Decreased risk for substance use disorders in individuals with high-functioning autism spectrum disorder.

The objective of this study was to evaluate the risk for developing a substance use disorder (SUD, alcohol or drug abuse or dependence) in individuals with high-functioning autism spectrum disorder (ASD). Subjects with high-functioning ASD were derived from consecutive referrals to a specialized ambulatory program for ASD at a major academic center from 2007 to 2016. Age-matched controls and attention-deficit hyperactivity disorder (ADHD) comparison subjects were derived from three independent studies of children and adults with and without ADHD using identical assessment methodology. Cox proportional hazard models were used to analyze the prevalence of SUD (alcohol or drug use disorder). Age of onset of SUD was analyzed with linear regression models. Our sample included 230 controls, 219 subjects with ADHD, and 230 subjects with ASD. The mean age for the ASD subjects was 20.0 ± 10.3 years. Among ASD subjects, 69% had a lifetime prevalence of ADHD, and the ASD subjects had significantly higher rates of other psychiatric psychopathology compared to ADHD and control subjects (p < 0.001) ASD subjects were at significantly decreased risk for developing a SUD compared to ADHD (hazard ratio (HR) = 0.22, p < 0.001) and control subjects (HR = 0.62, p = 0.04). The age of onset of a SUD was significantly older in ASD subjects, mean age 21.7 years, when compared to ADHD and control subjects (both p < 0.005). Individuals with ASD are at decreased risk to develop a SUD, and when they do, the onset is significantly later than ADHD and controls.

Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

To examine current clinical research on the use of transcranial magnetic stimulation (TMS) in the treatment of pediatric and young adult autism spectrum disorder in intellectually capable persons (IC-ASD). We searched peer-reviewed international literature to identify clinical trials investigating TMS as a treatment for behavioral and cognitive symptoms of IC-ASD. We identified sixteen studies and were able to conduct a meta-analysis on twelve of these studies. Seven were open-label or used neurotypical controls for baseline cognitive data, and nine were controlled trials. In the latter, waitlist control groups were often used over sham TMS. Only one study conducted a randomized, parallel, double-blind, and sham controlled trial. Favorable safety data was reported in low frequency repetitive TMS, high frequency repetitive TMS, and intermittent theta burst studies. Compared to TMS research of other neuropsychiatric conditions, significantly lower total TMS pulses were delivered in treatment and neuronavigation was not regularly utilized. Quantitatively, our multivariate meta-analysis results report improvement in cognitive outcomes (pooled Hedges' g = 0.735, 95% CI = 0.242, 1.228; p = 0.009) and primarily Criterion B symptomology of IC-ASD (pooled Hedges' g = 0.435, 95% CI = 0.359, 0.511; p < 0.001) with low frequency repetitive TMS to the dorsolateral prefrontal cortex. The results of our systematic review and meta-analysis data indicate that TMS may offer a promising and safe treatment option for pediatric and young adult patients with IC-ASD. However, future work should include use of neuronavigation software, theta burst protocols, targeting of various brain regions, and robust study design before clinical recommendations can be made.

Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania.

BACKGROUND: Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder. METHODS: We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression. RESULTS: This study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint. CONCLUSIONS: These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.

Characterizing autistic traits in treatment-seeking young adults with substance use disorders.

