Effects of zuranolone on next-day simulated driving in healthy adults.

RATIONALE: Zuranolone is an oral positive allosteric modulator of GABAA receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving. OBJECTIVE: Evaluate the effect of zuranolone on simulated driving performance. METHODS: In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1-7, zuranolone 50 mg on days 1-6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1-7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety. RESULTS: Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20%) were CNS-related; most were mild/moderate. CONCLUSION: Zuranolone impaired simulated driving and reduced cognitive function versus placebo 9 h after administration. Although many impairments resolved after 7 days of dosing, driving remained impaired. These results may inform prescriber decision-making.

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.

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.

Disentangling the heterogeneity of emotional dysregulation in referred youth using the Child Behavior Checklist attending to age and sex effects.

PURPOSE: To assess the utility of the Child Behavior Checklist (CBCL) to identify meaningful subtypes of emotional dysregulation in an outpatient pediatric psychiatry clinic. METHODS: The sample consisted of 417 newly referred youth 6-18 years of age. Parents completed the CBCL and rating scales measuring executive function deficits, social functioning, and quality of life. Patients were stratified into subtypes of emotional dysregulation and compared on clinical correlates based on the A-A-A profile consisting of the CBCL Anxious/Depressed, Aggressive Behavior, and Attention Problems (A-A-A) scales. RESULTS: 67% of youth had emotional dysregulation (CBCL A-A-A T-score ≥ 180) and of these, 39% had a positive CBCL-Bipolar (BP) profile (A-A-A T-score ≥ 210), 24% had depression without the BP profile (CBCL Anxious/Depressed and/or Withdrawn/Depressed T-scores ≥70 and A-A-A T-score ≥ 180 and ã€ˆ210), and 37% had emotional impulsivity (A-A-A T-score ≥ 180 and <210) with normal CBCL Anxious/Depressed and Withdrawn/Depressed T-scores. Patients with the CBCL-BP profile were significantly more impaired on all measures of social and executive functioning compared to the other two groups. LIMITATIONS: Since our findings relied on the CBCL, other instruments may have led to different results. Because we included youth from a single clinic, largely Caucasian and referred, our findings may not generalize to other ethnic groups or settings. CONCLUSIONS: The CBCL can aid in the identification of subtypes of emotional dysregulation affecting youth seeking mental health services.

A "Proof of Concept" Randomized Controlled Trial of a Video Game Requiring Emotional Regulation to Augment Anger Control Training.

Emotional dysregulation leading to clinically significant anger and aggression is a common and substantial concern for youth and their families. While psychotropic medications and cognitive behavioral therapies can be effective, these modalities suffer from drawbacks such as significant side effects, high rates of attrition, and lack of real-world skill translation. Regulate and Gain Emotional Control (RAGE-Control) is a video game designed as an engaging augment to existing treatments. The game facilitates emotional regulation skill building through practice modulating physiological arousal while completing a challenging inhibitory task. We compared reduction in anger, aggression, oppositionality, and global severity between two treatment conditions: Anger Control Training (ACT) augmented with RAGE-Control and ACT with a sham version of the game, in a pilot double-blind randomized controlled trial. To begin to understand mechanisms of change, we examined heart rate during game play over the course of the study and explored associations between symptom changes and heart rate changes. Materials and Methods: Forty youth with clinically significant anger dyscontrol (age 10-17) were randomly assigned to 10 sessions of ACT with RAGE-Control or ACT with sham video game. Results: Both treatments similarly reduced self-reported anger. However, ACT with RAGE-Control led to larger improvements in aggression (CI: -17 to -1.0, ES: 0.55, p = 0.015); oppositionality (CI: -9.0 to -7e-6, ES: 0.48, p = 0.032); and global severity (CI: -1.0 to -5e-6, ES: 0.51, p = 0.023) relative to sham. Participants in the RAGE-Control group saw a decrease in median heart rate during game play (ß = 1.2, p < 0.001). Larger pre to post decreases in heart rate were significantly associated with larger pre to post decreases in aggression and oppositional behaviors. Discussion: Augmenting ACT with RAGE-Control reduced behavioral expression of anger, but not the experience of angry feelings, as compared to ACT with a sham version of the game. Increased heart rate control, demonstrated by reduction in median heart rate during gameplay, was associated with decreased aggression and oppositional behavior. Together these findings support that augmenting traditional treatment with technology facilitating heart rate control through skill practice translates to enhancements in real-life behavioral change. Therefore, further exploration into engaging skill-focused games such as RAGE-Control is warranted. Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01551732.

