the evidence for other suggested therapies being purely empirical.

Flibanserin attenuates L: -DOPA-sensitized contraversive circling in the unilaterally 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

A central problem in the treatment of Parkinson's disease (PD) is the development of motor disturbances like L: -DOPA-induced dyskinesia (LID) after long-term treatment. Preclinical and clinical studies demonstrated that serotonin 5-HT(1A) receptor agonists attenuate this disabling motor side effect. The aim of this study was to investigate the ability of flibanserin compared to buspirone to attenuate L: -DOPA-sensitized contraversive circling in hemiparkinsonian rats, which is an animal model of LID. Both drugs have a preferential affinity for the serotonin 5-HT(1A) receptors. Buspirone was in comparison because it was expected to have an effect in this model. Unilaterally 6-hydroxydopamine lesioned rats were treated twice daily intraperitoneally (ip) with L: -DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg) for 21 days (on days 1, 3, 5, 8, 11, 14, 17 and 21). On day 24, L: -DOPA-sensitized rats were treated ip 5 min prior to administration of L: -DOPA methyl ester and benserazide with either saline (controls), 2.5, 5 and 10 mg/kg buspirone or flibanserin. Acute administration of both flibanserin and buspirone, dose dependently, attenuated the increased contraversive circling. An almost complete inhibition of the turning response was observed at 5 mg/kg buspirone and 10 mg/kg flibanserin. The current preclinical findings further implicate the 5-HT(1A) receptor as a promising therapeutic target for the reduction of LID and predict a potential efficacy of flibanserin in the treatment of LID in PD.