BACKGROUND AND OBJECTIVES: Recent work highlights an increase in the overlap of autism spectrum disorder (ASD) and substance use disorder (SUD). Little is known about the presence of ASD symptoms in SUD-treatment-seeking populations. METHODS: The informant-rated Social Responsiveness Scale-2 (SRS-2) was completed at intake to an outpatient SUD clinic for youth aged 16-26 (N = 69). Comparisons were made between those with elevated SRS-2 scores on demographic, psychiatric, and substance use variables. RESULTS: Parents of sixty-nine patients with SUD completed the SRS-2. Fourteen (20%) (average age 18.7 ± 2.5) had elevated SRS-2 Total T-scores (≥66) and 55 (average age 18.1 ± 2.8) had non-clinical SRS-2 Total T-scores. There were few differences between groups; however, those with elevated SRS-2 Total T-scores were more likely to have a stimulant use disorder (odds ratio [OR] = 7.59, 95% confidence interval [CI] = 0.77, 101.88; p = 0.05) or an opioid use disorder (OR = 5.02, 95% CI = 0.59, 43.27; p = 0.08) than patients with normal SRS-2 Total T-scores as well as alcohol use in the week prior to intake. DISCUSSION AND CONCLUSIONS: A significant proportion of treatment-seeking SUD outpatients suffer from clinically elevated autistic traits. These findings highlight the importance of assessing for autistic traits in SUD treatment settings yet additional research is needed to determine if these findings are specific to the presence of ASD or secondary to sequelae of specific SUD presentations. SCIENTIFIC SIGNIFICANCE: This study is, to our knowledge, the first to have examined the prevalence, morbidity, or clinical characteristics, associated with ASD symptoms in a SUD-specific population.

Predictive utility of autistic traits in youth with ADHD: a controlled 10-year longitudinal follow-up study.

The objective of this study was to investigate the stability and predictive utility of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD). Participants were referred youth with and without ADHD, without a diagnosis of autism spectrum disorder, and their siblings, derived from identically designed longitudinal case-control family studies of boys and girls with ADHD. Subjects were assessed with structured diagnostic interviews and measures of social, cognitive, and educational functioning. The presence of ATs at baseline was operationalized using a unique profile of the Child Behavior Checklist (CBCL) consisting of an aggregate T score of ≥ 195 on the Withdrawn, Social, and Thought Problems subscales (CBCL-AT profile). At the follow-up, 83% of the ADHD youth with a positive AT profile at baseline continued to have a positive CBCL-AT profile. The presence of a positive CBCL-AT profile at baseline in youth with ADHD heralded a more compromised course characterized by a greater burden of psychopathology that emerged at an earlier age, along with poorer interpersonal, educational, and neurocognitive outcomes. Findings indicate a high level of persisting ATs in ADHD youth over time, as indexed through the CBCL-AT profile, and the presence of this profile prognosticates a compromised course in adult life in multiple domains of functioning.

A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder.

This prospective 12-week open-label trial evaluates the tolerability and efficacy of memantine hydrochloride for the treatment of core social and cognitive deficits in adults with high-functioning autism spectrum disorder (ASD). Measures for assessment of therapeutic response included the Social Responsiveness Scale-Adult Research Version (SRS-A), disorder-specific Clinical Global Impression scales, Behavior Rating Inventory of Executive Functioning-Adult Self-Report, Diagnostic Analysis of Nonverbal Accuracy Scale, and Cambridge Neuropsychological Test Automated Battery. Eighteen adults (mean age, 28 ± 9.5 years) with high-functioning ASD (SRS-A raw score, 99 ± 17) were treated with memantine (mean dose, 19.7 ± 1.2 mg/d; range, 15-20 mg), and 17 (94%) completed the trial. Treatment with memantine was associated with significant reduction on informant-rated (SRS-A, -28 ± 25; P < 0.001) and clinician-rated (Clinical Global Impression-Improvement subscale ≤2, 83%) measures of autism severity. In addition, memantine treatment was associated with significant improvement in ADHD and anxiety symptom severity. Significant improvement was noted in nonverbal communication on the Diagnostic Analysis of Nonverbal Accuracy Scale test and in executive function per self-report (Behavior Rating Inventory of Executive Functioning-Adult Self-Report Global Executive Composite, -6 ± 8.8; P < 0.015) and neuropsychological assessments (Cambridge Neuropsychological Test Automated Battery). Memantine treatment was generally well tolerated and was not associated with any serious adverse events. Treatment with memantine appears to be beneficial for the treatment of ASD and associated psychopathology and cognitive dysfunction in intellectually capable adults. Future placebo-controlled trials are warranted.

A study of the neuropsychological correlates in adults with high functioning autism spectrum disorders.

