Gender Diverse Autistic Young Adults: A Mental Health Perspective.

Gender diverse autistic young adults often face mental health challenges which can increase the challenge of obtaining gender-affirming care. Social and communication differences associated with autism compounds the already complex process of navigating a path toward gender affirmation for individuals with these intersecting identities. In this case series of four gender diverse autistic adults, we demonstrate that success in management of their mental health crises was achieved through enlisting family and social support, obtaining effective mental health treatment, and accessing gender-affirming healthcare. These cases selected from two neuropsychiatric outpatient tertiary referral clinics demonstrate that effective mental health treatment supports ultimate success for these individuals in their journeys toward living as the gender with which they identify. We conclude that healthcare practices and treatment recommendations which incorporate internationally recognized standards of care guidelines for gender diverse individuals improve patient outcomes.

Psychiatry training in autism spectrum disorder and intellectual disability: Ongoing gaps and emerging opportunities.

LAY ABSTRACT: Children, adolescents, and adults with autism spectrum disorder and intellectual disability experience high rates of co-occurring psychiatric conditions throughout their lifetime. However, there is a shortage of psychiatrists to treat these populations. We evaluated how much education psychiatrists-in-training receive on how to care for individuals with autism spectrum disorder/intellectual disability. We found that in many psychiatry programs, residents receive limited training experiences in autism spectrum disorder/intellectual disability involving lectures and patient contact and that psychiatry program directors would benefit from more resources to strengthen education in autism spectrum disorder/intellectual disability.

Overnight versus progressive conversion of multiple daily-dose divalproex to once-daily divalproex extended release: which strategy is better tolerated by adults with intellectual disabilities?

Divalproex (DVP) delayed release and DVP extended release (DVP ER) are approved by the Food and Drug Administration for bipolar disorder, epilepsy, and migraine prophylaxis. Divalproex ER is given once daily, improving compliance and reducing adverse events. Overnight switch to DVP ER is advised in the package insert but could produce more adverse events in this susceptible population. In this pilot study, we compared tolerability of overnight versus gradual switching to DVP ER in 16 adults with intellectual and developmental disabilities receiving DVP, in 9 for epilepsy and in all 16 for comorbid bipolar disorder. The study design was open with parallel groups. Sixteen subjects with intellectual and developmental disabilities were randomized to overnight or gradual conversion for 4 to 6 days. A blinded rater completed the Multidimensional Observation Scale for Elderly Subjects on days +1, +4, and +8 after the switch began. We found no major differences between the 2 groups at each time point. Neither group of subjects, except for 1 subject in the overnight group, manifested sedation, seizures, worsening of tremor, or gastrointestinal adverse events. One subject in the overnight group manifested acute diarrhea and vomiting, followed by a very brief tonic leg seizure 6 days later. Larger studies are warranted.

Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline.

INTRODUCTION: Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.

A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension.

OBJECTIVE: A previous study reported on a 16-week placebo-controlled, randomized clinical trial (RCT) of metformin for weight stabilization in 61 children and adolescents 6 to 17 years old with autism spectrum disorder who were prescribed atypical antipsychotics. The present study describes the results of a 16-week open-label extension. METHOD: Fifty-two participants from the acute trial (85%) entered the extension; 22 had been on metformin during the initial RCT and 30 had been on placebo. Participants were re-titrated to 500 mg twice a day (6- to 9-year-olds) or 850 mg twice a day (10- to 17-year-olds) during the open-label extension. Primary outcome measure was change in body mass index (BMI) z-score after 16 weeks; secondary outcomes were change in additional body composition and metabolic parameters. RESULTS: After 16 weeks of open-label treatment, participants initially taking placebo during the RCT had lower BMI z-scores (mean 16-week change -0.10, p = .004). Statistically significant improvements also were noted in secondary body composition measures (weight z-score and BMI and weight percentile) but not in metabolic variables. Participants who initially had been taking metformin during the 16-week RCT maintained prior decreases in BMI z-scores but did not have additional weight loss. Three participants discontinued treatment because of an adverse event. No significant changes were noted on metabolic measures, although the decrease in hemoglobin A1c was large (∼1 mmol) and consistent across the acute and open-label phases. CONCLUSION: Metformin can be effective for decreasing weight gain associated with atypical antipsychotic use and maintaining prior improvement in children and adolescents with autism spectrum disorder. Clinical trial registration information-Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD); http://clinicaltrials.gov/; NCT01825798.

