Haven't lost the positive feeling: a dose-response, oral alcohol challenge study in drinkers with alcohol use disorder.

Models of addiction are based on neurobiological, behavioral, and pharmacological studies in animals, but translational support from human studies is limited. Studies are lacking in examining acute responses to alcohol in drinkers with alcohol use disorder (AUD), particularly in terms of relevant intoxicating doses and measurement of stimulating and rewarding effects throughout the breath alcohol concentration (BrAC) time curve. Participants were N = 60 AUD drinkers enrolled in the Chicago Social Drinking Project and examined in three random-order and blinded sessions for subjective and physiological responses to a beverage containing 0.0 g/kg, 0.8 g/kg, and 1.2 g/kg alcohol. BrAC in the alcohol sessions at 60 min was 0.09 g/dL and 0.13 g/dL, respectively. Both doses of alcohol produced significant biphasic effects on subjective measures of stimulation, euphoria, reward (liking and wanting), sedation, and neuroendocrine and cardiovascular factors. Increased pleasurable effects of alcohol were pronounced during the rising limb-to-peak BrAC and sedating effects emerged during the declining limb. Alcohol dose-dependently increased feel drug ratings and rewarding effects at peak BrAC or early declining limb, and physiological responses at the rising limb. Thus, rather than the notion of an overall tolerance, results show an alcohol response phenotype characterized by sensitivity to alcohol's stimulating, rewarding and physiological effects. The results of this study may aid in the conceptualization of alcohol addiction as a disorder characterized by the persistence of enhanced hedonic alcohol responses rather than chronic tolerance and reward deficiency.

Caregiver perceptions of importance of COVID-19 preventative health guidelines and difficulty following guidelines are associated with child adherence rates.

OBJECTIVE: To describe child adherence to four preventative-health guidelines during the COVID-19 pandemic and investigate caregiver-level correlates of adherence. METHOD: Two hundred thirty-six caregivers (75% female) of children ages 6-12 years (Mage = 8 years; 53% male) living in the United States rated child adherence to four preventative-health guidelines between 10/16/2020 and 11/14/2020. Caregivers also rated perceived importance of each guideline in limiting virus spread and perceived difficulty in obtaining child compliance. RESULTS: Child adherence was highest for mask-wearing (median [Mdn] = 96%) and hand hygiene (Mdn = 95%). Adherence to social distancing guidelines was lower. Mdn adherence for social distancing with family outside the household was 80%, and Mdn adherence for social distancing with friends was 72%. Furthermore, for each of the four guidelines, fewer than half the sample reported 100% adherence (range = 20%-43%). Adherence was positively associated with caregiver perceptions of importance of a given behavior in limiting virus spread (rs = .38-.62) and negatively associated with perceived difficulty in gaining child compliance (rs = -.37-.25). DISCUSSION: Current results indicated parents perceive child adherence to social distancing more challenging than child adherence to mask wearing or hand hygiene. Lower caregiver perceptions of importance of the behavior and greater perceived difficulty in gaining child compliance were associated with lower adherence to all tasks. Brief targeted interventions (e.g., motivational interviewing, parent behavior management training) may be well suited to enhance caregivers' perceptions of value of the behavior, while also addressing behavioral challenges that interfere with child adherence. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Feasibility, Tolerability, and Safety of Administering a Very High Alcohol Dose to Drinkers with Alcohol Use Disorder.