OBJECTIVE: To examine the unique neuropsychological presentation in adults with high functioning autism spectrum disorders (HF-ASD) by comparison with adults with attention deficit hyperactivity disorder (ADHD). METHODS: Adults with ASD referred to a specialty clinic (n=26) were compared to two non-ASD groups with (n=52) and without (n=52) ADHD of similar age and sex. RESULTS: No differences in IQ were found. Subjects with HF-ASD were significantly more impaired than both comparison groups in processing speed, cognitive flexibility and sight words. Subjects with HF-ASD were more impaired than controls in working memory, but not the ADHD group. CONCLUSION: These findings suggest that there may be specific neuropsychological correlates of HF-ASD differing from ADHD that could have significant implications for identifying individuals at risk for ASD.

Do stimulants reduce the risk for cigarette smoking in youth with attention-deficit hyperactivity disorder? A prospective, long-term, open-label study of extended-release methylphenidate.

OBJECTIVE: Although attention-deficit hyperactivity disorder (ADHD) is a well-known risk factor for cigarette smoking, prospective studies aimed at reducing smoking risk in this population are critically needed. STUDY DESIGN: This was a 2-year, prospective, open-label clinical trial of extended-release methylphenidate for smoking prevention in adolescents with ADHD (n = 154). Smoking outcomes were assessed with the Fagerstrom Tolerance Questionnaire. Comparisons were made using data from a historical, naturalistic sample of ADHD (n = 103) and non-ADHD comparators (n = 188) of similar age and sex assessed with the same assessment battery as that used in subjects participating in the clinical trial. RESULTS: The smoking rate at endpoint (mean, 10 months of methylphenidate treatment) was low in the clinical trial subjects and not significantly different from that in the non-ADHD comparators or the ADHD comparators receiving stimulants naturalistically (7.1% vs 8.0% vs 10.9%; P > .20). In contrast, the smoking rate was significantly lower in the clinical trial subjects than in the naturalistic sample of ADHD comparators who were not receiving stimulant treatment (7.1% vs 19.6%; P = .009 [not significant], adjusting for comorbid conduct disorder and alcohol and drug abuse). CONCLUSION: Although considered preliminary until replicated in future randomized clinical trials, the findings from this single-site, open-label study suggest that stimulant treatment may contribute to a decreased risk for smoking in adolescents with ADHD. If confirmed, this finding would have significant clinical and public health impacts.

Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T.

The pilot study aimed at examining the neural glutamatergic activity in autism. Seven adolescent males (mean age: 14 ± 1.8; age range: 12-17 years) with intact intellectual capacity (mean IQ: 108 ± 14.26; IQ range: 85-127) suffering from autistic disorder and an equal number of age- and sex-matched healthy controls underwent a two-dimensional magnetic resonance spectroscopy scan at 4T. Results indicated significantly high glutamate (Glu) levels in the anterior cingulate cortex of autistic disorder versus control subjects (paired t test p = 0.01) and a trend for lower Glu in the right medial temporal lobe, which was not statistically different between the groups (paired t test p = 0.06). These preliminary findings support the glutamatergic dysregulation hypothesis in autism and need to be replicated in a larger sample.

A Manualized Behavioral Therapy Intervention for Youth with Autism Spectrum Disorder and Substance Use Disorder.

Research highlights the increasing overlap of autism spectrum disorder and substance use disorders in young people. However, no behavioral treatments exist addressing this comorbidity despite great need. A team of clinicians developed an integrated behavioral protocol addressing substance use in youth with autism spectrum disorder. The multidisciplinary team developed 12 youth, 7 parent, and 3 joint modules based on established evidence-based therapies shown to have effectiveness separately addressing autism spectrum and substance use. Two cases are discussed to illuminate this integrated intervention. Adaptations to the protocol were made during feedback from patients and their parents. Further research is needed to determine the effectiveness of this preliminary protocol.

Distinct and shared white matter abnormalities when ADHD is comorbid with ASD: A preliminary diffusion tensor imaging study.

