title: Autism after Adolescence: Population-based 13- to 22-year Follow-up Study of 120 Individuals with Autism Diagnosed in Childhood A Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism Design and Subject Characteristics in the Federally-Funded Citalopram Trial in Children with Pervasive Developmental Disorders Psychotropic Medication Use Among Medicaid-Enrolled Children With Autism Spectrum Disorders The Yale-Brown Obsessive-Compulsive Scale: Measures of internal consistency Risperidone in children with autism and serious behavioral problems. Clomipramine Versus Haloperidol in the Treatment of Autistic Disorder: A Double-Blind, Placebo-Controlled, Crossover Study Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. A pilot study of clomipramine in young autistic children. Clinical Efficacy of Fluvoxamine and Functional Polymorphism in a Serotonin Transporter Gene on Childhood Autism Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Reactivity of serotonin in whole blood: relationship with drug response in obsessive-compulsive disorder A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Clinical and neurochemical effects of fenfluramine in children with autism. A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders.
abstract: Background : Prospect i ve population -based follow-up study of 120 individuals with autism followed from childhood to adulthood . Methods : Individuals with autism , diagnosed in childhood , were followed prospect ively for a period of 13–22 years and re-evaluated at ages 17–40 years . The instruments used at follow-up were the  DISCO , WAIS-R , WISC-III , Vinel and Adaptive Behavior Scales , psychiatric-medical examination and GAF-scale .  A set of criteria was used for the classification of outcomes , taking into consideration employment , higher education/vocational training , independent living and peer relations . Results : Six of the 120 ( 5 % ) had died at the time of follow-up , and six declined participation . Overall outcome was poor in 78 % of cases . Only four individuals were independent albeit leading fairly isolated lives . Childhood IQ-level was positively correlated with better adult outcome , as was the existence of some communicative phrase speech at age six years . Conclusions : Children with autism as diagnosed in the 1960s , 1970s , and 1980s may have an even worse psychosocial outcome than previously believed 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 r and omized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine . Study design included two r and omized 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 The Studies to Advance Autism Research and Treatment Network conducted a r and omized trial with citalopram in children with Pervasive developmental disorders ( PDDs ) . We present the rationale , design and sample characteristics of the citalopram trial . Subjects ( 128 boys , 21 girls ) had a mean age of 9.3 ( ±3.12 ) years ; 132 ( 88.6 % ) were diagnosed with autistic disorder ( 4.7 % with Asperger ’s Disorder ; 6.7 % with PDD-not otherwise specified ) . Less than half of the subjects were intellectually disabled ; 117 ( 78.5 % ) were rated Moderate or Marked on the Clinical Global Impression for Severity . Study measures were similar to previous Research Units on Pediatric Psychopharmacology trials . Subjects in this trial were slightly older and more likely to have complaints of repetitive behavior  than participants in RUPP trials OBJECTIVE . The objective of this study was to provide national estimates of psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders and to examine child and health system characteristics associated with psychotropic medication use . METHODS . This cross-sectional study used Medicaid cl aims for calendar year 2001 from all 50 states and Washington , DC , to examine 60641 children with an autism spectrum disorder diagnosis .  Logistic regression with r and om effects was used to examine the child , county , and state factors associated with psychotropic medication use . RESULTS . Of the sample , 56 % used at least 1 psychotropic medication , 20 % of whom were prescribed ≥3 medications concurrently . Use was common even in children aged 0 to 2 years ( 18 % ) and 3 to 5 years ( 32 % ) . Neuroleptic drugs were the most common psychotropic class ( 31 % ) , followed by antidepressants ( 25 % ) and stimulants ( 22 % ) . In adjusted analyses , male , older , and white children ; those who were in foster care or in the Medicaid disability category ; those who received additional psychiatric diagnoses ; and those who used more autism spectrum disorder services were more likely to have  used psychotropic drugs  . Children who had a diagnosis of autistic disorder or who lived in counties with a lower percentage of white residents or greater urban density were less likely to use such medications . CONCLUSIONS . Psychotropic medication use is common among even very young children with autism spectrum disorders . Factors unrelated to clinical presentation seem highly associated with prescribing practice s. Given the limited evidence base , there is an urgent need to assess the risks , benefits , and costs of medication use and underst and the local and national policies that affect medication use We examined