A crossover study of risperidone in children, adolescents and adults with mental retardation.

Risperidone has shown safety and efficacy for aggressive and destructive behaviors in short-term studies. This longer-duration study includes a broad sample. Forty subjects, aged 8-56 years (mean=22), all with mental retardation and 36 with autism spectrum disorders participated in this 22-week crossover study, with 24 weeks of open maintenance thereafter. Of 40 subjects, 23 (57.5%) responded fully (50% decrease in Aberrant Behavior Checklist-Community Irritability subscale score), while 35 subjects (87.5%) showed a 25% decrease. Gender, mood disorder, and antiseizure medications did not alter response. Increased appetite and weight gain were common. Low dose risperidone was effective for aggressive behavior in persons with MR. More long-term studies are needed, incorporating weight control interventions.

Efficacy and safety of selective serotonin reuptake inhibitors in the treatment of depression in children and adolescents: practitioner review.

BACKGROUND: Given the widespread reports involving the use of selective serotonin reuptake inhibitors (SSRIs) in children, the present paper reviews and discusses published double-blind, placebo-controlled studies assessing the safety and efficacy of SSRIs in children and adolescents with major depressive disorder. METHODS: Published and unpublished double-blind, placebo-controlled studies of SSRIs in children and adolescents with depression during the years 1990-2004 were reviewed. A MEDLINE search was performed using the words 'depression', 'randomised controlled trial', 'SSRIs', 'children' and 'adolescents'. The GlaxoSmithKline website was also searched for relevant studies on paroxetine. Outcome measures were the Clinical Global Impressions scale, the Children's Depression Rating Scale-Revised, the Hamilton Rating Scale for Depression, the depression subscales of the Kiddie Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version, and the Montgomery and Asberg Depression Rating Scale. Adverse effects and withdrawal rates are reported. RESULTS: There were seven randomised, placebo-controlled trials involving 1619 children and adolescents aged 6-18 years in total. The SSRIs fluoxetine, paroxetine, sertraline and citalopram were reported to exhibit safety and efficacy for treatment of depression in children and adolescents. Reanalysis of published and unpublished studies by the US FDA and the UK's Medicines and Healthcare products Regulatory Agency (MHRA) raised alerts regarding higher suicidal ideation rates from SSRIs in this population. Present guidelines are discussed. CONCLUSIONS: SSRIs remain a first-line pharmacological treatment for depression in children and adolescents for whom psychotherapy has failed or is unavailable. Suicidal ideation and behaviours merit close monitoring. More studies are needed.

Loxapine for Reversal of Antipsychotic-Induced Metabolic Disturbances: A Chart Review.

Loxapine substitution is a promising option for patients with autism spectrum disorder (ASD) who develop antipsychotic-induced metabolic illness. We performed a chart review of 15 adolescents and adults meeting DSM-IV-TR criteria for ASD, all with antipsychotic-associated weight gain, who received low dose loxapine in an attempt to taper or discontinue the weight gain-associated antipsychotic. Mean weight loss was -5.7 kg, mean BMI reduction was -1.9, and mean triglyceride reduction was -33.7 mg/dl. At chart review, 14 of 15 subjects were rated 2 (Much Improved) or 1 (Very Much Improved) on the Clinical Global Impressions-Improvement scale (CGI-I). Low dose loxapine addition in most cases enabled taper of offending antipsychotics, significantly reversed drug-induced metabolic disturbances and improved irritability.

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.

IMPORTANCE: Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. OBJECTIVE: To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. DESIGN, SETTING, AND PARTICIPANTS: A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS: Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. RESULTS: Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). CONCLUSIONS AND RELEVANCE: Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01825798.

Risperidone-induced prolactin elevation in a prospective study of children, adolescents, and adults with mental retardation and pervasive developmental disorders.