INTRODUCTION: There remains a paucity of research quantifying alcohol's effects in drinkers with alcohol use disorder (AUD), particularly responses to very high alcohol doses (≥0.8 g/kg). As drinkers with AUD frequently engage in very heavy drinking (8 to 10 drinks/occasion), doses of ≤0.8 g/kg may lack ecological validity. The present study examined the feasibility, tolerability, and safety of administering a very high alcohol dose (1.2 g/kg) to non-treatment-seeking AUD participants. METHODS: Sixty-one young adult AUD drinkers enrolled in the Chicago Social Drinking Project and completed 3 laboratory sessions at which they consumed a beverage with 1.2, 0.8, and 0.0 g/kg alcohol. Physiological responses (vital signs, nausea and vomiting, breath alcohol concentrations [BrAC]) were monitored throughout the sessions. After each session, participants completed a next-day survey of substance use, engagement in risky behaviors, and related consequences. RESULTS: Overall, the sample demonstrated good compliance with study procedures; 93% of participants adhered to presession alcohol abstinence requirements (indicated by BrAC < 0.003 g/dl), with no participants exhibiting serious alcohol withdrawal symptoms at arrival to study visits. The 1.2 g/kg alcohol dose achieved an expected mean peak BrAC of 0.13 g/dl at 60 minutes after drinking, which was well tolerated; the majority of the sample did not experience nausea (70%) or vomiting (93%), and dose effects on vital signs were not clinically significant. Finally, we demonstrated that the 1.2 g/kg alcohol dose is safe and not associated with postsession consequences, including reduced sleep time, atypical substance use, accidents or injuries, and severe hangovers. CONCLUSION: Results support the feasibility, tolerability, and safety of administering a very high alcohol dose to young adult drinkers with AUD within the context of a well-validated laboratory alcohol challenge paradigm. Utilizing an alcohol dose more consistent with naturalistic drinking patterns may foster greater ecological validity of laboratory paradigms for persons with moderate to severe AUD.

Exposure to JUUL use: cue reactivity effects in young adult current and former smokers.

BACKGROUND: Exposure to the use of first, second and third generations of electronic cigarettes (e-cigarettes) elicits the desire to vape and smoke among observers, as well as facilitates smoking behaviour. Given the rapid rise in the popularity of the pod mod JUUL, we examined whether observing the use of this device would elicit similar responses in smokers. Exploratory analyses were also conducted to determine whether JUUL can act as a smoking cue for former smokers. METHODS: The sample consisted of 82 young adult participants (62 current smokers and 20 former smokers approximately 1 year smoke free). The study examined their response to observing use of bottled water (control cue) and JUUL (active cue) in a controlled laboratory paradigm. Both cues were delivered by a trained study confederate under the guise of a social interaction task, and participants completed mood and desire and urge surveys precue and postcue exposures. RESULTS: In current smokers, exposure to the JUUL cue increased smoking urge and desire for a cigarette, mod/vape pen and JUUL, and two-thirds chose to smoke in the behavioural analogue task. In former smokers, the JUUL cue evoked modest and transient increases in desire for a cigarette and JUUL. CONCLUSIONS: The use of JUUL affects the user and elicits responses in observers; this study is the first to demonstrate that exposure to JUUL use may act as a smoking cue and exposure to JUUL use may affect tobacco control efforts.

The role of E-liquid vegetable glycerin and exhaled aerosol on cue reactivity to tank-based electronic nicotine delivery systems (ENDS).

RATIONALE: Electronic nicotine delivery systems (ENDS or e-cigarettes) share salient features of combustible smoking, such as inhalation and exhalation behaviors, and evidence indicates that first- and second-generation ENDS generalize as smoking cues. The present study examined whether newer, tank-based third-generation ENDS ("mods") also evoke smoking urges, and whether enhancing the visibility of exhaled aerosol clouds-by increasing the e-liquid vegetable glycerin (VG) content-strengthens the cue salience of ENDS. OBJECTIVES: The objective was to assess the role of exhaled aerosol clouds on ENDS cue potency using a standardized laboratory paradigm designed to mimic real-world exposures. METHODS: Using a mixed design, young adult smokers (n = 50; mean age 26.5 years; ≥ 5 cigarettes/day) observed a study confederate drinking bottled water (control cue) and vaping an ENDS mod containing e-liquid with either high (73%) or low (0%) VG. Participants completed the Brief Questionnaire on Smoking Urges (BQSU) and visual analog scales (VAS) assessing cigarette and e-cigarette desire pre- and post-cue exposure. RESULTS: Increasing the e-liquid content of VG enhanced the size and visibility of the exhaled aerosol clouds and evoked a greater increase in smoking desire and a more sustained increase in e-cigarette desire relative to the low VG cue. Both cues elicited increases in smoking urges. These results remained after controlling for sex, prior ENDS experience, recent smoking behavior, and menthol preference. CONCLUSIONS: Observation of tank-based ENDS use generalizes as a smoking cue and its cue salience is strengthened by increasing the e-liquid content of VG to enhance the visibility of the exhaled aerosol cloud.