the construction of the Yale-Brown Obsessive-Compulsive Scale ( Y-BOCS ) and performance of subscale items based on data from 204 patients with obsessive-compulsive disorder ( OCD ) who participated in a multicenter drug treatment study . Factor analysis was used to examine the relationship among the 10 items that make up the Y-BOCS instrument . Models were computed in which both two- and three-factor solutions were estimated . Within the two-factor solution analyses , the factor distribution was not so consistent as in the three-factor solution analyses , and a shift in the factor distribution was noted after treatment . In the three-factor solution analyses , an independent resistance construct emerged in addition to the obsessive and compulsive constructs . Examination of the postreatment factor scores showed that the Y-BOCS resistance items did not assess OCD symptom change as sensitively as the rest of the Y-BOCS items did BACKGROUND Atypical antipsychotic agents , which block postsynaptic dopamine and serotonin receptors , have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances . However , data on the safety and efficacy of atypical antipsychotic agents in children are limited . METHODS We conducted a multisite , r and omized , double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums , aggression , or self-injurious behavior in children 5 to 17 years old . The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement ( CGI-I ) scale at eight weeks . RESULTS A total of 101 children ( 82 boys and 19 girls ; mean [ + /-SD ] age , 8.8+/-2.7 years ) were r and omly assigned to receive risperidone ( 49 children ) or placebo ( 52 ) . Treatment with risperidone for eight weeks ( dose range , 0.5 to 3.5 mg per day ) result ed in a 56.9 percent reduction in the Irritability score , as compared with a 14.1 percent decrease in the placebo group ( P<0.001 ) . The rate of a positive response , defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale , was 69 percent in the risperidone group ( 34 of 49 children had a positive response ) and 12 percent in the placebo group ( 6 of 52 , P<0.001 ) . Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg , as compared with 0.8+/-2.2 kg with placebo ( P<0.001 ) . Increased appetite , fatigue , drowsiness , dizziness , and drooling were more common in the risperidone group than in the placebo group ( P<0.05 for each comparison ) . In two thirds of the children with a positive response to risperidone at eight weeks ( 23 of 34 ) , the benefit was maintained at six months . CONCLUSIONS Risperidone was effective and well tolerated for the treatment of tantrums , aggression , or self-injurious behavior in children with autistic disorder . The short period of this trial limits inferences about adverse effects such as tardive dyskinesia Clomipramine , haloperidol , and placebo were compared with baseline in the treatment of autism , and overall outcome , specific symptoms , and side effects were examined . It was hypothesized that clomipramine would be better tolerated than haloperidol and prove superior on a measure of stereotypy . Individuals with a DSM-IV diagnosis of autistic disorder ( mean age , 16.3 years ; range , 10–36 years ) were r and omly assigned , by using a Latin square design , to the following 7-week trials : placebo , clomipramine ( mean daily dose , 128.4 mg ; range , 100–150 mg ) , or haloperidol ( mean daily dose , 1.3 mg ; range , 1–1.5 mg ) . Data on 36 subjects were analyzed and taken together ; the results favored haloperidol . In those patients who were able to complete a full therapeutic trial , clomipramine proved comparable to haloperidol in terms of improvement compared with baseline . However , significantly fewer individuals receiving clomipramine versus haloperidol were able to complete the trial ( 37.5 % vs. 69.7 % , respectively ) for reasons related to both side effects and efficacy or behavior problems . In the intent-to-treat sample , which is perhaps more clinical ly relevant , only haloperidol proved superior to baseline on a global measure of autistic symptom severity , as well as specific measures for irritability and hyperactivity . Clomipramine did not seem more effective on a measure of stereotypy , nor was it better tolerated The short-term efficacy and tolerability of sertraline for adults with pervasive developmental disorders ( PDDs ) were assessed in this investigation . Forty-two adults with PDDs ( autistic disorder , N = 22 ; Asperger 's disorder , N = 6 ; and PDD not otherwise specified [ NOS ] , N = 14 ) participated in a 12-week , open-label , systematic trial of sertraline .  