Attention deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder, is the most frequent comorbid condition seen in children with autism spectrum disorder (ASD). This high comorbidity between ADHD and ASD worsens symptom manifestations and complicates disease treatment and prognosis. It remains unclear whether individuals suffering with both ADHD and ASD, compared to individuals with ADHD only, share overlapping neural correlates associated with ADHD neuropathology, or exhibit a distinct neuropathological profile. Answering this question is critical to the understanding of treatment outcomes for the challenging comorbid ADHD symptoms. To identify the shared and the differentiated neural correlates of the comorbidity mechanisms of ADHD with ASD, we use diffusion tensor imaging (DTI) to characterize white-matter microstructure integrity in youth diagnosed with ADHD+ASD and youth with ADHD-only (excluding both the diagnosis and symptoms of ASD) compared with a healthy control group. Results show that the ADHD-only cohort exhibits impaired microstructural integrity (lower fractional anisotropy, FA) in the callosal-cingulum (CC-CG) tracts compared to the control cohort. The ADHD+ASD comorbid cohort shows impaired FA in an overlapping region within the CC-CG tracts and, additionally, shows impaired FA in the frontolimbic tracts including the uncinate fasciculus and anterior thalamic radiation. Across all participants, FA in the CC-CG showed a significantly negative relationship with the degree of ADHD symptom severity. Findings of this study suggest a specific role of CC-CG underlying ADHD neuropathology and symptom manifestations, and when comorbid with ASD a shared ADHD profile with a shift toward an anterior-brain, frontal impact. Results of this study may facilitate future targeted therapeutics and assist in diagnostic precision for individuals suffering with differing levels of comorbid ADHD with ASD, and ultimately contribute to improve prognostication and outcomes for these two highly prevalent and comorbid neurodevelopmental disorders.

Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder in Individuals with Autism Spectrum Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most frequent comorbid disorder that is observed at a higher rate and with greater morbidity in higher intellectually functioning populations with autism. Up to 85% of the populations with autism and 15% of individuals with ADHD suffer from a reciprocal comorbidity that is highly under-recognized in intellectually capable populations. Limited empirical evidence is available on the response of anti-ADHD agents in autism populations with ADHD. In autism spectrum disorder (ASD) populations, response to methylphenidate for the treatment of hyperactivity is worse than typically expected in the presence of the intellectual disability. The anti-ADHD response to atomoxetine in autism populations is worse than typically expected although tolerability is similar to that observed in the typicals. The hyperactivity response to guanfacine treatment in predominantly intellectually impaired populations with ASD is as robust as observed in the typicals although tolerability was worse than typically expected. Further trials are warranted to document the extent of atypical anti-ADHD response in intellectually capable populations with autism.

Transcranial Photobiomodulation in Adults with High-Functioning Autism Spectrum Disorder: Positive Findings from a Proof-of-Concept Study.

Objective: To assess the efficacy and safety of transcranial photobiomodulation (tPBM) in adults with autism spectrum disorder (ASD). Methods: Adults with high-functioning-ASD, between 18 and 59 years of age, were enrolled to receive twice a week tPBM for 8 weeks in an open-label single group design. ASD symptom severity was assessed at baseline, midpoint, and end-point, by clinician-, self-, and informant-rated measures. Treatment response was defined as a ≥30% reduction in Social Responsiveness Scale-2nd Edition (SRS-2) total score and ASD Clinical Global Impression-Improvement score ≤2. Any possible adverse events were recorded at each visit. Paired-samples t-test analyses were performed. Results: Eleven participants were enrolled, and 10 participants (9 males; 30.0 ± 11.9 years) completed the study. One participant withdrew consent before baseline. All 10 completers were included in efficacy and safety analyses. Five participants (50%) met responder criteria at end-point. Overall, 8-week tPBM was associated with significant reduction in SRS-2 total scores at end-point (SRS-2: -30.6 ± 23, p < 0.001) particularly in Social Awareness (-3.0 ± 1.9, p < 0.001), Social Communication (-10.3 ± 6, p < 0.001), Social Motivation (-5.0 ± 2.4, p < 0.001), and Restricted/Repetitive Behaviors (-7.4 ± 4.1, p < 0.001). There were statistically significant improvements at end-point in Global Assessment of Functioning scores (+12.8 ± 4.2, p < 0.001) and Quality of Life Enjoyment and Satisfaction Questionnaire scores (+6.0 ± 7.9, p = 0.02). Three participants experienced transient, mild side effects (insomnia, headache, and warmth at treatment application site). No adverse events required changes in tPBM protocol. Adherence rate was 98%. Conclusions: tPBM is a safe and feasible treatment approach that has the potential to treat core features of ASD. Further research is necessary and warranted. ClinicalTrials.gov Identifier: NCT03724552.