Neurofunctional Correlates of Response to Quetiapine in Adolescents with Bipolar Depression.

OBJECTIVES: Prior studies have shown that youth with bipolar disorder demonstrate neurofunctional changes in key prefrontal and subcortical brain regions implicated in emotional regulation following treatment with pharmacological agents. We recently reported a large response rate (>60%) to quetiapine (QUET) for treating depressive symptoms in adolescents with bipolar depression. This study investigates the neurofunctional effects of QUET using functional magnetic resonance imaging (fMRI). METHODS: Thirty-three unmedicated subjects, 10-17 years of age, with a current depressive episode (Children's Depression Rating Scale-Revised [CDRS-R] > 40) associated with bipolar I or II disorder were recruited in a two-site randomized, placebo (PBO)-controlled trial of QUET monotherapy for treatment of bipolar depression in adolescents. Twenty-three of these participants (nine male) underwent an MRI scan at baseline, then were randomized to QUET or PBO, followed for 8 weeks, and at the end of their study participation underwent another MRI scan. During the fMRI scan, subjects viewed negative and neutral pictures and rated the valence of each picture. RESULTS: Sixteen subjects had usable data at both time points: 10 subjects randomized to QUET, and 6 randomized to PBO. For QUET subjects, lower baseline activation in the left dorsolateral prefrontal cortex (p < 0.005) and higher baseline activation in the left ventrolateral prefrontal cortex (p = 0.0024) predicted greater improvement in CDRS-R scores from baseline to follow-up. When QUET and PBO groups were combined (n = 16), region-of-interest activation did not significantly predict change in CDRS-R. CONCLUSIONS: Baseline activation patterns in dorsal and ventral portions of the prefrontal cortex that are critical for the regulation of emotion-predicted response, but only within the QUET group. Thus, specific medications may be more effective in the context of specific prefrontal activation patterns in youth with bipolar depression. Larger studies of these youth would help to clarify the effects of QUET on brain activation.

Anomalous prefrontal-limbic activation and connectivity in youth at high-risk for bipolar disorder.

OBJECTIVE: Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD. METHODS: We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene. RESULTS: While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex CONCLUSIONS: Similar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.

Inhibited Temperament and Hippocampal Volume in Offspring of Parents with Bipolar Disorder.

BACKGROUND: Prior studies have suggested that inhibited temperament may be associated with an increased risk for developing anxiety or mood disorder, including bipolar disorder. However, the neurobiological basis for this increased risk is unknown. The aim of this study was to examine temperament in symptomatic and asymptomatic child offspring of parents with bipolar disorder (OBD) and to investigate whether inhibited temperament is associated with aberrant hippocampal volumes compared with healthy control (HC) youth. METHODS: The OBD group consisted of 45 youth, 24 of whom had current psychiatric symptoms (OBD+s) and 21 without any psychiatric symptoms (OBD-s), and were compared with 24 HC youth. Temperament characteristics were measured by using the Revised Dimensions of Temperament Survey. Magnetic resonance imaging was used to measure hippocampal volumes. The association between temperament and hippocampal volumes was tested by using multiple regression analysis. RESULTS: Compared with the OBD-s group, the OBD+s group had significantly more inhibited temperament traits, less flexibility, more negative mood, and less regular rhythm in their daily routines. In contrast, the OBD-s group was more likely to approach novel situations compared with OBD+s or HC groups. Within the OBD+s group, a more inhibited temperament was associated with smaller right hippocampal volumes. CONCLUSIONS: In this study, symptomatic OBD were characterized by an inhibited temperament that was inversely correlated with hippocampal volume. Additional longitudinal studies are needed to determine whether inverse correlations between hippocampal volume and inhibited temperament represent early markers of risk for later developing bipolar disorder.