Psychopharmacology of Treating Explosive Behavior.

Explosive and aggressive behavior in children can pose safety risks, disturb family functioning, and lead to significant impairments. Pharmacologic management should be based on the first-line treatment of the primary psychiatric diagnoses of the patient and initiated in combination with appropriate psychosocial interventions. Review of the literature suggests that risperidone has the most supporting evidence in the treatment of explosive behavior. Stimulants have been shown to be helpful in the treatment of explosive behavior in attention-deficit/hyperactivity disorder. Medication treatment can be associated with significant side effects and therefore the risks and benefits of medication management must be weighed carefully.

The child behavior checklist can aid in characterizing suspected comorbid psychopathology in clinically referred youth with ADHD.

OBJECTIVE: To examine the utility of the Child Behavior Checklist (CBCL) to aid in the identification of comorbid psychopathological conditions affecting referred youth with suspected ADHD prior to the evaluation. The CBCL is an easy-to-use assessment tool that may provide invaluable information regarding the severity and characteristics of the presenting complaints. METHODS: The sample included 332 youths consecutively referred to an ADHD program for the assessment of suspected ADHD. Parents completed the CBCL, parent-rated ADHD Self-Report Scale (ASRS), Social Responsiveness Scale (SRS), and Behavior Rating Inventory of Executive Function (BRIEF). Because of the established association between the CBCL Attention Problems scale and a structured diagnostic interview of ADHD, all youths analyzed had abnormal Attention Problems T-scores (≥60). RESULTS: Seventy-six percent of youths with elevated Attention Problems T-scores had ≥3 additional abnormal CBCL scales, suggesting they were likely affected with multiple comorbid psychopathological conditions. Moreover, 44% had ≥1 CBCL clinical scale with a T-score more severe than their Attention Problems T-score, suggesting the putative comorbid condition was more severe than the ADHD symptoms. Additional CBCL scale elevations were associated with more severe functional impairments as assessed by the ASRS, SRS, BRIEF, and CBCL competence scales. CONCLUSION: The CBCL obtained before the clinical assessment identified high rates of comorbid psychopathology in youths referred for the assessment of ADHD. It provided detailed information about the types and severity of suspected psychopathological conditions impacting a particular youth, which is critical to guide the assessing clinician on likely differing needs of the affected child.

L-Threonic Acid Magnesium Salt Supplementation in ADHD: An Open-Label Pilot Study.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is estimated to affect up to 5% of adults worldwide. Preclinical work demonstrates that L-Threonic Acid Magnesium Salt (LTAMS) administration is associated with neurobiological and neurofunctional effects that could offer clinical benefits in ADHD treatment.Methods: Participants were 15 adults with ADHD of moderate severity. Subjects received up to 12 weeks of open-label LTAMS administered as MMFS302 and MMFS202. The study was approved by the Institutional Review Board and posted on ClinicalTrails.Gov (NCT02558790).Results: 47% of subjects met our criteria of response attaining a CGI-Improvement score ≤2 and AISRS total reduction ≥25%. Significant improvement was seen in the AISRS, CGI-I, and the shifting subscale of the BRIEF. Changes in IQ and WASI-II performance were favorable and significant in the study population.Conclusion: LTAMS supplementation was found to be effective and well tolerated. Nearly half of participants met our definition of ADHD symptom clinical response. These results support the need to further evaluate this compound in larger samples under double-blind conditions.

Can the Child Behavior Checklist (CBCL) help characterize the types of psychopathologic conditions driving child psychiatry referrals?

BACKGROUND: Little is known about the scope of problems driving referrals to child and adolescent psychiatry services. Identifying the full range of mental disorders affecting a particular child can help triage the child to a clinician with the appropriate level of expertise. The Child Behavior Checklist (CBCL) is an easy-to-use assessment tool that may provide invaluable information regarding the severity of the presenting complaints and also aid in the referral process. OBJECTIVE: To assess the utility of the CBCL to gain insights into the type of clinical problems driving referrals of youth to an outpatient pediatric psychiatry clinic. METHOD: The sample consisted of 418 newly referred youth 4-18 years of age of both sexes. Parents completed the CBCL assessing psychopathology and competence. Rates of patients with elevated T-scores on each scale were calculated for the whole group and stratified by sex and age (≤12 versus >12). RESULTS: The CBCL identified high rates of psychopathology affecting referred youth. It also provided information on the type of suspected disorders affecting a particular child as well as their severity, critical information to guide likely differing clinical needs and therapeutic approaches. It also helped identify a high number of youth affected with multiple psychopathological conditions, likely to require a high level of clinical attention. Overall, males were significantly more impaired than females but there were no major differences between children and adolescents. CONCLUSIONS: The CBCL can aid in the identification of individual and comorbid mental disorders affecting youth seeking mental health services by providing specific information about the presence and the severity of specific suspected disorder. These findings have implications for prioritizing scarce resources in child mental health and for improved consideration of the complexity of clinical presentations to pediatric psychiatry programs of any type.