A Randomized, Double-Blind, Controlled Clinical Trial of Omega-3 Fatty Acids and Inositol as Monotherapies and in Combination for the Treatment of Pediatric Bipolar Spectrum Disorder in Children Age 5-12.

Objectives: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. Methods: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. Results: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. Conclusion: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

Can pediatric bipolar disorder be successfully treated when comorbid with conduct disorder? A secondary analysis of clinical trials of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

BACKGROUND: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. AIMS: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. METHODS: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% (N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 (p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% (p = 0.61). CONCLUSION: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

Long term outcomes of pediatric Bipolar-I disorder: A prospective follow-up analysis attending to full syndomatic, subsyndromal and functional types of remission.

OBJECTIVE: To examine patterns of remission of pediatric bipolar I (BP-I) disorder attending to syndromatic, symptomatic, and functional outcomes from childhood to adolescent and young adult years. METHODS: We analyzed data from a six-year prospective follow-up study of youths aged 6-17 years with BP-I disorder. Subjects were comprehensively assessed at baseline and subsequently at four, five, and six years thereafter. Assessments included structured diagnostic interviews and measures of psychosocial and educational functioning. Patterns of remission were calculated attending to whether syndromatic, symptomatic, and functional remission were achieved. RESULTS: Kaplan-Meier failure functions revealed that the probability of functional recovery from pediatric BP-I disorder was very low. Of the 88 youths assessed, only 6% (N = 5) of the sample were euthymic with normal functioning during the year prior to their last follow-up assessment (average follow-up time = 5.8 ± 1.8 years). CONCLUSIONS: These results provide compelling evidence of the high level of persistence of pediatric BP-I disorder. Symptomatic and functional remission were uncommon and most subjects continued to demonstrate high morbidity into late adolescence and early adulthood.

Discriminant and concurrent validity of a simplified DSM-based structured diagnostic instrument for the assessment of autism spectrum disorders in youth and young adults.

BACKGROUND: To evaluate the concurrent and discriminant validity of a brief DSM-based structured diagnostic interview for referred individuals with autism spectrum disorders (ASDs). METHODS: To test concurrent validity, we assessed the structured interview's agreement in 123 youth with the expert clinician assessment and the Social Responsiveness Scale (SRS). Discriminant validity was examined using 1563 clinic-referred youth. RESULTS: The structured diagnostic interview and SRS were highly sensitive indicators of the expert clinician assessment. Equally strong was the agreement between the structured interview and SRS. We found evidence for high specificity for the structured interview. CONCLUSIONS: A simplified DSM-based ASD structured diagnostic interview could serve as a useful diagnostic aid in the assessment of subjects with ASDs in clinical and research settings.

Pharmacotherapy of attention deficit/hyperactivity disorder in individuals with autism spectrum disorder: A systematic review of the literature.