Amygdalar volumetric correlates of social anxiety in offspring of parents with bipolar disorder.

The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29h and 17HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No significant difference was observed in amygdalar volume between the HRHSA and HC groups. However, there were significant negative correlations between amydalar volumes and MASC social anxiety score in the HRHSA group. These findings have implications for the link between amygdalar structure and both anxiety and mood control. This link may serve to implicate high social anxiety as a risk marker for future BD development.

Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype.

OBJECTIVE: Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status. METHODS: A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC). RESULTS: Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group. CONCLUSIONS: This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.

Widespread white matter tract aberrations in youth with familial risk for bipolar disorder.

Few studies have examined multiple measures of white matter (WM) differences in youth with familial risk for bipolar disorder (FR-BD). To investigate WM in the FR-BD group, we used three measures of WM structure and two methods of analysis. We used fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) to analyze diffusion tensor imaging (DTI) findings in 25 youth with familial risk for bipolar disorder, defined as having both a parent with BD and mood dysregulation, and 16 sex-, age-, and IQ-matched healthy controls. We conducted a whole brain voxelwise analysis using tract based spatial statistics (TBSS). Subsequently, we conducted a complementary atlas-based, region-of-interest analysis using Diffeomap to confirm results seen in TBSS. When TBSS was used, significant widespread between-group differences were found showing increased FA, increased AD, and decreased RD in the FR-BD group in the bilateral uncinate fasciculus, cingulum, cingulate, superior fronto-occipital fasciculus (SFOF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, and corpus callosum. Atlas-based analysis confirmed significant between-group differences, with increased FA and decreased RD in the FR-BD group in the SLF, cingulum, and SFOF. We found significant widespread WM tract aberrations in youth with familial risk for BD using two complementary methods of DTI analysis.

Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder.

Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES-IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction.

Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder.

BACKGROUND: Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms. METHODS: Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms. RESULTS: At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms. DISCUSSION: Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

Reward processing in healthy offspring of parents with bipolar disorder.

IMPORTANCE: Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder. OBJECTIVE: To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder. DESIGN, SETTING, AND PARTICIPANTS: This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children). MAIN OUTCOMES AND MEASURES: Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task. RESULTS: While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = -2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = -3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = -4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards. CONCLUSIONS AND RELEVANCE: Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

Deformations of amygdala morphology in familial pediatric bipolar disorder.

OBJECTIVE: Smaller amygdalar volumes have been consistently observed in pediatric bipolar disorder subjects compared to healthy control subjects. Whether smaller amygdalar volume is a consequence or antecedent of the first episode of mania is not known. Additionally, smaller volume has not been localized to specific amygdala subregions. METHODS: We compared surface contour maps of the amygdala between 22 youths at high risk for bipolar disorder, 26 youths meeting full diagnostic criteria for pediatric familial bipolar disorder, and 24 healthy control subjects matched for age, gender, and intelligence quotient. Amygdalae were manually delineated on three-dimensional spoiled gradient echo images by a blinded rater using established tracing protocols. Statistical surface mesh modeling algorithms supported by permutation statistics were used to identify regional surface differences between the groups. RESULTS: When compared to high-risk subjects and controls, youth with bipolar disorder showed surface deformations in specific amygdalar subregions, suggesting smaller volume of the basolateral nuclei. The high-risk subjects did not differ from controls in any subregion. CONCLUSIONS: These findings support previous reports of smaller amygdala volume in pediatric bipolar disorder and map the location of abnormality to specific amygdala subregions. These subregions have been associated with fear conditioning and emotion-enhanced memory. The absence of amygdala size abnormalities in youth at high risk for bipolar disorder suggests that reductions might occur after the onset of mania.

Prospective neurochemical characterization of child offspring of parents with bipolar disorder.

We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy.