Behavioral ratings of repetitive symptoms , aggression , and social relatedness were obtained at baseline and after 4 , 8 , and 12 weeks of sertraline administration . Twenty-four ( 57 % ) of 42 patients showed significant improvement , primarily in repetitive and aggressive symptoms . Statistically significant changes in measures of social relatedness did not occur . Patients with autistic disorder and PDD NOS did significantly better than those with Asperger 's disorder . Based on global improvement item criteria from the Clinical Global Impression Scale , 15 of 22 ( 68 % ) patients with autistic disorder , none of six ( 0 % ) patients with Asperger 's disorder , and 9 of 14 ( 64 % ) patients with PDD NOS were categorized as treatment responders . Sertraline was well tolerated ; no adverse cardiovascular effects , extrapyramidal symptoms , or seizures were identified . These findings suggested that sertraline may be an effective treatment for interfering repetitive and aggressive symptoms in adults with PDDs . Definitive statements about the efficacy and tolerability of sertraline for treating adults with PDDs must await results from double-blind , placebo-controlled trials . These preliminary results should not be generalized to include children and adolescents with PDDs BACKGROUND Autistic disorder is characterized by a fundamental disturbance in social interaction , impairments in communication , and a markedly restricted repertoire of activities and interests . Abnormalities in the serotonin neurotransmitter system have been identified in some persons with autism . No consistently effective and safe drugs have been developed for treating the symptoms of autism . METHODS Thirty adults with autistic disorder completed a 12-week double-blind , placebo-controlled trial of the potent and selective serotonin uptake inhibitor fluvoxamine maleate . Behavioral ratings were obtained at baseline and after 4 , 8 , and 12 weeks of treatment . RESULTS Eight ( 53 % ) of 15 patients in the fluvoxamine-treated group were categorized as responders compared with none of 15 in the placebo group ( P = .001 ) . Fluvoxamine was superior to placebo in reducing repetitive thoughts and behavior ( P < .001 ) , maladaptive behavior ( P < .001 ) , and aggression ( P < .03 ) , and in improving some aspects of social relatedness ( P < .04 ) , especially language usage ( P < .008 ) . Treatment response was not correlated with age level of autistic behavior , or full-scale IQ . Other than mild sedation and nausea in a few patients , fluvoxamine was well tolerated . No dyskinesias , adverse cardiovascular events , or seizures occurred . CONCLUSIONS Fluvoxamine is more effective than placebo in the short-term treatment of the symptoms of autistic disorder in adults . Controlled studies of fluvoxamine and other potent and selective serotonin uptake inhibitors seem warranted in children and adolescents with autism OBJECTIVE To assess the short-term efficacy and safety of clomipramine in hospitalized young children with autism . METHOD This was an open pilot study ; after a 1-week placebo baseline , subjects were treated with clomipramine for 5 weeks . Dosage was individually regulated ; starting dose was 25 mg/day ; increments were 25 mg/day . Maximum dose was 250 mg/day or 5.0 mg/kg per day , whichever was less . Multiple raters , under several conditions , used the Children 's Psychiatric Rating Scale , Clinical Global Impressions , Conners Parent Teacher Question naire , and the Clinical Global Consensus Ratings . RESULTS Eight children , aged 3.5 to 8.7 years , were enrolled in the study ; seven of these completed the study . A 3.5-year-old boy was excluded during the third week of treatment after having urinary retention on two occasions . At doses ranging from 2.50 to 4.64 mg/kg per day ( mean = 3.14 ) , one child improved moderately and six were rated as worse on the Clinical Global Consensus Ratings . Untoward effects were common . CONCLUSIONS ; Clomipramine was not therapeutic and was associated with serious untoward effects in this sample . Young autistic children may be more prone to experience untoward effects than older patients We studied the correlation between response to fluvoxamine and serotonin transporter gene promoter region polymorphism ( 5-HTTLPR ) . Eighteen children with autistic disorder completed a 12-week double-blind , placebo-controlled , r and omized crossover study of fluvoxamine .  Behavioral assessment  s were obtained before and at 12 weeks of treatment . 5-HTTLPR ( long ( l ) or short(s ) ) , was analyzed by the PCR method . Ten out of 18 patients responded to fluvoxamine treatment ; allele type analysis revealed that clinical global effectiveness was noted significantly more in the l allele than in the s allele . However , with respect to language use , a significant effectiveness was noted in the s allele . 5-HTTLPR may influence the individual responses to fluvoxamine administration 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 r and omized controlled trial . SETTING Six academic centers , including Mount Sinai School of Medicine , North Shore-Long Isl and 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 r and omized 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 Children 's 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 Children 's Yale-Brown Obsessive Compulsive Scales modified for pervasive developmental disorders . Adverse events were systematic ally 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 Children 's 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 clinical trials.gov Identifier : NCT00086645 BACKGROUND Obsessive-compulsive disorder responds almost only to potent serotonin reuptake inhibitors . Previous studies have suggested a relation between serotonergic function and clinical outcome in serotonin reuptake inhibitor treatment of obsessive-compulsive disorder . METHODS In a r and omized , double-blind trial , comparing clomipramine , paroxetine , and a placebo in obsessive-compulsive disorder ,  serotonin levels in whole blood ( WB-5-HT ) were measured at baseline , after 1 week , and after 4 weeks of treatment and related to clinical outcome in 36 patients . RESULTS In patients treated with serotonin reuptake inhibitors  there was a pronounced decrease of WB-5-HT , variable after 1 week and uniformly maximal after 4 weeks . The decrease of WB-5-HT after 1 week of serotonin reuptake inhibitor treatment correlated negatively with clinical outcome after 12 weeks ( r = -.61 , p = .0006 ) ; hence , patients with slower WB-5-HT reactivity eventually responded better to treatment . Baseline WB-5-HT , but not WB-5-HT reactivity , was related to season . Depression , autistic traits , and previous serotonin reuptake inhibitor treatment predicted nonresponse . CONCLUSIONS A fast decrease of WB-5-HT was associated with poor clinical outcome . This may be related to faster serotonin efflux from platelets , which has previously been linked to autism . Further studies are necessary to identify the underlying mechanism and discern whether serotonin reuptake inhibitor-induced WB-5-HT decrease is clinical ly useful OBJECTIVE To determine whether clomipramine hydrochloride , a serotonin reuptake blocker with unique anti-obsessional properties , is differentially effective for obsessive-compulsive and stereotyped motor behaviors in autistic disorder compared with placebo and with the noradrenergic tricyclic antidepressant agent , desipramine hydrochloride . DESIGN Following a 2-week , single-blind placebo washout phase , 12 autistic subjects completed a 10-week , double-blind , crossover comparison of clomipramine and placebo , and 12 different subjects completed a similar comparison of clomipramine and desipramine . SETTING Outpatient clinic . PATIENTS A referral sample of 30 male and female autistic patients were enrolled , and 24 completed the study . MEASURES Key outcome measures were the Autism Relevant Subscale of the Children 's Psychiatric Rating Scale , the Modified Comprehensive Psychopathological Rating Scale-Obsessive-Compulsive Disorder Subscale , and the Clinical Global Impressions Scale . RESULTS Clomipramine was superior to both placebo and desipramine on ratings of autistic symptoms ( including stereotypies ) , anger , and compulsive , ritualized behaviors ( P < .05 ) , with no differences between desipramine and placebo . Clomipramine was equal to desipramine and both tricyclic agents were superior to placebo for amelioration of hyperactivity . CONCLUSION Biological links between compulsions and stereotyped , repetitive behaviors in autistic disorder should be explored Fifteen children with autism were treated with 60 mg d , l-fenfluramine ( FEN ) or placebo in a double-blind A-B-A protocol followed immediately by double-blind placebo-controlled crossover administration of FEN ( total duration 62 weeks ) . Both biochemical and clinical outcomes were examined . Biochemically , FEN led to an increase in dihydroxyphenylacetic acid ( DOPAC ) and decreases in whole-blood serotonin ( 5-HT ) , plasma norepinephrine ( NE ) , and plasma 3-methoxy-4-hydroxyphenylglycol ( MHPG ) . The decrease in whole-blood 5-HT was seen only during treatment with FEN . However , NE levels did not return to baseline as long as 8 weeks after the first FEN treatment period . Increases in DOPAC were greater during the second FEN treatment period than the first . Persistent changes in catecholamine regulation may be related to previously reported long-term effects on central nervous system 5-HT after FEN . Clinical ly , FEN led to a modest decrease in parent , but not teacher , ratings of hyperactivity and to a small reduction in sensorimotor abnormalities . Abnormal social and affectual responses also decreased , but this was not directly related to FEN treatment . Effects on cognition were equivocal . Hyperserotonemic subjects did not differ from normoserotonemic subjects in clinical response . Overall , no significant advantage for the use of FEN could be established 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 r and omly 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 , result ed 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 st and in contrast to findings in a trial of citalopram for childhood autism
target: AUTHORS ' CONCLUSIONS There is no evidence of effect of SSRIs in children and emerging evidence of harm .
background: BACKGROUND Autism spectrum disorders ( ASD ) are characterised by abnormalities in social interaction and communication skills , as well as stereotypic behaviours and restricted activities and interests .
  Selective serotonin reuptake inhibitors ( SSRIs ) are prescribed for the treatment of conditions often comorbid with ASD such as depression , anxiety and obsessive-compulsive behaviours .
  OBJECTIVES To determine if treatment with an SSRI:1 .
  improves the core features of autism ( social interaction , communication and behavioural problems);2 .
  improves other non-core aspects of behaviour or function such as self-injurious behaviour;3 .
  improves the quality of life of adults or children and their carers;4 .
  has short- and long-term effects on outcome ; 5 .
  causes harm .