AIM: To assess the empirical evidence for the treatment of attention deficit/hyperactivity disorder (ADHD) in populations with autism spectrum disorder (ASD). METHODS: A systemic PubMed, PsychINFO, Embase, and Medline database search of peer-reviewed literature was conducted. Included in the review were controlled trials published in English with sample sizes ⩾10 participants examining the safety and efficacy of anti-ADHD medication in ASD populations. Data was extracted on relevant variables of study design, demographics, associated psychopathology, medication dose, efficacy, and tolerability. RESULTS: Nine controlled trials met the inclusion and exclusion criteria: five with methylphenidate, three with atomoxetine, and one with guanfacine. Sample sizes ranged from 10 to 128 with 430 children participating across all the trials. In all the trials, treatment response was significantly superior to placebo. However, almost all trials assessed only hyperactivity, and most included only participants with intellectual disability with high levels of irritability. None of the trials distinguished agitation from hyperactivity. The response on hyperactivity for methylphenidate and atomoxetine was less than that observed in the neurotypical population; however, the response for guanfacine surpassed results observed in neurotypical populations. Treatment-emergent mood lability (i.e. mood dysregulation and mood-related adverse events) was frequently associated with methylphenidate and guanfacine treatments. Worse treatment outcomes were associated with individuals with lower intellectual capability compared with those with higher IQs. CONCLUSIONS: here is a scarcity of controlled trials examining ADHD treatments in ASD populations, particularly in intellectually capable individuals with ASD and in adults. Response to ADHD medications in ASD were adversely moderated by the presence of intellectual disability and mood lability.

Impact of obsessive-compulsive disorder on the antimanic response to olanzapine therapy in youth with bipolar disorder.

OBJECTIVE: To compare antimanic response to olanzapine therapy in youth with bipolar disorder (BPD) based on the status of comorbidity with obsessive-compulsive disorder (OCD). METHODS: Secondary analysis of identically designed 8-week open-label trials of olanzapine therapy in youth with BPD. Severity of mania assessed with the Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) scales. RESULTS: Of the 52 BPD subjects (mean age 8.4 +/- 3.1 years) enrolled in the olanzapine trials (mean dose 8.5 +/- 4.3 mg/day), 39% (n = 20) met criteria for comorbid OCD. Antimanic response in BPD subjects was significantly worse in the presence of comorbid OCD (YMRS mean reduction: -5.9 +/- 13.1 versus -13.7 +/- 18.8, p = 0.04; > or = 30% reduction: 25% versus 63%, p = 0.008; CGI-Improvement score < or = 2: 25% versus 68%, p = 0.003). There was no difference in the rate of dropouts (50% versus 29%, p = 0.2) or adverse effects in BPD subjects with or without comorbid OCD. CONCLUSIONS: Less than expected antimanic response to olanzapine therapy in the presence of comorbidity with OCD suggests that OCD is an important functionally impairing psychiatric comorbidity that may impact the efficacy of antimanic agents in youth with BPD. This study is limited by its design of secondary analysis of data from trials of an uncontrolled nature. Further prospective controlled trials are warranted.

Clinical characteristics of comorbid obsessive-compulsive disorder and bipolar disorder in children and adolescents.

OBJECTIVE: To explore bidirectional comorbidity between bipolar disorder (BPD) and obsessive-compulsive disorder (OCD) in youth and to examine the symptom profile and clinical correlates of both disorders in the context of reciprocal comorbidity and ascertainment status. METHODS: Two samples of consecutively referred youth (ages 6-17 years) ascertained contemporaneously for respective studies of BPD and OCD were compared using clinical and scalar assessment and structured diagnostic interviews. RESULTS: A total of 21% (17/82) of the BPD subjects and 15% (19/125) of the OCD subjects met DSM-III-R diagnostic criteria for both disorders. In the presence of BPD, youth with OCD more frequently experienced hoarding/saving obsessions and compulsions along with a clinical profile of greater comorbidity, poorer global functioning, and higher rate of hospitalization that is characteristic of BPD. Multiple anxiety disorders (> or = 3), especially generalized anxiety disorder and social phobia, were present at a higher frequency when OCD and BPD were comorbid than otherwise. In subjects with comorbid OCD and BPD, the primary disorder of ascertainment was associated with an earlier onset and more severe impairment. CONCLUSIONS: An unexpectedly high rate of comorbidity between BPD and OCD was observed in youth irrespective of primary ascertainment diagnosis. In youth with comorbid OCD and BPD, the clinical characteristics of each disorder run true and are analogues to their clinical presentation in youth without reciprocal comorbidity, with the exception of increased risk for obsessions and compulsions of hoarding/saving and comorbidity with other anxiety disorders.