OBJECTIVE: Depression and brief periods of (hypo)mania are linked to an increased risk of progression to bipolar I or II disorder (BD) in children of bipolar parents. This randomized trial examined the effects of a 4-month family-focused therapy (FFT) program on the 1-year course of mood symptoms in youth at high familial risk for BD, and explored its comparative benefits among youth in families with high versus low expressed emotion (EE). METHOD: Participants were 40 youth (mean 12.3±2.8 years, range 9-17) with BD not otherwise specified, major depressive disorder, or cyclothymic disorder who had a first-degree relative with BD I or II and active mood symptoms (Young Mania Rating Scale [YMRS]>11 or Child Depression Rating Scale>29). Participants were randomly allocated to FFT-High Risk version (FFT-HR; 12 sessions of psychoeducation and training in communication and problem-solving skills) or an education control (EC; 1-2 family sessions). RESULTS: Youth in FFT-HR had more rapid recovery from their initial mood symptoms (hazard ratio = 2.69, p = .047), more weeks in remission, and a more favorable trajectory of YMRS scores over 1 year than youth in EC. The magnitude of treatment effect was greater among youth in high-EE (versus low-EE) families. CONCLUSIONS: FFT-HR may hasten and help sustain recovery from mood symptoms among youth at high risk for BD. Longer follow-up will be necessary to determine whether early family intervention has downstream effects that contribute to the delay or prevention of full manic episodes in vulnerable youth.

Reward processing in adolescents with bipolar I disorder.

OBJECTIVE: Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward seeking. Because youth with BD are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with the neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to "prime" the affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood before reward processing in adolescents with and without BD. METHOD: Neural activity and behaviors during the anticipation of and response to monetary reward and loss after an affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n = 24) and demographically matched healthy comparison youth (n = 24). RESULTS: Compared with the healthy control youth, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming. CONCLUSIONS: Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.

Socio-emotional processing and functioning of youth at high risk for bipolar disorder.

BACKGROUND: The goal of this study was to investigate differences in socio-emotional processing and functioning in children and adolescents at high risk for bipolar disorder (BD) and healthy control participants. METHODS: Children and adolescents with a parent with bipolar disorder, who had mood dysregulation but not fully syndromal BD (high risk, HR, n=24), were compared to participants with no personal or family history of psychopathology (healthy control, HC, n=27) across several neuropsychological domains. Social reciprocity was measured by the Social Responsiveness Scale, theory of mind was measured by use of the NEPSY, and affect recognition was measured by the NEPSY and the Diagnostic Test of Nonverbal Accuracy 2 (DANVA). RESULTS: The HR group demonstrated significant impairment in social reciprocity, including impairments in social awareness, social cognition, social communication, social motivation, and autistic mannerisms. There were no significant group differences in performance on theory of mind or affect recognition tasks. LIMITATIONS: Lack of impairment in tasks associated with theory of mind or affect recognition indicate that social functioning difficulties are not likely due to impairments in these areas, or that the measures employed were not sufficiently sensitive to detect group differences. CONCLUSIONS: Youth at high risk for BD demonstrated impairments in numerous social domains, which may be due to innate differences in brain development governing socio-emotional functioning or may be due to disruptions in normal development caused by mood regulation difficulties.

Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder.

OBJECTIVES: A range of prefrontal and subcortical volumetric abnormalities have been found in adults and adolescents with bipolar disorder. It is unclear, however, if these deficits are present early in the onset of mania or are a consequence of multiple mood episodes or prolonged exposure to medication. The goal of this study was to examine whether youth with bipolar I disorder who recently experienced their first episode of mania are characterized by brain volumetric abnormalities. METHODS: Anatomical images from magnetic resonance imaging of 26 13- to 18-year-old adolescents with bipolar I disorder and 24 age-comparable healthy controls with no personal or family history of psychopathology were analyzed using whole-brain voxel-based morphometry (VBM). RESULTS: Compared with healthy controls, adolescents with bipolar I disorder had significantly less gray matter volume in the left subgenual cingulate cortex [p<0.05, family-wise error (FWE)-corrected]. CONCLUSIONS: Adolescents with a recent single episode of mania have smaller subgenual cingulate cortex volume than do their healthy counterparts, suggesting that this anomaly occurs early in the onset of, or may predate the disorder. Longitudinal studies are needed to examine the impact of this volumetric reduction on the course and outcome of this disorder.