OBJECTIVE: Risperidone is widely prescribed for aggression and self-injury in children, adolescents, and adults with mental retardation (MR) and pervasive developmental disorders (PDD). Risperidone elevates prolactin more than other atypical antipsychotic medications. Females may show greater prolactin elevation than males. METHOD: In this relatively long-term study of risperidone efficacy and safety for aggression and self-injury in children, adolescents, and adults with MR and PDDs, serum prolactin was measured in a 21-subject subset during the course of a double-blind, placebo-controlled trial. Prolactin was measured in ng/mL at baseline, once during acute treatment, and once during maintenance. RESULTS: In children and adolescents (n=10), mean age of 12.5 years, prolactin increased from mean 13.2+/-8.6 at baseline to 31.0+/-11.6 acutely and remained elevated at 37.9+/-10.4 in maintenance. In adults, mean age of 35.3 years, prolactin increased more markedly from 11.6+/-7.4 baseline (n=11) to 93.3+/-54.2 acutely but decreased to 67.8+/-62.9 in maintenance (n=7). Prolactin remained significantly elevated above normal in all subjects for at least 26 weeks. Mean prolactin of adult females, while similar to that of adult males at baseline, was 2.2 times male levels acutely and 3.7 times greater in maintenance. CONCLUSION: In this small subset, mean prolactin elevation persisted for at least 26 weeks. In adults, females showed significantly greater elevations than males.

A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders.

OBJECTIVE: The aim of this study was to study valproate efficacy and safety for aggression in children and adolescents with pervasive developmental disorders (PDD). METHODS: In this prospective double-blind, placebo-controlled study, 30 subjects (20 boys, 10 girls) 6-20 years of age with PDD and significant aggression were randomized and received treatment with valproate (VPA) or placebo (PBO) for 8 weeks as outpatients. Mean VPA trough blood levels were 75.5 mcg/mL at week 4 and 77.8 mcg/mL at week 8. RESULTS: No treatment difference was observed statistically between VPA and PBO groups. The Aberrant Behavior Checklist--Community Scale (ABC-C) Irritability subscale was the primary outcome measure (p = 0.65), and CGI--Improvement (p = 0.16) and OAS (p = 0.96) were secondary outcome measures. Increased appetite and skin rash were significant side effects. Only 1 subject was dropped from the study owing to side effects, notably a spreading skin rash, which then resolved spontaneously. Two subjects receiving VPA developed increased serum ammonia levels, one with an associated parent report of slurred speech and mild cognitive slowing. Poststudy, of 16 VPA and PBO subjects receiving VPA, 10 subjects demonstrated sustained response, 4 of whom later attempted taper, with significant relapse of aggression. CONCLUSION: The present negative findings cannot be viewed as conclusive, partly owing to the large placebo response, subject heterogeneity, and size of the groups. Larger studies are needed to expand upon these findings.

Low Dose Loxapine: Neuromotor Side Effects and Tolerability in Autism Spectrum Disorders.

OBJECTIVE: New and repurposed drugs are urgently needed to treat individuals with autism spectrum disorders (ASD). Loxapine (LOX) in low doses of 5-15 mg/day resembles an atypical antipsychotic (Stahl 2002 ). Our recent open pilot study of LOX found significant behavioral improvements and overall weight neutrality in 16 adolescents and adults with ASD. The present study examined an outpatient sample for LOX neuromotor tolerability. METHODS: Consecutive outpatients with Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) ASD diagnoses receiving LOX were examined for tardive dyskinesia (TD) and extrapyramidal side effects (EPS) using the Dyskinesia Identification System: Condensed User Scale (DISCUS), and for akathisia using the Barnes Akathisia Rating Scale. Data were also then retrospectively extracted from clinic charts regarding age, gender, diagnoses, LOX doses, treatment duration, concomitant medications, and LOX dosage reductions. RESULTS: Thirty-four subjects (25 male, 9 female) participated. Mean age was 23.4 years at LOX initiation (range 8-52). Thirteen subjects (38.2%) received loxapine for ≥5 years. Mean LOX dose was 8.9 mg/day (range 5-30 mg) and mean duration was 4.2 years (range 0.8-13). Fourteen subjects (41.2%) received concomitant atypical antipsychotics. Benztropine was prescribed in 5 of 34 subjects (14.7%). Three subjects manifested tics at baseline, but lower final DISCUS scores. Subject 26, with Prader-Willi syndrome, manifested TD. Apart from LOX 5 mg daily he received paroxetine 40 mg daily, which reduces LOX metabolism significantly. Akathisia objective scores were positive in 6 subjects (17.6%): Subject 2 scored 3 (pacing was present also at baseline); subjects 6, 7, and 11 each scored 1; and subjects 18 and 23 each scored 2. Six of 9 subjects (66.7%) with expressive language were positive for subjective akathisia. CONCLUSIONS: Low dose LOX was well tolerated, with lower than expected TD rates. This confirms clinical resemblance to an atypical antipsychotic. Individuals with neuromuscular problems including Prader-Willi Syndrome receiving LOX require close monitoring. Further study of LOX in ASD is warranted.

Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability.

OBJECTIVES: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. METHODS: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. RESULTS: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. CONCLUSIONS: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.

Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study.

An adult female with congenital Rubinstein-Taybi syndrome (RTS) and severe mental retardation is described, who presented with symptoms of severe over-activity, short attention span, mood lability, and aggressive outbursts in a cyclical pattern, suggestive of recurrent manic-like episodes. These symptoms improved significantly with divalproex (Depakote) monotherapy. Review of the existing studies showed that 10-76% of persons with RTS may be identified with similar behavioral symptoms. We postulate other persons with RTS may respond to divalproex, and there may be some relationship between the chromosome 16p13.3 deletion and gamma-aminobutyric acid (GABA) receptor or neurotransmitter abnormalities. Recent molecular genetic studies suggest a linkage of this region to bipolar mood disorder and autism, both of which were diagnosed in this patient. Further prospective study is needed of RTS persons regarding behavioral problems, comorbid psychiatric diagnoses, and treatment responses, correlated with genetic abnormalities.

Use of functional analysis methodology in the evaluation of medication effects.

The atypical antipsychotic medication risperidone was evaluated using a double-blind, placebo-controlled design in the treatment of destructive behavior in two individuals with autism. Pre-medication functional analyses indicated that destructive behavior was maintained by escape from demands, attention, or access to tangible items. For both individuals, destructive behavior during the demand condition was significantly reduced during the medication phases, whereas destructive behavior continued to occur to obtain tangible items (Reggie) and attention (Sean). In addition, there appeared to be a differential effect of the medication on self-injurious behavior (SIB) versus aggression for Sean. Results of the study demonstrate how functional analysis may provide information on those conditions and behaviors that are most likely to be affected by a specific medication.

Multimodal evaluation of risperidone for destructive behavior: functional analysis, direct observations, rating scales, and psychiatric impressions.

Risperidone, an atypical neuroleptic, has become a popular option for treating destructive behaviors of persons with developmental disabilities. A few studies have been conducted that evaluate the effects of risperidone on destructive behavior; however, none of these studies have combined objective measures with rating scales to evaluate the effects of risperidone on destructive behavior across home and clinical settings. This study evaluated the wide range of effects of risperidone on destructive behavior of 2 persons with developmental disabilities using weekly functional analysis sessions, daily observations, hourly home data, weekly rating scales, and monthly psychiatric impressions. Results indicate that risperidone does decrease destructive behavior and that, for the most part, all of the various measures yielded similar results.

Effects of risperidone on destructive behavior of persons with developmental disabilities: III. Functional analysis.

Functional analyses were conducted during a double-blind, placebo-controlled study of the atypical antipsychotic medication risperidone with 13 individuals. Risperidone was effective in reducing destructive behavior (compared to placebo) for 10 participants. For 7 of these responders, an undifferentiated pattern of responding occurred across their baseline functional analysis conditions (i.e., a similar rate of responding across conditions), and risperidone treatment produced nonspecific reductions of their destructive behavior across functional analysis conditions. For the remaining 3 responders, a differentiated pattern of responding occurred across their baseline functional analysis conditions (i.e., an elevated rate of responding occurred in a specific condition), and risperidone treatment produced function-specific reductions of their destructive behavior.

Training of child and adolescent psychiatry fellows in autism and intellectual disability.

Patients with autism spectrum disorders and intellectual disability can be clinically complex and often have limited access to psychiatric care. Because little is known about post-graduate clinical education in autism spectrum disorder and intellectual disability, we surveyed training directors of child and adolescent psychiatry fellowship programs. On average, child and adolescent psychiatry directors reported lectures of 3 and 4 h per year in autism spectrum disorder and intellectual disability, respectively. Training directors commonly reported that trainees see 1-5 patients with autism spectrum disorder or intellectual disability per year for outpatient pharmacological management and inpatient treatment. Overall, 43% of directors endorsed the need for additional resources for training in autism spectrum disorder and intellectual disability, which, coupled with low didactic and clinical exposure, suggests that current training is inadequate.