The morbidity of subthreshold pediatric bipolar disorder: A systematic literature review and meta-analysis.

OBJECTIVE: The objective of this study was to evaluate the morbidity of subthreshold pediatric bipolar (BP) disorder. METHODS: We performed a systematic literature search in November 2017 and included studies examining the morbidity of pediatric subthreshold BP. Extracted outcomes included functional impairment, severity of mood symptoms, psychiatric comorbidities, suicidal ideation and behaviors, and mental health treatment. We used meta-analysis to compute the pooled standardized mean difference (SMD) for continuous measures and the pooled risk ratio (RR) for binary measures between two paired groups: subthreshold pediatric BP vs controls and subthreshold pediatric BP vs pediatric BP-I. RESULTS: Eleven papers, consisting of seven datasets, were included. We compared subthreshold pediatric BP (N = 244) to non-BP controls (N = 1125) and subthreshold pediatric BP (N = 643) to pediatric BP-I (N = 942). Subthreshold pediatric BP was associated with greater functional impairment (SMD = 0.61, CI 0.25-0.97), greater severity of mood symptomatology (mania: SMD = 1.88, CI 1.38-2.38; depression: SMD = 0.66, CI 0.52-0.80), higher rates of disruptive behavior (RR = 1.75, CI 1.17-2.62), mood (RR = 1.78, CI 1.29-2.79) and substance use (RR = 2.27, CI 1.23-4.21) disorders, and higher rates of suicidal ideation and attempts (RR = 7.66, CI 1.71-34.33) compared to controls. Pediatric BP-I was associated with greater functional impairment, greater severity of manic symptoms, higher rates of suicidal ideation and attempts, and higher rates of mental health treatment compared to subthreshold pediatric BP. There were no differences between full and subthreshold cases in the severity of depressive symptoms or rates of comorbid disorders. CONCLUSIONS: Subthreshold pediatric BP disorder is an identifiable morbid condition associated with significant functional impairment including psychiatric comorbidities and high rates of suicidality.

Does L-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?: Evidence of Lack of Benefit From a Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

PURPOSE/BACKGROUND: Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with L-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. METHODS: Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of L-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. RESULTS: L-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on L-methylfolate over time (χ = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). CONCLUSIONS: L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.

Similar familial underpinnings for full and subsyndromal pediatric bipolar disorder: A familial risk analysis.

OBJECTIVES: To examine the validity of subthreshold pediatric bipolar I disorder (BP-I), we compared the familial risk for BP-I in the child probands who had either full BP-I, subthreshold BP-I, ADHD, or were controls that neither had ADHD nor bipolar disorder. METHODS: BP-I probands were youth aged 6-17 years meeting criteria for BP-I, full (N=239) or subthreshold (N=43), and also included were their first-degree relatives (N=687 and N=120, respectively). Comparators were youth with ADHD (N=162), controls without ADHD or bipolar disorder (N=136), and their first-degree relatives (N=511 and N=411, respectively). We randomly selected 162 non-bipolar ADHD probands and 136 non-bipolar, non-ADHD control probands of similar age and sex distribution to the BP-I probands from our case-control ADHD family studies. Psychiatric assessments were made by trained psychometricians using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiological Version (KSADS-E) and Structured Clinical Interview for DSM-IV (SCID) structured diagnostic interviews. We analyzed rates of bipolar disorder using multinomial logistic regression. RESULTS: Rates of full BP-I significantly differed between the four groups (χ23 =32.72, P<.001): relatives of full BP-I probands and relatives of subthreshold BP-I probands had significantly higher rates of full BP-I than relatives of ADHD probands and relatives of control probands. Relatives of full BP-I, subthreshold BP-I, and ADHD probands also had significantly higher rates of major depressive disorder compared to relatives of control probands. CONCLUSIONS: Our results showed that youth with subthreshold BP-I had similarly elevated risk for BP-I and major depressive disorder in first-degree relatives as youth with full BP-I. These findings support the diagnostic continuity between subsyndromal and fully syndromatic states of pediatric BP-I disorder.