Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and methodology.

INTRODUCTION: Depressive symptoms predominate in the course of bipolar disorder (BD) and there is an urgent need to evaluate novel application of repurposed compounds that act on pre-specified treatment targets. Several lines of reasoning suggest that nitrous oxide (N2O) is an ideal medication to study as a potential treatment and as a strategy to identify the underlying pathophysiology of bipolar depression. N2O is a potent cerebral vasodilator and there is compelling evidence of reduced frontal cerebral blood flow (CBF; i.e. hypoperfusion) in depression. Therefore, N2O may increase CBF and thereby improve symptoms of depression. The goal of this randomized, double-blind trial is to study the effect of a single administration of N2O versus the active comparator midazolam on mood and CBF in adults with treatment-resistant bipolar depression. METHODS: Participants with BD-I/-II currently experiencing a major depressive episode will be randomized to one of two conditions (n = 20/group): 1) inhaled N2O plus intravenous saline, or 2) inhaled room air plus intravenous midazolam. Montgomery-Asberg Depression Rating Scale scores will serve as the primary endpoint. CBF will be measured via arterial spin labelling magnetic resonance imaging. CONCLUSIONS: N2O is a potential novel treatment for bipolar depression, as it causes cerebral vasodilation. This proof-of-concept study will provide valuable information regarding the acute impact of N2O on mood and on CBF. If N2O proves to be efficacious in future larger-scale trials, its ubiquity, safety, low cost, and ease of use suggest that it has great potential to become a game-changing acute treatment for bipolar depression.

Similarities and Differences Across Bipolar Disorder Subtypes Among Adolescents.

Objectives: To compare demographic, clinical, and familial characteristics across bipolar disorder (BD) subtypes in adolescents. Methods: A total of 168 participants, 13 to 19 years of age, with BD-I (n = 41), BD-II (n = 68), or operationalized BD-not otherwise specified (NOS) (n = 59) were recruited from a tertiary subspecialty clinic at an academic health sciences center. Diagnoses were determined using the semistructured K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) interview. Omnibus analyses were followed up with post hoc pairwise comparisons. Results: After controlling for age, race, and living with both natural parents, BD-I was associated with greater functional impairment, increased rates of psychiatric hospitalization, psychosis, and lifetime exposure to second-generation antipsychotics and lithium, less self-injurious behavior, less anxiety disorders, and less severe worst lifetime depression and lower levels of emotional dysregulation and lability compared with both BD-II and BD-NOS. Lifetime most severe manic symptoms were highest in BD-I, lowest in BD-NOS, with BD-II intermediate. Lifetime exposure to psychosocial treatment followed the opposite pattern: lowest in BD-I, highest in BD-NOS, with BD-II intermediate. Variables for which there were no significant between-group differences included suicidal ideation, suicide attempts, comorbidities other than anxiety, or family history of BD. Conclusion: Among observed differences, most distinguish BD-I from other subtypes, whereas few variables differed between BD-II and BD-NOS. Different BD subtypes share important similarities in multiple clinical and familial characteristics, including family history of BD. Present findings support and extend knowledge regarding the course and outcome of bipolar youth study operationalized definition of BD-NOS. Further research is warranted to evaluate intermediate phenotypes and treatment strategies that address these subtype-related differences.

Elevated Familial Cardiovascular Burden Among Adolescents With Familial Bipolar Disorder.

Background: Bipolar disorder (BD) is one of the most heritable medical conditions, and certain phenotypic characteristics are especially familial in BD. BD is also strongly associated with elevated and premature cardiovascular disease (CVD) morbidity and mortality. Thus, far, little is known regarding the familiality of cardiovascular risk in BD. We therefore examined the extent of CVD-related conditions among relatives of: adolescents with BD with a family history of BD (familial BD), adolescents with BD without a family history of BD (non-familial BD) and healthy controls (HC). Materials and Methods: The sample included 372 adolescents; 75 with familial BD, 96 with non-familial BD, and 201 HC. Parents of the adolescents completed the CARDIA Family Medical History interview regarding the adolescents' first- and second- degree adult relatives. We computed a "cardiovascular risk score" (CRS) for each relative, based on the sum of the presence of diabetes, hypertension, obesity, dyslipidemia, stroke, angina, and myocardial infarction (range 0-7). Primary analyses examined for group differences in mean overall CRS scores among first and second- degree relatives combined, controlling for age, sex, and race. Secondary analyses examined first- and second-degree relatives separately, controlling for age, sex, and race. Results: There were significant between-group differences in CRS in first- and second- degree relatives combined, following the hypothesized ordering: CRS was highest among adolescents with familial BD (1.14 ± 0.78), intermediate among adolescents with non-familial BD (0.92 ± 0.79) and lowest in HC (0.76 ± 0.79; F = 6.23, df = 2, p = 0.002, η p 2 = 0.03). There was a significant pairwise difference between adolescents with familial BD and HC (p = 0.002, Cohen's d = 0.49). A similar pattern of between-group differences was identified when first-degree and second-degree relatives were examined separately. Limitations: familial cardiovascular burden was determined based on parent interview, not evaluated directly. Conclusions: Adolescents with BD with a family history of BD have elevated rates of CVD-related conditions among their relatives. This may be related to genetic overlap between BD and CVD-related conditions, shared environmental factors that contribute to both BD and CVD-related conditions, or a combination of these factors. More research is warranted to better understand the interaction between familial risk for BD and CVD, and to address this risk using family-wide preventive approaches.

Elementary school children's cheating behavior and its cognitive correlates.

Elementary school children's cheating behavior and its cognitive correlates were investigated using a guessing game. Children (n=95) between 8 and 12 years of age were asked to guess which side of the screen a coin would appear on and received rewards based on their self-reported accuracy. Children's cheating behavior was measured by examining whether children failed to adhere to the game rules by falsely reporting their accuracy. Children's theory-of-mind understanding and executive functioning skills were also assessed. The majority of children cheated during the guessing game, and cheating behavior decreased with age. Children with better working memory and inhibitory control were less likely to cheat. However, among the cheaters, those with greater cognitive flexibility use more tactics while cheating. Results revealed the unique role that executive functioning plays in children's cheating behavior: Like a double-edged sword, executive functioning can inhibit children's cheating behavior, on the one hand, while it can promote the sophistication of children's cheating tactics, on the other.

Caucasian infants scan own- and other-race faces differently.

Young infants are known to prefer own-race faces to other race faces and recognize own-race faces better than other-race faces. However, it is entirely unclear as to whether infants also attend to different parts of own- and other-race faces differently, which may provide an important clue as to how and why the own-race face recognition advantage emerges so early. The present study used eye tracking methodology to investigate whether 6- to 10-month-old Caucasian infants (N = 37) have differential scanning patterns for dynamically displayed own- and other-race faces. We found that even though infants spent a similar amount of time looking at own- and other-race faces, with increased age, infants increasingly looked longer at the eyes of own-race faces and less at the mouths of own-race faces. These findings suggest experience-based tuning of the infant's face processing system to optimally process own-race faces that are different in physiognomy from other-race faces. In addition, the present results, taken together with recent own- and other-race eye tracking findings with infants and adults, provide strong support for an enculturation hypothesis that East Asians and Westerners may be socialized to scan faces differently due to each culture's conventions regarding mutual gaze during interpersonal communication.